CN100572377C - 治疗中枢神经障碍、胃肠障碍和心血管障碍的吲哚-2-酮衍生物 - Google Patents
治疗中枢神经障碍、胃肠障碍和心血管障碍的吲哚-2-酮衍生物 Download PDFInfo
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- CN100572377C CN100572377C CNB2005800202712A CN200580020271A CN100572377C CN 100572377 C CN100572377 C CN 100572377C CN B2005800202712 A CNB2005800202712 A CN B2005800202712A CN 200580020271 A CN200580020271 A CN 200580020271A CN 100572377 C CN100572377 C CN 100572377C
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- Prior art keywords
- dihydro
- indol
- ethyl
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- compound
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- 125000000217 alkyl group Chemical group 0.000 claims description 22
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- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
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Abstract
本发明涉及新的通式(I)的3,3-二取代的吲哚-2-酮衍生物。这些新化合物可用于治疗或预防中枢神经系统、胃肠系统或心血管系统障碍。
Description
技术领域
本发明涉及新的3,3-二取代的吲哚-2-酮衍生物、其制备方法、含有所述新的吲哚-2-酮衍生物的药物组合物和所述化合物治疗疾病的用途。
更具体的说,本发明涉及新的通式(I)的3,3-二取代的吲哚-2-酮衍生物,
其中
R1和R2独立地代表氢、卤素、具有1至7个碳原子的烷基或氨磺酰基;
R3表示氢或者具有1至7个碳原子的直链或支链烷基;
R4代表具有1至7个碳原子的烷基;
R5是氢,且R6表示可选携带1至3个取代基的苯基,所述取代基选自卤素和携带1至3个卤素取代基的具有1至7个碳原子的烷基,或者
R5和R6与四氢吡啶环的相邻碳原子一起构成苯基或者含有硫作为杂原子的5-或6-元杂环,它可以可选地携带卤素取代基;
m是1、2、3、4、5或6;
及其药学上可接受的酸加成盐。
背景技术
美国专利No.4,452,808公开了具有选择性D2受体活性的4-氨基烷基-吲哚-2-酮衍生物。这些化合物能够用于治疗高血压。由该专利所提供的化合物之一、即4-[2-(二-N-丙基氨基)乙基]-2(3H)-吲哚酮用在临床治疗中。
欧洲专利No.281,309提供了在5位携带芳基哌嗪基-烷基取代基的吲哚-2-酮衍生物,它们能够用于治疗精神病症。在该专利中所描述的化合物之一、即5-[2-[4-(1,2-苯并异噻唑-3-基)-1-哌嗪基]-乙基]-6-氯-1,3-二氢-2H-吲哚-2-酮借助与D2、5-HT1A和5-HT2受体的相互作用发挥其活性,用在临床治疗中。
欧洲专利No.376,607公开了在3位被烷基哌嗪基-芳基取代的吲哚-2-酮衍生物,它们对5-HT1A受体发挥它们的活性,可用于治疗中枢神经障碍。
在国际专利申请WO 98/008816中,公开了在3位含有取代的烷基哌嗪基、取代的烷基哌啶基或烷基-环己基的吲哚-2-酮衍生物。这些化合物发挥抗精神病活性。
二十世纪技术-社会发展的加速迫使人们一直去适应,在不利的情况下可能引起适应性障碍的发生。适应性障碍构成精神或身心起源的疾病发展中的重要危险因素,例如焦虑综合征、精神紧张性障碍、抑郁、精神分裂症、感觉器官障碍、胃肠疾病、心血管疾病或肾障碍。
就上述临床模式的治疗而言,最普遍应用的药物对苯并二氮杂系统(例如地西泮)或中枢5-HT1A受体(例如丁螺酮、齐拉西酮)发挥它们的活性。
不过,迄今已经在疗法中应用的作用于5-HT1A受体的药物伴有若干缺点和不需要的副作用。抗焦虑效果仅在治疗持续至少10-14天之后才能达到,这是一个缺点。此外,在最初的给药后发生焦虑产生效应。至于副作用,经常观察到瞌睡、困倦、眩晕、幻觉、头痛、认知紊乱或恶心的发生。
发明内容
本发明的目的是开发具有比当前可用那些更可取的活性的药物成分,它们没有上述缺点和不需要的与5-HT1A受体相结合的活性剂的特征性副作用,与此同时能够用于治疗和预防中枢神经系统的障碍。
本发明基于如下认识,即,通式(I)的3,3-二烷基取代的吲哚-2-酮衍生物具备显著的抗焦虑作用,但是令人意外的——与相似结构的现有技术化合物相反——不与5-HT1A受体结合。所以,根据本发明的化合物没有与所述受体结合的化合物的副作用特征。
按照本发明的一个方面,提供了新颖的通式(I)的3,3-二取代的吲哚-2-酮衍生物,其中
R1和R2独立地代表氢、卤素、具有1至7个碳原子的烷基或氨磺酰基;
R3表示氢或者具有1至7个碳原子的直链或支链烷基;
R4代表具有1至7个碳原子的烷基;
R5是氢,且R6表示可选携带1至3个取代基的苯基,所述取代基选自卤素和携带1至3个卤素取代基的具有1至7个碳原子的烷基,或者
R5和R6与四氢吡啶环的相邻碳原子一起构成苯基或者含有硫作为杂原子的5-或6-元杂环,它可以可选地携带卤素取代基;
m是1、2、3、4、5或6;
及其药学上可接受的酸加成盐。
用于本说明书全文的术语“烷基”旨在表示具有1至7个、优选1至4个碳原子的直链或支链饱和烃基(例如甲基、乙基、1-丙基、2-丙基、正丁基、异丁基或叔丁基等)。
术语“卤素”涵盖氟、氯、溴和碘原子,优选氯或溴。
离去基团可以是烷基磺酰氧基或芳基磺酰氧基,例如甲磺酰氧基或对-甲苯磺酰氧基;或者卤原子,优选溴或氯。
术语“药学上可接受的酸加成盐”涉及通式(I)化合物与药学上可接受的有机或无机酸所生成的无毒性盐。适合于成盐的无机酸例如有氯化氢、溴化氢、磷酸、硫酸或硝酸。作为有机酸,可以使用甲酸、乙酸、丙酸、马来酸、富马酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、丙二酸、草酸、扁桃酸、乙醇酸、邻苯二甲酸、苯磺酸、对-甲苯磺酸、萘甲酸或甲磺酸。此外,碳酸盐和碳酸氢盐也被视为药学上可接受的盐。
下列化合物属于具备宝贵的药学性质的通式(I)化合物亚组:其中R1和R2独立地代表氢、具有1至7个碳原子的直链或支链烷基或者卤素,R3是氢或者具有1至7个碳原子的直链或支链烷基,R4代表具有1至4个碳原子的直链或支链烷基,R5表示氢,且R6代表可选携带卤素或三氟甲基取代基的苯基,或者R5和R6与四氢吡啶环的相邻碳原子一起构成含有硫原子作为杂原子的5-或6-元杂环,并且可选地携带卤原子,优选氯,m是3、4或5,及其药学上可接受的酸加成盐。
下列衍生物属于具备特别优选的活性的通式(I)化合物亚组:其中R1、R2和R3独立地代表氢或卤素,R4是乙基,R5和R6与二氢吡啶环的相邻碳原子一起构成含有硫作为杂原子的5-元杂环,该环可选地携带卤素,m是5,及其药学上可接受的酸加成盐。
下列衍生物属于具备特别优选的活性的另一通式(I)化合物亚组:其中R1、R2和R3独立地代表氢或卤素,R4是乙基,R5代表氢,R6是携带卤素取代基的苯基,优选氟,m是4,及其药学上可接受的酸加成盐。
按照本发明的另一方面,提供了制备通式(I)化合物及其药学上可接受的酸加成盐的方法,包括
(a)使通式(II)化合物
其中R1-R4如上所述,且L是离去基团,优选氯或溴,m是1、2、3、4、5或6,
与通式(III)吡啶衍生物反应,
其中R5和R6如上所述,或者
(b)在强碱的存在下,使通式(IV)化合物
其中R1、R2、R3和R4如上所述,
与通式(V)化合物反应,
L-(CH2)m-L’ (V)
其中m是1、2、3、4、5或6,L和L’代表离去基团,优选氯或溴,可选地卤化所得通式(II)化合物,其中R2是氢,再在酸结合剂的存在下,使所得通式(II)化合物——其中L是离去基团,优选氯或溴,R2是氢或卤素,m是1、2、3、4、5或6——与通式(III)化合物反应,其中R5和R6如上所述,或者
(c)在强碱的存在下,使通式(IV)化合物——其中R1、R2、R3和R4如上所述——与通式(VI)吡啶衍生物反应,
其中L是磺酰氧基或卤素,优选氯或溴,R5和R6如上所述,m是1、2、3、4、5或6,可选地卤化所得产物,其中R2是氢,或者从其盐中释放游离碱或者转化为其药学上可接受的有机或无机酸加成盐。
通式(III)、(V)和(VI)化合物是文献已知的或者可以借助类似方法制备。
在应用任何一种上述方法变化时,可以在任何一种反应步骤期间按照文献已知方法引入或转化所需的取代基。如果需要的话,在应用任何方法变化之后,可以从其盐中释放相应于通式(I)产物的游离碱或者转化为其药学上可接受的酸加成盐。
在按照变化方式(a)进行时,通式(I)化合物可以制备如下,使通式(II)化合物——其中R1-R4和m如上所述,且L是离去基团,优选溴或氯——与通式(III)化合物——其中R5和R6如上所述——按照文献已知的方法反应[Houben-Weyl:Methoden der organischen Chemie,Georg Thieme Verlag,Stuttgart,1992,4th Edition,vol.E16d(ed.D.Klamann);R.C.Larock:Comprehensive OrganicTransformation ,2th Edition,John Wiley & Sons,New York,1999,789;D.A.Walsh,Y-H.Chen,J.B.Green,J.C.Nolan,J.M.Yanni J.Med.Chem.1990,33,1823-1827]。
在通式(II)化合物的制备期间,可以按照文献已知的方法以任选的次序进行取代基的生成。通式(II)化合物优选地制备如下,使通式(V)化合物——其中L和m如上所述,L’是离去基团或者能够转化为离去基团的基团——与通式(IV)化合物——其中R1-R4如上所述——反应[Houben-Weyl:Methoden der organischen Chemie,Georg ThiemeVerlag,Stuttgart,1977,4th Edition,vol.V/2b;A.R.Katritzky,Ch.W.Rees:Comprehensive Heterocyclic Chemistry,FirstEdition,Pergamon,Oxford,1984,vol.4(ed.:C.W.Bird,G.W.H.Cheeseman),98-150 and 339-366;G.M.Karp Org.Prep.Proc.Int.1993,25,481-513;B.Volk,T.Mezei,Gy.Simig Synthesis2002,595-597]。
通式(I)化合物也可以按照方法变化(c)制备如下,使通式(IV)化合物——其中R1-R4如上所述——与通式(VI)化合物——其中R5、R6和m如上所述,且L是离去基团——按照文献已知的方法反应[R.J.Sundberg:The chemistry of indoles,Academic Press,New York,1970,chapter VII;G.M.Karp Org.Prep.Proc.Int.1993,25,481-513;A.S.Kende,J.C.Hodges Synth.Commun.1982,12,1-10;W.W.Wilkerson,A.A.Kergaye,S.W.Tam J.Med.Chem.1993,36,2899-2907]。
在通式(I)化合物的制备期间,也可以在最后一步反应中以不同的次序进行取代基R1-R6的生成。在这种情况下,作为原料的通式(I)化合物含有氢代替所要生成的取代基。按照文献已知的方法进行取代基的引入和转化[Houben-Weyl:Methoden der organischen Chemie,Georg Thieme Verlag,Stuttgart,1977,4th Edition,IV/1a-d;vol.V/2b]。在取代基的引入期间,保护基团的应用或消去可能成为必要。这类方法参见T.W.Greene,Protective groups in organicsynthesis,John Wiley & Sons,1981。
其中R1-R4如上所述的通式(I V)化合物可以应用已知方法制备,按照文献已知的方法以任选的次序进行取代基的生成[A.R.Katritzky,Ch.W.Rees:Comprehensive Heterocyclic Chemistry,1th Edition,Pergamon,Oxford,1984,vol.4(ed.:C.W.Bird,G.W.H.Cheeseman),98-150 and 339-366;C.Gautier,M.Aletru,Ph.Bovy WO 99/62900;B.Volk,T.Mezei,Gy.Simig Synthesis2002,595-597;G.M.Karp Org.Prep.Proc.Int.1993,25,481-513;A.S.Kende,J.C.Hodges Synth.Commun.1982,12,1-10]。
按照文献已知的方法,由根据本发明的方法所制备的通式(I)化合物可以从它们的盐中释放出来或者转化为药学上可接受的酸加成盐。
按照本发明的另一方面,提供了药物组合物,包含作为活性成分的通式(I)化合物或其药学上可接受的酸加成盐,混合有一种或多种常规载体或助剂。
根据本发明的药物组合物一般含有0.1-95重量%、优选1-50重量%、特别是5-30重量%的活性成分。
本发明的药物组合物可以适合于口服(例如粉剂、片剂、包衣片、胶囊、微囊、丸剂、溶液、悬液或乳液)、肠胃外(例如静脉内、肌内、皮下或腹膜内用注射溶液)、直肠(例如栓剂)、透皮(例如硬膏)或局部(例如软膏或硬膏)给药或者以植入物的形式应用。根据本发明的固体、软性或液体药物组合物可以借助药学工业常用的方法生产。
含有通式(I)化合物或其药学上可接受的酸加成盐的口服给药用固体药物组合物可以包含填充剂或载体(例如乳糖、葡萄糖、淀粉、磷酸钾、微晶纤维素)、粘合剂(例如明胶、山梨糖醇、聚乙烯吡咯烷酮)、崩解剂(例如交联羧甲基纤维素、羧甲基纤维素钠、交联聚维酮)、压片助剂(例如硬脂酸镁、滑石、聚乙二醇、硅酸、二氧化硅)和表面活性剂(例如月桂基硫酸钠)。
适合于口服给药的液体组合物可以是溶液、悬液或乳液。这类组合物可以含有悬浮剂(例如明胶、羧甲基纤维素)、乳化剂(例如脱水山梨醇单油酸酯)、溶剂(例如水、油、甘油、丙二醇、乙醇)、缓冲剂(例如乙酸盐、磷酸盐、柠檬酸盐缓冲剂)和防腐剂(例如甲基-4-羟基苯甲酸酯等)。
适合于肠胃外给药的液体药物组合物一般是无菌的等渗溶液,除了溶剂以外可选地含有缓冲剂或防腐剂。
含有作为活性成分的通式(I)化合物或其药学上可接受的酸加成盐的软性药物组合物(例如栓剂)含有均匀分散在栓剂基质(例如聚乙二醇或可可脂)中的活性成分。
按照本发明的另一方面,提供了通式(I)吲哚-2-酮衍生物或其药学上可接受的酸加成盐用于制备药物组合物的用途,所述药物组合物适合于用于治疗或预防中枢神经系统障碍或身心障碍,包括焦虑综合征,特别是泛化性焦虑症、恐慌病、强迫症、社会恐怖、广场恐怖、与特定情形有关的恐怖、创伤后精神紧张性障碍、创伤后记忆紊乱、认知紊乱、中枢神经系统起源的性功能障碍、抑郁、精神分裂症、胃肠疾病和心血管疾病。
按照本发明的另一方面,提供了通式(I)吲哚-2-酮衍生物或其药学上可接受的酸加成盐用于制备药物组合物的用途,所述药物组合物适合于用于治疗或预防中枢神经系统障碍或身心障碍,包括焦虑综合征,特别是泛化性焦虑症、恐慌病、强迫症、社会恐怖、广场恐怖、与特定情形有关的恐怖、创伤后精神紧张性障碍、由创伤所导致的记忆紊乱、认知紊乱、中枢神经系统起源的性功能障碍、抑郁、精神分裂症、胃肠疾病和心血管疾病。
根据本发明的药物组合物可以借助药学工业已知的方法制备。将活性成分与药学上可接受的固体或液体载体和/或助剂混合,再将混合物制成盖仑剂型。在药学工业中可以使用的载体和助剂以及方法在文献中已有公开(Remington′s Pharma-ceutical Sciences,Edition 18,Mack Publishing Co.,Easton,USA,1990)。
根据本发明的药物组合物一般含有剂量单元。成人每日剂量一般可以是0.1-1000mg/kg体重的通式(I)化合物或其药学上可接受的酸加成盐。所述每日剂量可以以一份或者分多份给予。实际的每日剂量依赖于若干因素,并且取决于医师。
按照本发明的另一方面,提供了通式(I)化合物或其药学上可接受的酸加成盐的用途,用于治疗或预防中枢神经系统障碍和身心障碍,包括焦虑综合征,特别是泛化性焦虑症、恐慌病、强迫症、社会恐怖、广场恐怖、与特定情形有关的恐怖、精神紧张性障碍、创伤后记忆障碍、认知紊乱、中枢神经系统起源的性功能障碍、抑郁、精神分裂症、胃肠疾病和心血管疾病。
从欧洲专利说明书No.376,607和技术文献已知(A.Dekeyne,J.M.Rivet,A.Gobert,M.J.Millan:Neuropharmacology 40(7)p.899-910(2001);J.S:Sprouse et al.:Neuropsychopharmacology21(5)p.622-631(1999);A.Newman-Tancredi et al.:Eur.J.Pharmacol.355(2-3)pp.245-246(1998)),1,3-二氢-2H-吲哚-2-酮类型的现有技术化合物选择性地与5-HT1A受体结合,因而影响中枢神经系统。所以,它们能够用于治疗抑郁和焦虑症,此外还有心血管、胃肠和肾疾病。
本发明基于如下令人意外的认识,即,通式(I)化合物发挥抗焦虑活性,但是不与5-HT1A受体结合。因而可以预期它们没有与5-HT1A受体结合的成分的上述不良副作用特征。
按照Peroutka的方法研究通式(I)化合物与5-HT1A受体的结合(S.J.Peroutka:J.Neurochem.47,p.529(1986))。
使用含氚8-羟基-N,N-二丙基-2-氨基-四氢化萘(8-OH-DPAT)配体,从所分离的额皮质膜制备物测定受体结合。就非特异性结合的测定而言,使用10μM血清素肌酸酐硫酸盐。应用下列条件:温育血液体积250μL,温育温度25℃,温育时间30分钟。反应终止于加入9mL50mM冰冷的TRIS-HCl缓冲液(pH=7.7),利用Whatman GFIB玻璃纤维滤纸快速真空过滤。借助液体闪烁分光计测量滤纸的放射性。
IC50是其中在10μM血清素肌酸酐硫酸盐的存在下完全结合与非特异性结合之差为50%的浓度。IC50值小于100nmol的化合物被视为在本试验中是有效的。实验结果如表1所示。
表1
5-HT1A受体结合实验
实施例No. | IC<sub>50</sub>nmol |
29 | >100 |
36 | >100 |
37 | >100 |
26 | >100 |
从表1结果可以看到,供试化合物不与5-HT1A受体结合。
按照所谓的抬升加迷路试验研究根据本发明的化合物对大鼠的抗焦虑作用(S.Pelow,P.Chopin,S.E.File,J.Briley:Neurosci.Methods 14,p.149(1985))。
实验使用木制十字架,距离地面50cm,宽15cm,臂长100cm。十字架的两支对侧臂的两侧和末端装有40cm高的壁,不过两臂打开成15cmx15cm中心区域(封闭的臂)。另外两支对侧臂不被壁所围绕(开放的臂)。
实验使用体重200-220g的雄性Sprague-Dawley大鼠。在处置后60min将动物置于设备的中心区域,观察下列四种参数达5分钟(min):
在开放臂中停留的时间(秒,sec);
在封闭臂中停留的时间(sec);
进入开放臂中的次数;
进入封闭臂中的次数。
效果以在开放臂中停留的时间或者进入开放臂中的次数的增加百分比表示。测定每种化合物的MED(最小有效剂量)。结果总结在表5中。
表5
大鼠抬升加迷路
实施例No. | MEDmg/kg p.o. |
36 | 1.0 |
39 | 0.01 |
从上表数据可以看到,通式(I)化合物具备显著的抗焦虑作用。
在上述实验的基础上,根据本发明的化合物在中枢神经系统障碍的治疗中显示明显的功效。它们可以证实特别适合于治疗焦虑症、混合型焦虑或者其他需要患者安定的以极端精神紧张条件为特征的精神障碍。它们也可以用于治疗身心疾病,例如精神起源的高血压、胃肠溃疡、结肠炎、哮喘等。在这些临床模式的情况下,可以假定在背景中存在慢性精神紧张、焦虑和/或原始冲突。根据本发明的新化合物令人意外的不经由5-HT1A受体而发挥它们可取的治疗活性,因此可以预期它们没有作用于5-HT1A受体的活性成分的副作用特征。
具体实施方式
下列实施方式提供本发明的进一步细节,但保护范围并不限于所述实施例。
实施例1
5-氯-3-乙基-1,3-二氢-2H-吲哚-2-酮
将1.68g(0.01mole)5-氯-羟吲哚溶于20mL乙醇,向该溶液加入1.0g阮内镍。使反应混合物在110℃高压釜中反应36小时。然后滤出催化剂,蒸发溶剂,使残余物从己烷与乙酸乙酯的混合物中重结晶。收率:0.86g白色粉末(44%)。
M.p.:121-123℃(己烷-乙酸乙酯)
IR(KBr):3156,1701(C=O),782cm-1.
1H-NMR(CDCl3):9.27(br s,1H,NH),7.21(1H,s,H-4),7.19(d,1H,J=8.8Hz,H-6),6.85(d,1H,J=8.1Hz,H-7),3.47(t,1H,J=5.5Hz,H-3),2.03(m,2H,CH2),0.92(t,3H,J=7.0Hz,CH3)ppm.
13C-NMR(CDCl3):180.5,140.4,131.2,127.8,127.6,124.5,110.7,47.5,23.5,9.9ppm.
式C10H10ClNO的元素分析(195.65):
计算值:C 61.39,H 5.15,N 7.16,Cl 18.12%.
实测值:C 61.16,H 5.10,N 6.93,Cl 18.11%.
实施例2
5-溴-3-乙基-1,3-二氢-2H-吲哚-2-酮
将3-乙基羟吲哚(16.1g;0.10mole)溶于350mL乙腈,将该溶液冷却至0℃,在2小时内在相同温度下向其中滴加N-溴琥珀酰亚胺(17.8g;0.10mole)的150mL乙腈溶液。将反应混合物先在0℃下搅拌1小时,再在室温下搅拌3小时。蒸发溶液,以结晶形式分离白色物质,用二氯甲烷和1M NaOH溶液萃取,有机相再次用碱水萃取,目的是除去琥珀酰亚胺。将有机相经硫酸钠干燥,过滤,蒸发。分离白色物质,从庚烷与乙酸乙酯的混合物中重结晶。收率:15.24g白色粉末(63%)。
M.p.:125-127℃(庚烷-乙酸乙酯)
IR(KBr):3154,1700(C=O),812cm-1.
1H-NMR(CDCl3,TMS,400MHz):8.90(1H,s),7.36-7.32(2H,m),6.81(1H,d,J=8.9Hz),3.43(1H,t,J=5.8Hz),2.03(2H,q,J=7.4Hz),0.92(3H,t,J=7.4Hz)ppm.
13C-NMR(CDCl3,TMS,101Mz):180.3,140.8,131.6,130.7,127.2,114.9,111.2,47.2,23.4,9.9ppm.
式C10H10BrNO的元素分析(240.10):
计算值:C 50.03,H 4.20,N 5.83,Br 33.28%.
实测值:C 50.16,H 4.20,N 5.85,Br 32.70%.
ω-卤代烷基化合物的制备(方法“A”)
向用氩冲洗的烧瓶量入2.5M正丁基锂(60mL;0.15mole)。向其中加入200mLTHF,将溶液在丙酮-干冰浴中冷却至-78℃。在该温度下,在搅拌下向其中滴加适当的3-烷基羟吲哚(0.20mole)的250mL THF溶液。将混合物再搅拌10分钟,向其中滴加二卤代烷(1-溴-4-氯丁烷、1-溴-3-氯丙烷、1,5-二溴戊烷或1,6-二溴己烷;0.50mol),使溶液升温至室温。然后搅拌另外3小时,向其中滴加20mL乙醇,目的是分解过量的丁基锂。用旋转蒸发器蒸馏溶液,残余的油用水和乙酸乙酯萃取。有机相经硫酸钠干燥。用己烷研制残余的油,进行结晶。分离灰白色晶体,在200mL己烷中搅拌,目的是除去过量的二卤代烷,过滤,用己烷洗涤。产物无需重结晶即可用于进一步的反应。从所示溶剂中重结晶,可以得到分析样品。
实施例3
3-(4-氯丁基)-3-乙基-1,3-氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-乙基-1,3-氢-2H-吲哚-2-酮和1-溴-4-氯丁烷。
M.p.:104-105℃(己烷-乙酸乙酯).
IR (KBr):3181,2941,1700,1306,755cm-1.
1H-NMR(CDCl3,TMS,400MHz):8.57(br s,1H,NH),7.21(dt,1H,J=7.6,1.5Hz,H-6),7.12(d,1H,J=7.4Hz,H-4),7.06(dt,1H,J=7.5,1.0Hz,H-5),6.92(d,1H,J=7.7Hz,H-7),3.39(t,2H,J=6.7Hz,CH2Cl),1.96-1.84(m,2H,CH2),1.83-1.74(m,2H,CH2),1.74-1.60(m,2H,CH2),1.24-1.18(m,1H),1.08-1.03(m,1H),0.64(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.4,141.2,132.3,127.7,123,0,122.5,109.6,54.1,44.4,36.8,32.7,31.0,21.8,8.5ppm.
式C14H18ClNO的元素分析(251.76):
计算值:C 66.79,H 7.21,N 5.56,Cl 14.08%.
实测值:C 66.89,H 7.16,N 5.84,Cl 14.19%.
实施例4
3-(4-氯丁基)-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮和1-溴-4-氯-丁烷。
M.p.:96-97℃(己烷-乙酸乙酯).
IR(KBr):3159,1716,817cm-1.
1H-NMR(CDCl3,TMS,400MHz):8.99(br s,1H,NH),6.95-6.85(m,3H),3.40(t,2H,J=6.7Hz,CH2Cl),1.97-1.88(m,2H,CH2),1.83-1.75(m,2H,CH2),1.73-1.62(m,2H),1.25-1.20(m,1H),1.09-1.04(m,1H),0.65(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.5,159.3(d,J=240.7Hz),137.2,134.1(d,J=7.6Hz),114.1(d,J=23.7Hz),111.9(d,J=24.4Hz),110.2(d,J=2.0Hz),54.8(d,J=2.0Hz),44.4,36.8,32.5,31.0,21.7,8.4ppm.
式C14H17ClFNO的元素分析(269.75):
计算值:C 62.34,H 6.35,N 5.19,Cl 13.14%.
实测值:C 62.49,H 6.20,N 4.98,Cl 13.48%.
实施例5
3-(4-氯丁基)-3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮和1-溴-4-氯丁烷。
M.p.:95-97℃(己烷-乙酸乙酯).
IR(KBr):3195,1728,1132cm-1.
1H-NMR(CDCl3,TMS,400MHz):9.34(br s,1H,NH),7.05(dd,1H,J=8.1,5.3Hz,H-4),6.75(ddd,1H,J=9.6,8.1,2.4Hz,H-5),6.71(dd,1H,J=8.8,2.4Hz,H-7),3.44(t,2H,J=6.7Hz,CH2Cl),2.00-1.70(m,4H,2x CH2),1.70-1.60(m,2H,CH2),1.23-1.18(m,1H),1.08-1.04(m,1H),0.64(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):183.3,162.5(d,J=244.1Hz),142.5(d,J=7.8Hz),127.5(d,J=13.0Hz),123.8(d,J=9.5Hz),108.8(d,J=22.5Hz),98.5(d,J=27.4Hz),53.8,44.4,36.8,32.5,31.0,21.6,8.4ppm.
式C14H17ClFNO的元素分析(269.75):
计算值:C 62.34,H 6.35,N 5.19,Cl 13.14%.
实测值:C 62.09,H 6.22,N 5.28,Cl 13.43%.
实施例6
3-(4-氯丁基)-3-乙基-5-甲基-1,3-二氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-乙基-5-甲基-1,3-二氢-2H-吲哚-2-酮和1-溴-4-氯丁烷。
M.p.:79-80℃(己烷).
IR(KBr):3286,1719cm-1.
1H-NMR(CDCl3,TMS,400MHz):8.70(br s,1H,NH),7.00(d,1H,J=7.8Hz,H-6),6.92(s,1H,H-4),6.81(d,1H,J=7.9Hz,H-7),3.39(t,2H,J=6.8Hz,CH2Cl),1.95-1.85(m,2H),1.82-1.70(m,2H),1.70-1.58(m,2H),1.30-1.12(m,1H),1.10.0.98(m,1H),0.63(t,3H,J=7.3Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.5,138.8,132.4,131.9,128.0,123.7,109.3,54.1,44.4,36.9,32.7,31.0,21.8,8.4ppm.
式C15H20ClNO的元素分析(265.79):
计算值:C 67.79,H 7.58,N 5.27,Cl 13.34%.
实测值:C 67.98,H 7.43,N 5.11,Cl 13.09%.
实施例7
3-(4-氯丁基)-3-乙基-7-甲基-1,3-二氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-乙基-7-甲基-1,3-二氢-2H-吲哚-2-酮和1-溴-4-氯丁烷。
M.p.:112-113℃(己烷-乙酸乙酯).
IR(KBr):3181,1703(C=O),748cm-1.
1H-NMR(CDCl3,TMS,400MHz):0.63(3H,t,J=7.4Hz),1.07-1.02(1H,m),1.25-1.17(1H,m),1.70-1.60(2h,m),1.81-1.72(2H,m),1.96-1.86(2H,m),2.31(3H,s),3.36(2H,t,J=6.8Hz),6.94(1H,dd,J=1.7,7.3Hz),6.97(1H,t,J=7.3Hz),7.03(1H,dd,J=1.4,7.2Hz),9.4(1H,br s)ppm.
13C-NMR(CDCl3,TMS,101MHz):8.5,16.5,21.8,31.0,32.7,36.8,44.4,54.4,119.1,120.3,122.4,129.1,131.9,140.1,183.1ppm.
式C15H20ClNO的元素分析(265.79):
计算值:C 67.79,H 7.58,N 5.27,Cl 13.34%.
实测值:C 67.56,H 7.49,N 5.24,Cl 13.29%.
实施例8
3-(3-氯丙基)-3-乙基-1,3-二氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-乙基-1,3-二氢-2H-吲哚-2-酮和1-溴-3-氯丙烷。
M.p.:91-93℃(己烷).
IR(KBr):3183,1701,751cm-1.
1H-NMR(CDCl3,TMS,400MHz):9.15(br s,1H,NH),7.23(dt,1H,J=7.7,1.3Hz,H-6),7.14(d,1H,J=6.8Hz,H-4),7.06(dt,1H,J=7.4,0.9Hz,H-5),6.95(d,1H,J=7.7Hz,H-7),3.48-3.36(m,2H,CH2Cl),2.02-1.93(m,3H),1.85-1.78(m,1H),1.66-1.54(m,1H),1.44-1.30(m,1H),0.65(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.6,141.3,132.0,127.9,123.0,122.6,109.8,53.7,44.8,34.8,31.0,27.5,8.5ppm.
式C13H16ClNO的元素分析(237.73):
计算值:C 65.68,H 6.78,N 5.89,Cl 14.91%.
实测值:C 65.51,H 6.70,N 5.82,Cl 14.68%.
实施例9
3-(5-溴戊基)-3-乙基-1,3-二氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-乙基-1,3-二氢-2H-吲哚-2-酮和1,5-二溴戊烷。
M.p.:77-78℃(己烷).
IR(KBr):3290,1718,772cm-1.
1H-NMR(CDCl3,TMS,400MHz):9.11(br s,1H,NH),7.20(dt,1H,J=7.6,1.4Hz,H-6),7.11(d,1H,J=7.3Hz,H-4),7.05(dt,1H,J=7.4,1.0Hz,H-5),6.94(d,1H,J=7.4Hz),3.27(t,2H,J=6.9Hz,CH2Br),1.98-1.86(m,2H,CH2),1.84-1.74(m,2H,CH2),1.71(quintet,2H,J=7.2Hz,CH2),1.38-1.24(m,2H),1.18-1.04(m,1H),0.96-0.84(m,1H),0.63(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.9,141.4,132.5,127.6,122.9,122.4,109.7,54.2,37.4,33.6,32.4,31.0,28.2,23.4,8.5ppm.
式C15H20BrNO的元素分析(310.24):
计算值:C 58.07,H 6.50,N 4.51,Br 25.76%.
实测值:C 57.95,H 6.42,N 4.67,Br 25.58%.
实施例10
3-(4-氯丁基)-3-异丁基-1,3-二氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-异丁基-1,3-二氢-2H-吲哚-2-酮和1-溴-4-氯丁烷。
M.p.:124-125℃(己烷-乙酸乙酯).
IR(KBr):3208,1713,747cm-1.
1H-NMR(CDCl3,TMS,400MHz):9.02(br s,1H,NH),7.21(dt,1H,J=7.5,1.4Hz,H-6),7.11(td,1H,J=7.4,0.6Hz,H-4),7.04(dt,1H,J=7.4,1.0Hz,H-5),6.95(d,1H,J=7.7Hz,H-7),3.37(t,2H,J=6.7Hz,CH2Cl),1.95-1.70(m,4H,2x CH2),1.70-1.58(m,2H,CH2),1.38-1.30(m,1H),1.23-1.17(m,1H),1.02-0.98(m,1H),0.73(d,3H,J=6.6Hz,CH3),0.61(d,3H,J=6.6Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):183.1,141.1,132.6,127.7,123.3,122.3,109.8,53.0,46.3,44.4,39.2,32.6,25.3,24.2,23.6,21.1ppm.
式C16H22ClNO的元素分析(279.81):
计算值:C 68.68,H 7.93,N 5.01,Cl 12.67%.
实测值:C 68.49,H 7.89,N 4.92,Cl 12.89%.
实施例11
3-(5-溴戊基)-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮和1,5-二溴戊烷。
M.p.:82-83C(己烷).
IR(KBr):3293,1720,1690,1175,817cm-1.
1H-NMR(CDCl3,TMS,400MHz):7.96(br s,1H,NH),6.92(dt,1H,J=8.8,2.6Hz,H-6),6.86(dd,1H,J=8.0,2.6Hz,H-4),6.82(dd,1H,J=8.4,4.3Hz,H-7),3.30(t,2H,J=6.9Hz,CH2Br),1.96-1.87(m,2H,CH2),1.80-1.68(m,4H,2x CH2),1.40-1.25(m,2H,CH2),1.18-1.04(m,1H),0.96-0.84(m,1H),0.64(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):181.8,159.3(d,J=240.7Hz),136.9,134.4(d,J=8.0Hz),114.0(d,J=23.3Hz),111.0(d,J=24.4Hz),109.9(d,J=8.0Hz),54.7,37.5,33.6,32.4,31.1,28.2,23.5,8.5ppm.
式C15H19BrFNO的元素分析(328.23):
计算值:C 54.89,H 5.83,N 4.27,Br 24.34%.
实测值:C 54.68,H 5.89,N 4.35,Br 24.16%.
实施例12
3-(5-溴戊基)-3-乙基-5-甲基-1,3-二氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-乙基-5-甲基-1,3-二氢-2H-吲哚-2-酮和1,5-二溴戊烷。
M.p.:72-73℃(己烷).
IR(KBr):3262,1726,1694,812cm-1.
1H-NMR(CDCl3,TMS,400MHz):7.55(br s,1H,NH),7.00(d,1H,J=7.9Hz,H-6),6.92(s,1H,H-4),6.75(d,1H,J=7.8Hz,H-7),3.30(t,2H,J=6.8Hz,CH2Br),1.94-1.84(m,2H,CH2),1.79-1.68(m,4H,2x CH2),1.35-1.24(m,2H,CH2),1.24-1.13(m,1H),0.93-0.84(m,1H),0.63(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):181.8,159.3(d,J=240.7Hz),136.9,134.4(d,J=8.0Hz),114.0(d,J=23.3Hz),111.0(d,J=24.4Hz),109.9(d,J=8.0Hz),54.7,37.5,33.6,32.4,31.1,28.2,23.5,8.5ppm.
式C16H22BrNO的元素分析(324.26):
计算值:C 59.27,H 6.84,N 4.32,Br 24.64%.
实测值:C 59.18,H 6.92,N 4.55,Br 24.51%.
实施例13
3-(5-溴戊基)-3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮
按照方法“A”制备标题化合物,始于3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮和1,5-二溴戊烷。
M.p.:95-96℃(己烷).
IR(KBr):3300,1722,857cm-1.
1H-NMR(CDCl3,TMS,400MHz):9.24(br s,1H,NH),7.01(dd,1H,J=8.1,5.3Hz,H-5),6.72(ddd,1H,J=9.6,8.2,2.3Hz,H-5),6.68(d,1H,J=8.8,2.3Hz,H-7),3.26(t,2H,J=7.4Hz,CH2Br),1.92-1.83(m,2H,CH2),1.80-1.65(m,4H,2x CH2),1.35-1.25(m,2H,CH2),1.09-1.00(m,1H),0.92-0.84(m,1H),0.60(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):183.3,162.4(d,J=244.1Hz),142.5(d,J=11.8Hz),127.7(d,J=3.1Hz),123.8(d,J=9.9Hz),108.7(d,J=22.1Hz),98.4(d,J=27.1Hz),53.9,37.4,33.6,32.3,31.0,28.2,23.4,8.4ppm.
式C15H19BrFNO的元素分析(328.23):
计算值:C 54.89,H 5.83,N 4.27,Br 24.34,F 5.79%.
实测值:C 54.69,H 5.67,N 4.39,Br 24.19%.
ω-卤代烷基化合物的5位氯化(方法“B”)
将卤代烷基化合物(5mmole)溶于15mL冰乙酸,冷却该溶液,直至冰乙酸开始分离(14-16℃),向其中滴加0.5mL(5.7mmole)磺酰氯的5mL冰乙酸溶液。将混合物在相同温度下搅拌2小时,然后吸移到冰水上。分离白色物质,过滤,用水和己烷洗涤,干燥,无需纯化即可用于偶联反应。从所示溶剂中重结晶可以得到分析样品。
实施例14
5-氯-3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮
按照方法“B”制备标题化合物,始于3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮。
M.p.:116-117℃(己烷-乙酸乙酯).
IR(KBr):3285,1717,818cm-1.
1H-NMR(CDCl3,TMS,400MHz):8.72(br s,1H,NH),7.15(dd,1H,J=8.2,2.1Hz,H-6),7.12(d,1H,J=2.1Hz,H-4),6.86(d,1H,J=8.2Hz,H-7),3.41(t,2H,J=6.7Hz,CH2Cl),2.00-1.86(m,2H,CH2),1.84-1.74(m,2H,CH2),1.74-1.60(m,2H),1.29-1.15(m,1H),1.12-0.95(m,1H),0.65(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.0,139.8,134.2,127.9,127.8,123.4,110.7,54.5,44.4,36.8,32.5,31.0,21.7,8.5ppm.
式C14H17Cl2NO的元素分析(286.20):
计算值:C 58.75,H 5.99,N 4.89,Cl 24.77%.
实测值:C 58.61,H 5.96,N 4.80,Cl 24.66%.
实施例15
5-氯-3-(3-氯丙基)-3-乙基-1,3-二氢-2H-吲哚-2-酮
按照方法“B”制备标题化合物,始于3-(3-氯丙基)-3-乙基-1,3-二氢-2H-吲哚-2-酮。
M.p.:105-107℃(己烷).
IR(KBr):3221,2963,1700(C=O),1677,1474cm-1.
1H-NMR(CDCl3,TMS,400MHz):9.15(br s,1H,NH),7.21(dd,1H,J=8.2,2.1Hz,H-6),7.12(d,1H,J=2.0Hz,H-4),6.88(d,1H,J=8.2Hz,H-7),3.43-3.39(m,2H,CH2Cl),2.10-1.77(m,4H,2x CH2),1.62-1.55(m,1H),1.42-1.38(m,1H),0.66(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.1,139.8,133.9,128.1,128.0,123.5,110.8,54.1,44.6,34.7,30.9,27.5,8.5ppm.
式C13H15Cl2NO的元素分析(272.18):
计算值:C 57.37,H 5.56,N 5.15,Cl 26.05%.
实测值:C 57.19,H 5.64,N 5.28,Cl 25.88%.
实施例16
5-氯-3-(4-氯丁基)-3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮
按照方法“B”制备标题化合物,始于6-氟-3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮。
M.p.:131-133℃(己烷-乙酸乙酯).
IR(KBr):3289,1720,1143cm-1.
1H-NMR(CDCl3,TMS,400MHz):8.90(br s,1H,NH),7.12(d,1H,J=7.1,H-4),6.79(d,1H,J=8.8Hz,H-7),3.42(t,2H,J=6.7Hz,CH2Cl),1.96-1.84(m,2H,CH2),1.80-1.63(m,4H,2x CH2),1.30-1.20(m,1H),1.20-1.04(m,1H),0.65(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.3,157.6(d,J=247.2Hz),140.9(d,J=11.1Hz),128.8(d,J=3.8Hz),124.8,114.3(d,J=18.3Hz),99.5(d,J=26.7Hz),54.2,44.3,36.8,32.4,31.0,21.6,8.4ppm.
式C14H16Cl2FNO的元素分析(304.19):
计算值:C 55.28,H 5.30,N 4.60,Cl 23.31%.
实测值:C 55.19,H 5.27,N 4.58,Cl 23.34%.
ω-氯烷基化合物的5,7-二氯化(方法“C”)
将氯烷基化合物溶于80mL(40mmole)冰乙酸,在室温下向其中滴加9.6mL(120mmole)磺酰氯,将溶液保持在60℃下达3小时。然后将反应混合物冷却,倒在冰上,用二乙醚萃取。将醚相用10体积%NaOH溶液萃取两次,经硫酸钠干燥,蒸发。所得淡黄色油用己烷研制,以结晶形式分离白色物质,在己烷中搅拌,过滤,用己烷洗涤,再次干燥,无需纯化即可用于偶联反应。使化合物从所示溶剂中重结晶,可以得到分析样品。
实施例17
5,7-二氯-3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮
按照方法“C”制备标题化合物,始于3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮。
M.p.:65-67℃(己烷).
IR(KBr):3165,2964,1713(C=O),1455cm-1.
1H-NMR(CDCl3,TMS,400MHz):8.38(br s,1H,NH),7.20(d,1H,J=1.9Hz,H-6),6.97(d,1H,J=1.8Hz,H-4),3.38(t,2H,J=6.7Hz,CH2Cl),1.95-1.84(m,2H,CH2),1.76-1.60(m,4H,2xCH2),1.19-1.16(m,1H),1.04-0.96(m,1H),0.62(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):180.5,137.7,135.1,128.3,127.6,121.9,115.7,55.7,44.3,36.8,32.5,31.0,21.7,8.5ppm.
式C14H16Cl3NO的元素分析(320.65):
计算值:C 52.44,H 5.03,N 4.37,Cl 33.17%.
实测值:C 52.37,H 4.97,N 4.27,Cl 33.18%.
实施例18
5,7-二氯-3-(4-氯丁基)-3-异丁基-1,3-二氢-2H-吲哚-2-酮
按照方法“C”制备标题化合物,始于3-(4-氯丁基)-3-异丁基-1,3-二氢-2H-吲哚-2-酮。
M.p.:93-94℃(己烷).
IR(KBr):3144,1719,1459cm-1.
1H-NMR(CDCl3,TMS,400MHz):8.49(br s,1H,NH),7.24(dt,1H,J=1.9Hz,H-6),7.01(d,1H,J=1.7Hz,H-4),3.41(t,2H,J=6.7Hz,CH2Cl),1.91(m,2H,CH2),1.67(m,4H,2x CH2),1.34(m,1H),1.20(m,1H),1.01(m,1H),0.74(d,3H,J=6.7Hz,CH3),0.66(d,3H,J=6.7Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):181.0,137.5,135.4,128.2,127.6,122.2,115.4,54.5,46.3,44.3,39.2,32.4,25.3,24.3,23.1,21.1ppm.
式C16H20Cl3NO的元素分析(348.70):
计算值:C 55.11,H 5.78,N 4.02,Cl 30.50%.
实测值:C 55.29,H 5.67,N 4.12,Cl 30.18%.
实施例19
7-氯-3-(4-氯丁基)-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮
将3-(4-氯丁基)-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮(5.40g;20mmoles)溶于40mL冰乙酸,在室温下向其中滴加3.2mL(40mmole)磺酰氯,将溶液保持在60℃下达4小时。然后将反应混合物冷却,倒在冰上,用二乙醚萃取。将醚相用10体积%NaOH溶液萃取两次,经硫酸钠干燥,蒸发。所得淡黄色油用己烷研制,以结晶形式分离白色物质,在己烷中搅拌,过滤,用己烷洗涤,干燥,无需纯化即可用于偶联反应。从己烷与乙酸乙酯的混合物中重结晶,可以得到分析样品。
M.p.:104-105℃(己烷-乙酸乙酯).
IR(KBr):3184,1709,1080,853cm-1.
1H-NMR(CDCl3,TMS,400MHz):8.22(br s,1H,NH),6.99(dd,1H,J=7.6,2.3Hz),6.81(dd,1H,J=7.6,2.3Hz),3.42(t,2H,J=6.7Hz),CH2Cl),2.00-1.88(m,2H,CH2),1.82-1.60(m,4H,2xCH2),1.30-1.16(m,1H),1.12-1.00(m,1H),0.66(t,3H,J=7.4Hz,CH3)
13C-NMR(CDCl3,TMS,101MHz):180.6,158.8(d,J=244.5Hz),135.1(d,J=2.3Hz),134.9(d,J=8.4Hz),114.8(d,J=26.3Hz),114.8(d,J=11.0Hz),109.7(d,J=24.4Hz),55.8(d,J=1.9Hz),44.3,36.8,32.5,31.1,21.7,8.5.
式C14H16Cl2FNO的元素分析(304.19):
计算值:C 55.28,H 5.30,N 4.60,Cl 23.31%.
实测值:C 55.19,H 5.28,N 4.65,Cl 23.19%.
实施例20
5-溴-3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮
将3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮(12.59g;50mmoles)溶于100mL二噁烷与100mL水的混合物。在80℃与90℃之间的温度下,在半小时内向该溶液滴加2.84mL溴(55mmole)、11.9g KBr(100mmole)与50mL水的混合物。将反应混合物保持在相同温度下达另外半小时,冷却。然后向其中滴加500mL水。以白色晶体形式分离产物。滤出所分离的物质,用水和己烷洗涤,无需纯化即可用于偶联反应。从己烷与乙酸乙酯的混合物中重结晶,可以得到分析样品。
M.p.:117-118℃(己烷-乙酸乙酯).
IR(KBr):3286,1717,1198,817cm-1.
1H-NMR(CDCl3,TMS,400MHz):δ9.28(br s,1H,NH),7.35(dd,1H,J=8.2,2.0Hz,H-6),7.24(d,1H,J=2.0Hz,H-4),6.84(d,1H,J=8.2Hz,H-7),3.41(t,2H,J=6.8Hz,CH2Cl),1.98-1.75(m,2H,CH2),1.74-1.60(m,4H,2x CH2),1.27-1.16(m,1H),1.11-1.01(m,1H),0.64(t,3H,J=7.4Hz,CH3);
13C-NMR(CDCl3,TMS,101MHz):182.3,140.4,134.6,130.7,126.1,115.3,111.3,54.5,44.3,36.7,32.8,30.9,21.7,8.5.
式C14H17BrClNO的元素分析(330.65):
计算值:C 50.86,H 5.18,N 4.24%.
实测值:C 50.79,H 5.09,N 4.38%.
实施例21
3-(4-氯丁基)-3-乙基-2-氧代二氢吲哚-5-磺酰氯
将90mL氯磺酸冷却至0℃,向其中分批加入3-(4-氯丁基)-3-乙基羟吲哚(11.34g;45mmole),以便温度不超过2℃。然后在搅拌下使溶液升温至室温,在半小时内吸移到冰上,滤出所分离的白色沉淀,用水和己烷洗涤,无需纯化即可用于偶联反应。从己烷与乙酸乙酯的混合物中重结晶,可以得到分析样品。
M.p.:141-143℃.
IR(KBr):3197,1729,1371,1176cm-1.
1H-NMR(CDCl3,TMS,400MHz):9.39(br s,1H,NH),7.99(dd,1H,J=8.4,1.9Hz,H-6),7.80(d,1H,J=1.9Hz,H-4),16(d,1H,J=8.4Hz,H-7),3.46-3.41(m,2H,CH2Cl),2.10-1.83(m,4H,2x CH2),1.73-1.66(m,2H),1.32-1.18(m,1H),1.14-1.00(m,1H),0.68(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.4,147.6,138.4,133.9,128.8,121.9,110.1,54.5,44.2,36.4,32.2,30.9,21.5,8.5ppm.
式C14H17Cl2NO3S的元素分析(350.27):
计算值:C 48.01,H 4.89,N 4.00,Cl 20.24,S 9.15%.
实测值:C 47.89,H 4.76,N 4.18,Cl 20.01,S 9.38%.
实施例22
3-(4-氯丁基)-3-乙基-2-氧代二氢吲哚-5-磺酰胺
将3-(4-氯丁基)-3-乙基-2-氧代二氢吲哚-5-磺酰氯(9.96g;30mmoles)溶于450mL乙醇,在0-2℃下向该溶液滴加25%氨水溶液(9mL,120mmole)。然后使混合物升温至室温,进一步搅拌1小时。然后蒸发溶液,将残余的白色物质在水中搅拌,过滤,用水和己烷洗涤,无需纯化即可用于偶联反应。从乙酸乙酯中重结晶,可以得到分析样品。
M.p.:171-172℃(乙酸乙酯).
IR(KBr):3343,3265,1725,1327,1169cm-1.
1H-NMR (DMSO-d6,TMS,400MHz):10.8(br s,1H,NH),7.70(dd,1H,J=8.1,1.8Hz,H-6),7.65(d,1H,J=1.7Hz,H-4),6.98(d,1H,J=8.1Hz,H-7),3.54-3.49(m,2H,CH2Cl),1.82-1.73(m,4H,2x CH2),1.59(quintet,2H,J=7.2Hz,CH2),1.15-1.00(m,1H),1.00-0.85(m,1H),0.52(t,3H,J=7.4Hz,CH3)ppm.
13C-NMR(DMSO-d6,TMS,101MHz):181.0,145.7,137.6,132.6,126.6,120.9,109.1,53.4,45.1,36.2,32.3,30.3,21.5,8.5ppm.
式C14H19ClN2O3S的元素分析(330.84):
计算值:C 50.83,H 5.79,N 8.47,Cl 10.72,S 9.69%.
实测值:C 50.79,H 5.74,N 8.51,Cl 10.71,S 9.72%.
ω-氯烷基化合物的偶联反应(方法“D”)
在偶联反应中,使适当的氯烷基化合物与仲胺偶联。在缓慢搅拌下,将碱(12mmole)的熔化物升温至180℃,在相同温度下向其中加入氯烷基化合物(12mmole)和碳酸钠(1.36g;12mmole)。使混合物反应1小时,冷却,向其中加入乙酸乙酯和水,分离各相。蒸发有机相,残余的油经过短柱色谱处理,使用乙酸乙酯作为洗脱剂。制得所需化合物,为主要产物。
方法“D”加工方法1
如果经过柱色谱纯化的产物在用二乙醚研制后变为结晶性,那么滤出,在既定物质的熔点之后从所示溶剂中重结晶。得到所需化合物,为白色晶体的形式。
方法“D”加工方法2
如果基本产物在加入二乙醚后没有变为结晶性,那么将其溶于200ml醚,滤出少量漂浮的沉淀,在剧烈搅拌下向纯溶液加入计算量(1摩尔当量)氯化氢的50ml二乙醚溶液。过滤所分离的白色的盐,用醚和己烷洗涤,在室温真空枪中干燥3小时。如果必要的话,使盐酸盐重结晶。
方法“D”加工方法3
如果基本产物在加入二乙醚后没有变为结晶性,并且没有与氯化氢生成可充分过滤的盐,那么将其溶于100ml热的乙酸乙酯,在搅拌下,在10分钟内向其中滴加1摩尔当量的草酸二水合物的50ml热乙酸乙酯溶液。冷却后分离白色草酸盐。在室温下滤出,用乙酸乙酯和己烷洗涤,干燥。
实施例23
3-[3-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-丙基]-3-乙基-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,应用加工方法1,始于3-(3-氯丙基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和2-氯-6,7-二氢-4H-噻吩并[3,2-c]吡啶。
M.p.:130-132℃(己烷-乙酸乙酯).
IR(KBr):3107,3059,1706(C=O)cm-1.
1H-NMR(CDCl3,TMS,400MHz):0.63(3H,t,J=7.4Hz),1.22-1.10(1H,m),1.46-1.30(1H,m),1.90-1.77(2H,m),1.98-1.90(2H,m),2.42(2H,t,J=7.4Hz),2.64(2H,t,J=5.7Hz),2.81(2H,t,J=5.4Hz),3.32(1H,d,J=14.4Hz),3.42(1H,d,J=14.4Hz),6.65(1H,d,J=5.2Hz),6.87(1H,d,J=7.7Hz),7.03(1H,d,J=5.2Hz),7.04(1H,dt,J=1.0,7.5Hz),7.12(1H,dd,J=0.6,7.3Hz),7.18(1H,dt,J=1.3,7.6Hz),8.80(1H,s)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.5,141.4,133.7,133.3,132.5,127.6,125.2,123.0,122.6,122.3,109.5,57.5,54.0,52.9,50.7,35.3,31.0,25.4,22.1,8.6ppm.
式C20H24N2OS的元素分析(340.49):
计算值:C 70.55,H 7.10,N 8.23,S 9.42%.
实测值:C 69.20,H 7.10,N 8.03,S 9.10%.
实施例24
5-氯-3-[3-(6,7-二氢-4H-噻吩并[3,2-c]-吡啶-5-基)-丙基]-3-乙基-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,应用加工方法1,始于5-氯-3-(3-氯丙基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和2-氯-6,7-二氢-4H-噻吩并[3,2-c]-吡啶。
M.p.:66-69℃(己烷-乙酸乙酯).
IR(KBr):1652(C=O)cm-1.
1H-NMR(CDCl3,TMS,400MHz):0.62(3H,t,J=7.4Hz),1.18-1.14(1H,m),1.40-1.36(1H,m),1.85-1.74(2H,m),1.98-1.90(2H,m),2.47-2.40(2H,m),2.67(2H,t,J=5.5Hz),2.83(2H,t,J=5.5Hz),3.42(2H,s),6.67(1H,d,J=5.2Hz),6.74(1H,d,J=8.2Hz),7.03(1H,d,J=5.1Hz),7.09(1H,d,J=2.1Hz),7.15(1H,dd,J=2.2,8.1Hz),9.39(1H,s)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.2,140.1,134.4,133.6,133.3,127.7,127.7,125.6,123.3,122.6,110.5,57.4,54.5,52.9,50.8,35.1,31.0,25.3,22.1,8.5ppm.
式C20H23ClN2OS的元素分析(374.94):
计算值:C 64.07,H 6.18,Cl 9.46,N 7.47,S 8.55%.
实测值:C 63.96,H 6.20,Cl 9.17,N 7.26,S 8.45%.
实施例25
3-乙基-3-{4-[4-(3-三氟甲基-苯基)-1,2,3,6-四氢吡啶-1-基]-丁基}-1,3-二氢-2H-吲哚-2-酮单草酸盐
按照方法“D”制备标题化合物,应用加工方法3,始于3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和4-(3-三氟甲基苯基)-1,2,3,6-四氢吡啶。
M.p.:136-139℃.
IR(KBr):3185,1707(C=O)cm-1.
1H-NMR(DMSO-d6,TMS,400MHz):10.4(1H,s),7.77(1H,d),7.75(1H,s),7.67(1H,d,J=7.7Hz),7.61(1H,t,J=7.7Hz),6.30(1H,s),5.2(4H,br s),3.69(2H,s),3.22(2H,s),2.90(2H,t,J=8.0Hz),2.73(2H,s),1.80-1.66(4H,m),1.62-1.48(2H,m),1.06-0.94(1H,m),0.88-0.76(1H,m),0.51(3H,t,J=7.4Hz)ppm.
13C-NMR(DMSO-d6,TMS,101MHz):180.9,164.6,142.7,139.9,139.1,132.2,129.9,129.6(q,J=31.7Hz),129.1,127.8,124.5(q,J=3.8Hz),124.4(q,J=272.4Hz)123.2,121.7,121.5(q,J=3.8Hz),110.4,109.4,54.8,53.2,49.9,48.2,36.7,30.4,24.1,24.0,21.6,8.6ppm.
式C28H31F3N2O5的元素分析(532.56):
计算值:C 63.1 5,H 5.87,N 5.26%.
实测值:C 62.7 2,H 5.92,N 5.22%.
实施例26
5-氯-3-[4-(6,7-二氢-4H-噻吩并[3,2-c]-吡啶-5-基)-丁基]-3-乙基-1,3-二氢-2H-吲哚-2-酮单盐酸盐
按照方法“D”制备标题化合物,应用加工方法1,始于5-氯-3-(4-氯丁基)-3-乙基-1,3-二氢-2 H-吲哚-2-酮和6,7-二氢-4H-噻吩并[3,2-c]吡啶。
M.p.:213-215 ℃.
IR(KBr):3186,2473,1708(C=O)cm-1.
1H-NMR(DMSO-d6,TMS,400MHz):0.51(3H,t,J=7.4Hz),0.90-0.75(1H,m),1.02-0.90(1H,m),1.87-1.69(6H,m),3.05(4H,br s),3.26(1H,br s),3.36(1H,br s),4.09(1H,br s),4.34(1H,brs),6.88(1H,d,J=8.1Hz),6.88(1H,d,J=5.2Hz),7.23(H,dd,J=2.1,8.2Hz),7.36(1H,d,J=2.0Hz),7.45(1H,d,J=5.2Hz),10.6(1H,s),11.1(1H, br s)ppm.
13C-NMR(DMSO-d6,TMS,101MHz):180.4,141.6,134.4,131.6,128.3,127.7,125.9,125.3,125.2,123.5,110.7,54.6,53.8,50.0,49.1,36.4,30.2,23.6,21.7,21.4,8.5ppm.
式C21H26Cl2NO2S的元素分析(425.42):
计算值:C 59.29,H 6.16,Cl 16.67,N 6.58%.
实测值:C 58.83,H 6.17,Cl 16.26,N 6.43%.
实施例27
5-溴-3-[4-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-丁基]-3-乙基-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,应用加工方法1,始于5-溴-3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和6,7-二氢-4H-噻吩并[3,2-c]吡啶。
M.p.:149-151℃(己烷-乙酸乙酯).
IR(KBr):3444,3110,1720(C=O)cm-1.
1H-NMR(CDCl3,TMS,400MHz):0.62(3H,t,J=7.4Hz),0.98-0.86(1H,m),1.18-1.04(1H,m),1.52-1.45(2H,m)1.80-0.71(2H,m),1.97-1.88(2H,m),2.41(2H,t,J=7.6Hz),2.71(2H,t,J=5.6Hz),2.83(2H,t,J=5.6Hz),3.47(2H,s) 6.72(1H,d,J=8.2Hz),6.68(1H,d,J=5.1Hz),7.04(1H,d,J=5.1Hz),7.22(1H,d,J=2.0Hz),7.30(1H,dd,J=2.0,8.2Hz),9.34(1H,s)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.3,140.6,134.9,133.7,133.3,130.5,126.1,125.2,122.6,115.0,111.1,57.3,54.6,52.9,50.7,37.5,37.5,31.0,25.3,22.2,8.5ppm.
式C21H25BrN2OS的元素分析(433.41):
计算值:C 58.20,H 5.81,Br 18.44,N 6.46,S 7.40%.
实测值:C 58.59,H 5.92,Br 18.01,N 6.31,S 7.16%.
实施例28
3-[4-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-丁基]-3-异丁基-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,应用加工方法1,始于3-(4-氯丁基)-3-异丁基-1,3-二氢-2H-吲哚-2-酮和6,7-二氢-4H-噻吩并[3,2-c]吡啶。
M.p.:114-116℃(己烷-乙酸乙酯).
IR(KBr):3201,1718(C=O)cm-1.
1H-NMR(CDCl3,TMS,400MHz):0.60(3H,d,J=6.7Hz),0.72(3H,d,J=6.7Hz),0.90-0.86(1H,m),1.16-1.04(1H,m),1.38-1.25(1H,m),1.48-1.40(2H,m),1.80-1.68(2H,m),1.94-1.88(2H,m),2.37(2H,t,J=7.8Hz),2.68(2H,t,J=5.7Hz),2.81(2H,t,J=5.5Hz),3.45(2H,s),6.67(1H,d,J=5.1Hz),6.89(1H,d,J=7.7Hz),7.02(1H,dt,J=0.9,7.5Hz),7.03(1H,d,J=5.1Hz),7.10(1H,d,J=6.8Hz),7.18(1H,dt,J=1.2,7.7Hz),9.06(1H,s)ppm.
13C-NMR(CDCl3,TMS,101MHz):183.2,141.2,133.7,133.3,132.9,127.5,125.2,123.3,122.5,122.2,109.6,57.4,53.1,53.0,50.0,46.3,40.0,27.4,25.3,24.2,23.1,21.7,21.7ppm.
式C23H30N2OS的元素分析(382.57):
计算值:C 72.21,H 7.90,N 7.32,S 8.38%.
实测值:C 71.17,H 8.18,N 7.07,S 8.21%.
实施例29
3-[4-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-丁基]-3-乙基-1,3-二氢-2H-吲哚-2-酮单盐酸盐
按照方法“D”制备标题化合物,应用加工方法2,始于3-(4-氯丁基)-3-异丁基-1,3-二氢-2H-吲哚-2-酮和6,7-二氢-4H-噻吩并[3,2-c]吡啶。
M.p.:143-144C.
IR(KBr):3427,1706(C=O)cm-1.
1H-NMR(DMSO-d6,TMS,400MHz):11.2(1H,br s),10.5(1H,s),7.48(1H,d,J=5.1Hz),7.25(1H,d,J=7.2Hz),7.21(1H,dt,J=1.2,7.6Hz),7.03(1H,dt,J =1.0,7.5Hz),6.91(1H,d,J=5.3Hz),6.90(1H,d,J=7.8Hz),4.37(1H,br s),4.11(1H,br s),3.63(1H,br s),3.25(1H,br s),3.20(1H,br s),3.07(3H,br s),1.83-1.72(6H,m),1.01(1H,br s),0.85(1H,br s),0.54(3H,t,J=7.4Hz)ppm.
13C-NMR(DMSO-d6,TMS,50MHz):180.7,142.7,132.1,131.5,128.2,127.7,125.3,123.2,121.6,109.3,54.6,53.1,49.9,49.0,36.5,30.3,23.6,21.7,21.4,8.5ppm.
式C21H27ClN2OS的元素分析(390.98):
计算值:C 64.51,H 6.96,Cl 9.07,N 7.16,S 8.20%.
实测值:C 64.44,H 7.00,Cl 8.87,N 7.07,S 8.04%.
实施例30
3-[4-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-丁基]-3-乙基-5-甲基-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,应用加工方法1,始于3-(4-氯丁基)-3-乙基-5-甲基-1,3-二氢-2H-吲哚-2-酮和6,7-二氢-4H-噻吩并[3,2-c]吡啶。
M.p.:138-140℃(己烷-乙酸乙酯).
IR(KBr):3239,1710(C=O),1493cm-1.
1H-NMR(CDCl3,TMS,400MHz):7.90(1H,br s),7.02(1H,d,J=5.1Hz),6.97(1H,m),6.90(1H,m),6.73(1H,d,J=7.8Hz),6.66(1H,d,J=5.1Hz),3.40(2H,s),2.81(2H,t,J=5.5Hz),2.68(2H,t,J=5.7Hz),2.38(2H,t,J=7.6Hz),2.32(3H,s),1.88(2H,m),1.75(2H,m),1.45(2H,m),1.10(1H,m),0.91(1H,m),0.61(3H,t,J=7.4Hz)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.31,138.77,133.79,133.33,132.64,131.77,127.88,125.19,123.78,122.54,109.08,57.50,54.18,53.01,50.79,37.67,31.10,27.50,25.35,22.33,21.21,8.56ppm.
式C22H28N2OS的元素分析(368.55):
计算值:C 71.70,H 7.66,N 7.60,S 8.70%.
实测值:C 71.19,H 7.61,N 7.42,S 8.55%.
实施例31
3-[4-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-丁基]-3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮单草酸盐
按照方法“D”制备标题化合物,应用加工方法1,始于3-(4-氯丁基)-3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮和6,7-二氢-4H-噻吩并[3,2-c]吡啶。
M.p.:167-168℃.
IR(KBr):1707(C=O),1140cm-1.
1H-NMR(DMSO-d6,TMS,400MHz):0.50(3H,t,J=7.3Hz),0.85-0.78(1H,m),0.99-0.85(1H,m),1.57-1.50(2H,m),1.79-1.67(2H,m),2.86(2H,t,J=7.4Hz),2.97(2H,s),3.2(2H,s),3.99(2H,s),5.0-4.2(2H,br s),6.66(1H,dd,J=2.3,9.3Hz),6.78(1H,dt,J=2.3,7.8Hz),6.84(1H,d,J=5.2Hz),7.2(1H,dd,J=5.7,8.1Hz),7.40(1H,d,J=5.2Hz),10.5(1H,s)ppm
13C-NMR (DMSO-d6,TMS,50MHz):8.3,21.4,22.5,24.5,30.2,36.5,49.4,50.8,52.8,55.1,97.5(d,J=27.1Hz),107.5(d,J=22.5Hz),124.34(d,J=10.7Hz),124.6,125.3,127.8,129.8,131.8,144.0(d,J=12.2Hz),161.9(d,J=240.7Hz),163.9,181.0ppm.
式C23H27FN2O5S的元素分析(462.54):
计算值:C 59.73,H 5.88,N 6.06,S 6.93%.
实测值:C 59.80,H 5.90,N 6.01,S6.83%.
实施例32
3-[4-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-丁基]-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮单盐酸盐
按照方法“D”制备标题化合物,始于3-(4-氯丁基)-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮和6,7-二氢-4H-噻吩并[3,2-c]吡啶。应用加工方法2从反应混合物中分离产物。
M.p.:119-121℃.
IR(KBr):3441,1712(C=O),1184cm-1.
1H-NMR(CDCl3,TMS,400MHz):0.60(1H,t,J=7.4Hz),1.00-0.86(1H,m),1.16-1.04(1H,m),1.95-1.66(6H,m),3.20-2.94(2H,m),3.22(2H,br s),3.50(2H,br s),4.33(2H,br s),6.78(1H,d,J=5.2Hz),6.81(1H,dd,J=2.5,8.1Hz),6.87(1H,dt,J=2.5,9.1Hz),6.95(1H,dd,J=4.5,8.5Hz),7.21(1H,d,J=5.1Hz),9.74(1H,s)ppm.
13C-NMR(CDCl3,TMS,101MHz):8.4,21.1,21.6,24.0,30.9,36.6,49.2,50.3,54.2,54.3(d,J=1.9Hz),110.5(d,J=24.4Hz),110.7(d,J=8.0Hz),114.1(d,J=23.7Hz),124.7,125.4,126.3,131.0,133.5(d,J=7.6Hz),137.7,159.0(d,J=239.9Hz),181.7ppm.
式C21H26ClFN2OS的元素分析(408.97):
计算值:C 61.68,H 6.41,Cl 8.67,N 6.85,S 7.84%.
实测值:C 60.75,H 6.43,Cl 8.02,N 6.73,S 7.77%.
实施例33
7-氯-3-[4-(6,7-二氢-4H-噻吩并[3,2-c]-吡啶-5-基)-丁基]-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,始于7-氯-3-(4-氯丁基)-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮和6,7-二氢-4H-噻吩并[3,2-c]-吡啶。应用加工方法1从反应混合物中分离产物。
M.p.:194-196℃(乙醇).
IR(KBr):1726(C=O)cm-1.
1H-NMR(DMSO-d6,TMS,400MHz):0.51(3H,t,J=7.4Hz),0.90-0.70(1H,m),1.08-0.90(1H,m),1.39-1.32(2H,m),1.82-1.70(4H,m),2.59(2H,t,J=5.6Hz),2.71(2H,t,J=5.2Hz),3.34(2H,m),6.74(1H,d,J=5.1Hz),7.25-7.22(3H,m),10.84(1H,s)ppm.
13C-NMR(DMSO-d6,TMS,101MHz):8.5,22.0,25.1,26.9,30.5,37.0,50.5,52.6,55.2(d,J=1.9Hz),56.8,110.4(d,J=24.0Hz),113.4(d,J=11.1Hz),114.6(d,J=26.7Hz),123.0,125.6,132.9,134.3,135.8(d,J=8.8Hz),136.8(d,J=2.3Hz),158.0(d,J=240.3Hz),180.7ppm.
式C21H24ClFN2OS的元素分析(406.95):
计算值:C 61.98,H 5.94,Cl 8.71,N 6.88,S 7.88%.
实测值:C 61.66,H 5.92,Cl 8.52,N 6.84,S 7.86%.
实施例34
3-[4-(2-氯-6,7-二氢-4H-噻吩并[3,2-c)-吡啶-5-基)-丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,始于3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和2-氯-6,7-二氢-4H-噻吩并[3,2-c]吡啶。应用加工方法1从反应混合物中分离产物。
M.p.:117-119℃(己烷-乙酸乙酯).
IR(KBr):3299,1705(C=O),769cm-1.
1H-NMR(CDCl3,TMS,400MHz):0.62(3H,t,J=7.4Hz),0,95-0.89(1H,m),1.18-1.08(1H,m),1.51-1.39(2H,m),1.84-1.74(2H,m),1.97-1.87(2H,m),2.36(2H,t,J=7.8Hz),2.70-2.64(4H,m),3.34(2H,s),6.49(1H,s),6.89(1H,d,J=7.8Hz),7.06(1H,dt,J=1.0,7.5Hz),7.10(1H,d,J=6.4Hz),7.20(1H,dt,J=1.3,7.6Hz),8.81(1H,br s)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.6,141.4,133.1,132.5,132.1,127.6,127.0,124.2,123.0,122.3,109.5,57.3,54.2,52.5,50.4,37.5,31.0,27.3,25.1,22.2,8.5ppm.
式C21H25ClN2OS的元素分析(388.96):
计算值:C 64.85,H 6.48,Cl 9.11,N 7.20,S 8.24%.
实测值:C 65.14,H 6.33,Cl 9.00,N 7.01,S 8.01%.
实施例35
5-氯-3-[4-(6,7-二氢-4H-噻吩并[3,2-c]-吡啶-5-基)-丁基]-3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,始于5-氯-3-(4-氯丁基)-3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮和6,7-二氢-4H-噻吩并[3,2-c]-吡啶。应用加工方法1从反应混合物中分离产物。
M.p.:155-157℃(乙醇).
IR(KBr):3112,1722(C=O),1160,727cm-1.
1H-NMR(CDCl3,TMS,400MHz):0.63(3H,t,J=7.4Hz),0.96-0.90(1H,m),1.18-1.05(1H,m),1.55-1.43(2H,m),1.80-1.70(2H,m),1.96-1.86(2H,m),2.42(2H,t,J=7.7Hz),2.72(2H,t,J=5.2Hz),2.83(2H,t,J=5.3Hz),3.48(2H,s),6.67(1H,d,J=8.8Hz),6.69(1H,J=5.1Hz),7.05(1H,J=5.1Hz),7.10(1H,d,J=7.1Hz),8.88(1H,s)ppm.
13C-NMR(CDCl3,TMS,101MHz):8.5,22.2,25.3,27.4,31.1,37.6,50.8,53.0,54.2,57.3,99.2(d,J=26.7Hz),114.1(d,J=18.7Hz),122.7,124.8,125.2,129.0(d,J=3.8Hz),133.3,133.7,141.0(d,J=10.7Hz),157.5(d,J=247.2Hz),182.1ppm.
式C21H24ClFN2OS的元素分析(406.95):
计算值:C 61.98,H 5.94,Cl 8.71,N 6.88,S 7.88%.
实测值:C 60.52,H 5.65,Cl 9.17,N 6.57,S 7.68%.
实施例36
3-[5-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-戊基]-3-乙基-1,3-二氢-2H-吲哚-2-酮单草酸盐
按照方法“D”制备标题化合物,始于3-(5-溴戊基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和6,7-二氢-4H-噻吩并[3,2-c]吡啶。应用加工方法3从反应混合物中分离产物。
M.p.:193-195℃.
IR(KBr):3200-3100,1763,1710cm-1.
1H-NMR(DMSO-d6,TMS,400MHz):0.50(3H,t,J=7.4Hz),0.83-0.78(1H,m),1.00-0.95(1H,m),1.20-1.12(2H,m),1.69-1.52(4H,m),2.95(2H,t,J =8.1Hz),3.03(2H,t,J=5.6Hz),3.36(2H,t,J=5.7Hz),4.14(2H,s),6.85(1H,d,J=7.5Hz),6.86(1H,d,J=5.2Hz),6.98(1H,dt,J=0.9,7.5Hz),7.16(1H,dt,J=1.2,7.7Hz),7.19(1H,d,J=7.3Hz),9.4-8.4(2H,br s),10.37(1H,s)ppm.
13C-NMR(DMSO-d6,TMS,101MHz):180.9,164.4,142.7,132.4,131.7,129.2,127.7,125.4,125.0,123.1,121.6,109.3,55.0,53.2,50.5,49.3,36.9,30.5,26.3,23.8,23.8,22.2,8.6ppm.
式C24H30N2O5S的元素分析(458.58):
计算值:C 62.86,H 6.59,N 6.11,S 6.99%.
实测值:C 62.43,H 6.58,N 6.10,S 6.83%.
实施例37
3-[5-(2-氯-6,7-二氢-4H-噻吩并[3,2-c]-吡啶-5-基)-戊基]-3-乙基-1,3-二氢-2H-吲哚-2-酮单盐酸盐
按照方法“D”制备标题化合物,始于3-(5-溴戊基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和2-氯-6,7-二氢-4H-噻吩并[3,2-c]吡啶。应用加工方法2分离产物。
M.p.:96-98℃.
IR(KBr):3426,2549,1708(C=O)cm-1.
1H-NMR(CDCl3,TMS,400MHz):0.61(3H,t,J=7.4Hz),0.96-0.86(1H,m),1.10-1.04(1H,m),1.29-1.20(2H,m),1.90-1.70(6H,m),3.10(2H,t,J=8.2Hz),3.6-3.2(4H,br s),4.5-3.8(2H,br s),6.62(2H,s),6.95(1H,d,J=7.7Hz),7.03(1H,dt,J=0.9,7.4Hz),7.09(1H,d,J=6.4Hz),7.19(1H,dt,J=1.4,7.5Hz),8.94(1H,s)ppm.
13C-NMR(CDCl3,TMS,101MHz):182.2,141.4,132.2,130.3,129.9,127.7,125.8,123.7,122.9,122.4,109.8,54.9,54.0,49.8,49.0,37.0,31.1,26.6,23.7,23.6,21.2,8.5ppm.
式C22H28Cl2N2OS的元素分析(439.45):
计算值:C 60.13,H 6.42,Cl 16.14,N 6.37,S 7.30%.
实测值:C 59.59,H 6.35,Cl 15.82,N 6.23,S 7.05%.
实施例38
3-[4-(3,4-二氢-1H-异喹啉-2-基)-丁基]-3-乙基-1,3-二氢-2H-吲哚-2-酮单盐酸盐
按照方法“D”制备标题化合物,始于3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和3,4-二氢-1H-异喹啉。应用加工方法2从反应混合物中分离产物。
M.p.:113-115℃.
IR(KBr):3420,2875,1709(C=O)cm-1.
1H-NMR(DMSO-d6,TMS,400MHz):0.47(3H,t,J=7.3Hz),0.83-0.80(1H,m),1.00-0.95(1H,m),1.76-1.65(6H,m),2.98-2.89(3H,m),3.18-3.15(2H,m),3.54(1H,br s),4.10(1H,m),4.15(1H,d,J=4.7Hz),6.83(1H,d,J=7.6Hz),6.96(1H,dt,J=0.9,7.5Hz),7.24-7.12(6H,m),10.4(1H,s),11.1(1H,br s)ppm.
13C-NMR(DMSO-d6,TMS,101MHz):8.6,21.5,23.5,24.9,30.4,36.6,48.7,51.5,53.2,54.9,109.4,121.7,123.2,126.7,126.7,127.7,127.8,128.6,128.7,131.6,132.1,142.7,180.8ppm.
式C23H29ClN2O的元素分析(384.95):
计算值:C 71.76,H 7.59,Cl 9.21,N 7.28%.
实测值:C 69.76,H 7.78,Cl 8.75,N 6.99%.
实施例39
3-乙基-3-{4-[4-(4-氟苯基)-1,2,3,6-四氢吡啶-1-基]-丁基}-1,3-二氢-2H-吲哚-2-酮单盐酸盐
按照方法“D”制备标题化合物,始于3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和4-(4-氟-苯基)-1,2,3,6-四氢吡啶。应用加工方法2从反应混合物中分离产物。
M.p.:108-111℃.
IR(KBr):3426,1705(C=O)cm-1.
1H-NMR(DMSO-d6,TMS,400MHz):0.51(3H,t,J =7.4Hz),0.78-0.88(1H,m),0.94-1.02(1H,m),1.64-1.83(6H,m),2.86-3.80(6H,m),2.98(2H,t,J=8.1Hz),6.12(1H,s),6.87(1H,d,J=7.7Hz),7.00(1H,dt,J=0.9,7.5Hz),7.15-7.23(4H,m),7.52(2H,m),10.45(1H,s),10.9(1H,br s)ppm.
13C-NMR(DMSO-d6,TMS,400MHz):8.6,21.5,23.6,23.8,30.4,36.6,48.0,49.4,53.2,54.6,109.3,115.5(d,J=21.4Hz),116.5,121.7,123.2,127.0(d,J=8.0Hz),127.8,132.1,133.3,134.9(d,J=3.1Hz),142.7,162.0(d,J=244.9Hz),180.8ppm.
式C25H30ClFN2O的元素分析(428.98):
计算值:C 70.00,H 7.05,Cl 8.26,N 6.53%.
实测值:C 66.90,H 6.60,Cl 7.67,N 6.22%.
实施例40
3-{4-[4-(4-氯苯基)-3,6-二氢-2H-吡啶-1-基]-丁基}-3-乙基-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,始于3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和4-(4-氯苯基)-1,2,3,6-四氢吡啶。应用加工方法1从反应混合物中分离产物。
M.p.:142-145℃(己烷-乙酸乙酯).
IR(KBr):3181,1715,1701(C=O)cm-1.
1H-NMR(DMSO-d6,TMS,400MHz):0.61(3H,t,J=7.4Hz),0.96-0.84(1H,m),1.17-1.04(1H,m),1.46-1.35(2H,m),1.95-1.73(4H,m),2.29(2H,t,J=7.8Hz),2.45(2H,m),2.58(2H,t,J=5.6Hz),3.03(2H,q,J=2.8Hz),5.99(1H,t,J=1.8Hz),6.88(1H,d,J=7.7Hz),7.02(1H,dt,J=1.0,7.5Hz),7.10(1H,d,J=6.4Hz),7.17(1H,dt,J=1.4,7.6Hz),7.27-7.21(4H,m),8.63(1H,s)ppm.
13C-NMR(DMSO-d6,TMS,101MHz):8.6,22.1,26.9,27.4,30.5,37.2,49.9,52.8,53.3,57.5,109.2,121.6,123.1,123.1,126.4,127.6,128.4,131.5,132.4,132.9,139.1,142.7,181.0ppm.
式C25H29ClN2O的元素分析(408.98):
计算值:C 73.42,H 7.15,Cl 8.67,N 6.85%.
实测值:C 71.98,H 7.07,Cl 8.41,N 7.09%.
实施例41
3-{4-[4-(3-氯苯基)-3,6-二氢-2H-吡啶-1-基]-丁基}-3-乙基-1,3-二氢-2H-吲哚-2-酮单盐酸盐
按照方法“D”制备标题化合物,始于3-(4-氯丁基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和4-(3-氯苯基)-1,2,3,6-四氢吡啶。应用加工方法2从反应混合物中分离产物。
M.p.:82-85℃.
IR(KBr):3421,3168,1706(C=O)cm-1.
1H-NMR(DMSO-d6,TMS,200MHz):0.51(3H,t,J=7.3Hz),1.03-0.83(2H,m),1.95-1.60(6H,m),4.0-2.76(8H,m),6.25(1H,s),6.87(1H,d,J=7.6Hz),7.00(1H,t,J=7.3Hz),7.52-7.15(6H,m),10.47(1H,s),10.92(1H,br s)ppm.
13C-NMR(DMSO-d6,TMS,50.3MHz):8.62,21.5,23.6,30.4,36.7,47.9,49.4,53.2,54.6,109.4,118.2,121.7,123.2,123.7,124.9,127.8,127.9,130.6,132.2,133.1,133.7,140.7,142.7,180.8ppm.
式C25H30Cl2N2O的元素分析(445.44):
计算值:C 67.41,H 6.79,Cl 15.92,N 6.29%.
实测值:C 65.14,H 6.64,Cl 15.26,N 6.02%.
实施例42
3-[6-(2-氯-6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-己基]-3-乙基-1,3-二氢-2H-吲哚-2-酮单盐酸盐
按照方法“D”制备标题化合物,始于3-(6-溴己基)-3-乙基-1,3-二氢-2H-吲哚-2-酮和2-氯-6,7-二氢-4H-噻吩并[3,2-c]吡啶。按照操作工艺2从反应混合物中分离产物。
熔点,82-85℃.
IR(KBr):3169,2560,1708(C=O),752(C-Cl)cm-1
1H-NMR(DMSO-d6,TMS,200MHz):0.49(3H,J=7.3Hz),0.95-0.78(2H,m),1.24-1.15(4H,m),1.74-1.65(6H,m),3.05(4H,t,J=7.3Hz),3.38(2H,m),4.14(2H,m),6.85(1H,d,J=7.7Hz),6.94(1H,s),7.01(1H,dt,J =1.1,8.4Hz),7.21-7.12(3H,m),10.42(1H,s),11.3(1H,sz)ppm.
13C-NMR(DMSO-d6,TMS,50.3MHz):8.4,1.7,23.3,23.7,25.9,28.7,30.3,36.9,48.6,49.3,53.1,54.7,109.1,121.4,122.9,124.8,127.0,127.5,128.1,131.0,132.2,142.5,180.8ppm.
式C23H30Cl2N2OS的元素分析(453.48):
计算值:C 60.92,H 6.67,Cl 15.64,N 6.18,S 7.07%.
测量值:C 60.48,H 6.85,Cl 15.08,N 6.20,S 6.84%.
实施例43
3-{4-[4-(3-氯苯基)-3,6-二氢-2H-吡啶-1-基]-丁基}-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,始于3-(4-氯丁基)-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮和4-(3-氯苯基)-1,2,3,6-四氢-吡啶。借助加工方法1分离产物。
熔点,112-114℃.
IR(KBr):3161,1706(C=O),817cm-1.
1H-NMR(DMSO-d6,TMS,500MHz):0.50(3H,t,J=7.4Hz),0.81-0.77(1H,m),0.98-0.94(1H,m),1.38-1.28(2H,m),1.80-1.68(4H,m),2.23(2H,t,J=7.2Hz),2.38(2H d,J=1.6Hz),2.52-2.48(2H,m),2.96(2H,t,J=2.6Hz),6.19(1H,kv,J=1.8Hz),6.80(1H,dd,J=4.5,8.2Hz),6.98(1H,ddd,J=2.7,8.5,9.8Hz),7.16(1H,dd,J=2.7,8.5Hz),7.28(1H,td,J=1.8,7.4Hz),7.33(1H,t,J=7.7Hz),7.37(1H,td,J=1.6,7.9Hz),7.42(1H,t,J=1.6Hz),10.35(1H,s)ppm.
13C-NMR (DMSO-d6,TMS,125.6MHz):8.5,22.0,26.8,27.3,30.4,37.0,49.8,52.8,54.1,57.4,109.8(d,J=7.8Hz),111.2(d,J=24.4Hz),113.8(d,J=23.4Hz),123.3,123.9,124.5,126.8,130.3,132.9,133.5,134.5(d,J=7.8Hz),138.8,142.5,158.3(d,J=236.3Hz),180.9ppm.
式C25H28ClFN2O的元素分析(426.97):
计算值:C 70.33,H 6.61,Cl 8.30,N 6.56%.
测量值:C 70.74,H 6.44,Cl 8.37,N 6.68%.
实施例44
3-{4-[4-(4-氯苯基)-3,6-二氢-2H-吡啶-1-基]-丁基}-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮
按照方法“D”制备标题化合物,始于3-(4-氯丁基)-3-乙基-5-氟-1,3-二氢-2H-吲哚-2-酮和4-(4-氯苯基)-1,2,3,6-四氢-吡啶。利用加工方法1分离产物。
熔点,146-148℃.
IR(KBr):3289,1717(C=O),1689,818cm-1.
1H-NMR(DMSO-d6,TMS,500MHz):0.50(3H,t,J=7.4Hz),0.83-0.77(1H,m),0.99-0.93(1H,m),1.40-1.31(2H,m),1.81-1.68(4H,m),2.28(2Hm sz),2.40(2H,sz),2.56(2H,sz),3.02(2H,sz),6.14(1H,kv,J=1.9Hz),6.81(1H,dd,J=4.5,8.4Hz),6.98(1H,ddd,J=2.7,8.4,9.7Hz),7.16(1H,dd,J=2.8,8.4Hz),7.37(2H,d,J=8.8Hz),7.43(2H,d,J=8.8Hz),10.38(1H,s)ppm.
13C-NMR (DMSO-d6,TMS,125.6MHz):8.5,22.0,26.5,27.1,30.4,37.0,49.7,52.5,54.1(d,J=2.0Hz),57.2,109.8(d,J=7.8Hz),111.1(d,J=23.9Hz),113.8(d,J=23.0Hz),122.6,126.4,128.4,131.6,132.9,134.5(d,J=7.8Hz),138.8(d,J=1.5Hz),138.9,158.3(d,J=236.3Hz),180.8ppm.
式C25H28ClFN2O的元素分析(426.97):
计算值:C 70.33,H 6.61,Cl 8.30,N 6.56%.
测量值:C 69.03,H 6.95,Cl 8.66,N 6.28%.
实施例45
3-{4-[4-(3-氯苯基)-3,6-二氢-2H-吡啶-I-基]-丁基}-3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮单盐酸盐
按照方法“D”制备标题化合物,使用3-(4-氯丁基)-3-乙基-6-氟-1,3-二氢-2H-吲哚-2-酮和4-(3-氯苯基)-1,2,3,6-四氢-吡啶作为起始化合物。按照加工方法2分离产物。
熔点,101-104℃.
IR(KBr):3158,2877,1715(C=O)cm-1.
1H-NMR(DMSO-d6,TMS,500MHz):0.51(3H,t,J=7.4Hz),0.970.80(2H,m),1.81-1.63(6H,m),3.73-2.51(8H,m),6.20(1H,s),6.82-6.67(2H,m),7.50-7.20(5H,m),8.8(1H,sz),10.6(1H,s)ppm.
式C25H29Cl2FN2O的元素分析(463.43):
计算值:C 64.80,H 6.31,Cl 15.30,N 6.04%.
测量值:C 64.74,H 6.51,Cl 14.55,N 6.26%.
Claims (13)
2、通式(I)的3,3-二取代的吲哚-2-酮衍生物,其中
R1、R2和R3独立地代表氢、卤素或者具有1至7个碳原子的直链或支链烷基,R4是乙基,R5表示氢,且R6代表可选携带卤素或三氟甲基取代基的苯基,或者
R5和R6与四氢吡啶环的相邻碳原子一起构成苯基或者含有硫原子作为杂原子的5-或6-元杂环,该环可选地携带卤原子,m是3、4或5,及其药学上可接受的酸加成盐。
3、根据权利要求1的通式(I)化合物,其为下列化合物:
3-乙基-3-{4-[4-(3-三氟甲基-苯基)-1,2,3,6-四氢吡啶-1-基]-丁基}-1,3-二氢-2H-吲哚-2-酮,
3-[4-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-丁基]-3-乙基-1,3-二氢-2H-吲哚-2-酮,
3-[5-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-戊基]-3-乙基-1,3-二氢-2H-吲哚-2-酮,
3-[5-(2-氯-6,7-二氢-4H-噻吩并[3,2-c]-吡啶-5-基)-戊基]-3-乙基-1,3-二氢-2H-吲哚-2-酮,
3-[4-(3,4-二氢-1H-异喹啉-2-基)-丁基]-3-乙基-1,3-二氢-2H-吲哚-2-酮,
3-乙基-3-{4-[4-(4-氟苯基)-1,2,3,6-四氢吡啶-1-基]-丁基}-1,3-二氢-2H-吲哚-2-酮,
3-乙基-3-{4-[4-(4-氟苯基)-1,2,3,6-四氢吡啶-1-基]-丁基}-1,3-二氢-2H-吲哚-2-酮,
3-{4-[4-(4-氯苯基)-3,6-二氢-2H-吡啶-1-基]-丁基}-3-乙基-1,3-二氢-2H-吲哚-2-酮,
3-{4-[4-(3-氯苯基)-3,6-二氢-2H-吡啶-1-基]-丁基}-3-乙基-1,3-二氢-2H-吲哚-2-酮,
及其药学上可接受的酸加成盐。
4、根据权利要求1的化合物,其为3-[5-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-戊基]-3-乙基-1,3-二氢-2H-吲哚-2-酮及其药学上可接受的酸加成盐。
5、根据权利要求1的化合物,其为3-乙基-3-{4-[4-(4-氟苯基)-1,2,3,6-四氢吡啶-1-基]-丁基}-1,3-二氢-2H-吲哚-2-酮及其药学上可接受的酸加成盐。
6、药物组合物,包含作为活性成分的至少一种通式(I)化合物或其药学上可接受的酸加成盐,混合有一种或多种常规载体或助剂。
7、根据权利要求6的药物组合物,包含作为活性成分的3-[5-(6,7-二氢-4H-噻吩并[3,2-c]吡啶-5-基)-戊基]-3-乙基-1,3-二氢-2H-吲哚-2-酮或3-乙基-3-{4-[4-(4-氟苯基)-1,2,3,6-四氢吡啶-1-基]-丁基}-1,3-二氢-2H-吲哚-2-酮或其药学上可接受的酸加成盐,混合有一种或多种常规载体或助剂。
8、制备通式(I)化合物的方法,其中
R1和R2独立地代表氢、卤素、具有1至7个碳原子的烷基或氨磺酰基;
R3表示氢或者具有1至7个碳原子的直链或支链烷基;
R4代表具有1至7个碳原子的烷基;
R5是氢,且R6表示可选携带1至3个取代基的苯基,所述取代基选自卤素和携带1至3个卤素取代基的具有1至7个碳原子的烷基,或者
R5和R6与四氢吡啶环的相邻碳原子一起构成苯基或者含有硫作为杂原子的5-或6-元杂环,它可以可选地携带卤素取代基;
m是1、2、3、4、5或6;
该方法包括
(a)使通式(II)化合物
其中L是离去基团,m是1、2、3、4、5或6,
与通式(III)哌啶衍生物反应,
其中R5和R6如上所述,或者
(b)在强碱的存在下,使通式(IV)化合物
其中R1、R2、R3和R4如上所述,
与通式(V)化合物反应,
L-(CH2)m-L’ (V)
其中m是1、2、3、4、5或6,L和L’代表离去基团,可选地卤化所得通式(II)化合物,其中R2是氢,再在酸结合剂的存在下,使所得通式(II)化合物——其中L是离去基团,R2是氢或卤素,且m是1、2、3、4、5或6——与通式(III)吡啶衍生物反应,其中R5和R6如上所述,或者
(c)在强碱的存在下,使通式(IV)化合物——其中R1、R2、R3和R4如上所述——与通式(VI)吡啶衍生物反应,
其中L是磺酰氧基或卤素,R5和R6如上所述,m是1、2、3、4、5或6,可选地卤化所得产物,其中R2是氢,或者从其盐中释放游离碱或者转化为其药学上可接受的有机或无机酸加成盐。
9.根据权利要求8的方法,其中L和L’代表氯或溴。
10、根据权利要求1-5任一项的通式(I)化合物制备药物的用途。
11、通式(I)化合物或者其药学上可接受的有机或无机酸加成盐制备用于治疗或预防中枢神经系统障碍的药物的用途。
12、根据权利要求11的用途,其中所述障碍是抑郁、焦虑、精神分裂症、心境障碍、躁狂、精神衰退、中风、中枢神经系统某些区域细胞死亡、精神紧张性疾病、胃肠疾病、心血管疾病。
13、根据权利要求8的变化方式(a)-(c)任一种的方法,包括在熔化物中进行反应。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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HU0400955A HU0400955D0 (en) | 2004-05-11 | 2004-05-11 | Pyridine derivatives of dialkyl oxindoles |
HUP0400955 | 2004-05-11 | ||
HUP0500463 | 2005-05-05 |
Publications (2)
Publication Number | Publication Date |
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CN101010313A CN101010313A (zh) | 2007-08-01 |
CN100572377C true CN100572377C (zh) | 2009-12-23 |
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HU (1) | HU0400955D0 (zh) |
ZA (1) | ZA200610347B (zh) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1081136A1 (en) * | 1998-04-22 | 2001-03-07 | Meiji Seika Kaisha, Ltd. | Optically active tetrahydrobenzindole derivatives |
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EP1081136A1 (en) * | 1998-04-22 | 2001-03-07 | Meiji Seika Kaisha, Ltd. | Optically active tetrahydrobenzindole derivatives |
Non-Patent Citations (8)
Title |
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A new carbanionic one-carbon ring enlargement-alkylation oflactams. VALACCHI M. ET AL.SYNLETT,Vol.13 . 2003 |
A new carbanionic one-carbon ring enlargement-alkylation oflactams. VALACCHI M.ET AL.SYNLETT,Vol.13. 2003 * |
Catalytic asymetric synthesis of quaternary carbon centers. ASHIMORI ET AL.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,Vol.120 No.26. 1998 |
Indole alkaloid synthesis. A stereospecific preparation offunctionalized cis-hexahydrocarbazoles. MCCARTHY C. ET AL.J. CHEM. SOC. CHEMICAL COMMUNICATIONS,Vol.22 . 1989 |
Reactions of 2-hydroxytryptophol.. NOZOYE T. ET AL.CHEM. PHARM. BULL.,Vol.36 No.12. 1988 |
Reactions of 2-hydroxytryptophol: results of strong acid andalkaline treatments of 2-hydroxytryptophol. NOZOYE ET AL.CHEM. PHARM. BULL.,Vol.31 No.9. 1983 |
Syntheses in the oxindole series, an anomalous course of thecondensation reactions of tertiary Mannich bases. HELLMANN H. ET AL.CHEMISCHE BERICHTE,Vol.84 . 1951 |
Synthesis of 3-ethyloxindole derivatives and the reactivity ofthe amide function. SHINICHIRO SAKAI ET AL.YAKUGAKU ZASSHI,Vol.95 No.12. 1975 |
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HU0400955D0 (en) | 2004-07-28 |
CN101010313A (zh) | 2007-08-01 |
ZA200610347B (en) | 2008-05-28 |
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