CN101563321B - 4-(杂环基)烷基-n-(芳基磺酰基)吲哚化合物及其作为5-ht6配体的用途 - Google Patents
4-(杂环基)烷基-n-(芳基磺酰基)吲哚化合物及其作为5-ht6配体的用途 Download PDFInfo
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- CN101563321B CN101563321B CN200780047442XA CN200780047442A CN101563321B CN 101563321 B CN101563321 B CN 101563321B CN 200780047442X A CN200780047442X A CN 200780047442XA CN 200780047442 A CN200780047442 A CN 200780047442A CN 101563321 B CN101563321 B CN 101563321B
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- ylmethyl
- methyl piperazine
- methyl
- alkylsulfonyl
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Abstract
本发明涉及式(I)的新的4-(杂环基)烷基-N-(芳基磺酰基)吲哚化合物、其衍生物、其立体异构体、其可药用盐以及含有所述物质的可药用组合物。本发明还涉及制备上述新的化合物、其衍生物、其立体异构体、其可药用盐以及含有所述物质的可药用组合物的方法。这些化合物可用于治疗与5-HT6受体功能相关的多种疾病。具体地,本发明的化合物还可用于治疗多种CNS疾病、血液病、进食障碍、与疼痛有关的疾病、呼吸疾病、生殖泌尿***疾病、心血管疾病和癌症。
Description
技术领域
本发明涉及式(I)的新的4-(杂环基)烷基-N-(芳基磺酰基)吲哚化合物、其衍生物、其立体异构体、其可药用盐以及含有所述物质的可药用组合物。
本发明还涉及制备上述新的化合物、其衍生物、其立体异构体、其可药用盐以及含有所述物质的可药用组合物的方法。
这些化合物可用于治疗与5-HT6受体功能相关的多种疾病。具体而言本发明的化合物还可用于治疗多种CNS疾病、血液病、进食障碍、与疼痛相关的疾病、呼吸疾病、生殖泌尿***疾病、心血管疾病和癌症。
背景技术
据信多种中枢神经***疾病(比如焦虑、抑郁、运动障碍等)与神经递质5-羟色胺(5-HT)或血清素的紊乱有关。血清素位于中枢神经***和外周神经***中,并已知影响多种类型疾病,包括精神疾病、运动活动(motor activity)、进食行为、性活动和神经内分泌调节等。5-HT受体亚型调节血清素的多种效应。已知的5-HT受体家族包括5-HT1家族(例如5-HT1A)、5-HT2家族(例如5-HT2A)、5-HT3、5-HT4、5-HT5、5-HT6和5-HT7亚型。
5-HT6受体亚型在1993年首次从大鼠组织中克隆出来(Monsma,F.J.;Shen,Y.;Ward,R.P.;Hamblin,M.W.,Molecular Pharmacology,1993,43,320-327),随后从人组织中克隆出来(Kohen,R.;Metcalf,M.A.;Khan,N.;Druck,T.;Huebner,K.;Sibley,D.R.,Journal ofNeurochemistry,1996,66,47-56)。该受体是与腺苷酸环化酶正性偶联的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,BiochemicalBiophysical Research Communications,1993,193,268-276)。在大鼠和人中几乎都仅在中枢神经***(CNS)区域中发现该受体。
利用mRNA在大鼠脑中进行的5-HT6受体的原位杂交研究表明,5-HT投射的主要定位区域包括纹状体、伏核、嗅结节和海马结构(Ward,R.P.;Hamblin,M.W.;Lachowicz,J.E.;Hoffman,B.J.;Sibley,D.R.;Dorsa,D.M.,Neuroscience,1995,64,1105-1111)。已经在溴结节、纹状体、伏核、齿状回和海马CA1、CA2和CA3区域中观察到最高水平的5-HT6受体mRNA。较低水平的5-HT6受体mRNA见于小脑、几个间脑的核、杏仁核的颗粒层中以及见于皮层中。Northern印迹已经表明,5-HT6受体mRNA似乎仅存在于脑中,很少有证据表明其存在于外周组织中。
多种抗精神病药剂对5-HT6受体的高亲和力、5-HT6受体mRNA在纹状体、溴结节和伏核中的定位表明,这些化合物的一些临床作用可通过该受体介导。其与用于精神病学中的多种治疗性化合物相结合的能力及其在脑中令人感兴趣的分布已经引起了人们对能与所述受体相互作用的新型化合物的极大兴趣(参见:Sleight,AJ.et al.(1997)5-HT6 and5-HT7 receptors:molecular biology,functional correlates and possibletherapeutic indications,Drug News Perspect.10,214-224)。人们正做出巨大努力以理解5-HT6受体在精神病、认知障碍、运动功能和控制、记忆、情绪等中的可能作用。人们积极寻找显示出对5-HT6受体的结合亲和力的化合物,将其作为研究5-HT6受体的辅助物,也作为治疗中枢神经***疾病的潜在治疗剂,例如参见Reavill C.和Rogers D.C,CurrentOpinion in Investigational Drugs,2001,2(1):104-109,Pharma PressLtd.
Monsma FJ.等(1993)和Kohen,R.等(2001)已经表明,几种三环类抗抑郁化合物(例如阿米替林)以及非典型的抗抑郁化合物(例如米赛林)对5-HT6受体都具有高亲和力。这些发现导致了5-HT6受体与情感障碍的发病机制和/或治疗有关的假说。焦虑相关行为的啮齿类模型对于5-HT6受体在焦虑中的作用得到了相矛盾的结果。利用5-HT6受体拮抗剂的治疗提高了大鼠最大电癫痫休克试验中的癫痫阈值[Stean,T.等(1999)Anticonvulsant properties of the selective 5-HT6 receptorantagonist SB-271046 in the rat maximal electroshock seizure thresholdtest.Br.J.Pharmacol.127,131P;Routledge,C.等(2000)Characterization of SB-271046:a potent,selective and orally active5-HT6)receptor antagonist.Br.J.Pharmacol.130,1606-1612]。虽然这表明5-HT6受体可能调节癫痫阈值,但效果并没有已知抗癫痫药显著。
我们对5-HT6受体配体作用的理解在其中该受体可能发挥主要作用的两种治疗指征中最深入:学习和记忆缺陷以及异常进食行为。虽然5-HT6受体的确切作用还未在其它CNS指征(比如焦虑)中得以确认;尽管一种5-HT6激动剂已在近期进入I期临床试验,但是该受体的确切作用仍有待确认,并且其是重点研究所关注的。基于5-HT6受体配体的直接作用和来自可利用科学研究的指示,其在人中具有多种潜在的治疗用途。这些研究包括所述受体的定位、具有已知体内活性的配体的亲和力、以及迄今为止所进行的多种动物研究。优选地,寻找5-HT6受体拮抗剂化合物作为治疗剂。
5-HT6受体功能调节剂的一个潜在治疗用途是在人疾病(如阿尔茨海默病)中增强认知和记忆。在例如前脑(包括尾状核/壳核)、海马、伏核和皮质的结构中发现的高水平的受体表明了该受体在记忆和认知中的作用,因为已知这些区域在记忆方面发挥着至关重要的作用(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)。已知的5-HT6受体配体增强胆碱能传递的能力也支持了该潜在认知用途(Bentey,J.C;Boursson,A.;Boess,F.G.;Kone,F.C;Marsden,C.A.;Petit,N.;Sleight,A.J.,British Journalof Pharmacology,1999,126(7),1537-1542)。
研究发现,已知的5-HT6选择性拮抗剂显著提高额叶皮质中的谷氨酸和天冬氨酸水平,而不提高去甲肾上腺素、多巴胺或5-HT的水平。这种特定神经化学物质的选择性升高现于记忆和认知过程中,强烈地表明了5-HT6配体在认知中的作用(Dawson,L.A.;Nguyen,H.Q.;Li,P.BritishJournal of Pharmacology,2000,130(1),23-26)。利用已知的选择性5-HT6拮抗剂对动物的记忆和学习进行的研究有一些积极的效果(Rogers,D.C.;Hatcher,P.D.;Hagan,J.J.Society of Neuroscience,Abstracts,2000,26,680)。
5-HT6配体的相关潜在治疗用途是治疗儿童和成年人的注意力缺陷症(ADD,也称为注意力缺陷多动症或ADHD)。因为5-HT6拮抗剂看起来提高了黑质纹状体多巴胺途径的活性,以及因为ADHD与尾状核中的异常有关(Ernst,M;Zametkin,A.J.;Matochik,J.H.;Jons,P. A.;Cohen,R.M.,Journal of Neuroscience,1998,18(15),5901-5907),所以5-HT6拮抗剂可以减轻注意力缺陷症。
目前,有少数完全选择性激动剂可用。Wyeth的激动剂WAY-181187目前处在针对焦虑症的I期试验中[Cole,D.C.等(2005)Discovery of apotent,selective and orally active 5-HT6 receptor agonist,WAY-181187.230th ACS Natl.Meet.(Aug 28-Sept 1,Washington DC),Abstract MEDI17]。
国际专利公开WO 03/066056A1报道了5-HT6受体的拮抗作用能够促进哺乳动物中枢神经***内的神经元生长。另一个国际专利公开WO03/065046A2公开了人5-HT6受体的新型变体,并提出5-HT6受体与多种其它疾病有关。
检验具有已知治疗效用或与已知药物结构非常相似的各种CNS配体的亲和力的早期研究表明了5-HT6配体在治疗精神***症和抑郁症中的作用。例如,氯氮平(一种有效的临床抗精神病药)对5-HT6受体亚型具有高亲和力。并且,几种临床抗抑郁药也对该受体具有高亲和力并在该位点作为拮抗剂(Branchek,T.A.;Blackburn,T.P.,Annual Reviews inPharmacology and Toxicology,2000,40,319-334)。
此外,近来在大鼠中的体内研究表明,5-HT6调节剂可以用于治疗包括癫痫的运动障碍(Stean,T.;Routledge,C.;Upton,N.,British Journal ofPharmacology,1999,127 Proc.增刊-131页;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 Journal ofPharmacology,2000,30(7),1606-1612)。
总之,上述研究强烈地表明,作为5-HT6受体调节剂(即配体)的化合物可用于包括如下的治疗适应症:与记忆、认知和学习缺陷有关的疾病例如阿尔茨海默病和注意力缺陷症的治疗;人格障碍例如精神***症的治疗;行为障碍例如焦虑、抑郁和强迫症的治疗;行动或运动障碍例如帕金森病和癫痫的治疗;与神经退行性有关的疾病例如中风或头部创伤的治疗;或者对药物成瘾(包括对烟碱、酒精和其它滥用物质成瘾)的戒断。
这些化合物还预计可用于治疗某些胃肠道(GI)疾病,例如功能性肠疾病。参见例如Roth B.L.等,Journal of Pharmacology and ExperimentalTherapeutics,1994,268,第1403-1412页,Sibley D.R.等,MolecularPharmacology,1993,43,320-327,Sleight A.J.等,Neurotransmission,1995,11,1-5,以及Sleight A.J.等,Serotonin ID Research Alert,1997,2(3),115-118。
此外,已报道了5-HT6拮抗剂和5-HT6反义寡核苷酸对降低大鼠食物摄取量的作用,由此可能用于治疗肥胖。参见例如Bentey 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;Wooley等,Neuropharmacology,2001,41:210-129;以及WO 02/098878。
进来,Holenz,Jo¨rg等的综述Drug Discovery Today,11,7/8,2006.4,Medicinal chemistry strategies to 5-HT6 receptor ligands as potentialcognitive enhancers and antiobesity agents对5-HT6配体的进展作了详细阐述。其总结了用于评价疾病(例如精神***症、其它与多巴胺相关的疾病以及抑郁症)中5-HT6受体以及描述阻断或活化5-HT6受体的神经化学和电生理作用的药理学工具和临床前候选物。此外,它们还已被用于表征5-HT6受体以及研究其分布。
迄今为止,几种临床候选物形成了吲哚型结构的部分并且在结构上与内源性配体5-HT密切相关,例如以下文献中提出的化合物:Glennon,R.A.等2-Substituede tryptamines:agents with selectivity for 5-HT6 serotoninreceptors,J.Med.Chem.43,1011-1018,2000;Tsai,Y.等N1-(Benzenesulfonyl)tryptamines as novel 5-HT6 antagonists,Bioorg.Med.Chem.Lett.10,2295-2299,2000;Demchyshyn L.等,ALX-1161:pharmacological properties of a potent and selective 5-HT6 receptorantagonist,31st Annu.Meet.Soc.Neurosci.(Nov 10-15),Abstract 266.6,2001;Slassi,A.等Preparation of 1-(arylsulfonyl)-3-(tetrahydropyridinyl)indoles as 5-HT6 receptor inhibitors,WO 200063203,2000;Mattsson,C.等,Novel,potent and selective2-alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as 5-HT6 receptoragonists,XVIIth International Symposium on Medicinal Chemistry,2002;Mattsson,C.等,2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles asnovel 5-HT6 receptor agonists,Bioorg.Med.Chem.Lett.15,4230-4234,2005]。
构效关系描述于吲哚样结构部分和受体-建模研究(其中Pullagurla等宣称激动剂和拮抗剂有不同结合位点)中[Pullagurla,M.R.等(2004)Possible differences in modes of agonist and antagonist binding at human5-HT6 receptors.Bioorg.Med.Chem.Lett.14,4569-4573]。所报道的大多数拮抗剂构成所述单环、双环和三环芳基哌嗪类的一部分[Bromidge,S.M.等(1999)5-Chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2-benzothiophenesulfonamide(SB-271046):A potent,selective and orallybioavailable 5-HT6 receptor antagonist.J.Med.Chem.42,202-205;Bromidge,S.M.等(2001)Phenyl benzenesulfonamides are novel andselective 5-HT6 antagonists:Identification ofN-(2,5-dibromo-3-fluorophenyl)-4-methoxy-3-piperazin-1-ylbenzenesulfonamide(SB-357134).Bioorg.Med.Chem.Lett.11,55-58;Hirst,W.D.等(2003)Characterisation of SB-399885,a potent and selective 5-HT6receptor antagonist.33rd Annu.Meet.Soc.Neurosci.(Nov.8-12,NewOrleans),Abstract 576.7;Stadler,H.等(1999)5-HT6 antagonists:A novelapproach for the symptomatic treatment of Alzheimer′s disease.37thIUPAC Cong.Berlin,Abstract MM-7;Bonhaus,D.W.等(2002)Ro-4368554,a high affinity,selective,CNS penetrating 5-HT6 receptorantagonist.32nd Annu.Meet.Soc.Neurosci.,Abstract 884.5.;Beard,C.C.等(2002)Preparation of new indole derivatives with 5-HT6 receptor affinity.WO patent 2002098857]。
Ro 63-0563:Potent and selective antagonists at human and rat 5-HT6receptors.Br.J.Pharmacol.124,(556-562).II期拮抗剂候选物有来自GlaxoSmithKline的SB-742457(用于与阿尔茨海默病相关的认知障碍治疗指征)[Ahmed,M.等(2003)Novel compounds.WO2003080580]以及Lilly的化合物LY-483518[Filla,S.A.等(2002)Preparation of benzenesulfonicacid indol-5-yl esters as antagonists of the 5-HT6 receptor. WO2002060871]。SB-271046(第一个进入I期临床研究的5-HT6受体拮抗剂)已经被中止(可能由于对血脑屏障的低渗透性)。此外,所述选择性5-HT6受体拮抗剂SB-271046在有或无癫痫症状的动物试验中均无活性[Pouzet,B.等(2002)Effects of the 5-HT6 receptor antagonist,SB-271046,in animalmodels for schizophrenia.Pharmacol.Biochem.Behav.71,635-643]。
国际专利公开WO 2004/055026 A1、WO 2004/048331 A1、WO2004/048330 A1和WO 2004/048328 A2(均已转让给Suven Life SciencesLimited)描述了相关的现有技术。此外,WO 98/27081、WO 99/02502、WO 99/37623、WO 99/42465和WO01/32646(均已转让给Glaxo SmithKlineBeecham PLC)公开了一系列作为5-HT6受体拮抗剂的芳基磺酰胺和亚砜化合物,其被声称为可用于治疗各种CNS疾病。虽然已经公开了一些5-HT6调节剂,但是仍然需要可用于调节5-HT6的化合物。出乎意料地,发现式(I)的4-(杂环基)烷基-N1-(芳基磺酰基)吲哚化合物显示出非常高的5-HT6受体亲和力。因此,本发明的一个目的是提供可用作治疗受5-HT6受体影响的多种中枢神经***疾病的治疗剂的化合物。
发明内容
本发明涉及式(I)的新的4-(杂环基)烷基-N-(芳基磺酰基)吲哚化合物、其衍生物、其立体异构体、其可药用盐以及含有所述物质的可药用组合物,
其中
Ar表示苯基、萘基、单环或双环,其可被一个或多个选自R1的独立取代基所取代;
R1表示选自氢、羟基、卤素、(C1-C3)烷基、卤代(C1-C3)烷基、(C1-C3)烷氧基、卤代(C1-C3)烷氧基、环(C3-C6)烷基或环(C3-C6)烷氧基中的一个或多个独立取代基;
R2表示氢、卤素、(C1-C3)烷基、卤代(C1-C3)烷基、(C1-C3)烷氧基或卤代(C1-C3)烷氧基;
R3表示氢、卤素、(C1-C3)烷基或卤代(C1-C3)烷基、(C1-C3)烷氧基或卤代(C1-C3)烷氧基;
R表示氢原子、(C1-C3)烷基或卤代(C1-C3)烷基;
R4和R5表示氢、卤素、(C1-C3)烷基、卤代(C1-C3)烷基、(C1-C3)烷氧基或卤代(C1-C3)烷氧基。
本发明涉及治疗有效量的式(I)化合物在制备用于治疗或预防与5-HT6受体选择性亲和力有关的疾病之药物中的用途。
具体而言,本发明的化合物还可用于治疗多种CNS病、血液病、进食障碍、与疼痛相关的疾病、呼吸疾病、生殖泌尿***疾病、心血管病以及癌症。
在另一个方面,本发明涉及药物组合物,所述药物组合物含有与至少一种合适的载体相混合的治疗有效量的至少一种式(I)化合物、或其各立体异构体、立体异构体的外消旋或非外消旋混合物、或其可药用盐或溶剂化物。
在另一个方面,本发明涉及含有式(I)化合物的组合物以及使用式(I)化合物的方法。
在又一个方面,本发明涉及治疗有效量的式(I)化合物在制备用于治疗或预防与5-HT6受体选择性亲和力有关的疾病之药物中的用途。
在又一个方面,本发明还涉及制备式(I)化合物的方法。
以下是属于通式(I)的化合物、其立体异构体及其盐的部分列举:
1-苯磺酰基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(4-溴苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2-溴-4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-[4-(1-甲基乙基)苯磺酰基]-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2-溴苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(3-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2,4-二氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2,5-二氯-3-噻吩磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(5-溴-2-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2,6-二氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2,6-二氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(3-氯-2-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2-氯-4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-苯磺酰基-3-溴-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(2-溴-4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-[4-(1-甲基乙基)苯磺酰基]-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(3-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(1-萘基磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(5-氯-2-甲氧基-4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-苯磺酰基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-[4-(1-甲基乙基)苯磺酰基]-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(2-溴苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(3-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(1-萘基磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(5-氯-2-甲氧基-4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2-溴苯磺酰基)-4-(哌嗪-1-基甲基)-1H-吲哚二盐酸盐;
1-苯磺酰基-4-(哌嗪-1-基甲基)-1H-吲哚二盐酸盐;
1-(4-甲基苯磺酰基-4-(哌嗪-1-基甲基)-1H-吲哚二盐酸盐;
1-萘基磺酰基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2,4-二氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(3-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-苯磺酰基-5-羟基-3-甲基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(4-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-6-羟基-1H-吲哚;
1-(4-羟基苯磺酰基)-5-甲基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(4-氯苯磺酰基)-6-甲氧基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
6-氯-1-(4-氯苯磺酰基)-4-(3,4-二甲基哌嗪-1-基甲基)-3-甲基-1H-吲哚;
6-氯-1-(4-羟基苯磺酰基)-3-甲基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
4-(3,4-二甲基哌嗪-1-基甲基)-1-(4-甲氧基苯磺酰基)-1H-吲哚;
1-(4-氟苯磺酰基)-4-(3-甲氧基-4-甲基哌嗪-1-基甲基)-1H-吲哚;
4-(3-氯-4-甲基哌嗪-1-基甲基)-1-(4-甲基苯磺酰基)-1H-吲哚;
4-(4-甲基-3-三氟甲基哌嗪-1-基甲基)-1-(4-甲基苯磺酰基)-1H-吲哚;
1-苯磺酰基-4-(4-甲基哌嗪-1-基甲基)-2-三氟甲基-1H-吲哚。
具体实施方式
除非另有说明,否则说明书和权利要求书中所用的下述术语具有下述含义:
“卤素”意指氟、氯、溴或碘。
“(C1-C3)烷基”意指含有一至三个碳原子的直链和支链烷基,包括甲基、乙基、正丙基和异丙基。
“(C1-C3)烷氧基”意指含有一至三个碳原子的直链和支链烷基,包括甲氧基、乙氧基、丙氧基和异丙氧基。
“卤代(C1-C3)烷基”意指含有一至三个碳原子的直链和支链烷基,包括氟代甲基、二氟甲基、三氟甲基、三氟乙基、氟代乙基、二氟乙基等。
“卤代(C1-C3)烷氧基”意指含有一至三个碳原子的直链和支链烷基,包括氟代甲氧基、二氟甲氧基、三氟甲氧基、三氟乙氧基、氟代乙氧基、二氟乙氧基等。
“环(C3-C6)烷基”意指含有三至六个碳原子的环烷基和支链环烷基,包括环丙基、环丁基、环戊基或环己基。
“环(C3-C6)烷氧基”意指含有三至六个碳原子的环烷基和支链环烷基,包括环丙氧基、环丁氧基、环戊氧基或环己氧基。
“单环或双环体系”旨在意指杂芳基和杂环。
“杂芳基”意指含有1~3个选自氧、氮和硫的杂原子的5~6元单环芳环或稠合的8~10元双环芳环。单环芳环的合适实例包括噻吩基、呋喃基、吡咯基、***基、咪唑基、噁唑基、噻唑基、噁二唑基、异噻唑基、异噁唑基、噻二唑基、吡唑基、嘧啶基、哒嗪基、吡嗪基和吡啶基。稠合芳环的合适的例子包括苯并稠合的芳环,例如喹啉基、异喹啉基、喹唑啉基、喹喔啉基、噌啉基、萘啶基、吲哚基、异吲哚基、吲唑基、吡咯并吡啶基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并噁二唑基、苯并噻二唑基、苯并***基等。除了有与以上相反表述以外,如上所述的杂芳基可通过碳原子或合适的氮原子(如果存在的话)连接到所述分子的其余部分上。
“杂环”是指含有1~3个选自氧、氮和硫的杂原子的5~7元非芳族环。这种环可以是部分不饱和的。杂环的合适实例包括哌啶基、四氢吡啶基、吡咯烷基、吗啉基、氮杂环庚烷基(azepanyl)、二氮杂环庚烷基(diazepanyl)和哌嗪基。如上所述的5~7元杂环可通过碳原子或合适的氮原子连接到所述分子的其余部分上。
术语“精神***症”意指精神***症、精神***症样障碍、***情感性障碍和精神病性精神障碍,其中术语“精神病”是指妄想、明显的幻觉、无组织的语言或无组织行为或紧张性行为。参见Diagnostic and StatisticalManual of Mental Disorder,第四版,American Psychiatric Association,Washington,D.C.。
术语“可药用”是指物质或组合物必须与制剂中所包含的其它成分、和/或其所治疗的哺乳动物在化学上和/或毒理学上相容。
“治疗有效量”定义为“本发明化合物(i)治疗或预防特定疾病、病症或障碍,(ii)减弱、改善或消除特定疾病、病症或障碍的一种或多种症状,(iii)防止或延缓本文中所述的特定疾病、病症或障碍的一种或多种症状的发作的量”。
术语“治疗”包括所有含义,例如预防、防治和缓解。
术语“立体异构体”是仅其原子在空间方向上不同的各种分子的所有异构体的通称。其包括镜像异构体(对映体)、几何(顺-反)异构体和具有超过一个手性中心的彼此不是镜像的化合物异构体(非对映体)。
式(I)的某些化合物能够以立体异构体的形式(例如非对映体和对映体)存在,本发明扩展到这些立体异构体形式的每一种及其混合物,包括外消旋体。可以通过常规方法将不同的立体异构体形式彼此分离,或者可以通过立体选择性合成或不对称合成得到任意给定的异构体。本发明还扩展到任何互变异构体形式及其混合物。
一般地,立体异构体通常作为外消旋体得到,所述外消旋体可以以本身已知的方式被分离为光学活性的异构体。在具有一个不对称碳原子的通式(I)化合物的情况下,本发明涉及D-型、L-型和D,L-混合物;而在具有多个不对称碳原子的情况下,本发明涉及非对映体形式,并且本发明扩展到这些立体异构体形式中的每一种及其混合物,包括外消旋体。可以通过常规方法彼此分离那些具有不对称碳原子并且通常作为外消旋体得到的通式(I)化合物,或者可以通过立体专一性合成或不对称合成得到任意给定的异构体。然而,还可以从一开始就使用光学活性化合物,然后得到相应的光学活性性化合物或非对映体化合物作为最终化合物。
可以通过如下所示的一种或多种方法来制备通式(I)化合物的立体异构体:
i)可以以其光学活性形式使用一种或多种试剂。
ii)在还原过程中可以使用光学纯催化剂或者与金属催化剂一起使用的手性配体。所述金属催化剂可用于还原过程中。所述金属催化剂可以是铑、钌、铟等。手性配体可以优选为手性膦(Principles ofAsymmetric synthesis,J.E.Baldwin Ed.,Tetrahedron series,14,311-316)。
iii)可以通过常规方法拆分立体异构体的混合物,例如与手性酸或手性胺、或者手性氨基醇、手性氨基酸形成非对映体盐。然后可以通过例如分步结晶、色谱等方法分离所得的非对映体混合物,随后进行通过水解所述衍生物来分离所述光学活性产物的额外步骤(Jacques等,“Enantiomers,Racemates and Resolution”,Wiley Interscience,1981)。
iv)可以通过常规方法拆分立体异构体的混合物,例如微生物拆分、拆分与手性酸或手性碱形成的非对映体盐。
可以使用的手性酸可以是酒石酸、苯乙醇酸、乳酸、樟脑磺酸、氨基酸等。可以使用的手性碱可以是金鸡纳生物碱、二甲氧基马钱子碱或碱性氨基例如赖氨酸、精氨酸等。在通式(I)化合物包含几何异构体的情况下,本发明涉及所有的这些几何异构体。
合适的可药用盐对本领域技术人员而言将是显而易见的,并包括在J.Pharm.Sci.,1977,66,1-19中记载的那些,例如与无机酸(例如盐酸、氢溴酸、硫酸、硝酸或磷酸)和有机酸(例如琥珀酸、马来酸、乙酸、富马酸、柠檬酸、酒石酸、苯甲酸、对甲苯磺酸、甲磺酸或萘磺酸)形成的酸加成盐。本发明在其范围内包括所有可能的化学计量和非化学计量的形式。
可以通过利用1~6当量的碱(例如氢化钠、甲醇钠、乙醇钠、氢氧化钠、叔丁醇钾、氢氧化钙、乙酸钙、氯化钙、氢氧化镁、氯化镁等)处理式(I)化合物来制备构成本发明一部分的可药用盐。可以使用溶剂例如水、丙酮、醚、THF、甲醇、乙醇、叔丁醇、二氧六环、异丙醇、异丙醚或其混合物。
除了可药用盐之外,本发明还包括其它盐。其可以在所述化合物的纯化、其它盐的制备或者所述化合物或中间体的鉴定和表征中用作中间体。
可以以晶体或非晶体形式制备式(I)化合物,并且如果是晶体的话,可以任选地被溶剂化,例如作为水合物。本发明在其范围内包括化学计量的溶剂化物(例如水合物)以及含有可变量溶剂(例如水)的化合物。
本发明还提供了一种用于制备式(I)化合物或其可药用盐的方法,所述方法包括下述途径,其中所述关键中间体可通过文献中已知的多种方法来合成。
对所述中间体进一步进行如下处理:
方案-I
本发明的方法包括在惰性溶剂和合适的碱存在下于合适的温度下使下式(a)的化合物与式ArSO2Cl的芳基磺酰基化合物相接触以得到式(I)化合物:
其中所有取代基均如上文所述,在式ArSO2Cl的芳基磺酰基化合物中,Ar如式(I)化合物所定义,必要时,可对式(I)化合物进一步衍生。我们之前的专利申请WO 2004/048330 A1给出了式(I)化合物的互相转化中可用的反应条件和试剂的更多描述。
吲哚衍生物与芳基磺酰氯(ArSO2Cl)的反应可以在惰性有机溶剂存在下进行,所述惰性有机溶剂包括芳烃,例如甲苯、邻二甲苯、间二甲苯、对二甲苯;卤代烃,例如二氯甲烷、氯仿和氯苯;醚,例如二***、二苯醚、二异丙醚、叔丁基甲基醚、二氧六环、苯甲醚和四氢呋喃;腈,例如乙腈和丙腈;醇,例如甲醇、乙醇、正丙醇、正丁醇、叔丁醇以及DMF(N,N-二甲基甲酰胺)、DMSO(N,N-二甲基亚砜)和水。优选的溶剂清单包括DMSO、DMF、乙腈和THF。也可以使用这些溶剂的不同比例的混合物。合适的碱通常为无机化合物例如碱金属氢氧化物和碱土金属氢氧化物,例如氢氧化锂、氢氧化钠、氢氧化钾和氢氧化钙;碱金属氧化物和碱土金属氧化物,例如氧化锂、氧化钠、氧化镁和氧化钙;碱金属氢化物和碱土金属氢化物,例如氢化锂、氢化钠、氢化钾和氢化钙;碱金属氨化物和碱土金属氨化物,例如氨基锂、氨基钠、氨基钾和氨基钙;碱金属碳酸盐和碱土金属碳酸盐,例如碳酸锂和碳酸钙;以及碱金属碳酸氢盐和碱土金属碳酸氢盐,例如碳酸氢钠;有机金属化合物,尤其是碱金属烷基化物,例如甲基锂、丁基锂、苯基锂;卤化烷基镁,例如氯化甲基镁,以及碱金属醇盐和碱土金属醇盐,例如甲醇钠、乙醇钠、乙醇钾、叔丁醇钾和二甲氧基镁,以及有机碱,例如三乙胺、三异丙胺和N-甲基哌啶、吡啶。尤其优选氢氧化钠、甲醇钠、乙醇钠、氢氧化钾、碳酸钾和三乙胺。适当地,该反应可以在相转移催化剂例如四正丁基硫酸氢铵等存在下进行。通过使用惰性气体例如N2、Ar或He可以维持惰性气氛,反应时间可以为1~24小时,优选为2~6小时。如果需要的话,使所得的化合物转变成为其盐。
通过众所周知的反应(例如氧化、还原、保护、去保护、重排反应、卤化、羟基化、烷基化、烷硫基化、脱甲基化、O-烷基化、O-酰基化、N-烷基化、N-烯基化、N-酰基化、N-氰化、N-磺酰化、使用过渡金属的偶联反应等)的进一步化学修饰,可以将通过本发明的上述制备方法得到化合物转化为本发明的其它化合物。
如果必要的话,可以进行下列步骤中的任意一个或多个,
i)将式(I)化合物转化为其它的式(I)化合物;
ii)去除任意保护基团;或
iii)形成其可药用盐、溶剂化物或前药。
可以利用常规的互化步骤(例如差向异构化、氧化、还原、烷基化、亲核或亲电子芳族取代以及酯水解或酰胺键形成)进行方法(i)。
在方法(ii)中,在T.W.Greene′Protective Groups in Organic Synthesis′(J.Wiley and Sons,1991)中可以找到保护基团的实例及其去除方法。合适的胺保护基团包括磺酰基(例如甲苯磺酰基)、酰基(例如乙酰基、2′,2′,2′-三氯乙氧基羰基、苄氧基羰基或叔丁氧基羰基)和芳基烷基(例如苄基),其可以适当地通过水解(例如使用酸,例如盐酸或三氟乙酸)或通过还原(例如氢解苄基或在乙酸中用锌还原去除2′,2′,2′-三氯乙氧基羰基)而去除。其它合适的胺保护基团包括三氟乙酰基,其可以通过碱催化水解或固相树脂结合的苄基而去除,例如Merrifield树脂结合的2,6-二甲氧基苄基(Ellman连接基),其可以通过酸催化水解(例如利用三氟乙酸)而去除。
在方法(iii)中,可以通过与上文详细描述的合适的酸或酸衍生物反应来常规进行卤化、羟化、烷基化和/或制备其可药用盐。
为了在治疗中使用式(I)化合物,通常会根据标准药学实践将其配制成药物组合物。
可以使用一种或多种可药用载体以常规方式配制本发明的药物组合物。因此,可将本发明的活性化合物配制成用于经口、***、鼻内、肠胃外(例如静脉内、肌内或皮下)或直肠施用或适于通过吸入或吹入施用的方式。
对于经口施用而言,药物组合物可以采取例如通过常规方法利用可药用赋形剂制备的片剂或胶囊的形式,所述可药用赋形剂例如为粘合剂(例如预胶化玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素);填充剂(例如乳糖、微晶纤维素或磷酸钙);润滑剂(例如硬脂酸镁、滑石或二氧化硅);崩解剂(例如马铃薯淀粉或淀粉乙醇酸钠);或润湿剂(例如十二烷基硫酸钠)。可以通过本领域众所周知的方法对片剂进行包衣。用于经口施用的液体制剂可以采取例如溶液、糖浆或混悬液的形式,或者其可以作为干燥产物用于在使用前与水或其它合适的载体进行构建。这样的液体制剂可以通过常规方法利用可药用添加剂来制备,所述可药用添加剂例如为助悬剂(例如山梨醇糖浆、甲基纤维素或氢化可食用脂肪);乳化剂(例如卵磷脂或***胶);非水载体(例如杏仁油、油状酯或乙醇);以及防腐剂(例如对羟基苯甲酸甲酯、对羟基苯甲酸丙酯或山梨酸)。
对于***施用而言,所述组合物可以采取以常规方式配制的片剂或锭剂的形式。
可将本发明的活性化合物配制成用于通过注射进行肠胃外施用,包括使用常规导管***术的注射或输注。注射用制剂可以以单位剂型存在于例如添加有防腐剂的安瓿或多剂量容器中。所述组合物可以采取在油性或水性载体中的混悬液、溶液或乳液的形式,并且可以包含例如助悬剂、稳定剂和/或分散剂的配制试剂。或者,活性成分可以是供使用前与合适的载体(例如无菌无热原的水)重建的粉末形式。
本发明的活性化合物还可以配制成直肠组合物,例如栓剂或保留灌肠剂,例如含有常规的栓剂基质,比如可可脂或其它甘油酯。
对于鼻内施用或通过吸入施用而言,以来自加压容器或喷雾器或者来自利用吸入器或吹入器的胶囊的气雾剂喷雾的形式便利地递送本发明的活性化合物。在加压气雾剂的情况下,可以通过提供用于递送计量的量的阀来确定合适的抛射剂(例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体)和剂量单位。用于加压容器或喷雾器的药物可以包含活性化合物的溶液或混悬液,而对于胶囊,优选应该为粉末形式。可以配制用于吸入器或吹入器的胶囊和药筒(例如由明胶制成),其含有本发明化合物和合适粉末基质(例如乳糖或淀粉)的粉末混合物。
优选将用于治疗普通成人的上述疾病(例如偏头痛)的气雾剂配方设置成使得气雾剂的每个计量剂量或“喷一次”含有20μg~1000μg的本发明化合物。气雾剂的总日剂量将为100μg~10mg。每天可以施用几次,例如2、3、4或8次,每次例如给予1、2或3个剂量。
可以将有效量的通式(I)化合物或上述其衍生物连同常规药物辅助剂、载体和添加剂一起用于制备药物。
这样的治疗包括多种选择:例如,在单一剂型中同时施用两种相容的化合物或以分开的剂量单独施用每种化合物;或者如果需要,以相同的时间间隔或分开施用,以便根据已知的药理学原理使有益效果尽可能高或使药物的潜在副作用尽可能低。
活性化合物的剂量可以基于例如施用途径、患者的年龄和体重、待治疗疾病的性质和严重程度这些因素以及类似因素改变。因此,本文对通式(I)化合物的药物有效量的任何提及均参考上述因素。对普通成年人的上述疾病的治疗而言,对于口服、肠胃外、经鼻或***施用来说,本发明活性化合物的建议剂量是每单位剂量0.1~200mg活性成分,其每天可施用例如1~4次。
出于说明性目的,本文所描述的反应方案提供了合成本发明化合物以及关键中间体的可能途径。对于各个反应步骤的更详细描述,参见实施例部分。本领域技术人员会理解,可以使用其它合成路线来合成本发明的化合物。虽然在方案中描述了具体的原料和试剂并在下面进行了讨论,但是可容易地替换为其它原料和试剂,以提供多种衍生物和/或反应条件。此外,根据本公开内容,使用本领域技术人员众所周知的常规化学方法可以进一步修饰通过下述方法制得的多种化合物。
不经过进一步纯化使用商业试剂。室温是指25~30℃。使用KBr在固态下得到IR光谱。除非另有说明,所有质谱均采用ESI条件进行。在Bruker仪器上以400MHz记录1H NMR谱。使用氘代氯仿(99.8%D)作为溶剂。将TMS用作内标物。化学位移值以每百万的份数(δ)值表示。下列缩写用于表示NMR信号的多重性:s=单峰、bs=宽单峰、d=双峰、t=三重峰、q=四重峰、qui=五重峰、h=七重峰、dd=双双峰、dt=双三重峰、tt=三三重峰、m=多重峰。色谱是指使用60~120目硅胶并在氮气压力(快速色谱)条件下进行的柱色谱。
本发明的新化合物是根据下述方案和实施例利用合适的物质制备的并且通过下述具体方法进一步举例说明。本发明的最优选的化合物是这些实施例中具体列举的任意一种或全部。然而,这些化合物不能解释为构成本发明所认定唯一化合物种类,而且所述化合物的任意组合或其部分本身可构成一种。下述实施例进一步举例说明制备本发明化合物的细节。本领域技术人员容易理解,可使用下述制备步骤中的条件和方法的已知变化方案来制备这些化合物。
实施例1:(4-甲基哌嗪-1-基甲基)-1H-吲哚的制备
步骤(i):(2-甲基-3-硝基苯基)-(4-甲基哌嗪-1-基)甲酮的制备
将2-甲基-3-硝基苯甲酸(5.525mmol,1.0g)置于连有冷凝器(带有保护管)的25mL两颈圆底烧瓶中。向其中加入亚硫酰氯(6.07mmol,0.735g)和1,2-二氯乙烷(5mL),使溶液回流3小时。将该反应混合物加入到另一个含有N-甲基哌嗪(16.57mmol,1.66g)在10mL 1,2-二氯乙烷中的溶液的100mL烧瓶中,其中温度维持在5℃以下。然后在25℃搅拌所述反应混合物0.5小时。反应完成后,将反应混合物倒入50mL水中。收集1,2-二氯乙烷层,用水(2×10mL)、盐水(10mL)清洗,用无水硫酸钠干燥。减压下除去挥发物得到浓稠的糖浆状物质。该浓稠的糖浆状物质不经纯化而用于下一步反应中。
步骤(ii):(4-甲基哌嗪-1-基)-[3-硝基-2-[2-(吡咯烷-1-基-乙烯基)苯基]甲酮
的制备
在氮气气氛下,将(2-甲基-3-硝基苯基)-(4-甲基哌嗪-1-基)甲酮(3.8022mmol,1.0g)(得自步骤(i))置于连有冷凝器的25mL两颈圆底烧瓶中。向其中加入3mL N,N-二甲基甲酰胺、N,N-二甲基甲酰胺二甲基缩醛(5.7033mmol)和吡咯烷(5.7033mmol),回流6小时。反应完成后,将所述反应混合物倒在20g冰水上,利用20%NaOH溶液碱化(至pH为10),利用乙酸乙酯(2×30mL)萃取混合物。然后利用水(2×30mL)、盐水(30mL)清洗合并的乙酸乙酯萃取物,用无水硫酸钠干燥。减压下除去挥发物得到浓稠的糖浆状物质。该浓稠的糖浆状物质不经纯化而用于下一步反应中。
步骤(iii):(1H-吲哚-4-基)-(4-甲基哌嗪-1-基)甲酮的制备
在氮气气氛下,将(4-甲基哌嗪-1-基)-[3-硝基-2-(2-吡咯烷-1-基-乙烯基)苯基]甲酮(2.907mmol,1.0g)(得自步骤(ii))置于连有冷凝器的25mL两颈圆底烧瓶中。向其中加入THF(7mL),然后加入Raney-Nickel(Ra-Ni)(0.1g,10%w/w)。以使反应混合物开始回流的方式将水合肼(14.54mmol,0.73g)加入到上述反应混合物中。所述反应混合物再回流3小时。反应完成后,通过过滤除去Ra-Ni。蒸馏掉THF和甲醇,利用水(20mL)稀释浓缩物,利用20%NaOH溶液碱化至pH为10,利用乙酸乙酯(2×30mL)萃取混合物。然后利用水(2×30mL)、盐水(30mL)清洗合并的乙酸乙酯萃取物,并用无水硫酸钠干燥。减压下除去挥发物得到浓稠的糖浆状物质。该浓稠的糖浆状物质化合物通过硅胶柱以乙酸乙酯和三乙胺(0.2至1.0%)作为洗脱剂进行纯化。
步骤(iv):(4-甲基哌嗪-1-基甲基)-1H-吲哚的制备
在氮气气氛下,将氢化铝锂(LAH)(2.4691mmol,0.0938g)置于连有冷凝器的25mL两颈圆底烧瓶中。向其中加入溶解在5mL THF中的(1H-吲哚-4-基)-(4-甲基哌嗪-1-基)甲酮(2.0576mmol,0.5g)(得自步骤(iii)),然后回流混合物2小时。反应完成后,将反应混合物冷却至25℃,通过缓慢加入冰冷的水而猝灭反应,以分解过量的LAH。通过hy-flow过滤除去所得的氢氧化铝沉淀。将此乳液中的THF蒸出,利用水(20mL)稀释浓缩物,利用20%NaOH溶液碱化至pH为10,利用乙酸乙酯(2×20mL)萃取混合物。然后利用水(2×20mL)、盐水(20mL)清洗合并的乙酸乙酯萃取物,用无水硫酸钠干燥。减压下除去挥发物得到浓稠的糖浆状物质。该粗化合物通过硅胶柱以乙酸乙酯和三乙胺(0.2至1.0%)作为洗脱剂进行纯化。
实施例2:1-苯磺酰基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚的制备
将(4-甲基哌嗪-1-基甲基)-1H-吲哚(0.8733mmol,0.2g)(得自实施例1)溶解在2mL N,N-二甲基甲酰胺中。然后在氮气气氛下将上述溶液缓慢加入到含有氢化钠(1.31mmol,31.4mg)在1mL DMF中的混悬液的25mL烧瓶中,同时将温度维持在10℃以下。然后在25℃搅拌反应混合物1小时。将苯磺酰氯(1.31mmol,0.2312g)缓慢加入到该充分搅拌的溶液中,同时将温度维持在10℃以下。将所述反应混合物再搅拌2小时。反应完成后,在搅拌下将反应混合物倒在20g冰水混合物上,利用乙酸乙酯(2×20mL)萃取所得混合物。然后利用水(20mL)、盐水(20mL)清洗合并的乙酸乙酯萃取物,用无水硫酸钠干燥。减压下除去挥发物得到浓稠的糖浆状物质。通过硅胶柱以乙酸乙酯和三乙胺(0.2至1.0%)作为洗脱剂纯化化合物。
IR光谱(cm-1):1676,1447,1292,1164,1371;
质谱(m/z):370(M+H)+;
1H-NMR(ppm):2.26(3H,s),2.42(8H,bs),3.68(2H,s),6.90-6.91(1H,d),7.16-7.18(1H,d),7.22-7.26(1H,m),7.42-7.46(2H,m),7.51-7.53(1H,m),7.55-7.56(1H,d),7.88-7.90(3H,m);
实施例3:
依照实施例2中所述步骤并进行一些非关键性的改动来制备本发明的下述化合物(2-42)。
2 | 1-(4-溴苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1774,1163,745;质谱(m/z):448,450(M+H)+;1H-NMR(ppm):2.26(3H,s),2.43(8H,bs),3.68(2H,s),6.92-6.93(1H,d),7.18-7.20(1H,d),7.23-7.27(1H,t),7.51-7.52(1H,d),7.56-7.58(2H,m),7.72-7.74(2H,m),7.84-7.87(1H,d). |
3 | 1-(2-溴-4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚, | IR光谱(cm-1):1583,1480,1372,1278;质谱(m/z):478,480(M+H)+;1H-NMR(ppm):2.26(3H,s),2.43(8H,bs),3.69(2H,s),3.89(3H,s),6.86-6.88(1H,d),6.91-6.92(1H,d),7.17-7.19(1H,d),7.24-7.28(1H,t),7.52-7.53(1H,d),7.82-7.87(2H,m),8.04-8.04(1H,d). |
4 | 1-[4-(1-甲基乙基)苯磺酰基]-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1583,1480,1372,1278;质谱(m/z):412(M+H)+;1H-NMR(ppm):1.18-1.20(6H,d),2.26(3H,s),2.43(8H,bs),2.88-2.91(1H,m),3.69(2H,s),6.89-6.90(1H,d),7.16-7.18(1H,d),7.23-7.29(3H,m),7.56-7.56(1H,d),7.79-7.82(2H,m),7.89-7.91(1H,d). |
5 | 1-(4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1583,1480,1372;质谱(m/z):384(M+H)+;1H-NMR(ppm):2.28(3H,s)2.41(3H,s),2.45(8H,bs),3.70(2H,s),6.90-6.91(1H,d),7.17-7.19(1H,d),7.24-7.28(3H,m),7.57-7.58(1H,d),7.78-7.80(2H,m),7.89-7.91(1H,d). |
6 | 1-(2-溴苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1373,1184,758;质谱(m/z):448,450(M+H)+;1H-NMR(ppm):2.28(3H,s),2.45(8H,bs),3.73(2H,s),6.91-6.92(1H,d),7.16-7.17(2H,m),7.40-7.66(4H,m),7.76-7.77(1H,d),8.11-8.13(1H,m). |
7 | 1-(4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1588,1371,1188;质谱(m/z):388(M+H)+; |
1H-NMR(ppm):2.26(3H,s),2.43(8H,bs),3.68(2H,s),6.91-6.92(1H,d),7.0-7.13(2H,t),7.17-7.19(1H,d),7.23-7.26(1H,t),7.52-7.53(1H,d),7.86-7.92(3H,m). | ||
8 | 1-(4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1595,1367,1264,1160;质谱(m/z):400(M+H)+;1H-NMR(ppm):2.26(3H,s),2.43(8H,bs),3.68(2H,s),3.79(3H,s),6.87-6.89(3H,m),7.15-7.17(1H,d),7.22-7.26(1H,t),7.54-7.55(1H,d),7.82-7.84(2H,m),7.86-7.88(1H,d). |
9 | 1-(3-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1594,1376,1132;质谱(m/z):388(M+H)+;1H-NMR(ppm):2.30(3H,s),2.49(8H,bs),3.70(2H,s),6.93-6.94(1H,d),7.18-7.29(3H,m),7.43-7.44(1H,m),7.53-7.54(1H,d),7.56-7.59(1H,m),7.67-7.69(1H,m),7.86-7.89(1H,d). |
10 | 1-(2,4-二氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1382,1134;质谱(m/z):406(M+H)+;1H-NMR(ppm):2.34(3H,s),2.54(8H,bs),3.72(2H,s),6.81-6.88(1H,m),6.91-6.91(1H,d),6.99-7.05(1H,m),7.17-7.25(2H,m),7.61-7.64(1H,m),7.70-7.73(1H,d),8.08-8.15(1H,m) |
11 | 1-(2,5-二氯-3-噻吩磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1383,1130,765,664;质谱(m/z):444,446(M+H)+;1H-NMR(ppm):2.30(3H,s),2.51(8H,bs),3.73(2H,s),6.94-6.94(1H,d),7.12(1H,s),7.22-7.29(2H,m),7.58-7.59(1H,d),7.78-7.80(1H,d). |
12 | 1-(5-溴-2-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1480,1371,1280,1138,1010,559,528;质谱(m/z):478,480(M9+H)+;1H-NMR(ppm):2.17(3H,s),2.53(8H,bs),3.68(3H,s),3.72(2H,s),6.75-6.77(1H,d),6.84-6.85(1H,d),7.15-7.23(2H,m),7.58-7.61(2H,m),7.66-7.68(1H,d),8.22-8.23(1H,d). |
13 | 1-(2-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1373,1281,1184;质谱(m/z):404.5(M+H)+;1H-NMR(ppm):2.26(3H,s),2.56(8H,bs),3.74(2H,s), |
6.89-6.89(1H,d),7.16-7.17(2H,m),7.43-7.58(4H,m),7.73-7.74(1H,d),8.18-8.20(1H,m). | ||
14 | 1-(2,6-二氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1389,1189,1007;质谱(m/z):406(M+H)+;1H-NMR(ppm):2.29(3H,s),2.49(8H,bs),3.72(2H,s),6.91-6.92(1H,d),6.95-7.00(2H,m),7.19-7.26(2H,m),7.47-7.52(1H,m),7.63-7.64(1H,m),7.81-7.83(1H,d). |
15 | 1-(2,6-二氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1380,1184,1134,822;质谱(m/z):438,440(M+H)+;1H-NMR(ppm):2.32(3H,s),2.61(8H,bs),3.73(2H,s),6.90-6.91(1H,d),7.17-7.19(2H,m),7.40-7.45(2H,m),7.53-7.55(1H,m),7.69-7.70(1H,d),8.12-8.14(1H,d). |
16 | 1-(3-氯-2-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1454,1365,1287,1178,1084;质谱(m/z):418,420(M+H)+;1H-NMR(ppm):2.31(3H,s),2.52(8H,bs),2.60(3H,s),3.74(2H,s),6.95-6.96(1H,d),7.16-7.26(3H,m),7.56-7.57(2H,m),7.62-7.63(1H,d),7.65-7.67(1H,d). |
17 | 1-(2-氯-4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1586,1458,1392,1293,1184;质谱(m/z):422,424(M+H)+;1H-NMR(ppm):2.31(3H,s),2.51(8H,bs),3.73(2H,s),6.90-6.91(1H,d),7.12-7.18(4H,m),7.53-7.55(1H,m),7.70-7.71(1H,d),8.23-8.27(1H,m). |
18 | 1-苯磺酰基-3-溴-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1373,1185,1092,773,594;质谱(m/z):448,450(M+H)+;1H-NMR(ppm):2.26(3H,s),2.61(8H,bs),3.95(2H,s),7.23-7.27(2H,m),7.45-7.49(2H,m),7.55-7.57(1H,m),7.64(1H,s),7.89-7.94(3H,m). |
19 | 3-溴-1-(2-溴-4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1593,1372,1169,1093,773,576;质谱(m/z):556,558,560(M+H)+;1H-NMR(ppm):2.26(3H,s),2.54(8H,bs),3.91(3H,s),3.96(2H,s),6.88-6.90(1H,d),7.23-7.31(2H,m),7.61(1H,s),7.82-7.84(1H,m),7.89-7.92(1H,m),8.06-8.06(1H,weakd). |
20 | 3-溴-1-[4-(1-甲基乙基)苯磺酰基]-4-(4-甲基哌嗪- | IR光谱(cm-1):1372,1182,1089,775,586;质谱(m/z):490,492(M+H)+; |
1-基甲基)-1H-吲哚 | 1H-NMR(ppm):1.19-1.21(6H,d),2.26(3H,s),2.53(8H,bs),2.89-2.93(1H,m),3.95(2H,s),7.21-7.31(4H,m),7.64(1H,s),7.80-7.82(2H,m),7.94-7.96(1H,d). | |
21 | 3-溴-1-(4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1373,1177,1092,773,575;质谱(m/z):462,464(M+H)+;1H-NMR(ppm):2.26(3H,s),2.36(3H,s),2.51(8H,bs),3.95(2H,s),7.27-7.28(4H,m),7.63(1H,s),7.76-7.78(2H,m),7.91-7.93(1H,m). |
22 | 3-溴-1-(4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1590,1377,1183,1092,773,575;质谱(m/z):466,468(M+H)+;1H-NMR(ppm):2.26(3H,s),2.61(8H,bs),3.95(2H,s),7.12-7.16(2H,t),7.23-7.30(2H,m),7.62(1H,s),7.90-7.93(3H,m). |
23 | 3-溴-1-(4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1580,1380,1279,1178,1097,593;质谱(m/z):478,480(M+H)+;1H-NMR(ppm):2.26(3H,s),2.43(8H,bs),3.81(3H,s),3.95(2H,s),6.89-6.92(2H,m),7.21-7.28(2H,m),7.63(1H,s),7.82-7.84(2H,m),7.90-7.93(1H,m). |
24 | 3-溴-1-(3-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1458,1376,1183,774,681,588;质谱(m/z):482,484,486(M+H)+;1H-NMR(ppm):2.26(3H,s),2.61(8H,bs),3.96(2H,s),7.26-7.30(2H,m),7.39-7.43(1H,t),7.53(1H,m),7.61(1H,s),7.76-7.76(1H,m),7.87-7.88(1H,weakt),7.90-7.92(1H,m). |
25 | 3-溴-1-(1-萘基磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1372,1284,1136,1010,767,594;质谱(m/z):498,500(M+H)+;1H-NMR(ppm):2.26(3H,s),2.52(8H,bs),3.93(2H,s),7.19-7.20(2H,m),7.53-7.59(2H,m),7.69-7.74(2H,m),7.84(1H,s),7.90(1H,d),8.08-8.10(1H,d),8.21-8.23(1H,m),8.65-8.68(1H,d). |
26 | 3-溴-1-(5-氯-2-甲氧基-4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1595,1478,1383,1179,1092;质谱(m/z):526,528,530(M+H)+;1H-NMR(ppm):2.27(3H,s),2.36(3H,s),2.61(8H,bs),3.69(3H,s),3.98(2H,s),6.73(1H,s),7.20-7.24(2H,m),7.68-7.72(2H,m),8.07(1H,s). |
27 | 3-氯-1-苯磺酰基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):2963,1450,1381,1220;质谱(m/z):404,406(M+H)+;1H-NMR(ppm):2.26(3H,s),2.52(8H,bs),3.92(2H,s),7.22-7.30(2H,m),7.45-7.49(2H,m),7.55-7.59(2H,m),7.88-7.93(3H,m). |
28 | 3-氯-1-[4-(1-甲基乙基)苯磺酰基]-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1457,1374,1179,1091;质谱(m/z):446,448(M+H)+;1H-NMR(ppm):1.19-1.21(6H,d),2.28(3H,s),2.61(8H,bs),2.87-2.93(1H,m),3.93(2H,s),7.21-7.23(1H,d),7.26-7.31(3H,m),7.56(1H,s),7.79-7.82(2H,m),7.93-7.95(1H,dd). |
30 | 3-氯-1-(2-溴苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1374,1185,748,580;质谱(m/z):482,484,486(M+H)+;1H-NMR(ppm):2.27(3H,s),2.55(8H,bs),3.97(2H,s),7.11-7.24(2H,m),7.43-7.43(1H,m),7.51-7.51(1H,m),7.55-7.57(1H,m),7.68-7.70(1H,m),7.77(1H,s),8.17-8.19(1H,m). |
31 | 3-氯-1-(4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):3133,2935,1587,1491,1369;质谱(m/z):422,424(M+H)+;1H-NMR(ppm):2.29(3H,s),2.54(8H,bs),3.93(2H,s),7.11-7.17(2H,m),7.23-7.31(2H,m),7.54(1H,s),7.89-7.94(3H,m). |
32 | 3-氯-1-(4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):2932,1596,1269,1166;质谱(m/z):434,436(M+H)+;1H-NMR(ppm):2.26(3H,s),2.53(8H,bs),3.81(3H,s),3.93(2H,s),6.88-6.92(2H,m),7.21-7.29(2H,m),7.55(1H,s),7.81-7.84(2H,m),7.89-7.91(1H,d). |
33 | 3-氯-1-(3-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1379,1183,752,674;质谱(m/z):438(M+H)+;1H-NMR(ppm):2.27(3H,s),2.54(8H,bs),3.93(2H,s),7.27-7.33(2H,m),7.39-7.43(1H,t),7.53-7.54(2H,m),7.75-7.77(1H,m),7.87-7.88(1H,weakt),7.89-7.91(1H,d). |
34 | 3-氯-1-(1-萘基磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H- | IR光谱(cm-1):1373,1285,1136,1078;质谱(m/z):454,456(M+H)+; |
吲哚 | 1H-NMR(ppm):2.25(3H,s),2.51(8H,bs),3.92(2H,s),7.19-7.21(2H,m),7.52-7.58(2H,m),7.68-7.73(2H,m),7.76(1H,s),7.89(1H,d),8.07-8.09(1H,d),8.20-8.22(1H,dd),8.65-8.68(1H,d). | |
35 | 3-氯-1-(5-氯-2-甲氧基-4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1595,1477,1378,1179;质谱(m/z):482,484(M+H)+;1H-NMR(ppm):2.34(3H,s),2.37(3H,s),2.60(8H,bs),3.70(3H,s),3.97(2H,s),6.74(1H,s),7.19-7.25(2H,m),7.61(1H,s),7.68-7.71(1H,m),8.07(1H,s). |
36 | 1-(2-溴苯磺酰基)-4-(哌嗪-1-基甲基)-1H-吲哚二盐酸盐 | IR光谱(cm-1):1371,1141,758;质谱(m/z):434.2,436.2(M+H)+;1H-NMR(ppm):3.46(8H,bs),4.57(2H,s),7.11(1H,d),7.35-7.37(1H,m),7.45-7.46(1H,m),7.55-7.57(1H,dt),7.62-7.65(1H,t)7.76-7.8(2H,m),7.99-8.00(1H,d),8.33-8.35(1H,dd). |
37 | 1-苯磺酰基-4-(哌嗪-1-基甲基)-1H-吲哚二盐酸盐 | IR光谱(cm-1):1365,1186,731;质谱(m/z):356.2(M+H)+;1H-NMR(ppm):3.21(8H,bs),4.32(2H,s),6.89-6.90(1H,d,J=3.5Hz),7.25-7.27(1H,d),7.32-7.34(1H,t),7.38-7.42(2H,m),7.51-7.54(1H,t),7.74-7.75(1H,d,J=3.55Hz),7.83-7.85(2H,d,J=7.88Hz),7.96-7.98(1H,d,J=8.18Hz). |
38 | 1-(4-甲基苯磺酰基-4-(哌嗪-1-基甲基)-1H-吲哚二盐酸盐 | IR光谱(cm-1):1363,1165,578;质谱(m/z):370.2(M+H)+;1H-NMR(ppm):2.11(3H,s),3.23(8H,bs),4.31(2H,s),6.82(1H,d,J=3.59Hz),7.12-7.14(2H,d,J=8.13),7.19-7.28(2H,m),7.63-7.67(3H,m),7.88-7.90(1H,d,J=8.16). |
39 | 1-萘基磺酰基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1361,1171,1129,765;质谱(m/z);420.5(M+H)+;1H-MR(ppm):2.27(3H,s),2.45(8H,bs),3.68(2H,s),6.92-6.93(1H,d,J=3.4Hz),7.157.17(2H,m),7.50-7.56(2H,m),7.62-7.72(2H,m),7.78-7.79(1H,d,J=3.76),7.88-7.91(1H,d)8.04-8.06(1H,d,J=8.28),8.14-8.16(1H,dd,J=7.48),8.69-8.71(1H,d,J=8.72Hz). |
40 | 1-(2,4-二氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1);1380,1184,1134,822;质谱(m/z):438.4,440.4,442.4(M+H)+;1H-NMR(ppm):2.32(3H,s),2.45-2.55(8H,bs),3.73(2H,s),6.90-6.91(1H,d,J=3.84),7.17-7.19(2H,m),7.40-7.45(2H,m),7.54-7.55(1H,m),7.69-7.70(1H,d,J=3.76Hz)8.12-8.14(1H,d,J=8.48). |
41 | 1-(3-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | IR光谱(cm-1):1377,1184,1134,759;质谱(m/z):404(M+H)+;1H-NMR(ppm):2.30(3H,s),2.48(8H,bs),3.69(2H,s),6.93-6.94(1H,d,J=3.92),7.18-7.20(1H,d,J=7.08),7.25-7.29(1H,m),7.36-7.4(1H,J=7.96),7.49-7.52(1H,m),7.53-7.54(1H,d,J=3.68),7.75-7.78(1H,m),7.85-7.88(2H,m). |
42 | 1-苯磺酰基-5-羟基-3-甲基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 | 质谱(m/z):400.2(M+H)+;1H-NMR(ppm):2.29(3H,s),2.31(3H,s),2.40-2.70(8H,bs),4.04(2H,s),6.80-6.82(1H,d,J=8.92),7.22(1H,s),7.40-7.44(2H,,m),7.49-7.51(1H,m),7.78-7.80(1H,d,J=8.92),7.82-7.84(2H,m). |
实施例4:
本领域技术人员可依照实施例2中所述步骤制备本发明的下述化合物(43-52)。
43 | 1-(4-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-6-羟基-1H-吲哚 |
44 | 1-(4-羟基苯磺酰基)-5-甲基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 |
45 | 1-(4-氯苯磺酰基)-6-甲氧基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 |
46 | 6-氯-1-(4-氯苯磺酰基)-4-(3,4-二甲基哌嗪-1-基甲基)-3-甲基-1H-吲哚 |
47 | 6-氯-1-(4-羟基苯磺酰基)-3-甲基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚 |
48 | 4-(3,4-二甲基哌嗪-1-基甲基)-1-(4-甲氧基苯磺酰基)-1H-吲哚 |
49 | 1-(4-氟苯磺酰基)-4-(3-甲氧基-4-甲基哌嗪-1-基甲基)-1H-吲哚 |
50 | 4-(3-氯-4-甲基哌嗪-1-基甲基)-1-(4-甲基苯磺酰基)-1H-吲哚 |
51 | 4-(4-甲基-3-三氟甲基哌嗪-1-基甲基)-1-(4-甲基苯磺酰基)-1H-吲哚 |
52 | 1-苯磺酰基-4-(4-甲基哌嗪-1-基甲基)-2-三氟甲基-1H-吲哚 |
实施例5:食物摄入测量(行为模型)
使用从N.I.N.(National Institute of Nutrition,Hyderabad,India)得到的雄性Wister大鼠(120-140g)。然后如下测定通式(I)化合物对喂养很好的大鼠的食物摄入的长期作用。
将大鼠在单个的舍笼中饲养28天。在此期间,给大鼠口服或腹膜内(ip)给予含有式(I)化合物的组合物或相应的不含所述化合物的组合物(载体)(对照组),每日一次。给所述大鼠随意提供进食和饮水。
在第0、1、7、14、21和28天,给予大鼠预先称重量的食物。基于常规基础测量食物摄入和重量增加。食物摄取方法还公开于文献(Kask等,European Journal of Pharmacology,414,2001,215-224和Turnball等,Diabetes,vol 51,August,2002以及某些自己做出的改动)中。这些说明中的相应部分在此通过引用并入本文,它们构成本发明公开内容的一部分。
当以上述方式以10mg/kg或30mg/kg或者这两种剂量进行测量时,一些代表性化合物显示出食物摄取的统计学显著性降低。
实施例6:含有式化合物的片剂
根据实施例2的化合物 | 5mg |
乳糖 | 60mg |
结晶纤维素 | 25mg |
K90聚维酮 | 5mg |
预胶化淀粉 | 3mg |
胶体二氧化硅 | 1mg |
硬脂酸镁 | 1mg |
每片总重 | 100mg |
合并所述成分并使用溶剂(例如甲醇)造粒。然后干燥制剂并用合适的压片机制成片剂(含有约20mg活性化合物)。
实施例7:口服施用的组合物
成分 | 重量/重量% |
活性成分 | 20.0% |
乳糖 | 79.5% |
硬脂酸镁 | 0.5% |
将成分混合并分散到各含有约100mg的胶囊中;一粒胶囊大致为全天剂量。
实施例8:液体口服制剂
成分 | 量 |
活性化合物 | 1.0g |
富马酸 | 0.5g |
氯化钠 | 2.0g |
对羟基苯甲酸甲酯 | 0.15g |
对羟基苯甲酸丙酯 | 0.05g |
砂糖 | 25.5g |
山梨醇(70%溶液) | 12.85g |
Veegum K(Vanderbilt Co.) | 1.0g |
调味剂 | 0.035g |
着色剂 | 0.5g |
蒸馏水 | 适量至100mL |
将成分混合以形成供口服施用的混悬液。
实施例9:肠胃外制剂
成分 | 重量/重量% |
活性成分 | 0.25g |
氯化钠 | 适量,使等渗 |
注射用水至 | 100mL |
将活性成分溶于一部分注射用水中。然后搅拌下加入足量的氯化钠,以使所述溶液等渗。用剩余的注射用水使溶液补足重量,通过0.2微米的滤膜过滤并在无菌条件下包装。
实施例10:栓剂制剂
成分 | 重量/重量% |
活性成分 | 1.0% |
聚乙二醇1000 | 74.5% |
聚乙二醇4000 | 24.5% |
使组分熔解在一起,在蒸汽浴上混合,倾倒到容纳2.5g总重量的模具中。
实施例11:局部用制剂
成分 | 克 |
活性化合物 | 0.2-2g |
Span 60 | 2g |
Tween 60 | 2g |
矿物油 | 5g |
石油醚 | 10g |
对羟基苯甲酸甲酯 | 0.15g |
对羟基苯甲酸丙酯 | 0.05g |
BHA(丁基羟基茴香醚) | 0.01g |
水 | 100mL |
合并除水外的所有成分并在搅拌下加热到约60℃。然后在剧烈搅拌下加入足量的约60℃的水,以乳化所述各成分,然后加入水补足至约100g。
实施例12:对象识别任务模型
使用动物认知模型(对象识别任务模型)来评估本发明化合物的提高认知特性。
将从N.I.N.(National Institute of Nutrition,Hyderabad,India)得到的雄性wistar大鼠(230~280g)用作实验动物。每一个笼子中关四只动物。在试验前一天保持给动物减少20%的食物,在整个试验过程中随意地给予水,并维持12小时的光照/黑暗周期。并且,在没有任何对象的情况下使大鼠习惯于单独的场地1小时。
在熟悉(T1)和选择试验(T2)的一小时前,一组12只大鼠口服接受载体(1mL/Kg),而另一组动物口服或在腹膜内注射(i.p.)接受式(I)化合物。
在由丙烯酸树脂制成的50×50×50cm的敞开区域中进行试验。在熟悉阶段(T1)中,将大鼠单独置于所述敞开区域中3分钟,在所述区域中将两个单独被黄色遮盖带(a1和a2)遮盖的相同对象(塑料瓶,12.5cm高×5.5cm直径)放置在两个相邻的距墙壁10cm的角落中。在用于长期记忆测试的(T1)试验24小时后,如在T1试验中一样,将相同的大鼠放在相同的场地中。在选择阶段(T2)中,在一个熟悉对象(a3)和一个新对象(b)(琥珀色玻璃瓶,高为12cm,直径为5cm)的存在下,允许大鼠在所述敞开区域中探索3分钟。熟悉的对象呈现类似的质地、颜色和尺寸。在T1和T2试验期间,通过秒表分别记录对每个对象的探索(定义为嗅、舔、咀嚼或移动触须并同时将鼻子转向对象距离小于1cm处)。坐在对象上不被视为探索性活动,但是这也是很少观察到的。
T1是探索熟悉对象(a1+a2)所花费的总时间。
T2是探索熟悉对象和新对象(a3+b)所花费的总时间。
如Ennaceur,A.,Delacour,J.,1988,A new one-trial test forneurobiological studies of memory in rats-Behavioral data,Behav.BrainRes.,31,47-59所述进行对象认知测试。
一些有代表性的化合物已显示出表明对新对象认知提高的积极效果,即对新对象的探索时间增加和较高的区别指数。
实施例13:由5-HT6受体拮抗剂诱导的咀嚼/打哈欠/伸展
使用重200~250g的雄性Wister大鼠。在测试日的前两天中每天给予大鼠注射载体并置于单独透明的室中1小时,以使其***均数。
参考资料:(A)King M.V.,Sleight A.,J.,Woolley M.L.,and et.al.Neuropharmacology,2004,47,195-204。(B)Bentey J.C.,Bourson A.,Boess F.G.,Fone K.C.F.,Marsden C.A.,Petit N.,Sleight A.J.,BritishJournal of Pharmacology,1999,126(7),1537-1542)。
实施例14:水迷宫
水迷宫装置由黑色珀斯佩(Perspex)有机玻璃(TSE systems,Germany)构成的圆形池(直径为1.8m,高为0.6m)组成,注水(24±2℃),并在其下设置广角摄影机以跟踪动物。将位于水面下1cm的10cm2有机玻璃平台放置到四个假想象限之一的中心,其对所有大鼠保持不变。用于构建迷宫和平台的黑色珀斯佩有机玻璃不提供引导逃离行为的迷宫内提示。相反,训练室提供几个强的迷宫外视觉提示,以有助于形成逃离学习所必需的空间地图。采用自动跟踪***[Videomot 2(5.51),TSE systems,Germany]。该程序分析通过数码摄像机和图像采集板所得到的视频图像,所述图像采集板确定路径长度、游泳速度以及在水迷宫每个象限中的进入次数和所花费的持续游泳时间。
参考资料:(A)Yamada N.,Hattoria A.,Hayashi T.,Nishikawa T.,Fukuda H.等,Pharmacology,Biochem.And Behaviour,2004,78,787-791。(B)Linder M.D.,Hodges D.B.,Hogan J.B.,Corsa J.A.,等,The Journalof Pharmacology and Experimental Therapeutics,2003,307(2),682-691。
实施例15:被动躲避装置
以单次试验避暗法(step through)光亮-黑暗被动躲避模式训练动物。训练装置由长300mm、宽260mm、高270mm的室组成,按已确定的设计构建而成。前部和顶部是透明的,以允许试验人员观察在该装置中的动物行为。所述室被分为两个隔室,由包含小孔的中部隔离物隔开,所述小孔设置在接近室的前部,其宽50mm,高75mm。测得较小隔室的宽度为9mm并包含低功率(6V)光源。测得较大隔室的宽度为210mm并且无光照。该黑暗隔室的地板由16根直径为5mm、间隔为12.5mm的水平不锈钢棒的栅格组成。电流发生器给栅格地板提供0.75mA的电流,所述电流每0.5秒跨越16根棒通过栅格地板一次。对于大鼠的对照组计算出40~60微欧的电阻,并由此校正装置。检测动物电阻的电路通过随电阻变化而自动改变电压来确保精确的电流传输。
实验步骤
如先前所述(Fox等,1995)进行该试验。使用重200~230g的成年雄性Wistar大鼠。在试验前1小时将动物带到试验室。在训练当天,以面对装置的明亮室后部的方式放置动物。一旦动物完全转过来面对室的前面时就启动计时器。记录进入暗室的延迟(通常<20秒钟),并且完全进入暗隔室后将无法逃脱的0.75mA的持续3秒钟的足部刺激施加给动物。然后将动物放回到它们的笼子中。在每个训练期之间,清理室的两个隔室以除去任何混杂的嗅觉线索。通过使动物返回到明亮室中并记录其进入暗室的延迟来评价训练后24h、72h和第7天的该抑制刺激的回忆,采用300秒钟的标准时间。
参考资料:(A)Callahan P.M.,Ilch C.P.,Rowe N.B.,Tehim A.,Abst.776.19.2004,Society for neuroscience,2004。(B)Fox G.B.,Connell A.W.U.,Murphy K.J.,Regan C.M.,Journal of Neurochemistry,1995,65,6,2796-2799。
实施例16:人5-HT6受体的结合试验
材料和方法:
受体源:在HEK293细胞中表达的人重组受体
放射性配体:[3H]LSD(60-80Ci/mmol)
最终配体浓度-[1.5nM]
非特异性决定子:甲磺酸美赛西平(Methiothepin mesylate)-[0.1μM]
参比化合物:甲磺酸美赛西平
阳性对照:甲磺酸美赛西平
孵育条件:
在37℃下在含有10μM MgCl2、0.5mM EDTA的50μMTRIS-HCl(pH 7.4)中进行反应60分钟。通过快速真空过滤到玻璃纤维过滤器上终止反应。测定在过滤器上捕获的放射性并与对照值进行比较,以便确定测试化合物与克隆的血清素5-HT6结合位点之间的任何相互作用。
参考文献:Monsma F.J.Jr.,等,Molecular Cloning and Expressionof Novel Serotonin Receptor with High Affinity for Tricyclic PsychotropicDrugs.Mol.Pharmacol.(43):320-327(1993)。
实施例17:cAMP的5-HT6功能性分析
通过测试化合物对稳定转染的HEK293细胞内cAMP积聚的作用来确定该化合物对人5-HT6受体的拮抗特性。激动剂与5-HT6受体的结合会导致腺苷酸环化酶活性的提高。作为激动剂的化合物将表现出cAMP产生增加,而作为拮抗剂的化合物将阻断激动剂效应。
克隆并在HEK293细胞内稳定地表达人5-HT6受体。将这些细胞接种于含有10%胎牛血清(FCS)和500μg/mL G418的DMEM/F12培养基的6孔板中,并在CO2培养箱中于37℃下孵育。在实验开始前允许细胞生长到约70%汇合。在实验当天,移去培养基,并用无血清培养基(SFM)清洗细胞一次。加入2mL SFM+IBMX培养基并在37℃下孵育10分钟。移去培养基,将含有不同化合物和1μM血清素(作为拮抗剂)的新鲜SFM+IBMX培养基加到适当的孔中,并孵育30分钟。孵育后,移去培养基并用1mL PBS(磷酸盐缓冲液)清洗细胞一次。在4℃下用1mL冷的95%乙醇和5μM EDTA(2∶1)处理每个孔1小时。然后将细胞刮下来并转移到Eppendorf管中。在4℃下将管离心分离5分钟,并将上清液储存在4℃下,直到测试。
通过EIA(酶免疫分析法)使用Amersham Biotrak cAMP EIA试剂盒(Amersham RPN 225)测定cAMP含量。所用的方法如试剂盒所述。简言之,通过未标记的cAMP与固定量的过氧化物酶标记cAMP之间针对抗cAMP抗体上结合位点的竞争来测定cAMP。将抗体固定到预包被第二抗体的聚苯乙烯微滴定孔上。通过将50μL过氧化物酶标记的cAMP加入到在4℃下与抗血清(100mL)预孵育2小时的样品(100μL)中来开始反应。在4℃下孵育1小时后,通过简单的清洗步骤分离未结合的配体。然后加入酶底物-三甲基联苯胺(1)并在室温下孵育60分钟。通过加入100mL 1.0M硫酸停止反应,并在30分钟内通过微量滴定板分光光度计在450nm读取所得到的颜色。
在功能性腺苷酸环化酶试验中,发现本发明的一些化合物是相对于多种其它受体(包括其它5-羟色胺受体例如5-HT1A和5-HT7)而言具有良好选择性的竞争性拮抗剂。
实施例18:啮齿类动物的药代动力学研究
将从N.I.N.(National Institute of Nutrition,Hyderabad,India)得到的雄性wistar大鼠(230~280g)用作实验动物。
每个笼子中有三到五只动物。在试验前一天,给动物减少20%的食物,在整个试验过程中随意地给予水,并维持12小时的光照/黑暗周期。一组大鼠口服接受NCE化合物(3-30mg/kg),另一组大鼠静脉内接受相同的化合物。
在每个时间点,通过颈静脉采集血液。将血浆冻存于-20℃直到用于分析。利用LC-MS/MS法测定血浆中NCE化合物的浓度。
计划时间点:给药前、给药后0.25小时、0.5小时、1小时、1.5小时、2小时、3小时、4小时、6小时、8小时、10小时、12小时和24小时(n=3)。利用固相萃取技术通过已验证的LC-MS/MS法对血浆中NCE化合物进行定量。在血浆和脑匀浆中2-2000ng/ml的校准范围内对NCE化合物进行定量。利用批次内的校准样品和批次间的质量控制样品分析研究样品。
采用非室模型利用软件WinNonlin version 4.1计算药代动力学参数Cmax、Tmax、AUCt、AUCinf、半衰期、分布体积、清除率、平均停留时间以及口服生物利用度。
实施例19:啮齿类动物的脑通透性研究
将从N.I.N.(National Institute of Nutrition,Hyderabad,India)得到的雄性wister大鼠(230~280g)用作实验动物。
每个笼子中有三到五只动物。在试验前一天给动物减少20%的食物,在整个试验过程中随意地给予水,并维持12小时的光照/黑暗周期。每组大鼠口服或腹膜内注射接受NCE化合物(3-30mg/kg)。
在每个时间点,通过颈静脉采集血液。处死动物以收集脑组织并匀浆。将血浆和脑冻存于-20℃直到分析。利用LC-MS/MS法测定血浆和脑中NCE化合物的浓度。
计划时间点:给药前、给药后0.25小时、0.5小时、1小时、1.5小时、2小时、3小时、4小时、6小时、8小时、10小时、12小时和24小时(n=3)。利用固相萃取技术通过已验证的LC-MS/MS法对血浆和脑匀浆中的NCE化合物进行定量。在血浆和脑匀浆中2-2000ng/ml的校准范围内对NCE化合物进行定量。利用批次内的校准样品和批次间的质量控制样品分析研究样品。
采用非室模型利用软件WinNonlin version 4.1计算药代动力学参数Cmax、Tmax、AUCt、AUCinf、半衰期、分布体积、清除率、平均停留时间以及脑与血浆中的NCE比Cb/Cp。
实施例20:针对可能的神经递质调节作用的啮齿类动物脑微透析研究
将从N.I.N.(National Institute of Nutrition,Hyderabad,India)得到的雄性wistar大鼠(230~280g)用作实验动物。
组分配组1:载体(水;5mL/kg;经口(p.o.)),组2:NCE(3mg/kg;经口),组3:NCE(10mg/kg;经口)。
手术过程:将大鼠用水合氯醛麻醉并置于立体定位框架中。参照Paxinos和Watson的图谱(1986)将导管插管(CMA/12)置于相对于前卤AP:-5.2mm,ML:+5.0mm,以及相对于脑表面DV:-3.8mm处。当动物仍然处于麻醉时,通过导管插管***微透析针(CMA/12,4mm,PC)并原位固定。手术后,维持48-72小时的恢复期,然后对动物进行研究。
研究前1天,将动物转移到笼室中以适应环境,以设定为0.2μL/分钟的速率通过微量输注泵(PicoPlus,Harward)用改良的林格氏液灌注植入探针过夜,所述改良的林格氏液包含以下成分:1.3μM CaCl2(Sigma),1.0μM MgCl2(Sigma),3.0μM KCl(Sigma),147.0μM NaCl(Sigma),1.0μMNa2HPO4·7H2O和0.2μM NaH2PO4·2H2O以及0.3μM溴化新斯的明(Sigma)(pH至7.2)。在实验当天,将输注速率变为1.2μL/分钟并稳定3小时。稳定期后,在给药之前以20分钟的间隔采集4个基线样品。利用CMA/170冷冻级分收集器将透析液样品收集到玻璃瓶中。
收集4个级分的样品之后,通过管饲法施用载体或NCE(3mg/kg或10mg/kg)。施用后收集灌注液6小时。
通过LC-MS/MS(API 4000,MDS SCIEX)法测量透析液样品中的乙酰胆碱浓度。在0.250至8.004ng/mL的校准范围内对透析液中的乙酰胆碱进行定量。
微透析实验结束后,处死动物,取出脑并保存在10%***溶液中。在低温恒温器(Leica)上对每个脑切50μ的切片,染色,在显微镜下观察以确保探针的放置。将来自探针放置不正确的动物的数据弃除。
微透析数据表示为以给药前4个样品平均绝对值(fM/10μL)所定义的基线的变化百分率(平均值±S.E.M.)。
通过单因素ANOVA然后进行Dunnett多重比较检验对NCE(3和10mg/kg)和载体处理的作用进行了统计学评价。在所有的统计学测量中,p<0.05被认为是显著的。采用Graph Pad的Prism程序对数据进行统计学评价。
Claims (3)
1.一种化合物或其可药用盐,其选自以下化合物或其可药用盐:
1-苯磺酰基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(4-溴苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2-溴-4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-[4-(1-甲基乙基)苯磺酰基]-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2-溴苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(3-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2,4-二氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(5-溴-2-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2,6-二氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2,6-二氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(3-氯-2-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2-氯-4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-苯磺酰基-3-溴-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(2-溴-4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-[4-(1-甲基乙基)苯磺酰基]-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(3-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-溴-1-(5-氯-2-甲氧基-4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-苯磺酰基-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-[4-(1-甲基乙基)苯磺酰基]-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(2-溴苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(4-氟苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(4-甲氧基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(3-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
3-氯-1-(5-氯-2-甲氧基-4-甲基苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(2,4-二氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚;
1-(3-氯苯磺酰基)-4-(4-甲基哌嗪-1-基甲基)-1H-吲哚。
2.一种化合物,其选自:
1-(2-溴苯磺酰基)-4-(哌嗪-1-基甲基)-1H-吲哚二盐酸盐;
1-苯磺酰基-4-(哌嗪-1-基甲基)-1H-吲哚二盐酸盐;或
1-(4-甲基苯磺酰基)-4-(哌嗪-1-基甲基)-1H-吲哚二盐酸盐。
3.权利要求1或2的化合物在制备用于治疗选自阿尔茨海默病、抑郁、帕金森病或精神***症的临床病症的药物中的用途。
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