CN101400642A - 具有中枢神经系统活性的环丙烷 - Google Patents
具有中枢神经系统活性的环丙烷 Download PDFInfo
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- CN101400642A CN101400642A CNA200780008384XA CN200780008384A CN101400642A CN 101400642 A CN101400642 A CN 101400642A CN A200780008384X A CNA200780008384X A CN A200780008384XA CN 200780008384 A CN200780008384 A CN 200780008384A CN 101400642 A CN101400642 A CN 101400642A
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明披露了具有CNS活性的芳基环丙烷化合物。这些化合物可以被用于减轻CNS紊乱的症状。
Description
本申请要求于2006年3月10日提交的美国专利申请序列第60/781,245号的优先权，将其全部内容以引用方式结合于此作为参考。
本发明是在(美国)国立卫生研究所(National Institutes ofHealth)的授予的基金编号NO1 DA-18826和5R01DA15225-03的资助下进行的。政府对本发明具有一定的权利。
技术领域
本申请大体上涉及中枢神经系统紊乱，并尤其涉及CNS紊乱症状的减轻。
背景技术
中枢神经系统紊乱是对经济和社会具有破坏性的。例如，精神分裂症是全世界导致残疾的首要原因之一，终生发病率为0.6至1.3％，其特征为高发病率和高死亡率。仅有少于15％具有这种残疾的人可以竞争地被雇用，同时仅有约20％的人可以独立生活。
精神分裂症通常具有阳性症状(例如妄想、幻觉、错乱行为(disorganized behavior)、阴性症状(例如无力)、情感症状(例如烦躁不安、绝望、焦虑、敌意、攻击性)和/或认知缺陷。
对于这种紊乱的典型治疗包括作用于单胺(monanine)受体系统的药物。例如，第一代抗精神病药的主要作用(primary effect)为多巴胺(D2受体)阻断。虽然这些对于治疗神经分裂症的阳性症状是有效的，然而它们对于阴性症状和认知缺陷所发挥的作用却不大。因此，尽管可以使用一些用于治疗诸如神经分裂症之类的中枢神经系统紊乱的药物，但对于用于治疗中枢神经系统紊乱的改进方法和化合物仍存在许多未满足的需求。
发明内容
本发明提供了芳香族环丙烷化合物。本发明的化合物包括具有以下通式的化合物：
或它的对映异构体(其中具有含氨基取代基的环丙烷碳是R构型的(如图所示，与S构型相对)，而其余的结合芳基的丙烷碳是S构型的(如图所示，与R构型相对))，以及两种对映异构体的外消旋混合物。
基团R1可选自由具有三个或更少个碳原子的烷烃基团组成的组中，并且可选地，氨基氮以盐(例如盐酸盐)的形式存在。基团R2和R3可以是一种或多种选自以下组的取代基：氢、卤素、三个或更少个碳的烷烃、或相邻的环，以使具有R的环包含一个多环、轭合基团(共轭基团，conjugated group)。
本发明还提供了一种利用环丙烷化合物减轻CNS紊乱的症状的方法。该方法包括对个体给予治疗有效量的环丙烷化合物以减轻CNS紊乱的症状。这样的疾病包括但不限于广义上的精神病，例如双相精神性障碍、抑郁症、心境障碍、成瘾、认知障碍和神经变性疾病，例如阿尔茨海默病、帕金森病。
具体实施方式
本发明提供了可用作治疗CNS紊乱和药物滥用的治疗剂的新型化合物。这些化合物包括以下更加详细描述的芳香族环丙烷化合物。
1，2-二芳基环丙烷甲胺
已经表明单胺转运体(transporter)抑制剂具有很好的治疗功用。选择性5-羟色胺转运体(SERT)抑制剂是一些最广泛使用的抗抑郁药。结合至SERT以及去甲肾上腺素转运体(NET)的非选择性配体也已经被推出用作抗抑郁药。尽管诸如可卡因之类的多巴胺转运体(DAT)抑制剂有可能会被滥用，但DAT抑制剂仍被用于治疗注意力缺陷障碍(Attention Deficit Disorders)。5-羟色胺受体被分为若干个亚型并且许多亚型的选择性配体是有益的治疗剂。已经表明5-HT2a拮抗剂作为抗抑郁药以及对于其他的CNS紊乱具有有益的治疗潜力。最近，已经发现用5-HT2a拮抗剂作为治疗剂来治疗可卡因成瘾具有前景性成效(promising result)。
本发明的化合物包括具有以下通式的化合物
或它的对映异构体(其中具有含氨基取代基的环丙烷碳是R构型的(如图所示，与S构型相对)，而其余的结合芳基的丙烷碳是S构型的(如图所示，与R构型相对))，以及两种对映异构体的外消旋混合物。
基团R1可选自由具有三个或更少个碳原子的烷烃基团组成的组，并且可选地，氨基氮以盐(例如盐酸盐)的形式存在。基团R2和R3可以是一种或多种选自以下组的取代基：氢、卤素、三个或更少个碳的烷烃、或相邻的环，以使具有R的环包含一个多环、轭合基团。
优选地，R1是甲基，而R2和/或R3包括1)氢或2)间位或对位氯取代，或者R3包括在含有R3的芳基环的2位和3位上的相邻环，因而具有R3的芳基环包含萘基。
除了可由杂环/化合物/稠环结构代替在上述结构中示出的一个或两个芳香环之外，本发明的化合物还包括如上所述的化合物。这种结构的实例可以是吡啶、噻吩、吡咯、呋喃、苯并呋喃、吲哚、苯并噻吩等。
芳香/杂环/稠环结构可以被取代。实例包括用例如，烷基、烯基、烷氧基、卤素、硝基、氰基、酮基、氨基、羧酸酯基、取代或未取代的，或它们的组合的取代基进行一元取代、二元取代和三元取代。芳香/杂环/稠环结构可以被取代。实例包括用例如，烷基、烯基、烷氧基、卤素、硝基、氰基、酮基、氨基、羧酸酯基、取代或未取代的芳烃(aromatic)，或它们的组合的取代基进行一元取代、二元取代和三元取代。
本发明还包括对映异构体的纯净组合物，包含上述R，S或S，R对映异构体。如上所述，可以在以下方案1中的成环反应中利用催化剂Rh2(DOSP)4的适合的对映异构体来实现所给出的对映异构体的制备。本发明还包括R，S和S，R对映异构体的外消旋混合物。可以利用催化剂对映异构体的混合物，并通过以所需比率简单混合该对映异构体来制备这种混合物。
在具体实施方式中，本发明提供了可被用作CNS紊乱治疗剂的顺-1，2-二芳基环丙烷甲胺。可以用这类化合物的某些成员来获得在单胺转运体处选择性成键结合在5HT2a处成键的受体。生物活性与这两个芳香环的官能度和所使用的环丙烷甲胺的对映异构体(镜像)相关。
化学
示出了用于合成1-苯基-2-萘基衍生物5(方案1)的环丙烷合成的基本方案。第一步是铑催化的苯基重氮醋酸酯2与乙烯基萘1的反应。可根据所使用的催化剂Rh2(DOSP)4的对映异构体来形成环丙烷3的对映异构体。3到环丙烷甲胺5的转化是通过还原为乙醇、氧化为醛然后进行还原性胺化来完成的。该方案非常灵活，因为可使用一定范围内的芳基重氮醋酸酯和乙烯基取代的芳烃(arenas)。此外，可在还原性胺化步骤中加入一定范围内的伯胺和仲胺。
方案1
在另一种实施方式中，本发明提供了一种用于减轻CNS紊乱的症状的方法。该方法包括对个体给予减轻CNS紊乱症状有效量的包含芳基环丙烷的组合物。
本发明的方法适用于减轻各种CNS紊乱的一种或多种症状。患有CNS紊乱的个体经常表现出为特定紊乱的特征的一种或多种症状。并且预期同一个体中多重CNS紊乱的一组症状可通过本方法得到减轻。在这点上，在实施本发明方法的过程中或在实施本发明方法之后，识别CNS紊乱的症状并确定所述症状的减轻，是本领域中普通技术人员力所能及的，并且可利用任何适合的临床、诊断、观察或其他技术来进行。例如，精神分裂症的症状包括但不限于妄想、幻觉和紧张性行为。任何由于实施了本发明的方法而导致的这些具体症状的减少都被认为是症状的减轻。所表现的症状适合于通过本发明的方法而减轻的特定的CNS紊乱包括但不限于：广义上的精神病，例如双相性精神障碍、抑郁症、心境障碍、药物成瘾、认知障碍和神经变性疾病(例如阿尔茨海默病和帕金森病)，以及它们的组合。这些紊乱中的每一种的症状都是已知的。本领域技术人员可以容易地识别和确定任意这些特定紊乱的症状的减少。
组合物包括有效量的可通过常规途径给药的化合物。这样的途径包括但不限于口服、肠胃外给药、肌内给药、静脉内给药和粘膜给药。在一种实施方式中，给药途径为口服。确定该化合物的给药方案是本领域技术人员力所能及的。例如，剂量水平可以从每千克体重4微克一直到每千克体重50毫克。再例如，剂量可以从20微克/Kg一直到15mg/Kg。将明了的是，关于剂量参数(dosingparameter)，除了个体的体重之外还要考虑个体年龄和疾病的阶段，并且这可通过常规程序来确定。
可将该化合物与其他组分组合以形成用于本方法的药物制剂。这样的组分可以根据多种因素进行选择，这些因素尤其包括但不限于剂型、患者的特殊需要、制造方法。这样的组分的实例包括但不限于粘合剂、润滑剂、填充剂、调味剂、防腐剂、着色剂、稀释剂等。Remington′s Pharmaceutical Sciences(18th Edition，A.R.Gennaroet al.Eds.，Mack Publishing Co.，Easton，Pa.，1990)中描述了伴随本发明的方法所使用的药物组合物组分有关的其他信息。因此，本领域中普通技术人员可以容易地确定具体物质的选择和它们与本发明的组合物的相容性。在美国专利第5,763,455号中提供了其他细节，其以引用方式结合于此作为参考。
虽然将通过以下实施例来阐述本发明，然而这些实施例仅是为了举例说明本发明的具体实施方式而不是为了以任何方式限制本发明。
实施例1
本实施例提供了用于制造本发明的化合物的典型技术。
(1S，2R)-甲基-2-(萘-2-基)-1-苯基环丙烷羧酸酯
开始于1.05g(6.82mmol)的2-乙烯基萘、1.01g(5.71mmol)的甲基2-重氮基-2-萘基醋酸酯和0.075g(0.040mmol)的Rh2(S-DOSP)4，得到白色固体的酯26。产量：1.28g(4.23mmol，74％)。将材料从己烷重结晶获得>99％ee的材料。Rf：0.15(9:1己烷/乙醚)；1HNMR(300MHz，CDCl3)δ 7.78-7.91(m，2H)，7.71(d，J＝8.5Hz，1H)，7.50-7.61(m，3H)，7.24-7.37(m，5H)，7.04(dd，J＝8.5；1.1Hz，1H)，3.85(s，3H)，3.56(dd J＝8.8，7.7Hz，1H)，2.48(dd J＝4.9；9.3Hz，1H)，2.46(dd J＝7.1，5.2Hz，1H)；13C NMR(75mHz，CDCl3)δ 174.0(C)，134.5(C)，133.9(C)，131.7(CH)，127.5(CH)，127.3(CH)，126.9(CH)，125.8(CH)，125.6(CH)，125.1(CH)，52.3(CH3)，37.4(C)，33.1(CH)，20.6(CH2)；IR(净(neat))cm-1 3064，3027，1714，1257，729,699；
(c 0.65，CHCl3)；HPLC RR-Whelk，5％ i-PrOH/己烷，1ml/mintR＝9.3分钟(少数(minor))，10.7分钟(多数(major))；mp 84-87℃；对C21H18O2进行分析计算：C，83.42；H，6.00。发现C，83.29；H，5.94。
(1S，2R)-2-(萘-2-基)-1-苯基环丙烷甲醛
由0.65g(2.2mmol)的酯26和2.2mmol LiAlH4的试样得到乙醇的无色油。产量为0.58g(2.1mmol，97％)。RF：0.12(4:1己烷/乙酸乙酯)；1H NMR(300MHz，CDCl3)δ 7.58-7.73(m，2H)，7.20-7.40(m，2H)，7.07-7.19(m，5H)，6.82(dd，J＝8.5，1.7Hz，1H，3.95(d，J＝11Hz，1H)，3.68(d，J＝11Hz，1H)，2.55(dd，J＝8.8，6.0Hz，1H)，1.63(dd，J＝11，5.8Hz，1H)，1.55(m，2H)；IR(neat)cm-1 3350(br)。
利用斯文(Swern)条件将粗制乙醇氧化得到乙醛的白色固体。产量为0.49g(1.8mmol，95％)；Rf0.38(4:1己烷/乙酸乙酯)；1HNMR(300MHz，CDCl3)δ 9.7(s，1H)，7.60-7.70(m，2H)，7.57(d，J＝8.5Hz，1H)，7.40-7.43(m，3H)，7.13-7.19(m，4H)，6.9(d，J＝8.5Hz，2H)，3.2(dd，J＝8.5，8.5Hz，1H)，2.20-2.30(m，2H)。13C NMR(75MHz，CDCl3)，δ 200.6(CH)，133.8(C)，133.1(C)，132.9(C)，132.1(C)，131.2(CH)，128.3(CH)，127.5(CH)，127.4(CH)，127.3(CH)，127.0(CH)，125.9(CH)，125.8(CH)，125.5(CH)，46.5(C)，35.8(CH)，20.0(CH2)。
N-甲基((IR，2S)-2-(萘-2-基)-1-苯基环丙基)甲胺(5)
开始于用过量甲胺与0.49g(1.8mmol)的乙醛进行还原性胺化获得0.23g(0.88mmol，44％)为浅黄色油的胺5。Rf 0.30(9:1乙醚/三乙胺)；1H NMR(300MHz，CDCl3)δ 7.6-7.7(m，1H)，7.55-7.57(m，1H)，7.47(d，J＝8.5，1H)，7.20-7.30(m，3H)，7.00-7.10(m，4H)，6.76(dd，J＝8.5，1.3Hz，1H)，3.12(d，J＝12.0Hz，1H)，2.63(d，J＝12.1Hz，1H)，2.39-2.43(m，4H)，1.65(dd，J＝11.5Hz，1H)，1.47(dd，J＝8.8，5.5Hz，1H)；13C NMR(75MHz，CDCl3)δ 138.7(C)，136.7(C)，133.0(C)，131.6(C)，130.8(CH)，128.0(CH)，127.3(CH)，127.2(CH)，126.8(CH)，126.4(CH)，126.1(CH)，126.0(CH)，125.6(CH)，124.8(CH)，63.0(CH2)，36.4(CH3)，36.0(C)，28.5(CH)，18.2(CH2)。
在醚中用HCl将0.20g(0.73mmol)的胺试样转化为盐酸盐。通过乙酸乙酯/甲醇对黄色固体进行重结晶以得到为白色斜方晶(prism)的盐。产量为0.090g(0.28mmol，39％)。1H NMR(300MHz，CD3OD)δ；7.36-7.59(m，3H)，6.95-7.27(m，8H)，6.84(d，J＝8.2Hz，1H)，3.73(d，J＝12.9Hz，1H)，3.32-3.55(m，2H)，2.96(d，J＝12.9Hz，1H)，2.62(dd，J＝7.5，7.5Hz，4H)，2.54(s，3H)，1.91(dd，J＝6.0，6.0Hz，1H)，1.56(dd，J＝6.8，6.8Hz，1H)；对C21H22C1N进行分析计算：C，77.88；H6.85；N，4.32。发现：C，77.74；H，7.00，N4.33。
实施例2
本实施例提供了关于本发明的特定实施方式对神经受体的作用的验证。
单胺重摄取结合方法
将未知物称重并溶解于DMSO中来制备10mM储备溶液。在用于结合的测定缓冲液中稀释至50μM或在用于摄取的水中稀释至1mM来制备初始稀释液。用补充有DMSO的测试缓冲液来制备后成稀释液，保持终浓度为0.1％DMSO。用Biomek 2000机器人工作台(robotic workstation)来进行移液。
Colonla细胞中[125I]RTI-55至hDAT、hSERT或hNET的放射配体结合的抑制
细胞制备：在直径为150mm的组织培养皿上使表达hDAT、hSERT或hNET嵌入体的HEK293细胞生长至80％融合(confluence)并作为组织来源。如下制备细胞膜。将培养基倒出平板并将平板用10ml的不含钙和镁的磷酸盐缓冲液冲洗。加入溶胞缓冲液(Lysisbuffer)(10ml；具有1mm EDTA的2mM HEPES)。10分钟后，从平板上刮掉细胞，注入离心管中，并在30,00xg下离心20分钟。除去上清液并利用Ploytron设定为7持续10秒将片状沉淀(pellet)重新悬浮于12-32ml的0.32m蔗糖中。再悬浮的容积取决于细胞系中结合位点的密度并且对再悬浮的容积进行选择以反映对10％或更少的总放射性的结合。
测定条件：每个测定管包含50μl的膜制剂(约10-15μg的蛋白质)、25μl的用于定义非特异性结合的未知化合物、或缓冲液(Krebs-HEPES，pH 7.4；122mM NaCl、2.5mM CaCl2、1.2mM MgSO4、10μM帕吉林、100μM托酚酮、0.2％葡萄糖和0.2％抗坏血酸，用25mMHEPES缓冲)、25M1的[125I]RTI-55(40-80pM终浓度)以及足以使最终体积达到250μl的另外的缓冲液。在加入[125I]RTI-55之前，用未知物与膜预培养10分钟。将测定管温育至25℃保持90分钟。通过在利用Tomtec96-孔细胞收集器通过在GF/F过滤器上进行过滤来终止结合。用冰冷的盐水将过滤器清洗6秒。在每一方格中加入闪烁液并利用Wallacμ-或β平板读取器来确定余留在过滤器上的放射性。将特异性结合定义为在存在或不存在5μM马吲哚(HEK-hDAT和HEK-hNET)或5M丙咪嗪(HEK-hSERT)的情况下所观察到的结合的差异。用双份测定(duplicate determination)来进行两次或三次独立的竞争实验。使用GraphPAD Prism来分析随后的数据，其中用Cheng-Prusoff公式(Ki＝IC50I/(1+([125I]RTI-55/KdRTI55)))将IC50值转化为Ki值。
受体结合测试方法
5HT1A受体
使HA7细胞(人类受体)生长至融合于含有10％胎牛血清(FBS)、0.05％盘尼西林-链霉素(pen-strep)和400μg/mL的遗传霉素(G418)的DMEM中。将细胞从100×20mm的平板上刮下并在500g下离心5分钟。将片状沉淀在50mM Tris-HCl(pH7.7)中用匀浆器(polytron)进行均质化，在27,000xg下离心并在相同的缓冲液中以10mg蛋白质/mL重新悬浮。然后以1-mL的等份将匀浆在-70℃下储存。
将解冻的细胞清洗一次并以10mg蛋白质/80mL重新悬浮在pH7.4下10μM尼亚拉胺中含有100μM抗坏血酸的25mM Tris-HCl中，测定在96-孔板中重复进行三次。将100μl的测试化合物或缓冲液以及0.80mL的细胞匀浆(0.10mg蛋白质/孔)加入到10μl的[3H]8-OH-DPAT(0.5nM终浓度)中。用1.0μM的双氢麦角胺(dihyderoergotamine)来确定非特异性结合。将平板在25℃下温育60分钟然后通过玻璃纤维过滤器在Tomtec细胞收集器上进行过滤。用冷的50mM Tris-HCl(pH 7.7)将过滤器清洗四次并干燥过夜，并装入10mL闪烁液(scintillation cocktail)，随后在Wallac Betaplate 1205液体闪烁中心上计数2分钟。
5-HT2A受体
NIH-3T3-GF6细胞(大鼠受体)生长成为所述的HA7细胞。将该细胞解冻，重新悬浮于50mM的Tris-0HCl中，并以27,000xg离心12分钟。然后将颗粒状物以1mg蛋白质/80ml重新悬浮于25mM的Tris-HCl(pH 7.7)中，并向含有100μl的测试药物或缓冲液以及100μl的[3H]酮色林(ketanserin)(0.40nM的终浓度)的孔中加入0.80ml的细胞匀浆(0.01mg蛋白质/孔)。将孔板在25℃下温育60分钟。用1.0μM的酮色林测定非特异性结合。
5-HT2C-受体
NIH-3T3-P细胞(大鼠受体)生长成为所述的HA7细胞。将最后的颗粒状物以3mg蛋白质/80ml重新悬浮于50mM的Tris-HCl(pH7.7)、4mM的CaCl2、10μM的帕吉林和0.1％的抗坏血酸中。将含有100μl的测试药物或缓冲液、100μl的[3H]美舒麦角(mesurlergine)(0.40nM的终浓度)和0.80Ml的细胞匀浆(0.03mg蛋白质/孔)的孔在25℃下温育60分钟。用10μM的美舒麦角测定非特异性结合。
生物学活性
在本实施例中如所述对典型的二芳基环丙烷甲胺的生物学数据进行测定，并将其示于表1中。表中包括几对对映异构体；选择性彼此不同。这可从项目(entry)1和2中看出。(1S，2R)对映异构体以合理的效价(potency)结合至SERT、NET和5-HT2a而(1R，2S)对映异构体对于SET是选择性的。1-芳基基团对单胺转运体亲和力有很大影响。当1-芳基基团为3，4-二氯苯基和2-萘基时获得非常大的亲和力。生物学数据显示1，2-二芳基环丙烷甲胺是一类对于治疗CNS紊乱有益的药剂。
表1
前面的具体实施方式的描述是为了举例说明的目的而不应理解为限制本发明。本领域技术人员可从本发明的教导中认识到，在不脱离本发明精神的前提下可以进行各种修改和变化。
Claims (15)
1.一种具有以下结构的化合物或其对映异构体，
其中，R1是三个或更少个碳原子的烷烃，R2包含一种或多种选自由氢、卤素、三个或更少个碳的烷烃、或相邻的环组成的组的取代基，以及R3包括一种或多种选自由氢、卤素、三个或更少个碳的烷烃、或相邻的环组成的组的取代基。
2.根据权利要求1所述的化合物，其中，R1是甲基，并且其中可选地，氨基氮作为盐酸盐而存在。
3.根据权利要求2所述的化合物，其中，R2或R3包含氢取代基。
4.根据权利要求2所述的化合物，其中，R2或R3包含对氯取代基和间氯取代基。
5.根据权利要求2所述的化合物，其中，R2和R3均包含对氯取代基和间氯取代基。
6.根据权利要求1所述的化合物，其中，R3是在含有R3的所述芳基的2位和3位上的相邻环，从而形成萘基。
7.一种具有以下结构的化合物的S，R和R，S对映异构体的外消旋混合物，
其中，R1是三个或更少个碳原子的烷烃，R2和R3独立地包含一种或多种选自由氢、卤素、三个或更少个碳的烷烃、链烯基、烷氧基、卤代、硝基、氰基、酮基、氨基、羧酸酯、取代或未取代的芳烃，相邻的环或它们的组合组成的组的取代基。
8.根据权利要求7所述的外消旋混合物，其中，R1是甲基，并且其中可选地，氨基氮作为盐酸盐而存在。
9.根据权利要求8所述的外消旋混合物，其中，R2或R3包含对氯取代基和间氯取代基。
10.根据权利要求8所述的外消旋混合物，其中，R2和R3均包含对氯取代基和间氯取代基。
11.根据权利要求7所述的外消旋混合物，其中，R3是在含有R3的所述芳基的2位和3位上的相邻环，从而形成萘基。
12.一种具有以下结构的化合物或它的对映异构体，
其中，R1是3个或更少个碳原子的烷烃；R2和/或R3独立地是取代或未取代的杂环或稠环结构，其中，可选地，R1或R3是取代或未取代的苯基。
13.根据权利要求12所述的化合物，其中，所述杂环或稠环结构选自由吡啶、噻吩、吡咯、呋喃、苯并呋喃、吲哚、苯并噻吩，以及萘基组成的组。
14.根据权利要求13所述的化合物，其中，所述杂环或稠环结构用选自由烷基、链烯基、烷氧基、卤素、硝基、氰基、酮基、氨基、羧酸酯、取代或未取代的，或它们的组合组成的组的取代基进行一元取代、二元取代和三元取代。
15.一种用于减轻个体的CNS紊乱的一种或多种症状的方法，包括给予所述个体有效量的包含如权利要求1中所述的化合物的组合物，以减轻所述CNS紊乱的症状，并且其中所述组合物的给予能减轻所述CNS紊乱的一种或多种症状。
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