CN1328553A - 用于治疗精神疾病的3－四氢吡啶－4－基吲哚 - Google Patents

用于治疗精神疾病的3－四氢吡啶－4－基吲哚 Download PDF

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CN1328553A
CN1328553A CN99813580A CN99813580A CN1328553A CN 1328553 A CN1328553 A CN 1328553A CN 99813580 A CN99813580 A CN 99813580A CN 99813580 A CN99813580 A CN 99813580A CN 1328553 A CN1328553 A CN 1328553A
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M·T·M·图尔普
J·A·M·范德尔海基顿
B·范威莱特
J·泰普科尔
R·范赫斯
C·G·克斯
G·M·维瑟尔
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Abstract

本发明涉及一组新的具有有用的药理特性的3－四氢吡啶－4－基吲哚。这些化合物及其盐具有通式(Ⅰ)结构,其中R1为卤素、CF3、C1－3烷基、C1－3烷氧基、CN或SCH3;m为0、1或2;R2为H或C1－3烷基;n为3、4、5或6;R3为卤素、C1－4烷基;或C1－4烷氧基;p为0、1或2。

Description

用于治疗精神疾病的3-四氢吡啶-4-基吲哚
本发明涉及一组新的式(I)化合物3-四氢吡啶-4-基吲哚衍生物及其盐：其中：
R1为卤素、CF3、C1-3烷基、C1-3烷氧基CN或SCH3-m为0、1或2-R2为H或C1-3烷基-n为3、4、5或6-R3为卤素、C1-4烷基或C1-4烷氧基-p为0、1或2
已发现式(I)化合物对多巴胺D2-受体有高度的亲和力并且是很好的5-羟色胺再摄取抑制剂(SRI′S)。
本发明化合物优选的式(I)化合物及其盐是，其中R1为H(即m＝0)或F、Cl、CH3、或CN，和m＝1，R2为H或CH3，n＝4，R3为H(即p＝0)，或F或烷基C1-4，p＝1。特别优选式(I)化合物及其盐中的(R1)m为F，R2为H，n＝4和p＝0。
已经发现本发明化合物对多巴胺D2-受体和5-羟色胺再摄取位点均有高度的亲和力。这种联合作用对于治疗精神分裂症和其他精神疾病是有用的，并且可确保对所有疾病症状(例如阳性症状和阴性症状)能进行更彻底的治疗。
化合物在小鼠中有潜力对抗由阿扑吗啡诱导的爬行行为，显示了其对多巴胺D2-受体有拮抗剂的活性。化合物加强了小鼠的5-HTP(5-羟色胺)诱导的行为，也显示了其对5-羟色胺再摄取有抑制剂活性。
化合物在对临床上相关的抗精神病药(例如，条件化躲避反应(Theconditioned avoidance response)；Van der Heyden和Bradford，脑行为学研究(Behav.Brain.Res.)，1988，31：61-67)和抗抑郁药或抗焦虑药(Suppression of stress-induced vocolization；vander Poel等.，精神药理学(Psychoharmacology)，1989，97：147-148)敏感的治疗模型具有活性。
与临床上相关的多巴胺D2-受体拮抗剂相反的是，在此所描述的化合物对啮齿动物具有较低的僵住症诱导趋势，并且与现有抗精神病药相比，化合物的锥体外系副反应较低。
这些化合物对抗抑郁药或抗焦虑药敏感的行为模型的治疗效果表明，这种疗效可能是化合物所固有的对5-羟色胺再摄取的抑制活性所致。
化合物可用于由多巴胺能或5-羟色胺能系统紊乱所致的中枢神经系统病变或疾病，例如：攻击、焦虑症、孤独症、眩晕、抑郁、识别或记忆失调和尤其是精神分裂症和其他精神疾病。
用于与本发明化合物形成适宜酸加成盐的药理可接受的酸包括如盐酸、硫酸、磷酸、硝酸，和有机酸如柠檬酸、富马酸、马来酸、酒石酸、乙酸、苯甲酸、对甲苯磺酸、甲磺酸和萘磺酸。
通过用辅助物质如液体和固体载体材料处理，可将化合物及其酸加成盐制成适于给药的形式。
按下述获得式(I)化合物：
a)式(II)化合物与式(III)化合物反应，其中的符号含义同上并且L是所谓的离去基团，例如溴基。
Figure A9981358000051
回流温度下，于三乙胺或K2CO3和KI存在下的溶剂如乙腈中进行反应，或
b)(ⅰ)将式(IV)化合物中的氰基还原成-(CH2)n-NH2
Figure A9981358000062
其中A代表-(CH2)n-1-CN基团；和
(ⅱ)将所得的胺与任选取代的邻苯二甲酸酐式(V)化合物反应式中所用符号含义同上。
反应步骤b(ⅰ)可用如LiAlH4在有机溶剂如四氢呋喃中于回流温度下进行。
反应步骤(ⅱ)可例如在有机溶剂如四氢呋喃和甲苯中于回流温度下进行。
采用本领域已知方法，用4-哌啶酮与任选取代的吲哚衍生物反应可获得方法a)中的式(II)起始化合物。
采用本领域已知方法，用式(II)化合物与式Br-(CH2)n-1-CN的溴烷基腈反应可获得方法b)中式(IV)的起始化合物。
下述实施例将详细描述式(I)化合物的制备。
实施例1
1-甲基-3-(1，2，3，6-四氢吡啶-4-基)吲哚的制备
于室温下，向含4-哌啶酮·H2O·盐酸盐(50g，0.32mol)的100ml乙酸和150ml三氟乙酸溶液中滴加1-甲基吲哚(11.5ml，0.09mol，于100ml乙酸中)。反应混合物搅拌1小时后浓缩(真空，约30℃)、加水，加碳酸钾碱化并且用乙酸乙酯提取。分离有机层，干燥并用硅胶柱色谱(二氯甲烷/甲醇/氢氧化铵＝85/15/1)纯化获得9g(47％)标题所示化合物。
实施例2
5-氟-3-(1，2，3，6-四氢吡啶-4-基)吲哚的制备
向1000ml含钠(60g，2.6mol)的甲醇溶液中加入5-氟吲哚(49g，0.36mol)和4-哌啶酮·H2O·盐酸盐(170g，1.11mol)。混合物回流加热18小时后浓缩、加水，用乙酸乙酯提取。合并的有机层用硫酸钠干燥并浓缩。所得固体用甲醇(约200ml)溶解并用水(约1000-1500ml)稀释。收集沉淀并用水和石油醚洗涤，然后于真空下60℃烘干。获得74g(95％)黄色固体物。
实施例3
N-[4-[4-[(5-氟-1H-吲哚-3-基)-1，2，3，6-四氢吡啶-1-基]丁基]-邻苯二甲酰亚胺·盐酸盐(化合物1)的制备
5-氟-3-(1，2，3，6-四氢吡啶-4-基)吲哚(7.5g，34.7mmol)、N-(4-溴丁基)邻苯二甲酰亚胺(10.8g，38.3mmol)、三乙胺(4.5ml)和碘化钾(5.5g)在150ml乙腈中的溶液回流加热18小时。反应混合物浓缩并用硅胶柱色谱(二氯甲烷/甲醇/氢氧化铵＝92/7.5/0.5)纯化获得8.3g标题所示的游离碱化合物，熔点为186℃。将该游离碱溶于20ml1MHCl乙醇中制得其盐酸盐。浓缩溶液并用醚洗涤所得固体。获得8.4g(54％)化合物1，熔点为224℃(分解)。
实施例4
5-氟-3-[1-(3-氰丙基)-(1，2，3，6-四氢吡啶-4-基)吲哚的制备
将5-氟-3-(1，2，3，6-四氢吡啶-4-基)吲哚(10g，46mmol)、4-溴丁腈(5.6ml，56mmol)、碳酸钾(6.3g)和碘化钾(7.6g)在100ml乙腈中的溶液回流加热18小时。过滤混合物并用84/15/1的二氯甲烷/甲醇/氢氧化铵冲洗滤器中的残余物。浓缩有机层得到10.9g(83％)标题所示的化合物，熔点为152℃。
实施例5
5-氟-3-[1-(4-氨基丁基)-1，2，3，6-四氢吡啶-4-基]吲哚的制备
向含有5-氟-3-[1-(3-氰丙基)-1，2，3，6-四氢吡啶-4-基]吲哚(10g，35mmol)的300ml干THF溶液中缓慢加入LiAlH4(2.0g)。搅拌混合物并加热回流18小时。然后冷却反应混合物并依次缓慢加入含水(1.9ml)的THF(10ml)和2N氢氧化钠(1.9ml)。混合物加热回流0.25小时，用hyflo过滤和浓缩获得8.76g(88％)标题所示化合物。
实施例6
N-[4-[4-[(5-氟-1H-吲哚-3-基)-1，2，3，6-四氢吡啶-1-基]丁基]-4-氟邻苯二甲酰亚胺(化合物19)的制备
向含有5-氟-3-[1-(4-氨基丁基)-1，2，3，6-四氢吡啶-4-基]吲哚(1.46g，5mmol)的20ml THF溶液中加入4-氟邻苯二甲酸酐和50ml甲苯。蒸馏除去THF并将所得混合物加热回流18小时，共沸除去水。反应混合物浓缩并用硅胶柱色谱(二氯甲烷/甲醇/氢氧化铵＝92/7.5/0.5)纯化获得1.52g(69％)标题所示的化合物19，熔点为197-199℃。
按实施例1-3所示的方法a)，或按实施例4-6所示的方法b)制备下表所示化合物：                                                              表
化合物编号   (R1)m   R2  n      (R3)p    盐/碱 熔点℃
1  5-F  H  4  H HCl 224(分解)
2  H  H  4  H 碱 193-4
3  H  H  3  H 碱 190-2
4  H  CH3  4  H HCl 230
5  7-CH3  H  4  H 碱 175-8
6  5-F  H  3  H 碱 174-6
7  H  H  4  3-F 碱 173-4
8  H  H  4  3-CH3 碱 184-5
9  H  H  4  4-CH3 碱 195-8
10  5-CN  H  3  H 碱 无定形
11  5-CN  H  4  H 碱 无定形
12  5-Cl  H  4  H 碱 无定形
13  H  H  4  4-F 碱 197-8
14  H  H  4  4-t.C4H9 富马酸盐 243-5
15  5-F  H  4  4-t.C4H9 富马酸盐 193-5
16  5-F  H  4  3-CH3 碱 167-8
17  5-F  H  4  4-CH3 碱 199-200
18  5-F  H  4  3-F 碱 188-190
19  5-F  H  4  4-F 碱 197-9
20  H  H  6  H 碱 196-7
21  5-F  H  6  H 碱 170-2
22  5-F  H  4  4，5-二氯 碱 216-8
23  H  H  4  4，5-二氯 碱 217-8
24  5-F  H  5  H 碱 194-8
25  5-F  H  4  4-Cl 碱 186-8
26  H  H  4  4-Cl 碱 209-215

Claims (7)

1.式(I)化合物及其药理可接受的酸加成盐，
Figure A9981358000021
其中：-R1为卤素、CF3、C1-3烷基、C1-3烷氧基、CN或SCH3-m为0、1或2-R2为H或C1-3烷基-n为3、4、5或6-R3为卤素、C1-4烷基或C1-4烷氧基-p为0、1或2。
2.如权利要求1的化合物及其药理可接受的酸加成盐，其中(R1)m为H、F、Cl、CH3或CN，m＝1，R2为H或CH3，n＝4，(R3)p为H、F或C1-4烷基而p＝1。
3.如权利要求1的化合物及其药理可接受的酸加成盐，其中(R1)m为F，m＝1，R2为H，n＝4而p＝0。
4.制备如权利要求1的化合物的方法，其特征在于：a)将式(II)化合物与式(III)化合物反应，其中L为离去基团；
或b)(ⅰ)将式(IV)化合物，
Figure A9981358000031
其中A为-(CH2)n-1-CN基团被还原成相应的-(CH2)n-NH2基团；和
(ⅱ)将所得的胺与式(V)的邻苯二甲酸酐化合物反应，
Figure A9981358000032
其中R1、m、R2、n、R3和p的含义权利要求1所述。
5.一种药用组合物，其中含有至少一种如权利要求1的化合物作为活性成分。
6.制备如权利要求5的组合物的方法，其特征在于将权利要求1的化合物制成适于给药的形式。
7.一种治疗中枢神经系统疾病的方法，其特征在于使用如权利要求1的化合物。
CNB998135801A 1998-10-16 1999-10-15 用于治疗精神疾病的3-四氢吡啶-4-基吲哚 Expired - Fee Related CN1140524C (zh)

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Cited By (3)

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US8568869B2 (en) 2005-04-06 2013-10-29 3M Innovative Properties Company Optical bodies including rough strippable boundary layers and asymmetric surface structures
US9709700B2 (en) 2005-04-06 2017-07-18 3M Innovative Properties Company Optical bodies including rough strippable boundary layers
US10228502B2 (en) 2005-04-06 2019-03-12 3M Innovative Properties Company Optical bodies including strippable boundary layers

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EP1121356B1 (en) 2003-01-08
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KR100619464B1 (ko) 2006-09-05
JP4659984B2 (ja) 2011-03-30
TR200101808T2 (tr) 2001-10-22
WO2000023441A1 (en) 2000-04-27
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CA2346896A1 (en) 2000-04-27
PL195734B1 (pl) 2007-10-31
AU750811B2 (en) 2002-07-25
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