CN101072563A - 同时对多巴胺－d2受体和5－羟色胺重摄取部位具有亲合力的苯并二噁烷哌嗪衍生物 - Google Patents
同时对多巴胺－d2受体和5－羟色胺重摄取部位具有亲合力的苯并二噁烷哌嗪衍生物 Download PDFInfo
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Abstract
本发明涉及一组具有双重作用方式：5－羟色胺重摄取抑制作用和对多巴胺－D2受体的亲合力的新3－(2－哌啶－4－基－乙基)－1H－吲哚衍生物，并涉及这些化合物的制备方法。本发明还涉及本文公开的化合物用于制备提供有益效果的药物的应用。该化合物具有通式(1)，其中的符号具有说明书中给出的含义。
Description
本发明涉及一组具有双重作用方式：5-羟色胺重摄取抑制作用和对多巴胺-D2受体的亲合力的新苯并二噁烷哌嗪衍生物，并涉及这些化合物的制备方法。本发明还涉及本文公开的化合物用于制备提供有益效果的药物的应用。有益效果在本文中公开或对于本领域技术人员来说根据本说明书和技术常识是显而易见的。本发明还涉及本发明的化合物用于制备治疗或预防疾病或症状的药物的应用。更为具体而言，本发明涉及一种用于治疗疾病或症状的新应用，该疾病或症状在本文中公开或对本领域技术人员来说根据本说明书和技术常识是显而易见的。在本发明的实施方案中，本文公开的特定化合物用于制备用于治疗涉及多巴胺-D2受体和5-羟色胺重摄取部位或者可以通过操作这些靶而治疗的疾病的药物。
根据WO01/014330已知具有作为多巴胺-D2拮抗剂和5-羟色胺重摄取抑制剂双重作用的苯基哌嗪衍生物。这种结合可用于治疗精神***症和其它精神病，从而能够对所有的疾病症状(例如阳性症状和阴性症状)进行更为完全的治疗。具有作为多巴胺-D2拮抗剂和5-羟色胺重摄取抑制剂的双重作用的四氢吡啶-4-基吲哚衍生物根据WO00/023441和WO00/069424是已知的，而且Van Hes等人(Bioorganicand Medicinal Chemistry Letters，13(3)，405-408，2003)进一步描述了在这些专利申请中公开的有希望的临床候选物。
在EP0376607A1中公开了哌嗪基丁基吲哚类、-吲唑啉类(indazolines)、对应的2，3-二氢衍生物和2-吲哚酮。这些化合物表征为5-羟色胺5-HT1A受体配体。在WO99/05140中描述了具有作为5-羟色胺重摄取抑制剂和5-HT1A受体拮抗剂的双重作用机制的吲哚和2，3-二氢吲哚衍生物，而在WO2004/054972中将一系列N-(吲哚乙基-)环胺衍生物描述为5-羟色胺重摄取抑制剂和5-HT1A和5-HT2A受体的激活剂。在后三篇专利申请中都没有公开多巴胺-D2受体的拮抗性。
本发明的目的在于提供进一步的具有作为多巴胺-D2拮抗剂和5-羟色胺重摄取抑制剂的双重作用的化合物。
本发明涉及一组式(1)的新苯并二噁烷哌嗪衍生物及其互变异构体、立体异构体和N-氧化物，以及该式(1)的化合物及其互变异构体、立体异构体和N-氧化物的药理学上可接受的盐、水合物和溶剂合物：
其中：
Y为CH2、O或S
X为CH2、O、NH或S
m为1、3、5或6，
n为0、1、2或3，
R4为氢或卤素
R2和R3独立地为H或烷基(C1-3)，或者R2+R3代表基团-(CH2)-p，其中p的值为3、4或5，和
R1为烷基(C1-3)、烷氧基(C1-3)、卤素或氰基，或者当R1在吲哚基的7位时R1+R3可以代表基团-(CH2)q，其中q的值为2、3或4。
在取代基的说明中，缩写‘烷基(C1-3)’意指‘甲基、乙基、正丙基或异丙基’。
上述化合物的前药在本发明的范围内。前药是本身无活性但可转化成一种或更多种活性代谢产物的治疗剂。前药是用于克服母体药物分子应用的某些障碍的药物分子的生物可逆衍生物。这些障碍包括但不限于溶解度、渗透性、稳定性、***前代谢(presystemicmetabolism)和靶向限制(Medicinal Chemistry：Principles andPractice，1994，Ed.：F.D.King，p.215；J.Stella，“Prodrugsas therapeutics”，
Expert Opin.Ther.Patents，14(3)，277-280，2004；P.Ettmayer等人，“Lessons learned from marketed andinvestigational prodrugs”，J.Med.Chem.，47，2393-2404，2004)。前药，即在通过任何已知的途径对人给药时代谢成具有式(1)的化合物的化合物，属于本发明。特别是，这涉及具有伯或仲氨基或者羟基的化合物。这些化合物可以与有机酸反应得到具有式(1)的化合物，其中存在给药后容易除去的附加基团，例如但不限于脒(amidine)、烯胺、曼尼希碱(Mannich base)、羟基-亚甲基衍生物、O-(酰氧基亚甲基氨基甲酸酯)衍生物、氨基甲酸酯、酯、酰胺或烯胺酮(enaminone)。
上述化合物的N-氧化物在本发明的范围内。叔胺可能产生或不产生N-氧化物代谢产物。N-氧化发生的程度为痕量至接近定量转化。N-氧化物可能比它们的对应的叔胺的活性更大或更小。虽然N-氧化物容易通过化学方法还原成为它们的对应的叔胺，但在人体中这以不同的程度发生。某些N-氧化物接近定量地还原转化成对应的叔胺，在其它情况下该转化仅仅是痕量反应或者甚至完全不存在。(M.H.Bickel：“The pharmacology and Biochemistry of N-oxides”，Pharmaco-logical Reviews，
21(4)，325-355，1969).
本发明尤其涉及通式(1)的化合物及其互变异构体、立体异构体和N-氧化物，以及该式(1)的化合物及其互变异构体、立体异构体和N-氧化物的药理学上可接受的盐、水合物和溶剂合物，其中在式(1)中：Y为O，X为CH2或O，m为1、3或5，n为1，R2、R3和R4为氢，而R1为氢、甲基、氟、氯或甲氧基。
已发现根据本发明的化合物表现出对多巴胺D2受体和5-羟色胺重摄取部位都具有高度亲合力。该化合物表现为作为多巴胺D2受体拮抗剂的活性，因为它们潜在地拮抗阿朴***(apomorphine)诱导的小鼠攀爬行为(B.Costall等人，‘Climbing behaviour induced byapomorphine in mice：a potential model for the detection ofneuroleptic activity’，
Eur.J.Pharmacol.，1978，
1，39-50)。该化合物还表现出作为5-羟色胺重摄取抑制剂的活性，因为它们加强5-HTP诱导的小鼠的行为(B.L.Jacobs.，‘An animal behaviourmodel for studying central serotonergic synapses’，
Life Sci.，1976，
19(6)，777-785)。该化合物在对临床相关的抗精神病药敏感的治疗模型(例如条件回避反应(conditioned avoidance response)；Van der Heyden & Bradford，Behav.Brain Res.，1988，31：61-67)和对抗抑郁药或抗焦虑药敏感的治疗模型(例如压力诱发的发声抑制(suppression of stress-induced vocalization)；van der Poel等人，Psychopharmacology，1989，97：147-148)中具有活性。与临床相关的多巴胺D2受体拮抗剂相反，所述化合物诱导啮齿动物僵住症的倾向性小，且因此与现有的抗精神病药相比可能诱导较少的锥体束外副反应。这些化合物固有的5-羟色胺重摄取的抑制活性可能导致在对抗抑郁药或抗焦虑药敏感的行为模型中观察到的治疗效果。该化合物可以用于治疗由多巴胺能或5-羟色胺能***障碍导致的中枢神经***病症或疾病，例如攻击(aggression)、焦虑症(anxiety disorders)、孤独症(autism)、眩晕(vertigo)、抑郁、认知或记忆障碍、帕金森氏病(Parkinson’s disease)，特别是精神***症(schizophrenia)和其它精神障碍。
合成概况
具有式(1)的化合物可以通过式(2)的化合物：
在碱性条件下与式(3)的化合物反应来制备：
在这些式子中，符号具有上文给出的含义，而L为离去基团，例如卤原子或甲磺酸酯基(mesylategroup)(参见下文：方案1，路线B)。具有式(1)的化合物的一种可替代的路线在方案1中描述为路线A(参见下文)，其中化合物(2)与化合物(4)通过两步法反应。具有式(3)和(4)的起始化合物可以根据关于类似化合物已知的方法制备，例如如Organic Process Res.And Dev.
1997(1)，300-310所述制备。具有式(2)的哌嗪化合物可以如在EP0138280、EP0189612和/或EP0900792中所述，或者通过类似的方式获得。
具体合成方法的选择取决于本领域技术人员已知的因素，例如官能团与所用试剂的相容性，使用保护基、催化剂、活化和偶合试剂的可能性，以及制备的最终化合物中存在的最终的结构特征。
可以用本领域技术人员公知的标准方法获得药学上可接受的盐，例如通过将本发明的化合物与适宜的酸，例如无机酸如盐酸或者有机酸混合。
药物制剂
可以通过常规的方法，使用辅料如液体或固体载体材料将本发明的化合物转变成适于给药的形式。本发明的药物组合物可以进行肠、口、肠胃外(肌内或静脉内)、直肠或区域(局部)给药。它们可以以溶液、粉末、片剂、胶囊(包括微胶囊)、软膏(乳膏或凝胶)或栓剂形式给药。用于这些制剂的适宜的赋形剂为药学上的常规液体或固体填充剂和膨胀剂、溶剂、乳化剂、润滑剂、调味剂、着色和/或缓冲物质。可以提及的常用的辅料为碳酸镁、二氧化钛、乳糖、甘露醇和其它糖、滑石、乳蛋白、明胶、淀粉、纤维素和它的衍生物、动物和植物油如鱼肝油、向日葵油、花生油或芝麻油、聚乙二醇，和溶剂如无菌水和一或多羟基醇如甘油。
本发明的化合物一般作为药物组合物给药，该药物组合物由于存在该化合物，尤其是本文公开的特定化合物，因而是本发明的重要和新的实施方案。可以使用的药物组合物的类型包括但不限于片剂、咀嚼片、胶囊、溶液、肠胃外溶液、栓剂、悬浮液和本文公开的或者本领域技术人员根据说明书和技术常识明显知道的其它类型。在本发明的实施方案中，提供一种包含一个或多个填充了一种或多种本发明的药物组合物的成分的容器的药物包装或药盒。与这些容器有关的可以是多种书面材料，例如使用说明书，或者由管理药品的生产、使用或销售的政府机构规定的标记，该标记反映被该机构准许进行生产、使用或销售以用于人或兽给药。
药理学方法
对多巴胺-D2受体的体外亲合力
用I.Creese，R.Schneider和S.H.Snyder：“[3H]-Spiroperidollabels dopamine receptors in rat pituitary and brain”，Eur.J.Pharmacol.，46，377-381，1977所述的受体结合试验测定化合物对多巴胺-D2受体的亲合力。
对5-羟色胺重摄取部位的体外亲合力
用E.Habert等人，：“Characterisation of [3H]-paroxetinebinding to rat cortical membranes”，Eur.J.Pharmacol.，118，107-114，1985所述的受体结合试验测定化合物对5-羟色胺重摄取部位的亲合力。
剂量
如上述测定本发明化合物对多巴胺-D2受体和5-羟色胺重摄取部位的亲合力。根据对确定的式(1)的化合物测定的结合亲合力可以估算理论最小有效剂量。在等于测定的Ki-值两倍的化合物的浓度下，100％的受体可能被化合物占据。假设理想的生物利用度，将该浓度转化成mg化合物/kg患者，得到理论最小有效剂量。药代动力学、药效学和其它考虑可能将实际给药剂量改变至较高或较低的值。适宜的给药剂量为0.001-1000mg/kg，优选0.1-100mg/kg患者体重。
治疗
本文所用的术语“治疗”指哺乳动物，优选人症状或疾病的任何治疗，包括：(1)预防疾病或症状在可能有患病倾向但尚未诊断患病的受试者身上发生，(2)抑制疾病或症状，即阻止它的发展，(3)减轻疾病或症状，即导致疾病消退，或者(4)减轻疾病导致的症状，即停止疾病的症状。
缩写
在此申请中使用一些对本领域技术人员而言可能不完全明确的缩写。那些缩写是：
DCC＝二环己基碳二亚胺
DCM＝二氯甲烷
DIPEA＝二异丙基乙基胺
HRMS＝高分辨率质谱
5-HTP＝5-羟基色氨酸
OMes＝-O-甲磺酸酯(-O-mesylate)(离去基团之一)
RT＝室温
现在在以下实施例中更为详细地描述具有式(1)的化合物的制备。
实施例
实施例1：材料和方法
在Bruker Avance DRX600仪器(600MHz)、Varian UN400仪器(400MHz)或Varian VXR200仪器(200MHz)上，用DMSO-D6或CDCl3作为溶剂，并用四甲基硅烷作为内标，记录1H和13C NMR光谱。以ppm(δ刻度)为单位，从四甲基硅烷低磁场给出化学位移。用以下符号表示NMR光谱的峰形：‘q’(四重峰)、‘dq’(两个四重峰)、‘t’(三重峰)、‘dt’(两个三重峰)、‘d’(双重峰)、‘dd’(两个双重峰)、‘s’(单峰)、‘bs’(宽的单峰)和‘m’(多重峰)。用硅胶60(0.040-0.063mm，Merck)进行快速色谱处理(Flash chromatography)。用硅胶60(0.063-0.200mm，Merck)进行柱色谱处理。在带有用于获取和再造数据的MassLynx应用软件的Micromass QTOF-2仪器上记录质谱。完成准分子离子(quasimolecular ion)[M+H]+的准确质量测量。在Büchi B-545熔点仪上测定熔点。产率指分离的纯产物。
实施例2：合成具体化合物
如方案(见下文)1所述制备的化合物
3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基-甲基]-1H-吲哚(化合物5a).将在乙醇(30ml)中的化合物2a(2.2g，8.5mmol)、吲哚(1g，8.5mmol)和甲醛(37％，0.7ml)的溶液回流18小时。将该混合物冷却至室温，并在真空下浓缩得到粗产物5a，为一种褐色油，用硅胶柱色谱法(EtOAc/甲醇，95/5，v/v)纯化。得到化合物5a，为一种白色固体(850mg，33％)；mp85-86℃；1H-NMR(400MHz，DMSO-d6)：δ10.8(s，1H，NH-吲哚)；7.65(d，1H，J＝8Hz，H-芳族)；7.35(d，1H，J＝8Hz，H-芳族)；7.18(d，1H，J＝2Hz，H2-吲哚)；7.07(t，1H，J＝7Hz，H-芳族)；6.98(t，1H，J＝7Hz，H-芳族)；6.67(t，1H，J＝7Hz，H-芳族)；6.4-6.48(2x d，2H，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.7(bs，2H，CH2)；3.0，2.55(2x bs，8H，哌嗪).HRMS(C21H24N3O2)[M+H]+：实测值m/z350.1899，计算值350.1869。
化合物5b-n的一般合成方法
路线(A).往在无水THF(5ml/mmol)中的化合物2a的溶液加入3-(ω-烷基-羧酸)-1H-吲哚(化合物4)、二环己基碳二亚胺(DCC，1当量)，并将混合物在氮气氛下搅拌过夜。将反应混合物过滤并真空浓缩。用硅胶柱色谱法纯化剩余物得到粗化合物6。将所得的油溶于无水THF(5ml/mmol)，冷却至0℃，并往此混合物加入无水THF(10ml/mmol)中LiAlH4(1.5当量)的溶液。将该反应混合物回流2小时，并冷却于室温。往该冷却的混合物加入1N NaOH溶液(5ml/mmol)，并将该混合物搅拌1小时。用DCM(2x)萃取混合物，用水洗涤合并的有机层，并用MgSO4干燥。用硅胶柱色谱法纯化粗剩余物得到化合物5。除非另外指出，通过加入0.5当量富马酸将化合物转化成富马酸盐。
路线A.还原酰胺
a试剂和条件：(i)n＝1；CH2O，吲哚，乙醇，回流，18h；(ii)无水THF，DCC，RT，18h；iii)LiAlH4，回流，2h；iv)甲磺酰氯，DIPEA，EtoAc，RT；v)2a，CH3CN，KI，DIPEA，回流，18h
路线B).往在无水乙腈(10ml/mmol)中的化合物2a的溶液加入甲磺酸(1H-吲哚-3-基)链烷醇酯(alkanoic ester)(化合物3，L＝OMes)(1当量)、碘化钾(1当量)和DIPEA(3当量)。将该反应混合物回流18小时，然后TLC分析表明化合物3完全转化。将该混合物真空浓缩，并用硅胶柱色谱法将该粗剩余物纯化得到化合物5。除非另外指出，通过加入0.5当量富马酸将该化合物转化成富马酸盐。
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-1H-吲哚(化合物5b).通过路线B)制备化合物5b，并将其分离成为一种白色固体，为一种游离碱，产率为77％。TLC分析和硅胶柱色谱法：DMA0.25，Rf0.4；mp150-152℃；1H-NMR(400MHz，DMSO-d6)：δ10.7(s，1H，NH-吲哚)；7.5(d，1H，J＝8Hz，H-芳族)；7.32(d，1H，J＝8Hz，H-芳族)；7.06(d，1H，J＝2Hz，H2-吲哚)；7.04(t，1H，J＝7Hz，H-芳族)；6.95(t，1H，J＝7Hz，H-芳族)；6.7(t，1H，J＝8Hz，H-芳族)；6.4-6.5(2x dd，2H，J＝2Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.0(bs，4H，哌嗪)；2.72(t，2H，CH2)；2.55(bs，4H，哌嗪)；2.4(t，2H，CH2)；1.85(q，2H，CH2)；13C-NMR(DMSO-d6)：144.1，141.9，136.6，136.4，127.5，114.8(6x C-quart)；122.7，121.0，120.5，118.6，118.3，111.6，111.3，110.4(8xCH-芳族)；64.1，64.0(2x C-O)；50.5，53.4(C-哌嗪)；58.0，27.5，22.8(3xCH2-丙基)。
3-{5-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-戊基}-1H-吲哚(化合物5c)2.5-富马酸盐.通过路线A制备化合物5c。将化合物2转化成化合物5c，产率为45％。TLC分析和硅胶柱色谱法：洗脱液DMA0.5，Rf0.5。化合物5c得到一种含3当量的富马酸的白色固体。1H-NMR(400MHz，DMSO-d6)：δ10.6(s，1H，NH-吲哚)；7.48(d，1H，J＝8Hz，H-芳族)；7.32(d，1H，J＝8Hz，H-芳族)；7.04(m，2H，H2-吲哚，H-芳族)；6.95(t，1H，J＝7Hz，H-芳族)；6.7(t，1H，J＝7Hz，H-芳族)；6.6(3当量富马酸)；6.4-6.5(2x dd，2H，J＝2Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.0，2.7(2x bs，8H，哌嗪)；2.7(t，2H，CH2)；2.5(m，2H，CH2)；1.7(m，2H，CH2)；1.58(m，2H，CH2)；1.4(m，2H，CH2)。
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-4-氟-1H-吲哚(化合物5d)0.5富马酸.通过路线B制备化合物5d，为一种0.5富马酸盐，非最优产率为30％。TLC分析：洗脱液EtOAc，Rf0.1；mp207-208℃；1H-NMR(400MHz，DMSO-d)：δ11.0(s，1H，NH-吲哚)；7.15(d，1H，J＝8Hz，H-芳族)；7.07(d，1H，J＝2Hz，H2-吲哚)；7.0(m，1H，H-芳族)；6.62-6.72(m，2H，H-芳族)；6.6(s，0.5当量富马酸)；6.4-6.5(2x dd，2H，J＝2Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.0，2.6(2x bs，8H，哌嗪)；2.8(t，2H，J＝7Hz，CH2)；2.5(m，2H，CH2)；1.9(m，2H，CH2).
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-5-氟-1H-吲哚(化合物5e)0.5富马酸.通过路线B制备化合物5e，为一种0.5富马酸盐，产率为70％。TLC分析：洗脱液EtOAc，Rf0.2；1H-NMR(400MHz，DMSO-d6)：δ10.8(s，1H，NH-吲哚)；7.3(dd，1H，J＝5Hz，J＝8Hz，H-芳族)；7.2(dd 1H，J＝2Hz，J＝8Hz，H-芳族)；7.15(d，1H，J＝2Hz，H2-吲哚)；6.85(dt，1H，J＝2Hz，J＝8Hz，H-芳族)；6.7(t，1H，J＝7Hz，H-芳族)；6.6(s，0.5当量富马酸)；6.4-6.5(2xd，2H，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.0，2.6(2xd，8H，哌嗪)；2.7(t，2H，J＝7Hz，CH2)；2.44(t，2H，J＝7Hz，CH2)；1.84(m，2H，CH2).
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-6-氟-1H-吲哚(化合物5f)0.5富马酸盐.通过路线B制备化合物5f，产率为56％。TLC分析和硅胶柱色谱：洗脱液EtOAc，Rf0.3；mp205-206℃；1H-NMR(400MHz，DMSO-d6)：δ10.8(s，1H，NH-吲哚)；7.5(dd 1H，J＝5Hz，J＝8Hz，H-芳族)；7.08(m，2H，H2-吲哚，H-芳族)；6.8(m，1H，H-芳族)；6.7(t，1H，J＝7Hz，H-芳族)；6.6(s，0.5当量富马酸)；6.4-6.5(2x dd，2H，J＝1.5Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.0，2.6(2x bs，8H，哌嗪)；2.7(t，2H，CH2)；2.47(t，2H，CH2)；1.85(m，2H，CH2)。
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-7-氟-1H-吲哚(化合物5g)0.5富马酸盐.通过路线B制备化合物5g，产率为68％。TLC分析和硅胶色谱：洗脱液EtOAc，Rf0.25；1H-NMR(400MHz，DMSO-d6)：δ11.2(s，1H，NH-吲哚)；7.32(d1H，J＝8Hz，H-芳族)；7.14(d，1H，J＝2Hz，H2-吲哚)；6.9-6.96(m，1H，H-芳族)；6.82(dd，1H，J＝8Hz，J＝11Hz，H-芳族)；6.7(t，1H，J＝7Hz，H-芳族)；6.6(s，0.5当量富马酸)；6.4-6.5(2x dd，2H，J＝1.5Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.0，2.6(2x bs，8H，哌嗪)；2.73(t，2H，J＝7Hz，CH2)；2.48(t，2H，J＝7Hz，CH2)；1.87(m，2H，CH2).
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-5-甲氧基-1H-吲哚(化合物5h)富马酸盐.通过路线B制备化合物5h，产率为83％；TLC分析和硅胶色谱：洗脱液二***，Rf0.15；1H-NMR(400MHz，DMSO-d6)：δ10.5(s，1H，NH-吲哚)；7.22(d，1H，J＝9Hz，H-芳族)；7.04(d，1H，J＝2Hz，H2-吲哚)；6.96(d，1H，J＝2Hz，H-芳族)；6.7(m，2H，H-芳族)；6.6(s，2H，富马酸)；6.4-6.5(2x dd，2H，J＝1.5Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.78(s，3H，OMe)；3.04，2.63(2x bs，8H，哌嗪)；2.7(t，2H，J＝7Hz，CH2)；2.5(t，2H，CH2)；1.87(q，2H，CH2).HRMS(C24H30N3O3)[M+H]+：实测值m/z408.2292，计算值408.2292.
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-4-氯-1H-吲哚(化合物5i)0.5富马酸.通过路线B制备化合物5i，为一种0.5富马酸盐，产率为69％。TLC分析和硅胶柱色谱：洗脱液EtOAc，Rf0.2；1H-NMR(400MHz，DMSO-d6)：δ11.1(s，1H，NH-吲哚)；7.29(d，1H，J＝8Hz，H-芳族)；7.14(d，1H，J＝2Hz，H2-吲哚)；7.0(t，1H，J＝7Hz，H-芳族)；6.94(d，1H，J＝8Hz，H-芳族)；6.7(t，1H，J＝7Hz，H-芳族)；6.6(s，1H，0，5当量富马酸)；6.4-6.5(2x dd，2H，J＝1.5Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.0，2.6(2x bs，8H，哌嗪)；2.92(t，2H，J＝7Hz，CH2)；2.5(t，2H，J＝7Hz，CH2)；1.87(m，2H，CH2)。
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-5-氯-1H-吲哚(化合物5j)0.5富马酸盐.通过路线B制备化合物5j，产率为62％.Mp61-63℃(游离碱)；0.5当量富马酸的mp220-222℃(dec)；1H-NMR(400MHz，DMSO-d6)：δ11.0(s，1H，NH-吲哚)；7.54(d，1H，J＝2Hz，H-芳族)；7.34(d，1H，J＝8Hz，H-芳族)；7.14(d，1H，J＝2Hz，H2-吲哚)；7.03(dd，1H，J＝2Hz，J＝8Hz，H-芳族)；6.7(t，1H，J＝8Hz，H-芳族)；6.6(s，1H，富马酸)；6.4-6.5(2xdd，2H，J＝1.5Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.06，2.7(2x m，10H，8H哌嗪，CH2)；2.5(m，2H，CH2)；1.87(m，2H，CH2).HRMS(C23H27ClN3O2)[M+H]+：实测值m/z412.1798，计算值412.1792.
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-6-氯-1H-吲哚(化合物5k)0.5富马酸.通过路线B制备化合物5k，为一种0.5富马酸盐，产率为61％。硅胶柱色谱：洗脱液EtOAc，Rf0.25；1H-NMR(400MHz，DMSO-d6)：δ10.8(s，1H，NH-吲哚)；7.5(d，1H，J＝8Hz，H-芳族)；7.35(d，1H，J＝1.5Hz，H-芳族)；7.14(d，1H，J＝2Hz，H2-吲哚)；6.96(dd，1H，J＝2Hz，J＝8Hz，H-芳族)；6.7(t，1H，J＝7Hz，H-芳族)；6.6(s，1H，0.5当量富马酸)；6.4-6.5(2x dd，2H，J＝1.5Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.0，2.6(2x bs，8H，哌嗪)；2.72(t，2H，J＝7Hz，CH2)；2.46(t，2H，J＝7Hz，CH2)；1.85(m，2H，CH2).
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-7-氯-1H-吲哚(化合物51)0.5富马酸盐.通过路线B制备化合物51，产率为73％.硅胶柱色谱：洗脱液二***，Rf0.1；1H-NMR(400MHz，DMSO-d6)：δ11.1(s，1H，NH-吲哚)；7.5(d，1H，J＝8Hz，H-芳族)；7.17(d，1H，J＝2Hz，H2-吲哚)；7.12(d，1H，J＝8Hz，H-芳族)；6.96(t，1H，J＝7Hz，H-芳族)；6.7(t，1H，J＝7Hz，H-芳族)；6.6(s，1H，0.5当量富马酸)；6.4-6.5(2x dd，2H，J＝1.5Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.0，2.6(2x bs，8H，哌嗪)；2.72(t，2H，J＝7Hz，CH2)；2.48(t，2H，J＝7Hz，CH2)；1.86(m，2H，CH2).
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-5-甲基-1H-吲哚(化合物5m)0.5富马酸盐.通过路线B制备化合物5m，产率为65％。Mp游离碱：65-67℃；富马酸盐：mp215-217℃(dec)；1H-NMR(400MHz，DMSO-d6)：δ10.6(s，1H，NH-吲哚)；7.31(bs，1H，H-芳族)；7.23(d，1H，J＝8Hz，H-芳族)；7.04(d，1H，J＝2Hz，H2-吲哚)；6.90(dd，1H，J＝1.5Hz，J＝8Hz，H-芳族)；6.74(t，1H，J＝8Hz，H-芳族)；6.6(s，1H，0.5当量富马酸)；6.4-6.5(2x dd，2H，J＝1.5Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.06，2.7(2xm，10H，CH2，8H-哌嗪)；2.57(bm，2H，CH2)；2.40(s，3H，Me)；1.90(m，2H，CH2).HRMS(C24H30N3O2)[M+H]+：实测值m/z392.2356，计算值392.2338。
3-{3-[4-(2，3-二氢-苯并[1，4]二氧杂环己烯-5-基)-哌嗪-1-基]-丙基}-7-甲基-1H-吲哚(化合物5n)0.5富马酸盐.通过路线B制备化合物5n，产率为78％。TLC分析和硅胶柱色谱：洗脱液EtOAc，Rf0.3；1H-NMR(400MHz，DMSO-d6)：δ10.65(s，1H，NH-吲哚)；7.32(d，1H，J＝8Hz，H-芳族)；7.06(d，1H，J＝2Hz，H2-吲哚)；6.82-6.92(m，2H，H-芳族)；6.7(t，1H，J＝7Hz，H-芳族)；6.6(s，1H，0.5当量富马酸)；6.4-6.5(2x dd，2H，J＝1.5Hz，J＝8Hz，H-芳族)；4.2(bm，4H，OCH2CH2O)；3.0，2.6(2x bs，8H，哌嗪)；2.72(t，2H，J＝7Hz，CH2)；2.48(t，2H，J＝7Hz，CH2)；2.44(s，3H，Me)；1.86(q，2H，CH2).HRMS(C24H30N3O2)[M+H]+：实测值m/z392.2362，计算值392.2338.
合成化合物14(根据方案2)
1-苄基-4-(3-丙-2-炔氧基-苯基)-哌嗪(化合物10).往在MeOH(200ml)中的化合物9(27g，90mmol)的溶液加入在MeOH(200ml)中的钠(4.15g，180mmol)的溶液。将该混合物于RT下搅拌30分钟，然后在真空下浓缩。将剩余物溶于DMF(200ml)，并加入在DMF(50ml)中的炔丙基溴(11.3g，95mmol)的溶液。将该混合物于室温下搅拌过夜。用水淬灭反应混合物，并用DCM(2×300ml)萃取所得的混合物。用水洗涤合并的有机层，干燥(MgSO4)并浓缩得到粗化合物10，为一种黑色油，用硅胶柱色谱(DCM/MeOH，98/2，v/v)将其纯化得到化合物10(20g，60％)，为一种无色油。1H-NMR(400MHz，DMSO-d6)：δ7.0-7.4(m，6H，H-芳族)；6.4-6.6(m，3H，H-芳族)；4.7(d，2H，J＝2Hz，O-CH2)；3.5(s，2H，N-CH2)；3.1，2.5(2x m，8H，哌嗪)；1.98(s，H，CH).
方案2a
a试剂和条件：i)NaOMe，MeOH，然后用在DMF中的炔丙基溴，RT；ii)在220℃下加热，二乙基苯胺，1h；iii)H2，Pd/C，2摩尔当量在EtOH中的HCl，2h，RT；iv)3，CH3CN，KI，DIPEA，回流，16h，THF，RT
1-苄基-4-(2H-色烯-5-基)-哌嗪(化合物12).将化合物10溶于二乙基苯胺(45ml)，将该溶液于220℃下加热1小时，然后TLC分析表明化合物10完全转化成两种新产物。将该反应混合物冷却至室温，并在真空下浓缩得到一种褐色油，用硅胶柱色谱法纯化得到纯化合物12(10.6g，69％)和化合物11(3.4g，22％)，为无色油。化合物11：1H-NMR(400MHz，CDCl3)：δ7.3-7.4(m，5H，苯基)；6.84(d，1H，J＝8Hz，H-芳族)；6.42(dd，1H，J＝2Hz，J＝8Hz，H-芳族)；6.32-6.38(m，2H，H-4，H-芳族)；5.6(m，1H，H3)；4.76(dd，2H，H-2)；3.54(s，2H，CH2 Bn)；3.0，2.6(2x m，8H，哌嗪).化合物12：1H-NMR(400MHz，CDCl3)：δ7.24-7.4(m，5H，苯基)；7.06(t，1H，J＝8Hz，H-芳族)；6.7(m，1H，J＝2Hz，J＝8Hz，H-4)；6.55(d，2H，J＝8Hz，H-芳族)；5.7-5.8(dt，1H，J＝3Hz，J＝8Hz，H-3)；4.66(dd，2H，J＝2Hz，J＝4Hz，H-2)；3.6(s，2H，CH2 Bn)；3.0，2.6(2x m，8H，哌嗪)。
1-色满-5-基-哌嗪(化合物13).将化合物12(2.4g，8mmol)溶于含有盐酸(2mol.当量)的乙醇，并加入催化剂担载在炭上的Pd(100mg)。将该混合物于氢气氛下振荡2小时。将该混合物过滤，并在真空下浓缩得到粗化合物13，为一种油，用硅胶柱色谱将其纯化得到纯化合物13(2g，85％)，为盐酸盐；1H-NMR(400MHz，CDCl3)：δ7.2(t，1H，J＝8Hz，H-b)；6.7-6.8(2xd，2H，J＝8Hz，H5，H7)；4.2(t，2H，J＝5Hz，H2)；3.4，3.2(2x m，8H，哌嗪)；2.8(t，2H，H4)；2.0(m，2H，H3)。
3-[3-(4-色满-5-基-哌嗪-1-基)-丙基]-1H-吲哚(化合物14)0.5富马酸盐.通过路线B将化合物13(1.75g，6mmol)和化合物3b转化成化合物14(1.4g，50％)，为一种白色固体。TLC分析和硅胶柱色谱：洗脱液：DMA0.5 Rf 0.7；1H-NMR(400MHz，DMSO-d6)：δ10.7(s，1H，NH-吲哚)；～7.5(d，1H，J＝8Hz，H-芳族)；7.32(d，1H，J＝8Hz，H-芳族)；7.06(d，1H，J＝2Hz，H2-吲哚)；7.04(t，1H，J＝7Hz，H-芳族)；6.9-7.0(m，2H，H-芳族)；6.6(s，1H，0.5富马酸)；6.5(d，1H，J＝8Hz，H-芳族)；6.44(d，1H，J＝8Hz，H-芳族)；4.1(t，2H，OCH2)；2.9，2.6(2x bs，8H，哌嗪)；2.72(t，2H，CH2)；2.64，2.5(2xt，4H，CH2)；1.9(m，4H，H-2，CH2)。
表1.合成具有通式(1)的化合物.
| 编号 | m | n | R1 | R | R3 | R4 | Y | X | Rt | 盐 | 产率 |
| 5a | 1 | 0 | - | H | H | H | O | O | - | - | 33％ |
| 5b | 3 | 0 | - | H | H | H | O | O | B | - | 77％ |
| 5c | 5 | 0 | - | H | H | H | O | O | A | 0.5fum | 35％ |
| 5d | 3 | 1 | 4-F | H | H | H | O | O | B | 0.5fum | 30％ |
| 5e | 3 | 1 | 5-F | H | H | H | O | O | B | 0.5fum | 70％ |
| 5f | 3 | 1 | 6-F | H | H | H | O | O | B | 0.5fum | 56％ |
| 5g | 3 | 1 | 7-F | H | H | H | O | O | B | 0.5fum | 68％ |
| 5h | 3 | 1 | 5-OCH3 | H | H | H | O | O | B | 0.5fum | 83％ |
| 5i | 3 | 1 | 4-Cl | H | H | H | O | O | B | 0.5fum | 69％ |
| 5j | 3 | 1 | 5-Cl | H | H | H | O | O | B | 0.5fum | 62％ |
| 5k | 3 | 1 | 6-Cl | H | H | H | O | O | B | 0.5fum | 61％ |
| 5l | 3 | 1 | 7-Cl | H | H | H | O | O | B | 0.5fum | 73％ |
| 5m | 3 | 1 | 5-CH3 | H | H | H | O | O | B | 0.5fum | 65％ |
| 5n | 3 | 1 | 7-CH3 | H | H | H | O | O | B | 0.5fum | 78％ |
| 14 | 3 | 0 | - | H | H | H | O | CH2 | - | - | 50％ |
编号＝文本中所用的化合物号，Rt＝方案1中所述的路线A或B；fum＝富马酸盐；百分产率基于化合物2。
合成如上述的特定化合物意在更为详细地进一步例示本发明。因此它们不被认为以任何方式限制本发明的范围。本发明的其它实施方案对于考虑了本文公开的本发明的说明和实施的本领域技术人员来说显而易见的。因此该说明书和实施例意欲被认为仅仅是例举，而本发真实范围和构思由权利要求表示。
实施例2：用于生物试验的化合物5e的制剂
为进行口服(p.o.)给药：往在玻璃管中的期望数量(0.5-5mg)的固体化合物5e加入一些玻璃珠，并通过涡旋2分钟将固体粉碎。加入1ml在水中的1％甲基纤维素和2％(v/v)的Poloxamer 188(Lutrol F68)的溶液之后，通过涡旋10分钟来悬浮化合物。用数滴NaOH水溶液(0.1N)调节pH至7。用超声浴进一步悬浮在悬浮液中的剩余颗粒。
为进行腹膜内(i.p.)给药：往在玻璃中的期望数量(0.5-15mg)固体化合物5e加入一些玻璃珠，并通过涡旋2分钟将固体粉碎。加入1ml在水中的1％甲基纤维素和5％甘露醇溶液之后，通过涡旋10分钟来悬浮化合物。最后将pH调节至7。
实施例3：药理学试验结果
表2.体外和体内试验结果
根据上文描述的方法得到下表的结果。结合数据是三个单独实验的平均值。
| 体外亲合力 | 体内活性 | |||
| 编号 | 多巴胺-D2 | 5-HT重摄取 | 多巴胺-D2 | 5-HT重摄取 |
| 结合 | 结合 | APO-climb* | 5-HTP** | |
| 编号 | Ki(nM) | Ki(nM) | ED50mg/kg po | ED50mg/kg po |
| 5a | 62.0±17 | 176.0±59 | - | - |
| 5b | 21.0±9.9 | 0.4±0.1 | 10 | 22 |
| 5c | 9.1±1.8 | 37.0±3 | - | - |
| 5d | 8.1±3.1 | 0.4±0.1 | 13 | 32 |
| 5e | 19.0±3 | 0.3±0.1 | 15 | 2.0 |
| 5f | 14.6±3.5 | 1.6±0.2 | 9 | 30 |
| 5g | 10.6±4 | 0.6±0.1 | 4.1 | 28.4 |
| 5h | 5.0±4 | 14.0±4 | - | - |
| 5i | 24.0±3 | 1.4±0.4 | - | - |
| 5j | 31.6±16 | 1.4±0.7 | - | - |
| 5k | 2.1±1 | 2.0±0.7 | 4.5 | 86 |
| 5l | 15.5±5.4 | 7.9±2.8 | - | - |
| 5m | 10.7±2.8 | 1.3±0.9 | - | - |
| 5n | 15.9±4.7 | 12.0±5 | - | - |
| 14 | 20.3±2.7 | 1.1±0.3 | - | - |
Claims (10)
1.通式(1)的化合物及其互变异构体、立体异构体和N-氧化物，以及该式(1)的化合物及其互变异构体、立体异构体和N-氧化物的药理学上可接受的盐、水合物和溶剂合物：
其中：
Y为CH2、O或S，
X为CH2、O、NH或S，
m为1、3、5或6，
n为0、1、2或3，
R4为氢或卤素，
R2和R3独立地为H或烷基(C1-3)，或者R2+R3代表基团-(CH2)-p，其中p的值为3、4或5，且
R1为烷基(C1-3)、烷氧基(C1-3)、卤素或氰基，或者当R1在吲哚基的7位时R1+R3可以代表基团-(CH2)q-，其中q的值为2、3或4。
2.权利要求1所要求的通式(1)的化合物及其互变异构体、立体异构体和N-氧化物，以及该式(1)的化合物及其互变异构体、立体异构体和N-氧化物的药理学上可接受的盐、水合物和溶剂合物，其中：Y为O，X为CH2或O，m为1、3或5，n为1，R2、R3和R4为氢，而R1为氢、甲基、氟、氯或甲氧基。
3.选自以下的权利要求1所要求的化合物及其互变异构体、立体异构体和N-氧化物，以及该式(1)的化合物及其互变异构体、立体异构体和N-氧化物的药理学上可接受的盐、水合物和溶剂合物：
其中的符号代表式(1)中的那些符号：
4.一种药物组合物，包含药学上可接受的载体和/或至少一种药学上可接受的辅料，和作为活性成分的药理学活性量的至少一种权利要求1-3之一的化合物或其盐。
5.权利要求4所要求的组合物的制备方法，其特征在于将至少一种权利要求1-3之一的化合物或其盐制成适于给药的形式。
6.权利要求1-3之任意项所要求的化合物或其盐，用作药物。
7.权利要求1-3之任意项所要求的化合物用于制备治疗CNS的药物组合物的应用。
8.权利要求7所要求的应用，其特征在于该疾病为攻击、焦虑症、孤独症、眩晕、抑郁、认知或记忆障碍、帕金森氏病、精神***症和其它精神障碍。
9.权利要求7所要求的应用，其特征在于该疾病为抑郁。
10.权利要求7所要求的应用，其特征在于该疾病为精神***症和其它精神障碍。
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- 2005-12-06 MX MX2007006758A patent/MX2007006758A/es active IP Right Grant
- 2005-12-06 RU RU2007125691/04A patent/RU2007125691A/ru not_active Application Discontinuation
- 2005-12-06 CA CA002587940A patent/CA2587940A1/en not_active Abandoned
- 2005-12-06 AU AU2005313388A patent/AU2005313388A1/en not_active Abandoned
-
2007
- 2007-05-22 ZA ZA200704156A patent/ZA200704156B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TW200631952A (en) | 2006-09-16 |
| WO2006061374A1 (en) | 2006-06-15 |
| JP2008523028A (ja) | 2008-07-03 |
| RU2007125691A (ru) | 2009-01-20 |
| AU2005313388A1 (en) | 2006-06-15 |
| KR20070087644A (ko) | 2007-08-28 |
| ZA200704156B (en) | 2008-05-28 |
| EP1824486B1 (en) | 2009-03-18 |
| EP1824486A1 (en) | 2007-08-29 |
| SA05260390B1 (ar) | 2009-04-01 |
| MX2007006758A (es) | 2007-11-09 |
| ATE425754T1 (de) | 2009-04-15 |
| CA2587940A1 (en) | 2006-06-15 |
| AR052332A1 (es) | 2007-03-14 |
| BRPI0518372A2 (pt) | 2008-11-18 |
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