CN1155596C - 新的苯基哌嗪 - Google Patents
新的苯基哌嗪 Download PDFInfo
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Abstract
本发明涉及一组具有目的药理性质的新的苯基哌嗪化合物。本发明涉及一组通式(I)所示的新的苯基哌嗪衍生物：其中：X是1)通式(1)所示基团，其中：S1是氢或卤素，S2和S3独立的是氢、具有1-6个碳原子的烷基、苯基或苄基，S4代表两个氢原子或一个氧代基，S5是氢或具有1-4个碳原子的烷基，且Y是C、O或S；或2)通式(2)所示基团，其中S1具有上述含义且R是H、具有1-4个碳原子的烷基、具有2-6个碳原子的烷氧基烷基，具有2-4个碳原子的链烯基或具有2-4个碳原子的炔基；或3)通式(3)所示基团，其中S1具有上述含义且Z是C、O或N，或4)通式(4)所示基团，其中S1具有上述含义；或5)通式(5)所示基团，其中S1具有上述含义且A是O或N，与哌嗪环的5位或8位相连；或6)通式(6)所示基团，其中S1具有上述含义且S6和S7代表氢原子或一个氧代基；或7)通式(7)所示基团，其中一条虚线可代表一个双键，S1具有上述含义，且P＝T＝Q＝氮或P＝T＝氮且Q＝C或P＝Q＝氮且T＝C或C-CH3或P＝氮，且T和Q是碳或P＝氮，T是碳且Q是硫，m的值为2-6；n的值为0-2；R5和R6独立的是氢或具有1-3个碳原子的烷基；或R5+R6代表-(CH2)-p，其中p的值为3-5，且R7是具有1-3个碳原子的烷基，具有1-3个碳原子的烷氧基，卤素或氰基；或R6+R7(R7在吲哚基的7位)代表-(CH2)q所示基团，其中q的值为2-4，及其盐。
Description
本发明涉及一组通式(I)所示的新的苯基哌嗪衍生物及其盐：
其中：
-X是通式(1)所示基团
其中
-S1是氢或卤素，
-S2和S3分别是氢、具有1-6个碳原子的烷基、苯基或苄基，
-S4代表两个氢原子或一个氧代基，
-S5是氢或具有1-4个碳原子的烷基，且
-Y是C、O或S，
或通式(2)所示基团
其中S1具有上述含义且R是H、具有1-4个碳原子的烷基、具有2-6个碳原子的烷氧基烷基，具有2-4个碳原子的链烯基或具有2-4个碳原子的炔基，
或通式(3)所示基团
其中S1具有上述含义且Z是C、O或N，
或通式(4)所示基团
其中S1具有上述含义，
或通式(5)所示基团
其中S1具有上述含义且A是O或N，与哌嗪环的5位或8位相连
或通式(6)所示基团
其中S1具有上述含义且S6和S7代表氢原子或一个氧代基，
或通式(7)所示基团
其中一条虚线可代表一个双键，S1具有上述含义，且
P＝T＝Q＝氮
或P＝T＝氮且Q＝C
或P＝Q＝氮且T＝C或C-CH3
或P＝氮，且T和Q是碳
或P＝氮，T是碳且Q是硫
-m的值为2-6；
-n的值为0-2；
-R5和R6独立的代表氢或具有1-3个碳原子的烷基；或R5+R6代表-(CH2)-p，其中p的值为3-5，且
-R7是具有1-3个碳原子的烷基，具有1-3个碳原子的烷氧基，卤素或氰基；或R6+R7(R7在吲哚基的7位)代表-(CH2)q团，其中q的值为2-4，
它们对多巴胺D2受体具有高亲和力，并且是良好的5-羟色胺重吸收抑制剂(SRI’s)。
本发明优选X代表通式(1)、(2)或(3)所示基团的通式(I)化合物及其盐，其中符号的含义如上所。
特别优选X代表通式(1)所示基团，其中S1＝H、S2＝CH3、S3＝H、S4＝氧代、S5＝H且Y是氧。m是3，R5＝R6＝H，n是0或1且R7是5-氟的通式(I)化合物及其盐。
现已发现本发明的化合物对多巴胺D2受体和5-羟色胺重吸收位点表现出高亲和力。这种结合可有效治疗精神分裂症和其他精神病症，它能够更完全的治疗多种病症(例如，阳性症状和阴性症状)。
然而，一些通式(I)化合物对多巴胺受体表现(部分)激动剂活性，这使它们特别适合用于治疗帕金森氏病。
这些化合物表现出多巴胺D2受体的拮抗剂活性，因为它们潜在的拮抗小鼠的阿扑吗啡诱导的爬升行为。由于它们加强了小鼠中5-HTP诱导的行为，因此这些化合物也显示作为5-羟色胺重吸收抑制剂的活性。
这些化合物在对临床相关的抑制精神病症(例如，条件性逃避反应；Van derHeyden和Bradford发表在Behav.Brain Res.，1988，31：61-67的文章)和抗抑郁药或抗焦虑药(例如，抑制紧张引起的发声；Van der Poel等人发表在《精神药理学》(Psychopharmacology)，1989，97：147-148的文章)敏感的治疗模型中有活性。
与临床相关的多巴胺D2受体拮抗剂相对，描述的化合物对诱导啮齿动物强直性昏厥的倾向较低。并因此可能比现有的抗精神病剂较少地诱导对锥体束外的副作用。
这些化合物固有的对5-羟色胺重吸收的抑制活性可产生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。
这些化合物可用于治疗由多巴胺能系统或5-羟色胺能系统紊乱引起的中枢神经系统病变或疾病，例如攻击、焦虑、孤独癖、眩晕、抑郁、识别或记忆障碍、帕金森氏病，且特别是精神分裂症和其它精神病症。
药学上可接受的酸与本发明的化合物可形成适宜的酸加成盐，这些酸的例子有，例如盐酸、硫酸、磷酸、硝酸，和有机酸如枸橼酸、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。
当化合物含有手性中心时，外消旋混合物和单个旋光异构体都属于本发明。
化合物和它们的酸加成盐可用辅料如液体和固体载体材料，通过适宜的方法制成适合的给药形式。
通式(I)化合物可由通式(II)化合物
在碱性条件下与通式(III)化合物反应制备而成。
通式中的符号的含义如上所述，且L是所谓的离去基团，如卤原子或甲磺酰基。
通式(II)的哌嗪化合物可按照EP0138280、EP0189612和/或EP0900792中描述的方法，或类似的方法得到。
通式(II)的哌嗪化合物可按照下面流程(i)-(iv)所示的步骤制备而成。某些路线产生光学纯的哌嗪衍生物。
流程(i)
流程(ii)
流程(iii)
通式(III)的起始化合物可根据制备类似化合物的已知方法制备，例如在Organic Process Res.and Dev.
1997(1)，300-310中描述的方法。
现在，通过下面的实施例说明本发明：
实施例1：化合物a.i(见流程i)的制备
步骤1(流程i)：向氯硝基儿茶酚(6.45g，34mmol)的无水DMSO(50ml)溶液中加入粉状NaOH(2.72g，68mmol)。将溶液搅拌30分钟后，加入R-甘油缩酮甲磺酸酯(8.0g，38mmol)的DMSO(20ml)溶液，将该混合物在80℃加热24小时。冷却至室温后，将反应混合物注入水(200ml)中，用1N盐酸酸化，并用甲基叔丁基醚萃取，有机部分用水洗涤，并用MgSO4干燥。在真空中除去干燥剂和溶剂，得到的油状物经过闪式色谱(SiO2，PE/丙酮＝3/1作为洗脱剂)，S-缩酮的收率为9.29g(90％)。
步骤2(流程i)：向S-缩酮(31g，102mmol)的乙酸(120ml)溶液中加入35％的HBr乙酸(80ml)溶液，并且将该混合物在50℃水浴条件下在旋转蒸发仪上旋转2小时。反应混合物用乙醇(96％，250ml)稀释，在盐/冰混合物中冷却，然后缓慢加入NaOH(50％水溶液，250ml)，温度始终保持在15℃以下。加入乙醇(250ml)和水(250ml)后，将反应混合物在室温下搅拌16小时。然后加入浓盐酸(大约300ml)和水，将混合物用乙酸乙酯萃取。将有机部分用5％NaHCO3(4×500ml)洗涤后，在真空中除去溶剂，得到的油状物经过闪式色谱(SiO2，PE/丙酮＝3/1作为洗脱剂)，得到黄色油状的R-苯并二噁烷为20.5g(81％)。
步骤3(流程i)：向R-苯并二噁烷(20g，81mmol)的DMF溶液(200ml)中加入KOH(4.56g，81mmol)。在冰/丙酮中冷却红色溶液后，加入二甲基硫酸酯(23ml)，并将反应混合物在室温下搅拌1.5小时。然后再加入KOH(4.56g，冷却)，并将混合物在室温下搅拌16小时，加入水(700ml)之后，产物用乙酸乙酯萃取。在真空中除去乙酸乙酯，得到的油状物经过闪式色谱(SiO2，PE/丙酮＝4/1作为洗脱剂)，得到黄油状的R-甲氧基甲基苯并二噁烷(12.3g，58％)。[α]D 25＝-97°(甲醇中)。
步骤4(流程i)：向R-甲氧基甲基苯并二噁烷(5g，19mmol)的乙醇(100ml)和乙酸乙酯(50ml)溶液中加入催化量为10％的Pd/C，将溶液在室温、H2大气压下振荡。计算量的H2被反应混合物吸收后，过滤除去催化剂，并将滤液在真空中浓缩。得到对应的苯氨基化合物3.7g(100％)。
步骤5(流程i)：将苯氨基化合物(4g，2mmol)和BCEA，也就是HN(CH2CH2Cl)2HCl(3.7g，2mmol)溶解在氯苯(100ml)中。将混合物加热到150℃，加热16小时，在真空中浓缩，并用闪式色谱纯化(SiO2，二氯甲烷/甲醇/氢氧化铵＝92/7.5/0.5)，得到哌嗪
a.i(3.67g，68％)。
实施例2：化合物no.126的制备
路径如上所述，也就是化合物(II)与化合物(III)反应。通式(III)的甲磺酸酯按照标准步骤从相应的醇制备得到，例如用MsCl/Et3N。
哌嗪
a.i的混合物(3.6g，13.6mmol)，5-氟吲哚-甲磺酸酯(4.1g，15.1mmol)，三乙胺(2ml)和催化剂KI在CH3CN(100ml)中加热回流18小时后，反应混合物在真空中浓缩，并用闪式色谱纯化(SiO2，二氯甲烷/甲醇/氢氧化铵＝92/7.5/0.5)，得到游离碱(油状物)3.77g。将游离碱溶于乙醇，并在乙醇中加入1当量的富马酸。除去溶剂后，得到化合物no.126(4.3g，57％)。[α]D 25＝-2°(甲醇中)。
实施例3：化合物b.ii(见流程ii)的制备
步骤1(流程ii)：将氨基苯酚(37.3g，198mmol)、S-乳酸甲酯(20ml)和三苯基膦(58g，220mol)的THF(2000ml)溶液在冰/盐(温度＜10℃)中冷却。然后将偶氮二羧酸酯(DIAD，43ml，218mmol)的THF(400ml)溶液缓慢加入。在室温下搅拌18小时后，将反应混合物在真空中浓缩，并向剩余物中加入乙醇(500ml)和36％的HCl(125ml)。将混合物加热到100℃(产生气体)。冷却后，过滤分离化合物并用96％的乙醇(大约100ml)洗涤得到42g(87％)。
步骤2(流程ii)：该步骤与流程i中的步骤4相似。
步聚3(流程ii)：该步骤与流程i中的步骤5相似，结果得到哌嗪b.ii。
实施例4：化合物no.89的制备
路径如上所述，也就是化合物(II)与化合物(III)反应。反应按照实施例2中描述的步骤进行，以哌嗪b.ii为起始原料，得到58％的化合物no.89，[α]D 25＝-24°(甲醇中)。
实施例5：化合物c.iii(见流程iii)的制备
步骤1(流程iii)：将苯并吗啉酮(10g，41mmol；见流程ii，步骤1)和粉状KOH(2.3g，41mmol)的DMF(100ml)溶液在冰(温度＜10℃)中冷却。加入1当量的MeI(2.55ml，41mmol)后，将反应混合物在室温下搅拌1.5小时，然后注入水中。滤出沉淀，用水洗涤并干燥。得到NCH3--化合物10g(95％)，mp.191-192；[α]D 25＝+7.5°(THF中)。
步聚2(流程iii)：该步骤与流程i中的步骤4相似。
步骤3(流程iii)：该步骤与流程i中的步骤5相似，结果得到哌嗪c.iii。
实施例6：化合物no.121的制备
路径如上所述，也就是化合物(II)与化合物(III)反应。反应按照实施例2中描述的步骤进行，以哌嗪c.iii为起始原料，得到44％的化合物no.121，[α]D 25＝-28°(甲醇中)。
实施例7：化合物d.iv(见流程iv)的制备
步骤1(流程iv)：将吡啶(81ml，1mol)加入2-羟基-5-氯苯胺(143.5g，1mol)的干燥CH2Cl2溶液，混合物在冰(温度＜10℃)中冷却，然后缓慢加入2-溴-2-甲基-丙酰溴(163ml，1mol)的CH2Cl2溶液(100ml)。将混合物在室温下搅拌18小时，然后注入CH2Cl2(5000ml)和水(2000ml)中。有机层用水洗涤，干燥并且在真空中浓缩至大约1升。滤出沉淀，用CH2Cl2洗涤并干燥。得到231g(79％)溴化合物，mp.172℃。
步聚2(流程iv)：冰冷却下，将浓硫酸(7ml)缓慢加入溴化合物(60g，205mmol)在水(95ml)中的悬浮液中，随后加入70％HNO3(16ml)，并在室温下连续搅拌2小时。在冰水中冷却后，滤出沉淀，用水洗涤，并用闪式色谱纯化(SiO2，甲基叔丁基醚)，得到硝基化合物49g(71％)。
步聚3(流程iv)：向硝基化合物(49g，145mmol)的DMF(500ml)溶液中加入K2CO3，将该混合物在150℃加热1小时，然后冷却并倒入水/乙酸乙酯的混合物中。有机部分分别用5％的碳酸氢钠水溶液、2N的HCl和水洗涤。在真空中除去溶剂，残留物用闪式色谱纯化(SiO2，甲基叔丁基醚/PE＝1/1)，得到23g(62％)。
步骤4(流程iv)：该步骤与流程i中的步骤4相似。
步骤5(流程iv)：该步骤与流程i中的步骤5相似，得到哌嗪d.iv。
实施例8：化合物no.115的制备
路径如上所述，也就是化合物(II)与化合物(III)反应。反应按照实施例2中描述的步骤进行，以哌嗪d.iv为起始原料，得到20％的化合物no.115。
下面表格中列出的化合物已根据上述实施例中的方法制备而成。
| 化合物序号 | X | m | Y | R5 | R6 | (R7)n | R | Z | A | S6+S7 | P | T | Q | 注释 |
| 1 | 通式2 | 3 | - | H | H | H | 2-CH2OH | - | - | - | - | - | - | S1＝H |
| 2 | 1 | 3 | C | H | H | H | - | - | - | - | - | - | - | S1-S5＝H |
| 3 | 3 | 3 | - | H | H | H | - | O | - | - | - | - | - | S1＝H |
| 4 | 3 | 4 | - | H | H | H | - | O | - | - | - | - | - | S1＝H |
| 5 | 3 | 4 | - | H | H | H | - | O | - | - | - | - | - | S1＝H |
| 6 | 3 | 3 | - | H | CH3 | H | - | O | - | - | - | - | - | S1＝H |
| 7 | 2 | 3 | - | H | H | H | 3-CH2OH | - | - | - | - | - | - | S1＝H |
| 8 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S1＝S2＝S3＝S6＝H |
| 9 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S1-S5＝H |
| 10 | 4 | 3 | - | H | H | H | - | - | - | - | - | - | - | S1＝H |
| 11 | 1 | 3 | C | H | H | H | - | - | - | - | - | - | - | S1，S3-S5＝HS2＝CH3 |
| 12 | 3 | 3 | - | H | -(CH2)3- | - | O | - | - | - | - | - | S1＝H | |
| 13 | 2 | 3 | - | H | H | H | 3-CH2OH | - | - | - | - | - | - | S1＝H * |
| 14 | 1 | 3 | C | -(CH2)4 | H | - | - | - | - | - | - | - | S1-S5＝H | |
| 15 | 3 | 3 | - | H | H | 5-OCH3 | - | O | - | - | - | - | - | S1＝H |
| 16 | 1 | 3 | C | CH3 | H | 5-Cl | - | - | - | - | - | - | - | S1-S5＝H |
| 17 | 3 | 3 | - | CH3 | H | 5-Cl | - | O | - | - | - | - | - | S1＝H |
| 18 | 1 | 3 | C | H | H | 5-Br | - | - | - | - | - | - | - | S1-S5＝H |
| 19 | 3 | 3 | - | H | H | 5-Br | - | O | - | - | - | - | - | S1＝H |
| 20 | 1 | 2 | C | H | H | H | - | - | - | - | - | - | - | S1-S5＝H |
| 21 | 1 | 3 | C | H | H | 5-F | - | - | - | - | - | - | - | S1-S5＝H |
| 22 | 3 | 3 | - | H | H | 5-F | - | O | - | - | - | - | - | S1＝H |
| 23 | 3 | 3 | - | H | H | H | - | CH2 | - | - | - | - | - | S1＝H |
| 24 | 5 | 3 | - | H | H | H | - | - | O | - | - | - | - | S1＝H；8位 |
| 25 | 1 | 3 | C | H | H | 7-Cl | - | - | - | - | - | - | - | S1-S5＝H |
*7连接在吲哚的7位上
| 化合物序号 | X | m | Y | R5 | R6 | (R7)n | R | Z | A | S6+S7 | P | T | Q | 注释 |
| 26 | 通式3 | 3 | - | H | H | 7-F | - | O | - | - | - | - | - | S1＝H |
| 27 | 1 | 3 | C | H | H | 7-F | - | - | - | - | - | - | - | S1-S5＝H |
| 28 | 3 | 3 | - | H | H | 7-CI | - | O | - | - | - | - | - | S1＝H |
| 29 | 3 | 3 | - | H | H | 7-CH3 | - | O | - | - | - | - | - | S1＝H |
| 30 | 2 | 3 | - | H | H | H | 2-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 31 | 7 | 3 | - | H | H | H | - | - | - | - | N | CH2 | CH2 | S1＝H |
| 32 | 1 | 3 | C | H | H | 6-CI | - | - | - | - | - | - | - | S1-S5＝H |
| 33 | 3 | 3 | - | H | H | 6-CI | - | O | - | - | - | - | - | S1＝H |
| 34 | 3 | 3 | - | H | H | 5-CN | - | O | - | - | - | - | - | S1＝H |
| 35 | 1 | 3 | C | H | H | 5-CN | - | - | - | - | - | - | - | S1-S5＝H |
| 36 | 1 | 3 | C | H | H | 4-CI | - | - | - | - | - | - | - | S1-S5＝H |
| 37 | 3 | 3 | - | H | H | 4-CI | - | O | - | - | - | - | - | S1＝H |
| 38 | 1 | 6 | C | H | H | H | - | - | - | - | - | - | - | S1-S5＝H |
| 39 | 1 | 5 | C | H | H | H | - | - | - | - | - | - | - | S1-S5＝H |
| 40 | 1 | 3 | C | H | H | H | - | - | - | - | - | - | - | S1-S4＝HS5＝CH3 |
| 41 | 1 | 3 | S | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S1-S3＝S5＝H |
| 42 | 6 | 3 | - | H | H | H | - | - | - | oxo | - | - | - | S1＝H |
| 43 | 1 | 3 | S | H | H | H | - | - | - | - | - | - | - | S1-S5＝H |
| 44 | 6 | 3 | - | H | H | H | - | - | - | H2 | - | - | - | S1＝H |
| 45 | 1 | 4 | C | H | H | H | - | - | - | - | - | - | - | S1-S5＝H |
| 46 | 1 | 3 | C | H | H | 6-F | - | - | - | - | - | - | - | S1-S5＝H |
| 47 | 3 | 3 | - | H | H | 6-F | - | O | - | - | - | - | - | S1＝H |
| 48 | 7 | 3 | - | H | H | H | - | - | - | - | N | CH | NH | S1＝H |
| 49 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝CH3，S1＝S3＝S5＝H |
| 50 | 1 | 3 | C | H | H | H | - | - | - | - | - | - | - | S1＝oxo，S1-S3＝S5＝H |
| 化合物序号 | X | m | Y | R5 | R6 | (R7)n | R | Z | A | S6+S7 | p | T | Q | 注释 |
| 51 | 通式3 | 3 | - | H | C2H5 | 5-CN | - | O | - | - | - | - | - | S1＝H |
| 52 | 3 | 3 | - | H | H | H | - | NH | - | - | - | - | - | S1＝H |
| 53 | 7 | 3 | - | H | H | H | - | - | - | - | N | C(CH3) | NH | S1＝H |
| 54 | 7 | 3 | - | H | H | H | - | - | - | - | NH | N | CH | S1＝H |
| 55 | 7 | 3 | - | H | H | H | - | - | - | - | N | N | NH | S1＝H |
| 56 | 1 | 3 | C | H | H | 4-F | - | - | - | - | - | - | - | S1-S5＝H |
| 57 | 3 | 3 | - | H | H | 4-F | - | O | - | - | - | - | - | S1＝H |
| 58 | 1 | 3 | C | H | H | 7-Br | - | - | - | - | - | - | - | S1-S5＝H |
| 59 | 3 | 3 | - | H | H | 7-Br | - | O | - | - | - | - | - | S1＝H |
| 60 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S1＝7-C1，S2＝S3＝S5＝H |
| 61 | 2 | 3 | - | H | H | 5-F | 2-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 62 | 1 | 3 | C | H | H | 5，7-F2 | - | - | - | - | - | - | - | S1-S5＝H |
| 63 | 3 | 3 | - | H | H | 5，7-F2 | - | O | - | - | - | - | - | S1＝H |
| 64 | 2 | 3 | - | H | H | 7-F | 2-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 65 | 5 | 3 | - | H | H | H | - | - | NH | - | - | - | - | S1＝H；5位 |
| 66 | 5 | 3 | - | H | H | 5-F | - | - | NH | - | - | - | - | S1＝H；5位 |
| 67 | 5 | 3 | - | H | H | 7-F | - | - | NH | - | - | - | - | S1＝H；5位 |
| 68 | 2 | 3 | - | H | H | H | 3-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 69 | 2 | 3 | - | H | H | H | 2-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 70 | 2 | 3 | - | H | H | 5-F | 2-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 71 | 2 | 3 | - | H | H | 5-F | 3-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 72 | 2 | 3 | - | H | H | 7-F | 3-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 73 | 2 | 3 | - | H | H | 7-F | 2-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 74 | 1 | 3 | S | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S1-S3＝S5＝H |
| 75 | 2 | 3 | - | H | H | H | 3-CH2OC3H7 | - | - | - | - | - | - | S1＝H |
| 化合物序号 | X | m | Y | R5 | R6 | (R7)n | R | Z | A | S6+S7 | P | T | Q | 注释 |
| 76 | 通式2 | 3 | - | H | H | 5-F | 3-CH2OC3H7 | - | - | - | - | - | - | S1＝H |
| 77 | 2 | 3 | - | H | H | H | 3-CH2OCH2C＝CH | - | - | - | - | - | - | S1＝H |
| 78 | 2 | 3 | - | H | H | 5-F | 3-CH2OCH2C＝CH | - | - | - | - | - | - | S1＝H |
| 79 | 2 | 3 | - | H | H | 7-F | 3-CH2OCH2C＝CH | - | - | - | - | - | - | S1＝H |
| 80 | 2 | 3 | - | H | H | H | 3-CH2OCH2CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 81 | 2 | 3 | - | H | H | 5-F | 3-CH2OCH2CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 82 | 2 | 3 | - | H | H | 7-F | 3-CH2OCH2CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 83 | 1 | 3 | S | H | H | 5-F | - | - | - | - | - | - | - | S1-S5＝H |
| 84 | 1 | 3 | S | H | H | H | - | - | - | - | - | - | - | S2＝CH3，S1＝S3-S5＝H |
| 85 | 1 | 3 | S | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝CH3，S1＝S3＝S5＝H |
| 86 | 7 | 3 | - | H | H | H | - | - | - | - | N | CH | S | S1＝H |
| 87 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝CH3，S1＝S3＝S5＝H |
| 88 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝CH3，S1＝S3＝S5＝H |
| 89 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S2＝CH3，S1＝S3＝S5＝H |
| 90 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S2＝CH3，S1＝S3＝S5＝H |
| 91 | 1 | 3 | O | H | H | 7-F | - | - | - | - | - | - | - | S4＝oxo，S2＝CH3，S1＝S3＝S5＝H |
| 92 | 1 | 3 | O | H | H | 7-F | - | - | - | - | - | - | - | S4＝oxo，S2＝CH3，S1＝S3＝S5＝H |
| 93 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝苯基，S1＝S3＝S5＝H |
| g4 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S2＝苯基，S1＝S3＝S5＝H |
| 95 | 1 | 3 | O | H | H | 7-F | - | - | - | - | - | - | - | S4＝oxo，S2＝苯基，S1＝S3＝S5＝H |
| 96 | 2 | 3 | - | H | H | H | 3-CH2OCH2CH＝CH2 | - | - | - | - | - | - | S1＝H |
| 97 | 2 | 3 | - | H | H | 5-F | 3-CH2OCH2CH＝CH2 | - | - | - | - | - | - | S1＝H |
| 98 | 2 | 3 | - | H | H | 7-F | 3-CH2OCH2CH＝CH2 | - | - | - | - | - | - | S1＝H |
| 99 | 2 | 3 | - | H | H | H | 2-CH2OCH2C＝CH | - | - | - | - | - | - | S1＝H |
| 100 | 2 | 3 | - | H | H | 5-F | 2-CH2OCH2C＝CH | - | - | - | - | - | - | S1＝H |
| 化合物序号 | X | m | Y | R5 | R6 | (R7)n | R | Z | A | S6+S7 | P | T | Q | 注释 |
| 101 | 通式2 | 3 | - | H | H | 7-F | 2-CH2OCH2C＝CH | - | - | - | - | - | - | S1＝H |
| 102 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝C3H7，S1＝S3＝S5＝H |
| 103 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S2＝C3H7，S1＝S3＝S5＝H |
| 104 | 1 | 3 | O | H | H | 7-F | - | - | - | - | - | - | - | S4＝oxo，S2＝C3H7，S1＝S3＝S5＝H |
| 105 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝S5＝CH3，S1＝S3＝H |
| 106 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S2＝S5＝CH3，S1＝S3＝H |
| 107 | 1 | 3 | O | H | H | 7-F | - | - | - | - | - | - | - | S4＝oxo，S2＝S5＝CH3，S1＝S3＝H |
| 108 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝苄基，S1＝S3＝S5＝H |
| 109 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S2＝苄基，S1＝S3＝S5＝H |
| 110 | 1 | 3 | O | H | H | 7-F | - | - | - | - | - | - | - | S4＝oxo，S2＝苄基，S1＝S3＝S5＝H |
| 111 | 2 | 3 | - | H | H | H | 3-CH2OCH2C＝CCH3 | - | - | - | - | - | - | S1＝H |
| 112 | 2 | 3 | - | H | H | H | 2-CH2OCH2C＝CCH3 | - | - | - | - | - | - | S1＝H |
| 113 | 2 | 3 | - | H | H | 5-F | 2-CH2OCH2C＝CCH3 | - | - | - | - | - | - | S1＝H |
| 114 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝S3＝CH3，S1＝S5＝H |
| 115 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S2＝S3＝CH3，S1＝S5＝H |
| 116 | 2 | 3 | - | H | H | H | 3-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 117 | 2 | 3 | - | H | H | 5-F | 3-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 118 | 2 | 3 | - | H | H | 5-F | 3-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 119 | 2 | 3 | - | H | H | H | 3-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 120 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝S5＝CH3，S1＝S3＝H |
| 121 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S2＝S5＝CH3，S1＝S3＝H |
| 122 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S2＝S5＝CH3，S1＝S3＝H |
| 123 | 1 | 3 | O | H | H | H | - | - | - | - | - | - | - | S4＝oxo，S2＝S5＝CH3，S1＝S3＝H |
| 124 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S1＝7-Cl，S2＝S3＝S5＝CH3 |
| 125 | 1 | 3 | O | H | H | 5-F | - | - | - | - | - | - | - | S4＝oxo，S1＝H，S2＝S3＝S5＝CH3 |
| 126 | 2 | 3 | - | H | H | 5-F | 3-CH2OCH3 | - | - | - | - | - | - | S1＝H |
| 化合物序号 | 盐或游离碱 | MP(℃) | [α]D 25(甲醇中) |
| 1 | 延胡索酸盐 | 192-4 | - |
| 2 | 2-HCl | 239-41 | - |
| 3 | 游离碱 | 203-4 | - |
| 4 | 游离碱 | 170-1 | - |
| 5 | 3.延胡索酸盐 | 98 | - |
| 6 | 游离碱 | 175-6 | - |
| 7 | 4/3.延胡索酸盐 | 140-3 | - |
| 8 | 游离碱 | 189-90 | - |
| 9 | 延胡索酸盐 | 200-1 | - |
| 10 | 3/2.延胡索酸盐 | 190-1 | - |
| 11 | 1/2.延胡索酸盐 | 210-2(dec.) | - |
| 12 | 游离碱 | 165-7 | - |
| 13 | 游离碱 | 70-1 | - |
| 14 | 延胡索酸盐 | 208 | - |
| 15 | 游离碱 | 无定形 | - |
| 16 | 2.延胡索酸盐 | 无定形 | - |
| 17 | 游离碱 | 无定形 | - |
| 18 | 延胡索酸盐 | ＞225(dec.) | - |
| 19 | 延胡索酸盐 | ＞170(dec.) | - |
| 20 | 游离碱 | 无定形 | - |
| 21 | 1/2.延胡索酸盐 | ＞245(dec.) | - |
| 22 | 1/2.延胡索酸盐 | ＞165玻璃态 | - |
| 23 | 游离碱 | 176-7 | - |
| 24 | 游离碱 | 无定形 | - |
| 25 | 1/2.延胡索酸盐 | 无定形 | - |
| 26 | 3/4.延胡索酸盐 | 无定形 | - |
| 27 | 1/2.延胡索酸盐 | ＞240(dec.) | - |
| 28 | 4/5.延胡索酸盐 | 无定形 | - |
| 29 | 4/5.延胡索酸盐 | 无定形 | - |
| 30 | 3/2.延胡索酸盐 | 玻璃态 | - |
| 31 | 5/4.延胡索酸盐 | 188-190 | - |
| 32 | 1/2.延胡索酸盐 | ＞230(dec.) | - |
| 33 | 延胡索酸盐 | 无定形 | - |
| 34 | 延胡索酸盐 | 150-2 | - |
| 35 | 1/2.延胡索酸盐 | 247-8(dec.) | - |
| 36 | 1/2.延胡索酸盐 | ＞240(dec.) | - |
| 37 | 延胡索酸盐 | 无定形 | - |
| 38 | HCl | 无定形 | - |
| 39 | HCl | 无定形 | - |
| 40 | HCl | 220-4 | - |
| 41 | HCl | ＞250(dec.) | - |
| 42 | 1/2.延胡索酸盐 | 214-7(dec.) | - |
| 43 | 1/2.延胡索酸盐 | 240-3 | - |
| 44 | 1/2.延胡索酸盐 | 220-2(dec.) | - |
| 45 | HCl | 无定形 | - |
| 46 | 延胡索酸盐 | 223-5 | - |
| 47 | 2/3.延胡索酸盐 | 200-2 | - |
| 48 | 游离碱 | 玻璃态 | - |
| 49 | 游离碱 | 196-7 | - |
| 50 | 游离碱 | 181-2 | - |
| 51 | 1/2.延胡索酸盐 | 138.5-41 | - |
| 52 | 游离碱 | 190-5(dec.) | - |
| 53 | 游离碱 | 玻璃态 | - |
| 54 | 游离碱 | 玻璃态 | - |
| 55 | 游离碱 | 玻璃态 | - |
| 56 | 1/2.延胡索酸盐 | 185-6 | - |
| 57 | 延胡索酸盐 | 210-1(dec.) | - |
| 58 | 2.延胡索酸盐 | 无定形 | - |
| 59 | 游离碱 | 无定形 | - |
| 60 | 1/2.延胡索酸盐 | ＞250 | - |
| 61 | 延胡索酸盐 | 玻璃态 | - |
| 62 | 1/2.延胡索酸盐 | 245-7 | - |
| 63 | 2/3.延胡索酸盐 | 175-8 | - |
| 64 | 延胡索酸盐 | 玻璃态 | - |
| 65 | 游离碱 | 220-4(dec.) | - |
| 66 | 游离碱 | 234-6(dec.) | - |
| 67 | 游离碱 | ＞280 | - |
| 68 | HCl | 玻璃态 | - |
| 69 | 延胡索酸盐 | 玻璃态 | +28(游离碱)，R-型 |
| 70 | 延胡索酸盐 | 玻璃态 | +28(游离碱)，R-型 |
| 71 | 延胡索酸盐 | 玻璃态 | - |
| 72 | 延胡索酸盐 | 玻璃态 | - |
| 73 | 延胡索酸盐 | 玻璃态 | +25(游离碱)，R-型 |
| 74 | 游离碱 | 212.5-14.5 | - |
| 75 | 延胡索酸盐 | 玻璃态 | - |
| 76 | 延胡索酸盐 | 玻璃态 | - |
| 77 | 延胡索酸盐 | 玻璃态 | - |
| 78 | 延胡索酸盐 | 玻璃态 | - |
| 79 | 延胡索酸盐 | 玻璃态 | - |
| 80 | 延胡索酸盐 | 玻璃态 | - |
| 81 | 延胡索酸盐 | 玻璃态 | - |
| 82 | 延胡索酸盐 | 玻璃态 | - |
| 83 | 延胡索酸盐 | 无定形 | - |
| 84 | 游离碱 | 无定形 | - |
| 85 | 游离碱 | 无定形 | - |
| 86 | 1/2.延胡索酸盐 | 218-20 | - |
| 87 | 游离碱 | 玻璃态 | -26 R型 |
| 88 | 游离碱 | 玻璃态 | +27 S型 |
| 89 | 游离碱 | 玻璃态 | -24 R型 |
| 90 | 游离碱 | 玻璃态 | +24 S型 |
| 91 | 游离碱 | 184-5 | -25 R型 |
| 92 | 游离碱 | 181-3 | +25 S型 |
| 93 | 游离碱 | 玻璃态 | - |
| 94 | 游离碱 | 玻璃态 | - |
| 95 | 游离碱 | 玻璃态 | - |
| 96 | 游离碱 | 70-3 | - |
| 97 | 游离碱 | 73-5 | - |
| 98 | 延胡索酸盐 | 玻璃态 | - |
| 99 | 延胡索酸盐 | 玻璃态 | +39(游离碱)，R-型 |
| 100 | 延胡索酸盐 | 玻璃态 | +36(游离碱)，R-型 |
| 101 | 延胡索酸盐 | 玻璃态 | +37(游离碱)，R-型 |
| 102 | 游离碱 | 158-60 | - |
| 103 | 游离碱 | 181-2 | - |
| 104 | 游离碱 | 174-6 | - |
| 105 | 游离碱 | 玻璃态 | - |
| 106 | 游离碱 | 玻璃态 | - |
| 107 | 游离碱 | 玻璃态 | - |
| 108 | 游离碱 | 玻璃态 | - |
| 109 | 游离碱 | 207-10(dec.) | - |
| 110 | 游离碱 | 197-9(dec.) | - |
| 111 | 延胡索酸盐 | 玻璃态 | - |
| 112 | 延胡索酸盐 | 玻璃态 | +31(游离碱)，R-型 |
| 113 | 延胡索酸盐 | 玻璃态 | +31(游离碱)，R-型 |
| 114 | 游离碱 | 191-4 | - |
| 115 | 游离碱 | 190-2 | - |
| 116 | 游离碱 | 无定形 | OS-型 |
| 117 | 延胡索酸盐 | 无定形 | S-型 |
| 118 | 游离碱 | 无定形 | R-型 |
| 119 | 游离碱 | 无定形 | OR-型 |
| 120 | 游离碱 | 无定形 | -31R-型 |
| 121 | 游离碱 | 无定形 | -28R-型 |
| 122 | 游离碱 | 无定形 | +28S-型 |
| 123 | 游离碱 | 无定形 | +32S-型 |
| 124 | 游离碱 | 无定形 | - |
| 125 | 游离碱 | 无定形 | - |
| 126 | 延胡索酸盐 | 无定形 | -2R-型 |
Claims (7)
1、本发明涉及一组通式(I)所示的新的苯基哌嗪衍生物及其盐：
其中：
-X是通式(1)所示基团
其中
-S1是氢或卤素，
-S2和S3独立表示氢、具有1-6个碳原子的烷基、苯基或苄基，
-S4代表两个氢原子或一个氧代基，
-S5是氢或具有1-4个碳原子的烷基，且
-Y是CH2、O或S，
或通式(2)所示基团
其中S1具有上述含义且R是H、具有1-4个碳原子的烷基、具有2-6个碳原子的烷氧基烷基，具有2-4个碳原子的链烯基或具有2-4个碳原子的炔基，
或通式(3)所示基团
其中S1具有上述含义且Z是C、O或N，
或通式(4)所示基团
其中S1具有上述含义，
或通式(5)所示基团
其中S1具有上述含义且A中O或N，与哌嗪环的5位或8位相连，
或通式(6)所示基团
其中S1具有上述含义且S6和S7代表氢原子或一个氧代基，
或通式(7)所示基团
其中一条虚线可代表一个双键，S1具有上述含义，且
P＝T＝Q＝氮
或P＝T＝氮且Q＝CH或CH2
或P＝Q＝氮且T＝CH，CH2，C-CH3或CH-CH3
或P＝氮，且T和Q是CH或CH2
或P＝氮，T是CH或CH2，且Q是硫
-m的值为2-6；
-n的值为0-2；
-R6和R6独立地代表氢或具有1-3个碳原子的烷基；或R5+R6代表-(CH2)-p，其中p的值为3-5，且
-R7有1-3个碳原子的烷基，具有1-3个碳原子的烷氧基，卤素或氰基；或R6+R7(R7在吲哚基的7位)代表-(CH2)q团，其中q的值为2-4。
2、权利要求1的化合物，其中X代表通式(1)、(2)或(3)所示基团，其中符号的含义如权利要求1所述。
3、权利要求1的化合物及其盐，其中X代表通式(1)所示基团，其中S1＝S3＝S5＝H、S4＝氧代且S5＝CH3，m是3，R5＝R6＝H，n是0或1，并且R7是5-氟。
4、制备权利要求1化合物的方法，其特征在于通式(II)化合物
在碱性条件下与通式(III)化合物反应
通式中的符号的含义如权利要求1所述，且L是所谓的离去基团。
5、药物组合物，其中至少含有一种权利要求1所述的化合物作为活性成分。
6、制备权利要求5组合物的方法，其特征在于将权利要求1的化合物制成适宜的给药形式。
7、权利要求1的化合物用于制备治疗CNS病症的药物组合物的用途。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL1012888 | 1999-08-23 | ||
| EP99202710 | 1999-08-23 | ||
| NL1012888 | 1999-08-23 | ||
| EP99202710.2 | 1999-08-23 |
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| Publication Number | Publication Date |
|---|---|
| CN1390214A CN1390214A (zh) | 2003-01-08 |
| CN1155596C true CN1155596C (zh) | 2004-06-30 |
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| EP (1) | EP1212320B1 (zh) |
| JP (1) | JP4919565B2 (zh) |
| KR (1) | KR100634039B1 (zh) |
| CN (1) | CN1155596C (zh) |
| AR (1) | AR031526A1 (zh) |
| AT (1) | ATE299142T1 (zh) |
| AU (1) | AU772189B2 (zh) |
| BR (1) | BR0013498A (zh) |
| CA (1) | CA2379021C (zh) |
| CZ (1) | CZ298533B6 (zh) |
| DE (1) | DE60021194T2 (zh) |
| DK (1) | DK1212320T3 (zh) |
| ES (1) | ES2244469T3 (zh) |
| HK (1) | HK1051199A1 (zh) |
| HU (1) | HUP0203194A3 (zh) |
| IL (2) | IL148218A0 (zh) |
| MX (1) | MXPA02001919A (zh) |
| NO (1) | NO321887B1 (zh) |
| NZ (1) | NZ517900A (zh) |
| PL (1) | PL201178B1 (zh) |
| PT (1) | PT1212320E (zh) |
| RU (1) | RU2246494C2 (zh) |
| SI (1) | SI1212320T1 (zh) |
| SK (1) | SK287018B6 (zh) |
| TR (1) | TR200200460T2 (zh) |
| TW (1) | TWI286136B (zh) |
| UA (1) | UA74160C2 (zh) |
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| AR032711A1 (es) | 2001-02-21 | 2003-11-19 | Solvay Pharm Bv | Derivados de fenilpiperazina, un metodo para la preparacion de los mismos y una composicion farmaceutica que los contiene |
| AR032712A1 (es) * | 2001-02-21 | 2003-11-19 | Solvay Pharm Bv | Un mesilato de derivados de fenilpiperazina y composiciones farmaceuticas que lo contienen |
| US7041683B2 (en) | 2001-04-24 | 2006-05-09 | Wyeth | Antidepressant azaheterocyclylmethyl derivatives of 2,3-dihydro-1, 4-benzodiozan |
| US6559169B2 (en) | 2001-04-24 | 2003-05-06 | Wyeth | Antidepressant azaheterocyclymethyl derivatives of 2,3-dihydro-1,4-benzodioxan |
| US6656950B2 (en) | 2001-04-25 | 2003-12-02 | Wyeth | Antidepressant azaheterocyclylmethyl derivatives of 1,4-dioxino[2,3-b]pyridine |
| EP1336406A1 (en) * | 2002-02-14 | 2003-08-20 | Solvay Pharmaceuticals B.V. | Partial dopamine-D2 receptor agonist plus serotonin and/or noradrenaline inhibitory activity |
| DE60303376T2 (de) * | 2002-05-13 | 2006-11-16 | F. Hoffmann-La Roche Ag | Benzoxazinderivate als 5-ht6-modulatoren und deren verwendungen |
| DE10233500A1 (de) * | 2002-07-24 | 2004-02-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylen]-6-methoxycarbonyl-2-indolinon-Monoethansulfonat und dessen Verwendung als Arzneimittel |
| DK1562918T3 (da) * | 2002-11-08 | 2008-05-05 | Hoffmann La Roche | Substituerede benzoxazinoner og anvendelser deraf |
| US7276603B2 (en) * | 2003-05-02 | 2007-10-02 | Wyeth | Benzofuranyl-and benzothienyl-piperazinyl quinolines and methods of their use |
| WO2004108671A1 (en) * | 2003-06-06 | 2004-12-16 | Suven Life Sciences Limited | Substituted indoles with serotonin receptor affinity, process for their preparation and pharmaceutical compositions containing them |
| BRPI0518370A2 (pt) * | 2004-12-07 | 2008-11-18 | Solvay Pharm Bv | composto, composiÇço farmacÊutica, mÉtodo para preparar uma composiÇço, e, uso de um composto |
| US7371769B2 (en) | 2004-12-07 | 2008-05-13 | Solvay Pharmaceuticals B.V. | Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites |
| SA05260390B1 (ar) * | 2004-12-07 | 2009-04-01 | سولفاي فارماسوتيكالز بي . في | مشتقات بنزدايوكسان ببرازين ذات الفة مشتركة تجاه مستقبلات دوبامين - d2 ومواقع إعادة امتصاص السيروتونين |
| PT1827427E (pt) * | 2004-12-08 | 2008-11-03 | Solvay Pharm Bv | Compostos, composição farmacêutica, método de preparar uma composição, e, uso de um composto |
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| GT200600414A (es) | 2005-09-12 | 2007-09-20 | Sal de glucuranato de compuesto de piperazine | |
| GT200600416A (es) | 2005-09-12 | 2007-09-20 | Sales salicilato y gentisato de un compuesto de piperazina | |
| US9066903B2 (en) | 2006-02-28 | 2015-06-30 | The United States Of America As Represented By The Department Of Veterans Affairs | Pharmacological treatment of Parkinson's disease |
| FR2941946B1 (fr) * | 2009-02-12 | 2011-03-25 | Sanofi Aventis | Derives de 3-benzofuranyl-indol-2-one-3-acetamidopiperazines substitues, leur preparation et leur application en therapeutique |
| US8686009B2 (en) * | 2009-06-25 | 2014-04-01 | Alkermes Pharma Ireland Limited | Prodrugs of NH-acidic compounds |
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