CN1681782A - 2,7-取代的吲哚以及它们作为5-ht6调节剂的用途 - Google Patents
2,7-取代的吲哚以及它们作为5-ht6调节剂的用途 Download PDFInfo
- Publication number
- CN1681782A CN1681782A CNA03821590XA CN03821590A CN1681782A CN 1681782 A CN1681782 A CN 1681782A CN A03821590X A CNA03821590X A CN A03821590XA CN 03821590 A CN03821590 A CN 03821590A CN 1681782 A CN1681782 A CN 1681782A
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- Prior art keywords
- alkyl
- amino
- compound
- indoles
- carbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000011591 potassium Substances 0.000 description 1
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明提供式(I)化合物、其药学上可接受的盐或前药,在(I)中,R1、R2、R3、R4和n如文中定义。本发明还提供含有式I化合物的组合物、式(I)化合物的使用方法和制备方法。
Description
本发明涉及2,7-取代的吲哚、含有它们的组合物、它们作为治疗药物使用的方法,以及制备它们的方法。
作为大脑中主要的调节性神经递质,神经递质5-羟色胺(5-HT)的作用是通过大量称作5-HT1、5-HT2、5-HT3、5-HT4、5-HT5、5-HT6和5-HT7的受体家族介导的。基于大脑中高水平的5-HT6受体mRNA,表明5-HT6受体可能在中枢神经***紊乱的病理学和治疗中起作用。特别地,5-HT6选择性配体已经被认定为可能用于治疗某些CNS紊乱,如帕金森病、亨廷顿病、焦虑症、抑郁症、躁狂型抑郁症、精神病、癫痫、强迫症(obsessivecompulsive disorder)、偏头痛、阿尔茨海默氏病(增强认知记忆)、睡眠障碍、饮食障碍如厌食症和暴食症、惊恐发作、注意缺陷多动障碍(ADHD)、注意力缺陷障碍(ADD)、滥用药物如***、酒精、尼古丁和苯并二氮杂而引起的戒断症状、精神***症和与脊椎创伤和/或头部损伤如脑积水相关的紊乱。这些化合物还被期望用于治疗某些胃肠(GI)紊乱如功能性肠紊乱。参见例如B.L.Roth等,J.Pharmacol.Exp.Ther.,1994,268,1403-14120页、D.R.Sibley等,Mol.Pharmacol.,1993,43,320-327、A.J.Sleight等,Neurotransmission,1995,11,1-5和A.J.Sleight等,Serotonin ID ResearchAlert,1997,2(3),115-8。5-HT6拮抗剂也已经被认定为是治疗肥胖症的潜在有效化合物。参见例如Bentley等,Br.J.Pharmac.1999,Suppl 126;Bently等,J.Psychopharmacol.1997,Suppl A64:255;Wooley等,Neuropharmacology 2001,41:210-129;和WO 02/098878。
尽管已经公开了一些5-HT6调节剂,然而仍然需要有用于调节5-HT6的化合物。
本发明的一个目标为(i)式I化合物或其药学上可接受的盐:
其中:
n为0、1或2;
p为1或2;
R1为任选取代的芳基或任选取代的杂芳基;
R2为任选取代的杂环基;
R3为氢、烷基或-C(=O)-R5,其中R5为烷基、烷氧基、芳基或芳氧基;且
每个R4独立地为氢、羟基、氰基、烷基、烷氧基、硫代烷基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、烷基羰基、烷基磺酰基、芳基磺酰基、卤代烷基磺酰基、氨基、烷基氨基、二烷基氨基、烷基(芳基)氨基、烷基氨基羰基、烷基羰基氨基、烷基羰基(烷基氨基)、烷基氨基磺酰基、烷基磺酰基氨基或亚甲二氧基,优选为氢、烷基、烷氧基、卤素或卤代烷基。
本发明的另一目标为:
(ii)(i)中的化合物,
其中:
n为2;
R1为任选取代的芳基;
R2为任选取代的杂环基;
R3为氢,且
R4为氢。
(iii)(ii)中的化合物,其中R2为任选被烷基取代的哌嗪-1-基或哌啶-4-基。
(iv)(iii)中的化合物,其中R2为哌-1-基、4-甲基哌嗪-1-基、N-甲基哌啶-4-基或哌啶-4-基。
(v)(ii)中的化合物,其中R1为任选取代的苯基或任选取代的噻吩基。
(vi)(v)中的化合物,其中R1为任选被烷基、卤素或卤代烷基取代的噻吩-2-基或苯基。
(vii)(vi)中的化合物,其中R1为苯基、2,3-二氯苯基、2-氟苯基、2-三氟甲基苯基或3-溴苯基。
(viii)(ii)中的化合物,其为下列化合物:
2-苯磺酰基-7-哌嗪-1-基-1H-吲哚,
2-苯磺酰基-7-(4-甲基-哌嗪-1-基)-1H-吲哚,
2-(2,3-二氯-苯磺酰基)-7-哌嗪-1-基-1H-吲哚,
2-(2,3-二氯-苯磺酰基)-7-(4-甲基-哌嗪-1-基)-1H-吲哚,
2-(2-氟代-苯磺酰基)-7-哌嗪-1-基-1H-吲哚,
2-苯磺酰基-7-哌啶-4-基-1H-吲哚,
2-苯磺酰基-7-(1-甲基-哌啶-4-基)-1H-吲哚,
7-(4-甲基-哌嗪-1-基)-2-(2-三氟甲基-苯磺酰基)-1H-吲哚,
7-哌嗪-1-基-2-(2-三氟甲基-苯磺酰基)-1H-吲哚,
2-(3-溴-苯磺酰基)-7-(4-甲基-哌嗪-1-基)-1H-吲哚,
2-(3-溴-苯磺酰基)-7-哌嗪-1-基-1H-吲哚。
(ix)制备式I的2-取代吲哚的方法:
其中:
n为0、1或2;
p为1或2;
R1为任选取代的芳基或任选取代的杂芳基;
R2为任选取代的杂环基;
R3为氢、烷基或-C(=O)-R5,其中R5为烷基、烷氧基、芳基或芳氧基;且
每个R4独立地为氢、羟基、氰基、烷基、烷氧基、硫代烷基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、烷基羰基、烷基磺酰基、芳基磺酰基、卤代烷基磺酰基、氨基、烷基氨基、二烷基氨基、烷基(芳基)氨基、烷基氨基羰基、烷基羰基氨基、烷基羰基(烷基氨基)、烷基氨基磺酰基、烷基磺酰基氨基或亚甲二氧基,优选为氢、烷基、烷氧基、卤素或卤代烷基;
所述方法包括使式(II)的取代吲哚:
其中R2′为任选取代的杂环基,其可任选被保护基团保护;R3′为烷基或-C(=O)-R5;且每个R4′独立地为氢、羟基、氰基、烷基、烷氧基、硫代烷基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、烷基羰基、烷基磺酰基、芳基磺酰基、卤代烷基磺酰基、氨基、烷基氨基、二烷基氨基、烷基(芳基)氨基、烷基氨基羰基、烷基羰基氨基、烷基羰基(烷基氨基)、烷基氨基磺酰基、烷基磺酰基氨基或亚甲二氧基,优选为氢、烷基、烷氧基、卤素或卤代烷基,其可任选被保护基团保护,
(a)与碱接触,生成脱质子化的吲哚;以及
(b)使脱质子化的吲哚与下式的磺酰化剂反应:Y-SO2-R1,其中Y为卤离子,或者与式R1-S-S-R1的二硫化物反应,生成式III的2-取代吲哚:
其中取代基的定义如上文所述,
(c)任选用氧化剂氧化硫;以及
(d)任选除去保护基团,生成式I的2-取代吲哚。
(x)(ix)中的方法,其中Y为氟。
(xi)包含下列的组合物:
(a)治疗有效量的(i)-(viii)的式I化合物;以及
(b)药学上可接受的载体。
(xii)一种或多种(i)-(viii)的化合物在生产用于治疗或预防可被5HT6激动剂缓解的疾病的药物中的用途。
(xiii)(xii)中的用途,其中所述疾病包含CNS紊乱。
(xiv)(xiii)中的用途,其中所述疾病包含精神病、精神***症、躁狂型抑郁症、神经紊乱、记忆紊乱、注意力缺陷障碍、帕金森病、肌萎缩性脊髓侧索硬化、阿尔茨海默氏病和亨廷顿病。
(xv)(xii)中的用途,其中所述疾病包含胃肠道紊乱。
(xvi)(xii)中的用途,其中所述疾病包含肥胖症。
除非特别指明,本申请、包括说明书和权利要求书中所使用的下列术语具有下列定义。应当特别指出的是,除非文中明确指出,在说明书和权利要求书中使用的单数形式也包括指代物的复数形式。
“激动剂”意指增强另一化合物或受***点的活性的化合物。
“烷基”意指单价直链或支链饱和烃部分,其仅包含碳原子和氢原子,具有1-12个、优选1-4个碳原子。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、异丁基、仲-丁基、叔-丁基、戊基、正己基、辛基和十二烷基等。
“烷氧基”意指式-ORa部分,其中Ra为如此处定义的烷基。
“拮抗剂”意指降低或阻止另一化合物或受***点的作用的化合物。
“芳基”意指含有单-或双环芳环的单价环芳烃部分。除非特别指明,芳基任选被1、2或3个、优选被1或2个取代基取代,其中每个取代基独立地为羟基、氰基、烷基、烷氧基、硫代烷基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、烷基羰基、烷基磺酰基、芳基磺酰基、卤代烷基磺酰基、氨基、烷基氨基、二烷基氨基、烷基(芳基)氨基、烷基氨基羰基、烷基羰基氨基、烷基羰基(烷基氨基)、烷基氨基磺酰基、烷基磺酰基氨基或亚甲二氧基。优选的取代基为烷基、烷氧基、卤素或卤代烷基。芳基部分的实例包括但不限于任选取代的苯基和任选取代的萘基等。
“芳氧基”意指式-ORb部分,其中Rb为如此处定义的芳基。
“环烷基”意指含有单-或双环的单价饱和碳环部分。除非特别指明,环烷基可任选被一个或多个取代基取代,其中每个取代基独立地为羟基、烷基、烷氧基、卤素、卤代烷基、氨基、单烷基氨基或二烷基氨基。环烷基部分的实例包括但不限于环丙基、环丁基、环戊基、环己基和环庚基等。
“疾病”意指任何疾病、病症、症状或征候。
术语“卤代”、“卤化物”和“卤素”在此处可互换使用,其意指取代基氟、氯、溴或碘,优选指氟或溴。
“卤代烷基”意指如此处定义的烷基,其中一个或多个氢被相同或不同的卤素取代。示范性的卤代烷基包括-CH2Cl、-CH2CF3、-CH2CCl3和全氟烷基(例如-CF3)等。
“杂芳基”意指具有5-12个环原子的单价单-、双-或三-环芳族部分,并且所述环原子包含1、2、3或4个选自N、O或S的环杂原子,其余的环原子为C。除非特别指明,杂芳环可任选独立地被一个或多个取代基取代,优选被一个或两个取代基取代,所述取代基选自羟基、氰基、烷基、烷氧基、硫代烷基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、烷基羰基、烷基磺酰基、芳基磺酰基、卤代烷基磺酰基、氨基、烷基氨基、二烷基氨基、烷基(芳基)氨基、烷基氨基羰基、烷基羰基氨基、烷基羰基(烷基氨基)、烷基氨基磺酰基、烷基磺酰基氨基和亚甲二氧基。优选的取代基为烷基、烷氧基、卤代烷基或卤素。更特别地,术语杂芳基包括但不限于吡啶基、呋喃基、噻吩基、噻唑基、异噻唑基、***基、咪唑基、异噁唑基、吡咯基、吡唑基、嘧啶基、苯并呋喃基、异苯并呋喃基、苯并噻唑基、苯并异噻唑基、苯并***基、吲哚基、异吲哚基、苯并噁唑基、喹啉基、异喹啉基、苯并咪唑基、苯并异噁唑基、苯并噻吩基、二苯并呋喃和苯并二氮杂-2-酮-5-基等。
“杂环基”意指含有1-3个环的单价饱和部分,所述的环含有一、二或三个杂原子(选自氮、氧或硫)。除非特别指明,杂环可任选独立地被一个或多个取代基、优选被一个或两个取代基取代,所述的取代基选自羟基、氰基、烷基、烷氧基、硫代烷基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、烷基羰基、烷基磺酰基、芳基磺酰基、卤代烷基磺酰基、氨基、烷基氨基、二烷基氨基、烷基(芳基)氨基、烷基氨基羰基、烷基羰基氨基、烷基羰基(烷基氨基)、烷基氨基磺酰基、烷基磺酰基氨基和亚甲二氧基。优选的取代基为烷基、烷氧基、卤代烷基或卤素。更特别地,术语杂环基包括但不限于吗啉基、哌嗪基、哌啶基、吡咯烷基、四氢吡喃基和氮杂环丁基(azitidinyl)等。
“离去基团”意指具有合成有机化学中通常与之相关的含义的基团,即在取代反应条件下可被替换的原子或基团。可以理解的是,特定的离去基团取决于反应条件,包括离去基团所连接的原子。例如,磺酰基化合物的离去基团包括但不限于卤素和磺酸根等。
“调节剂”意指与靶点相互作用的分子。相互作用包括但不限于如此处定义的激动剂和拮抗剂等。
“任选的”或“任选地”意指随后描述的情况或状况可以但不是必须发生的,并意指描述包括其中所述情况或状况发生的情形以及未发生的情形。
“惰性有机溶剂”或“惰性溶剂”意指在与其相关的反应条件下为惰性的溶剂,其包括例如苯、甲苯、乙腈、四氢呋喃、N,N-二甲基甲酰胺、氯仿、二氯甲烷、二氯乙烷、***、乙酸乙酯、丙酮、甲基乙基酮、甲醇、乙醇、丙醇、异丙醇、叔-丁醇、二噁烷和吡啶等。除非特别指明,本发明的反应中所使用的溶剂为惰性溶剂。
“药学上可接受的”意指可用于制备通常为安全、无毒且即非生物学也非其它方面所不需要的药用组合物中可接受的,并且包括兽医学可接受的和人类制药用途可接受的。
化合物的“药学上可接受的盐”意指如此处定义的药学上可接受的盐,其具有母体化合物的所需的药物活性。这类盐包括:与无机酸形成的酸加成盐,所述的无机酸例如是盐酸、氢溴酸、硫酸、硝酸或磷酸等;或者与有机酸形成的酸加成盐,所述的有机酸例如是乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、羟萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、己二烯二酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、酒石酸、对甲苯磺酸、三氟乙酸或三甲基乙酸等;或者母体化合物中的酸性质子被金属离子如碱金属离子、碱土离子或铝离子替代或与有机或无机碱配位所形成的盐。可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺和氨丁三醇等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠。
优选的药学上可接受的盐为由乙酸、盐酸、硫酸、甲磺酸、马来酸、磷酸、酒石酸、柠檬酸、钠、钾、钙、锌和镁形成的盐。
应当理解的是,所有提及的药学上可接受的盐包括同一酸加成盐的如此处所定义的溶剂加成形式(溶剂化物)或晶形(多晶型物)。
“前药”意指化合物的药理学惰性的形式,该化合物必须在施用后被个体例如通过体液或酶在体内代谢为化合物的药理学活性形式,以产生所需的药理学作用。前药可以在吸收前、吸收中、吸收后或在特定位点代谢。尽管对多数化合物而言,代谢主要在肝脏中进行,然而几乎所有的其它组织和器官、特别是肺均可以进行不同程度的代谢。化合物的前药形式可用于例如提高生物利用度、提高个体的可接受性(例如通过掩蔽或减少令人不快的性质如苦味或胃肠刺激)、改变溶解性(例如对于静脉内使用)、提供延长或延缓的释放或传送、改善制剂的便利性或者提供化合物的位点-特异性传送。此处所述的化合物包括化合物的前药形式。
“保护基团”意指可选择性阻断多官能化合物的一个反应活性位点、以便使化学反应在另一未受保护的反应活性位点选择性进行的基团,具有在合成化合物中通常与之相关的含义。本发明的某些方法依赖保护基团来阻断反应物中存在的反应活性的氮和/或氧原子发生反应。例如,术语“氨基保护基团”和“氮保护基团”在此处可互换使用,其意指那些用于在合成过程中保护氮原子不进行不希望的副反应的有机基团。示范性的氮保护基团包括但不限于三氟乙酰基、乙酰氨基、苄基(Bn)、苄氧羰基(苄酯基,CBZ)、对甲氧基苄氧羰基、对硝基苄氧羰基和叔-丁氧羰基(BOC)等。类似地,术语“羟基保护基团”意指那些用于在合成过程中保护羟基的氧原子不进行不希望的副反应的有机基团。示范性的羟基保护基团包括但不限于苄基、甲硅烷基、四氢吡喃基和酯等。本领域技术人员知道如何选择便于除去且能经受随后的反应的基团。
“溶剂化物”意指含有化学计量或非化学计量的溶剂的溶剂加成形式。某些化合物在晶状固态时易于捕获固定摩尔比的溶剂分子,从而形成溶剂化物。如果溶剂为水,则所形成的溶剂化物为水合物,当溶剂为醇时,则所形成的溶剂化物为醇化物。水合物通过将一个或多个水分子与一个物质分子结合而形成,其中水保持其分子状态为H2O,这种结合可以形成一水合物或多水合物。
“个体”意指哺乳动物和非-哺乳动物。哺乳动物意指哺乳类的任何成员,其包括但不限于人;非人灵长类如猩猩和其它猿类和猴类;饲养动物,如牛、马、绵羊、山羊和猪;家畜,如兔子、狗和猫;实验动物,包括啮齿类如大鼠、小鼠和豚鼠等。非哺乳动物的实例包括但不限于鸟类等。术语“个体”不指特定的年龄或性别。
“治疗有效量”意指当施用于个体来治疗疾病时,足以有效治疗这种疾病的化合物的量。“治疗有效量”根据化合物、所治疗的疾病、严重程度或所治疗的疾病、个体的年龄和相关的健康状况、给药的途径和形式、所主治医师或兽医的判断以及其它因素而有所不同。
当术语“上文所定义的那些”和“此处所定义的那些”涉及变量时,其具有变量最宽范围的定义以及优选、更优选和最优选的定义(如果有的话)。
“治疗”疾病包括:
(i)预防疾病,即,使所述疾病的临床症状在遭受或易感染疾病但还未经历或呈现疾病的症状的个体中不会发展。
(ii)抑制疾病,即阻止疾病或其临床症状的发展,或者
(iii)缓解疾病,即引起疾病或其临床症状暂时或永久性消除。
当术语“处理”、“接触”和“反应”指化学反应时,其指在适当条件下将两种或多种试剂加入或混合以生成所指和/或所需产物。应当理解的是,生成所指和/或所需产物的反应并不一定由最初加入的两种试剂的组合直接产生,即,在混合物中可以产生一种或多种中间体,该中间体最终形成所指和/或所需产物。
通常,本申请中所用的术语基于AUTONOMTM,4.0版,其为用于产生IUPAC***命名法的Beilstein Institute计算机***。
在一方面,本发明提供了式I化合物、其药学上可接受的盐或前药:
p=1、2
其中n为0、1或2;优选n为2;
p为1或2,优选p为1;
R1为芳基或杂芳基;
R2为杂环基;
R3为氢、烷基或-C(=O)-R5,其中R5为烷基、烷氧基、芳基或芳氧基;且
每个R4独立地为氢、羟基、氰基、烷基、烷氧基、硫代烷基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧羰基、烷基羰基、烷基磺酰基、芳基磺酰基、卤代烷基磺酰基、氨基、烷基氨基、二烷基氨基、烷基(芳基)氨基、烷基氨基羰基、烷基羰基氨基、烷基羰基(烷基氨基)、烷基氨基磺酰基、烷基磺酰基氨基或亚甲二氧基;R4优选为氢、烷基、烷氧基、卤素或卤代烷基。
可以理解的是,本发明的范围不仅包含各种可能存在的异构体,而且还包含各种可能形成的异构体的混合物。另外,本发明的范围还包含式I化合物的溶剂化物和盐。
优选地,R1为噻吩基或苯基,其可以任选被一个或多个选自下列基团的取代基取代:烷基、烷氧基、卤素、卤代烷基、-SO2-Ra、-NRaRb、-NRb-C(=O)-Ra,其中Ra为烷基或芳基,且Rb为氢或烷基。更优选地,R1为噻吩-2-基、苯基、2,3-二氯苯基、2-氟苯基、2-甲基苯基、2-三氟甲基苯基或3-溴苯基。
优选地,R2为任选取代的哌嗪基或哌啶基。更优选地,R2为任选取代的哌嗪-1-基或哌啶-4-基。还更优选地,R2为哌嗪-1-基、4-甲基哌嗪-1-基、3,5-二甲基哌嗪-1-基、N-甲基哌啶-4-基或哌啶-4-基。在一个具体实施方案中,R2为4-甲基哌嗪-1-基。
优选R3为氢或甲基。
优选R4为氢。
进一步,此处所述的优选基团的组合可以形成其它优选的实施方案。例如,在一个特别优选的实施方案中,R1为苯基,n为2,R2为哌嗪-1-基,R3为氢或甲基且R4为氢。由此,可以形成多种本发明优选的化合物。
部分代表性的式I化合物如下表1所示:
表1.代表性的式I化合物:
本发明的另一方面提供了包含治疗有效量的式I化合物和药学上可接受的载体的组合物。
本发明的另一方面还提供了治疗个体CNS疾病的方法,该方法包括给予个体治疗有效量的式I化合物。所述疾病优选包含精神病、精神***症、躁狂型抑郁症、神经紊乱、记忆紊乱、注意力缺陷障碍、帕金森病、肌萎缩性脊髓侧索硬化、阿尔茨海默氏病和亨廷顿病。
本发明的另一方面还提供了治疗个体胃肠道紊乱的方法,该方法包括给予个体治疗有效量的式I化合物。
另外,本发明的另一方面提供了治疗个体肥胖症的方法,该方法包括给予个体治疗有效量的式I化合物。
本发明的另一方面提供了制备式I化合物的方法。
本发明化合物可通过在下述给出和描述的说明性合成反应流程中的多种方法制备。
制备这些化合物的原料和反应物通常可以自商业渠道获得,如AldrichChemical Co.,或者也可以通过本领域技术人员已知的方法、根据参考文献中所述的方法制备,例如Fieser and Fieser’s Reagents for OrganicSynthesis;Wiley & Sons:纽约,1991,第1-15卷;Rodd′s Chemistry of CarbonCompounds,Elsevier Science Publishers,1989,第1-5卷和增刊;以及Organic Reactions,Wiley & Sons:纽约,1991,第1-40卷。下列合成反应流程仅仅是对通过其可合成本发明的化合物的某些方法进行说明,可以对这些合成反应流程进行各种修改,并且这些修改对已经参考了本申请的公开内容的本领域技术人员来说是显而易见的。
如果需要,可以采用常规技术将合成反应流程的原料和中间体分离并纯化,所述常规技术包括但不限于过滤、蒸馏、结晶和层析等。这类原料可以以常规方式、包括物理常数和光谱数据来鉴定。
除非特别指明,此处所述的反应优选在惰性气氛中、在大气压下、于约-78℃至约150℃的反应温度进行,更优选在约0℃至约125℃进行,最优选和便利地在室温、例如约20℃进行。
在一个实施方案中,式I化合物可以通过用碱将式II的取代吲哚:
脱质子化并加入如下定义的式Y-SO2-R1的磺酰化剂来制备,其中R1、R2和R4如此处定义,R3’为烷基或-C(=O)-R5,其中R5如此处定义,且Y为离去基团,优选为卤离子,更优选为氟离子。应当理解的是,当R2和/或R4具有一个或多个酸性质子(相对于所用的碱)时,应当将其用适宜的保护基团保护。适于该酸性质子的保护基团是本领域技术人员所熟知的,并且取决于酸性质子的性质,例如它是氨基质子还是羟基质子等。
碱的强度应当足以主要使吲哚环系的2-位脱质子。这类碱是本领域技术人员已知的,其包括有机金属化合物(例如有机锂如叔-丁基锂)和格氏试剂(如叔-丁基镁卤化物)。通常,脱质子反应可以于温度约0℃或以下、优选约-40℃或以下、更优选约-70℃或以下进行。典型地,脱质子反应于约-75℃进行。
适宜的磺酰化剂包括芳基磺酰基卤化物,例如芳基磺酰氟。芳基磺酰氟易于通过用氟化物如氟化钾或其它适宜的金属氟化化合物处理相应的芳基磺酰氯来制备。典型地,芳基磺酰氯向其相应的氟化衍生物的转化通常包括使芳基磺酰氯与氟化钾在惰性有机溶剂如1,4-二噁烷中反应。反应通常于回流条件下进行约1至48小时,典型地为约24小时。通常,在反应中使用的过量氟化钾可在后处理中通过用水洗涤来容易地除去。得到的芳基磺酰氟可以不经任何其它纯化而使用。
或者,式I化合物还可以通过使脱质子化的吲哚基团与式R1-S-S-R1的二硫化物反应物反应生成式III的硫醚来制备:
其中p、R1、R2、R3’和R4如此处定义。典型地,在与加入碱时相同的温度下,将二硫化物反应物加至脱质子化的吲哚中。然后将反应混合物于该温度下搅拌数分钟至数小时,典型地为约1-2小时,并且使其逐渐温热至室温。
式III的硫醚化合物可以采用氧化剂氧化生成相应的亚砜和/或砜。适宜的氧化剂包括间-氯过苯酸(MCPBA)、高碘酸盐、Oxone*以及本领域技术人员已知的其它硫氧化剂。例如,硫醚III可与MCPBA通过于约0℃、在惰性溶剂如二氯甲烷中将两种反应物混合并于室温下将混合物搅拌数小时而反应。过量的MCPBA通过用水溶液、优选用碱性水溶液洗涤除去。氮原子任何不希望的氧化可以通过将粗品产物用膦化合物(如三苯膦)骤冷来还原。
当R1或R2基团含有保护基团时,或者当R3为保护基团时,这样的保护基团可在合成后采用本领域技术人员已知的常规反应条件除去。参见,例如,Protective Groups in Organic Synthesis,第3版,T.W.Greene和P.G.M.Wuts,John Wiley & Sons,纽约,1999,其全文在此处引入作为参考。
用于生成式I化合物的更详尽的细节在实施例部分有描述。
本发明的化合物对5-HT6受体具有选择性亲和性,因此可以用于治疗某些CNS紊乱,例如帕金森病、亨廷顿病、焦虑症、抑郁症、躁狂型抑郁症、精神病、癫痫、强迫症、偏头痛、阿尔茨海默氏病(增强认知记忆)、睡眠障碍、饮食障碍如厌食症和暴食症、惊恐发作、注意缺陷多动障碍(ADHD)、注意力缺陷障碍(ADD)、滥用药物如***、酒精、尼古丁和苯并二氮杂而引起的戒断症状、精神***症以及与脊椎创伤和/或头部损伤如脑积水相关的紊乱。另外,本发明的化合物还可用于治疗某些GI(胃肠)紊乱如功能性肠紊乱。
通过本领域公认的方法测定本发明的化合物的药理学性质。在放射性配体结合和功能分析中测定测试化合物对5-HT6受体的亲和力的体外技术在实施例6-8中有描述。
本发明包括含有下述成分的药用组合物:至少一种本发明的化合物或其单一异构体、异构体的外消旋或非外消旋混合物、药学上可接受的盐或溶剂化物,至少一种药学上可接受的载体,其还可任选地含有其它治疗和/或预防成分。
通常,可通过任何给予起相同效用的给药模式给予治疗有效量的本发明的化合物。适宜的剂量范围通常为1-500mg/日、优选为1-100mg/日,最优选为1-30mg/日,剂量依赖于许多因素如所治疗疾病的严重程度、个体的年龄和健康状况、所用化合物的效力、给药的途径和形式、给药所针对的适应症以及有关医师的偏好和经验。治疗该疾病的本领域普通技术人员不需要过多的试验即可根据个人知识和本申请的公开内容来确定本发明的化合物对于给定疾病的治疗有效量。
通常,本发明的化合物以药物制剂的形式给药,所述制剂包括适合经口腔(包括口腔含化和舌下)、直肠、经鼻、局部、经肺、***或胃肠道外(包括肌肉、动脉内、鞘内、皮下和静脉内)给药的制剂或者是适于吸入或吹入给药的形式。优选的给药方式通常是采用常规每日剂量方案的口服,其可根据困扰程度而调整。
本发明的一种化合物或多种化合物以及一种或多种常规辅料、载体或稀释剂可以是药用组合物和单位剂量的形式。药用组合物和单位剂型可包括常规比例的常规成分,可有或无其它活性化合物或成分,并且单位剂型可包含任何与所采用的预期日剂量范围相符的适宜有效量的活性成分。所采用的药用组合物可以是口服固态剂型如片剂或填充胶囊、半固态、散剂、缓释制剂,或者液态剂型如溶液、混悬剂、乳剂、酏剂或填充胶囊;或者是直肠或***给药的栓剂形式;或者是用于胃肠道外的无菌注射溶液的形式。因此,每片含有约1毫克或更宽范围的约0.01至约100毫克活性成分的制剂是适宜的代表性的单位剂型。
本发明的化合物可以配制成多种口服给药剂型。药用组合物和剂型可包括本发明的一种或多种化合物或其药学上可接受的盐作为活性成分。药学上可接受的载体可以是固态或液态。固态形式的制剂包括散剂、片剂、丸剂、胶囊、扁囊剂、栓剂和可分散的颗粒剂。固态载体可以是一种或多种物质,该物质还可以作为稀释剂、矫味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或微囊化材料。为散剂时,载体通常为细分固体,该细分固体是与细分活性成分的混合物。为片剂时,活性成分通常以适宜比例与具有必要粘合能力的载体相混合,并压制成所期望的形状和大小。散剂和片剂优选包含约1%至约70%的活性化合物。适宜载体包括但不限于碳酸镁、硬脂酸镁、滑石粉、糖、乳糖、果胶、糊精、淀粉、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡和可可脂等。术语“制剂”意指包括以微囊化材料作为载体的活性化合物的制剂,如果为胶囊时,其中活性成分(有或无载体)被相关载体包围。类似地,还包括扁囊剂和锭剂。片剂、散剂、胶囊、丸剂、扁囊剂和锭剂可以作为适于口服给药的固态形式。
适于口服给药的其他形式包括液态形式的制剂,其包括乳剂、糖浆、酏剂、含水溶液、含水混悬液或在临用前转化为液态形式制剂的固态形式制剂。乳剂可以在溶液例如丙二醇水溶液中制备,或可以包含乳化剂如卵磷脂、脱水山梨糖醇单油酸酯或***胶。经将活性成分溶于水中并加入适宜着色剂、矫味剂、稳定剂和增稠剂,可以制备含水溶液。经将细分活性成分与粘性物质如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠和其他众所周知的悬浮剂分散于水中,可以制备含水混悬液。固态形式的制剂包括溶液、混悬液和乳剂,并且除活性成分之外还可包含着色剂、矫味剂、稳定剂、缓冲剂、人工和天然甜味剂、分散剂、增稠剂和增溶剂等。
本发明的化合物可制备成用于胃肠道外给药(例如经注射,例如单次快速静脉注射或连续输注)的形式,且可以以单位剂型存在于安瓿、预装注射器、小体积输液或存在于还含防腐剂的多剂量容器中。组合物可为下列形式:在油性或水性溶媒中的混悬液、溶液或乳剂,例如在聚乙二醇水溶液中的溶液。油性或非水性的载体、稀释剂、溶剂或溶媒的实例包括丙二醇、聚乙二醇、植物油(例如橄榄油)以及可注射的有机酯(例如油酸乙酯),并且可含有配方试剂如防腐剂、润湿剂、乳化剂或悬浮剂、稳定剂和/或分散剂。或者,活性成分也可以是在临用前用适宜溶媒如无菌、无热原的水配制的粉末形式,该粉末形式通过无菌分装无菌的固体或者由溶液冷冻干燥而获得。
本发明的化合物也可制备成对表皮局部给药的形式,例如软膏、霜剂、洗剂或透皮贴剂。软膏和霜剂可以例如用水性或油性基质并加入适宜的增稠剂和/或胶凝剂来制备。洗剂可以用水性或油性基质来制备,并且通常还含有一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。适于在口腔中局部给药的制剂包括含有活性药物和矫味基质的糖锭剂,所述基质通常为蔗糖和***胶或西黄蓍胶;包含活性成分和惰性基质的软锭剂,所述基质例如是明胶、甘油或蔗糖以及***胶;和含有活性成分和适宜液态载体的嗽口剂。
本发明的化合物还可制备成以栓剂形式给药的形式。首先将低熔点蜡如脂肪酸甘油酯或可可脂的混合物熔化并将活性成分例如通过搅拌均匀分散于其中。然后将熔化的均匀混合物倾至适宜大小的模具中,冷却并固化。
本发明的化合物也制备成用于***给药的形式。除活性成分以外还含有本领域已知的载体的***栓剂、棉塞、霜剂、凝胶剂、糊剂、泡沫剂或喷雾剂是适宜的。
本发明的化合物可制备成经鼻给药的形式。通过常规方法如采用滴管、吸管或喷雾器将溶液或悬浮液直接用于鼻腔。制剂可以为单或多剂量的形式。当为滴管或吸管的多剂量形式时,可以对患者施用适宜的预定体积的溶液或悬浮液来进行给药。当采用喷雾器时,可例如通过计量雾化喷雾器泵来给药。
本发明的化合物可制备成气雾剂给药、特别是对呼吸道并包括鼻内给药的形式。化合物通常具有较小的粒径,例如5微米或更小。该粒径可以通过本领域已知的方法、例如微粉化获得。活性成分可以以含有适宜抛射剂的加压包装提供,所述的抛射剂例如是氯氟化碳(CFC)如二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷、二氧化碳或其它适宜的气体。气雾剂也可以便利地含有表面活性剂如卵磷脂。药物剂量可以通过计量阀控制。或者,活性成分可以以干粉末的形式提供,例如化合物与适宜的粉末基质如乳糖、淀粉、淀粉衍生物如羟丙基甲基纤维素和聚乙烯吡咯烷酮(PVP)的粉末混合物。粉末载体可在鼻腔中形成凝胶。粉末组合物可以以单位剂型提供,例如明胶或发泡包装的胶囊或药筒,粉末可从其中通过吸入给药。
如果需要,制剂可制备为含有适于将活性成分缓释或控释给药的肠溶包衣的形式。例如,本发明的化合物可以配制于成经皮或皮下药物传送装置中。当有必要缓释化合物和当患者对治疗方案的顺应性非常关键时,这些传送***是有利的。透皮传送***中的化合物通常连接于皮肤粘着固态支撑物上。目标化合物中也可加入渗透促进剂如氮酮(1-十二基氮杂环庚-2-酮)。缓释传送***可以通过手术或注射皮下植入于皮下层。皮下植入剂将化合物包封在脂溶性膜如硅橡胶或者生物可降解聚合物如聚乳酸中。
药物制剂优选是单位剂量的形式。在此类形式中,制剂被细分为含有适宜量活性成分的单位剂量。单位剂型可以为包装制剂,每个包装含有不同量的制剂,如包装片剂、胶囊以及在小瓶或安瓿中的粉末。单位剂型还可以为胶囊、片剂、扁囊剂或糖锭剂本身,或者其也可以是包装形式的适宜数量的任何这些剂型。
其它适宜的药物载体和它们的制剂在Remington:The Science andPractice of Pharmacy 1995.E.W.Martin编辑,Mack Publishing Company,第19版,伊斯顿,Pennsylvania中有描述。含有本发明的化合物的代表性药物制剂在实施例6-12中描述。
实施例
给出下列制备方法和实施例以便本领域的技术人员更清楚地理解且实施本发明。它们不应被认为限定了本发明的范围,而仅用作说明和示例。
实施例1
本实施例说明采用下述概括的合成流程来生成式I化合物的方法:
2-苯磺酰基-7-哌嗪-1-基-1H-吲哚的制备
步骤1
于室温下,向吲哚1-1(1.22g,4.0mmol)的THF(40mL)溶液中加入二碳酸二叔丁酯(1.3g,6.1mmol),然后加入DMAP(56mg,0.46mmol)。于室温和氮气氛下,将反应混合物搅拌3小时,然后真空浓缩。残留物在乙酸乙酯(50mL)和饱和碳酸氢钠水溶液(50mL)之间分配。有机层用饱和碳酸氢钠水溶液(2×25mL)洗涤,然后用盐水(25mL)洗涤。干燥(MgSO4)有机层,过滤并浓缩,得到澄清油状物。该油状物经硅胶层析,洗脱剂为己烷/乙酸乙酯(23∶1),得到1.5g(93%)叔丁氧羰基-哌嗪叔丁氧羰基-吲哚1-2,为白色固体。(M+H)+=402.2。
步骤2
于惰性气氛下,向-75℃的双-叔丁氧羰基-吲哚1-2(500mg,1.25mmol)的THF(25mL)溶液中缓慢加入t-BuLi(1.47mL,2.5mmol)。将反应混合物搅拌30分钟,同时加入二苯二硫(340mg,1.63mmol)。将反应物搅拌1.5小时,然后使其温热至室温(45分钟)。用饱和氯化铵溶液(55mL)淬灭反应混合物,并用乙酸乙酯(3×20mL)萃取。用盐水(25mL)洗涤合并的乙酸乙酯层,干燥(MgSO4),过滤并浓缩得到黄色油状物。该油状物经硅胶层析,洗脱剂为己烷/乙酸乙酯(23∶1),得到440mg(69%)2-苯基硫醚-7-哌嗪-1-基吲哚1-3。
步骤3和4
于0℃下,向化合物1-3(440mg,0.86mmol)的二氯甲烷(40mL)溶液中加入MCPBA(745mg,3.02mmol)。将反应物温热至室温并搅拌5小时,同时加入三苯膦(271mg,1.03mmol)。于室温下,将反应混合物搅拌过夜。反应混合物在水(50mL)和二氯甲烷(50mL)之间分配。有机层用1M氢氧化钠(3×35mL)和盐水(35mL)洗涤。干燥(MgSO4)有机层,过滤并浓缩。残余油状物经硅胶层析,洗脱剂为己烷/乙酸乙酯(17∶3),得到160mg(34%)产物1-4。M+H=542。
步骤5
将化合物1-4(160mg,0.3mmol)在异丙醇(15mL)和浓HCl(4mL)中的溶液回流1小时。浓缩反应混合物并将残余粉末用异丙醇(10mL)和***(20mL)研磨。过滤得到表1中的化合物1,为白色固体(90mg,89%)。M+H=342。
类似地,用与上述相同的方法合成上述表1中的化合物3和5:2-(2,3-二氯-苯磺酰基)-7-哌嗪-1-基-1H-吲哚和2-(2-氟-苯磺酰基)-7-哌嗪-1-基-1H-吲哚。
实施例2
本实施例说明表1中化合物2的制备方法。
2-苯磺酰基-7-(4-甲基-哌嗪-1-基)-1H-吲哚
向表1中的化合物1(参见上述实施例1)(340mg,1.04mmol)的THF(50mL)溶液中加入甲醛(37%,0.4mL,5.2mmol),然后加入三乙酰氧基硼氢化钠(330mg,1.56mmol)。于室温下,将反应混合物搅拌24小时。将混合物在乙酸乙酯(50mL)和水(50mL)之间分配。用盐水洗涤乙酸酯层,干燥(MgSO4)并浓缩,得到白色固体。将该固体溶于***(30mL)中并用过量的在***中的1M HCl处理。收集白色沉淀并干燥得到纯产物(表1中的化合物2)。
类似地,用与上述相同的方法合成上述表1中的化合物4:2-(2,3-二氯-苯磺酰基)-7-(4-甲基-哌嗪-1-基)-1H-吲哚。
实施例3
本实施例说明制备表1中的化合物6,即2-苯磺酰基-7-哌啶-4-基-1H-吲哚的方法。
步骤1
于氩气下,将7-溴代吲哚(1.25g,6.4mmol)的THF(15mL)溶液冷却至-70℃,并在20分钟内加入n-BuLi(9.6mL,19.2mmol)。在冰浴中将反应混合物温热至-5℃并在此温度下搅拌30分钟。混合物冷却至-70℃并在15分钟内加入N-丁氧羰基-哌啶酮(2.5g,12.8mmol)的THF(10mL)溶液。于-70℃将反应物搅拌45分钟,然后温热至室温。将反应用水(10mL)淬灭并在水(25mL)和乙酸乙酯(50mL)之间分配。有机层用水(15mL)和盐水(30mL)洗涤,然后干燥(MgSO4),过滤并浓缩。将残余的褐色油状物层析,洗脱剂为丙酮∶己烷(1∶4),得到1.17g(收率58%)4-羟基-4-(1-H-吲哚-7-基)-哌啶-1-甲酸叔丁酯XVI。
步骤2
于室温和氮气氛下,将4-羟基-4-(1-H-吲哚-7-基)-哌啶-1-甲酸叔丁酯XVI(1.17g,3.7mmol)与吡啶(20mL)和磷酰氯(0.7mL,7.4mmol)混合,并搅拌过夜。反应物在乙酸乙酯(55mL)和水(55mL)之间分配。用水(2×30mL)和盐水(55mL)洗涤乙酸乙酯层,然后干燥(MgSO4),过滤并浓缩,得到(700mg,64%)4-(1H-吲哚-7-基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯XVII。
步骤3
于H2氛和50磅/平方英寸下,将4-(1H-吲哚-7-基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯XVII(700mg,2.3mmol)和10%Pd/C(70mg)在乙醇(75mL)中的混合物置于parr振荡器上并振荡过夜。反应混合物经玻璃滤纸封端的(capped)硅藻土柱过滤。浓缩滤液,得到(680mg,95%)4-(1H-吲哚-7-基)-哌啶-1-甲酸叔丁酯XVIII。
步骤4
于室温下,向4-(1H-吲哚-7-基)-哌啶-1-甲酸叔丁酯XVIII(360mg,1.2mmol)的THF(30mL)溶液中加入二碳酸二叔丁酯(262mg,1.2mmol),然后加入催化量的DMAP(5.6mg,0.046mmol)。于室温和氮气氛下将反应混合物搅拌24小时,同时从反应混合物除去溶剂。残留物在乙酸乙酯(50mL)和饱和碳酸氢钠(50mL)之间分配。用饱和碳酸氢钠(2×25mL)和盐水(25mL)洗涤有机层。将有机层干燥(MgSO4),过滤并浓缩,得到澄清油状物。将油状物层析,洗脱剂为己烷/乙酸乙酯(23∶1),得到400mg(83%)7-(1-叔-丁氧羰基-哌啶-4-基)-吲哚-1-甲酸叔丁酯XIX。
步骤5
向-75℃的7-(1-叔-丁氧羰基-哌啶-4-基)-吲哚-1-甲酸叔丁酯XIX(440mg,1.0mmol)的THF(20mL)溶液中缓慢加入t-BuLi(1.2mL,2.0mmol)。将反应混合物于-75℃搅拌45分钟,加入苯磺酰氟(0.2mL,1.6mmol,参见以下实施例4)。将反应物搅拌2.5小时,同时移除冷浴并将反应物温热至室温。用饱和氯化铵溶液(25mL)淬灭反应,并用乙酸乙酯(3×20mL)萃取。合并的乙酸乙酯层用盐水(25mL)洗涤,干燥(MgSO4),过滤并除去溶剂,得到黄色油状物。该油状物经硅胶层析,洗脱剂为己烷/乙酸乙酯(4∶1),得到(330mg,60%)产物2-苯磺酰基-7(1-叔-丁氧羰基-哌啶-4-基)-吲哚-1-甲酸叔丁酯XX。
步骤6
将2-苯磺酰基-7-(1-叔-丁氧羰基-哌啶-4-基)-吲哚-1-甲酸叔丁酯XX(330mg,0.61mmol)溶于1M乙醇HCl(30mL)中并温热至回流。2.5小时后,将反应混合物冷却至室温并加入***(30mL)。收集白色沉淀,得到210mg(91%)的产物2-苯磺酰基-7-哌啶-4-基-1H-吲哚XXI。
类似地,用与上述相同的方法合成上述表1中的化合物9和11:7-哌嗪-1-基-2-(2-三氟甲基-苯磺酰基)-1H-吲哚和2-(3-溴-苯磺酰基)-7-哌嗪-1-基-1H-吲哚。
实施例4
本实施例说明制备苯磺酰氟的方法。
将氟化钾(99%)(12g,216mmol)加至苯磺酰氯(51mmol)的1,4二噁烷(35mL)溶液中。将反应混合物回流24小时。然后冷却至室温并倾至冰水(200mL)中。该冰水用氯仿(3×50mL)萃取。将合并的氯仿层干燥(MgSO4),过滤并浓缩,得到苯磺酰氟(4)。
实施例5
本实施例说明了制备表1中的化合物7,即2-苯磺酰基-7-(1-甲基-哌啶-4-基)-1H-吲哚的方法
于惰性气氛下,将三乙酰氧基硼氢化钠(110mg,0.52mmol)一次性加至2-苯磺酰基-7-哌啶-4-基-1H-吲哚XXI(130mg,0.34mmol,参见上述实施例3)和甲醛(30%)(0.14mL,1.7mmol)的THF(20mL)溶液中。将反应物搅拌24小时,然后真空浓缩。残留物在1M氢氧化钠(25mL)和乙酸乙酯(25mL)之间分配。水层用乙酸乙酯(2×15mL)萃取。将合并的有机层干燥(MgSO4),过滤并将1M HCl的***溶液加至滤液中。收集沉淀,得到130mg(98%)2-苯磺酰基-7-(1-甲基-哌啶-4-基)-1H-吲哚XXIII,为白色粉末。
类似地,用与上述相同的方法合成上述表1中的化合物8和10:7-(4-甲基-哌嗪-1-基)-2-(2-三氟甲基-苯磺酰基)-1H-吲哚和2-(3-溴-苯磺酰基)-7-(4-甲基-哌嗪-1-基)-1H-吲哚。
实施例6
本实施例说明式I化合物的体外放射配体结合研究。
如下测定本发明的化合物的体外结合活性。通过在衍生自稳定表达重组人5-HT6受体的HEK293细胞的细胞膜中竞争性结合[3H]LSD来进行配体亲和力的测定,该测定以一式两份进行。
所有测定于37℃在含有50mM Tris-HCl、10mM MgSO4、0.5mMEDTA、1mM抗坏血酸的测定缓冲液(pH 7.4)中进行,反应体积为250微升。将含有[3H]LSD(5nM)、竞争性配体和膜的测度试管在振荡水浴中培育60分钟。于37℃,采用Packard 96孔细胞收集器过滤至Packard GF-B板(用0.3%PEI预浸泡),并用冰冷的50mM Tris-HCl洗涤3次。采用Packard TopCount以每分钟放射计数测定结合的[3H]LSD。
通过将浓度-结合数据拟合为4-参数对数方程,对在结合位点[3H]LSD的置换进行定量:
此处Hill为Hill斜率,[配体]为竞争性放射配体的浓度,且IC50为产生半数放射配体特异性结合最大值的放射配体的浓度。特异性结合窗为最大结合率和本底参数的差。
实施例7
采用实施例6的方法,测试式I化合物,发现其为选择性5-HT6拮抗剂。表2中显示代表性的化合物的活性。
表2:放射配体结合数据
编号 | 名称 | pKi |
3 | 2-(2,3-二氯-苯磺酰基)-7-哌嗪-1-基-1H-吲哚 | 9.7 |
5 | 2-(2-氟-苯磺酰基)-7-哌嗪-1-基-1H-吲哚 | 9.3 |
8 | 7-(4-甲基-哌嗪-1-基)-2-(2-三氟甲基-苯磺酰基)-1H-吲哚 | 9.5 |
9 | 7-哌嗪-1-基-2-(2-三氟甲基-苯磺酰基)-1H-吲哚 | 9.5 |
10 | 2-(3-溴-苯磺酰基)-7-(4-甲基-哌嗪-1-基)-1H-吲哚 | 9.6 |
实施例8
本发明的化合物的认知增强特性可以在动物认知模型中:目标认知任务模型中测定。采用4月龄的雄性Wistar大鼠(查尔斯河,荷兰)。每日制备化合物,溶于生理盐水中,并以三个剂量测试。给药恒定在T1前60分钟i.p.(注射体积1mL/kg)给予。在注射化合物30分钟后,注射氢溴酸东莨菪碱。两个相等的测试组由24只大鼠组成,并由两名试验人员测试。随机确定剂量的测试次序。采用双盲试验方案进行实验。所有大鼠在每个剂量条件下处理一次。如Ennaceur,A.,Delacour,J.,1988,A new one-trial forneurobiological studies of memory in rats.1:Behavioral data.Behav.BrainRes.31,47-59中所述进行目标认知测定。
尽管已参照其具体实施方案对本发明进行了描述,但是本领域技术人员应当理解的是,在不背离本发明的宗旨和范围的情况下,可以进行各种改变和等同替代。此外,可以对具体条件、材料、组合、方法、方法步骤进行修改以适应本发明的宗旨和范围。所有修改均包括在所附的权利要求书的范围内。
Claims (17)
2.权利要求1的化合物,
其中:
n为2;
R1为任选取代的芳基;
R2为任选取代的杂环基;
R3为氢,且
R4为氢。
3.权利要求2的化合物,其中R2为哌嗪-1-基或哌啶-4-基,其可任选被烷基取代。
4.权利要求3的化合物,其中R2为哌嗪-1-基、4-甲基哌嗪-1-基、N-甲基哌啶-4-基或哌啶-4-基。
5.权利要求2的化合物,其中R1为任选取代的苯基或任选取代的噻吩基。
6.权利要求5的化合物,其中R1为噻吩-2-基或苯基,其可任选被烷基、卤素或卤代烷基取代。
7.权利要求6的化合物,其中R1为苯基、2,3-二氯苯基、2-氟苯基、2-三氟甲基苯基或3-溴苯基。
8.权利要求2的化合物,为:
2-苯磺酰基-7-哌嗪-1-基-1H-吲哚,
2-苯磺酰基-7-(4-甲基-哌嗪-1-基)-1H-吲哚,
2-(2,3-二氯-苯磺酰基)-7-哌嗪-1-基-1H-吲哚,
2-(2,3-二氯-苯磺酰基)-7-(4-甲基-哌嗪-1-基)-1H-吲哚,
2-(2-氟代-苯磺酰基)-7-哌嗪-1-基-1H-吲哚,
2-苯磺酰基-7-哌啶-4-基-1H-吲哚,
2-苯磺酰基-7-(1-甲基-哌啶-4-基)-1H-吲哚,
7-(4-甲基-哌嗪-1-基)-2-(2-三氟甲基-苯磺酰基)-1H-吲哚,
7-哌嗪-1-基-2-(2-三氟甲基-苯磺酰基)-1H-吲哚,
2-(3-溴-苯磺酰基)-7-(4-甲基-哌嗪-1-基)-1H-吲哚,
2-(3-溴-苯磺酰基)-7-哌嗪-1-基-1H-吲哚。
9.制备式I的2-取代吲哚的方法:
其中:
n为0、1或2;
p为1或2;
R1为任选取代的芳基或任选取代的杂芳基;
R2为任选取代的杂环基;
R3为氢、烷基或-C(=O)-R5,其中R5为烷基、烷氧基、芳基或芳氧基;且
每个R4独立地为氢、羟基、氰基、烷基、烷氧基、硫代烷基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、烷基羰基、烷基磺酰基、芳基磺酰基、卤代烷基磺酰基、氨基、烷基氨基、二烷基氨基、烷基(芳基)氨基、烷基氨基羰基、烷基羰基氨基、烷基羰基(烷基氨基)、烷基氨基磺酰基、烷基磺酰基氨基或亚甲二氧基,优选为氢、烷基、烷氧基、卤素或卤代烷基;
所述方法包括使式(II)的取代吲哚:
其中R2′为任选取代的杂环基,其可任选被保护基团保护;R3′为烷基或-C(=O)-R5;且每个R4′独立地为氢、羟基、氰基、烷基、烷氧基、硫代烷基、烷硫基、卤素、卤代烷基、羟基烷基、硝基、烷氧基羰基、烷基羰基、烷基磺酰基、芳基磺酰基、卤代烷基磺酰基、氨基、烷基氨基、二烷基氨基、烷基(芳基)氨基、烷基氨基羰基、烷基羰基氨基、烷基羰基(烷基氨基)、烷基氨基磺酰基、烷基磺酰基氨基或亚甲二氧基,优选为氢、烷基、烷氧基、卤素或卤代烷基,其可任选被保护基团保护,
(i)与碱接触,生成脱质子化的吲哚;以及
(ii)使脱质子化的吲哚与下式的磺酰化剂反应:Y-SO2-R1,其中Y为卤离子,或者与式R1-S-S-R1的二硫化物反应,生成式III的2-取代吲哚:
其中取代基的定义如上文所述,
(iii)任选用氧化剂氧化硫;以及
(iv)任选除去保护基团,生成式I的2-取代吲哚。
10.权利要求12的方法,其中Y为氟。
11.包含下列的组合物:
(a)治疗有效量的权利要求1-8的式I化合物;以及
(b)药学上可接受的载体。
12.权利要求1-8中任一项的一种或多种化合物在制备用于治疗或预防由5HT6激动剂缓解的疾病的药物中的用途。
13.权利要求12的用途,其中所述疾病包括CNS紊乱。
14.权利要求13的用途,其中所述疾病包括精神病、精神***症、躁狂型抑郁症、神经紊乱、记忆紊乱、注意力缺陷障碍、帕金森病、肌萎缩性脊髓侧索硬化、阿尔茨海默氏病和亨廷顿病。
15.权利要求12的用途,其中所述疾病包括胃肠道紊乱。
16.权利要求12的用途,其中所述疾病包括肥胖症。
17.如上所述的本发明。
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CA2992518A1 (en) | 2015-07-15 | 2017-01-19 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
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CA2194984C (en) | 1994-07-26 | 2002-07-02 | John Eugene Macor | 4-indole derivatives as serotonin agonists and antagonists |
US6114532A (en) * | 1998-02-03 | 2000-09-05 | Boehringer Ingelheim Pharma Kg | Bicyclic heterocycles, the preparation thereof, and their use as pharmaceuticals |
CO5080791A1 (es) | 1998-06-30 | 2001-09-25 | Lilly Co Eli | Derivados de la piperidina que tienen efectos sobre sistemas con serotonina |
FR2788772B1 (fr) * | 1999-01-26 | 2001-03-02 | Adir | Nouveaux composes cyano-indoles inhibiteurs de recapture de serotonine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
GB9912413D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
KR100600240B1 (ko) * | 2001-06-07 | 2006-07-13 | 에프. 호프만-라 로슈 아게 | 5-ht6 수용체 친화도를 갖는 신규한 인돌 유도체 |
JP2005501019A (ja) * | 2001-06-15 | 2005-01-13 | エフ.ホフマン−ラ ロシュ アーゲー | 5−ht6レセプター親和性を有する4−ピペラジニルインドール誘導体 |
JP2005527463A (ja) * | 2001-08-07 | 2005-09-15 | スミスクライン ビーチャム パブリック リミテッド カンパニー | Cns疾患を治療するための5−ht6受容体アフィニティーを有する3−アリールスルホニル−7−ピペラジニル−インドール、−ベンゾフランおよび−ベンゾチオフェン |
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Cited By (2)
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CN103288707A (zh) * | 2013-05-28 | 2013-09-11 | 浙江大学 | 一种3-亚磺酰基吲哚衍生物的制备方法 |
CN103288707B (zh) * | 2013-05-28 | 2015-12-23 | 浙江大学 | 一种3-苯巯基吲哚衍生物的制备方法 |
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