CN1056143C - 哌啶衍生物及其应用 - Google Patents

哌啶衍生物及其应用 Download PDF

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CN1056143C
CN1056143C CN95104192A CN95104192A CN1056143C CN 1056143 C CN1056143 C CN 1056143C CN 95104192 A CN95104192 A CN 95104192A CN 95104192 A CN95104192 A CN 95104192A CN 1056143 C CN1056143 C CN 1056143C
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dibenzo
suberene
piperidino
ethyl
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CN1112560A (zh
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牧野真吾
蚁坂晴美
山本浩史
东海林政孝
吉元良太
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Ajinomoto Co Inc
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Abstract

通式(I)的哌啶衍生物或其可药用盐在制备5-羟色胺拮抗药物中的应用。通式(I)中A1、X1、Y1和Z1的定义如说明书所述。

Description

哌啶衍生物及其应用
本发明涉及新的5-羟色胺拮抗剂和抗血小板剂，更具体地说，涉及一种以较低的不良副反应强烈而特异地抑制5-羟色胺2受体的5-羟色胺拮抗剂和抗血小板剂。
据认为，局部缺血性紊乱如心肌梗塞和脑血栓，在很大程度上与血栓有关。特别是，血小板在动脉血栓形成过程中起重要作用。已知的抗血小板剂包括花生四烯酸代谢抑制剂、血小板环核苷相关药剂、凝血噁烷胺受体拮抗剂。临床上曾使用阿司匹灵和氯苄噻啶，然而其作用并不充分，因而需要研制更有效的药剂。
另一方面，已知各种刺激会引起血小板激活而释放出贮存在血小板α颗粒中的5-羟色胺(5HT)，所释放的5-羟色胺通过血小板膜上的5-羟色胺2(5HT2)受体而提高细胞内的钙离子水平，从而导致血小板聚集。另据认为，存在于血管平滑肌中的5HT2受体参与血管收缩。据此预计5HT2受体拮抗剂除具有血小板聚集抑制活性外还具有血管收缩抑制活性，所以有可能用5HT2受体拮抗剂达到强烈的抗血栓功能。
本发明的目的是提供以较低的不良副作用强烈而特异地抑制5-羟色胺2受体的5-羟色胺拮抗剂和抗血小板剂。
本发明涉及一种5-羟色胺拮抗剂或一种抗血小板剂，它包含下列通式(I)所示的哌啶衍生物或其盐作为活性成分。
Figure C9510419200081
其中A1代表未取代的或取代的吡啶基、哌啶基、哌啶子基、吗啉基、吗啉代、硫代码啉基、硫代吗啉代或哌嗪基、含1-8个碳原子的取代烷基、含4-8个碳原子的取代环烷基、或含1-8个碳原子的未取代的或取代的烷氧基；
X1代表氢原子或卤原子；
Y1代表下列有机基团之一：
-CONH-，-NHCO-，-CONHCH2-，-(CH2)n-，-COO-，其中n是0-4的整数；
Z1代表下列有机基团之一：
-CH＝CH-，-S-CH2-，-S-，-CH2-CH2-。
作为上述通式(I)中A1的取代基，优选下列基团：R1-CO-，
Figure C9510419200082
其中R1为氢原子、含1-6个碳原子的烷基或烷氧基、可以被烷基取代的氨基、或酰氨基烷基；R2和R3可相同或不同，各自代表氢原子；含1-6个碳原子的烷基、酰基或烷氧羰基；或可被烷基取代的氨基羰基。
这些取代基的示例性实例包括甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、氨基甲酰基、N-甲基氨基甲酰基、N-乙基氨基甲酰基、N-丙基氨基甲酰基、N，N-二甲基氨基甲酰基、N，N-二乙基氨基甲酰基、N-甲酰基甘氨酰基、N-乙酰基甘氨酰基、N-甲酰基-β-丙氨酰基、N-乙酰基-β-丙氨酰基、N-甲基-N-甲酰基、N-甲基-N-乙酰基、N-甲基-N-丙酰基、N-乙基-N-甲酰基、N-乙基-N-乙酰基。
通式(I)中Y1的优选实例包括基团-CONH-，Z1的优选实例包括-CH＝CH-。
在通式(I)所示的化合物中，下列通式(II)所示的化合物是文献中未描述过的新化合物。其中A2代表未取代的或取代的吡啶基、哌啶基、哌啶子基、吗啉基、吗啉代、硫代码啉基、硫代吗啉代或哌嗪基、含1-8个碳原子的取代烷基、含4-8个碳原子的取代环烷基、或含1-8个碳原子的未取代的或取代的烷氧基；当A2带有取代基时，该取代基是下列基团之一：R4-CO-，
Figure C9510419200092
其中R4代表含1-6个碳原子的烷基或烷氧基、可以被烷基取代的氨基、或酰氨基烷基；R5和R6可相同或不同，各自代表氢原子；含1-6个碳原子的烷基、酰基或烷氧羰基；或可被烷基取代的氨基羰基；X2、Y2和Z2的含义分别与X1、Y1和Z1相同。
作为A2的取代基，优选乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、氨基甲酰基、N-甲基氨基甲酰基、N-乙基氨基甲酰基、N-丙基氨基甲酰基、N，N-二甲基氨基甲酰基、N，N-二乙基氨基甲酰基、N-甲酰基甘氨酰基、N-乙酰基甘氨酰基、N-甲酰基-β-丙氨酰基、N-乙酰基-β-丙氨酰基、N-甲基-N-甲酰基、N-甲基-N-乙酰基、N-甲基-N-丙酰基、N-乙基-N-甲酰基、N-乙基-N-乙酰基等。作为Y2和Z2，分别优选基团-CONH-和基团-CH＝CH-。
上述通式(I)所示的哌啶衍生物可以用常规方法来制备，例如用已公开的未审查日本专利申请3-47168所述的方法。例如，包括在通式(I)中的4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-(2-叔丁氧羰氨基)乙基)哌啶(化合物(3))易于用以下方法制得：在碱如三乙胺存在下，使N-叔丁氧羰基-2-溴乙胺(化合物(1))与4-(5H-二苯并[a，d]环庚烯-5-亚基)哌啶(化合物(2))进行缩合反应，如反应方案I所示：
类似地，包括在通式(I)中的1-甲酰基-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺(isonipecotamide)(化合物(6))易于用以下方法制得：利用缩合剂如1-(3-二甲氨基丙基)-3-乙基碳二亚胺，使通过用4M盐酸/二噁烷等脱除化合物3的叔丁氧羰基而得到的化合物4与1-甲酰基-4-哌啶甲酸化合物(isonipecotic acid)(化合物(5))进行缩合反应，如反应方案II所示：
Figure C9510419200111
将这些制备方法得到的反应产物分离纯化为游离化合物或其盐。分离纯化可以用萃取法、浓缩法、蒸发法、结晶法及各种类型的色谱法来进行。
哌啶衍生物盐的实例包括与无机酸和有机酸形成的酸加成盐，无机酸的例子有：盐酸、氢溴酸、硫酸、硝酸、磷酸；有机酸的例子有甲酸、乙酸、乳酸、水杨酸、扁桃酸、柠檬酸、草酸、马来酸、富马酸、酒石酸、单宁酸、苹果酸、对甲苯磺酸、甲磺酸、苯磺酸。
通式(I)所示的哌啶衍生物具有5-羟色胺拮抗活性，因此可作为一种药剂用于治疗局部缺血性紊乱、血栓形成、梗阻、精神病(抑郁、焦虑)、糖尿病并发症、动脉硬化、高血压、心律不齐、偏头痛、微循环衰竭等。特别是，作为抗血小板剂，通式(I)所示的哌啶衍生物可作为一种药剂用于治疗各种局部缺血性紊乱、血栓形成、梗阻、脉管炎、糖尿病并发症、动脉硬化、肾病，以及由于慢性动脉阻塞造成的溃疡、疼痛、寒觉等，还可作为治疗剂用于改善各种并发循环衰竭的局部缺血症、在外科手术治疗局部缺血性心脏病后预防再狭窄、以及改善血液循环。
通式(I)的哌啶衍生物作为5-羟色胺拮抗剂或抗血小板剂使用时，给药途径可以是口服或肠胃外给药。临床剂量可能会随患者的年龄、体重和身体状况及给药方法而变，但每个成年人的日剂量在口服给药时一般为0.01mg至500mg，在肠胃外给药时一般为1μg至100mg。
剂型可以采用常用剂型如片剂、粉剂、糖衣制剂、胶囊剂和溶液，这些剂型可以用常规方法利用常用的药物助剂来制备。
实施例
下面将用实施例来进一步说明本发明，但本发明不应被误认为是只限于这些实施例。
制备方法A
1-甲氧羰基-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺盐酸盐的合成
步骤1
2-叔丁氧羰氨基乙基溴的合成
在300ml乙醚和300ml水的混合溶剂中，加入2-氨基乙基溴氢溴酸盐(35.77g，174.6mmol)和二碳酸二叔丁酯(22.80g，104.5mmol)。然后逐渐加入碳酸氢钠(44.00g，523.7mmol)，混合物于室温下搅拌过夜。乙醚层用80ml 1N盐酸洗涤，再用80ml饱和氯化钠水溶液洗涤，用硫酸镁粉末干燥。蒸发溶剂，得到标题化合物。
得量：21.57g(96.25mmol)；收率：92％
步骤2
4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-(2-叔丁氧羰氨基)乙基)哌啶的合成
在乙腈(300ml)中加入2-叔丁氧羰氨基乙基溴(4.5g，20.1mmol)、4-(5H-二苯并[a，d]环庚烯-5-亚基)哌啶(2.7g，10.0mmol)和三乙胺(4.2ml，30mmol)，将混合物置于油浴上于50℃下搅拌16小时。将温度降至室温，蒸发溶剂，残余物溶于300ml乙酸乙酯中。过滤除去不溶物后，滤液用100ml 1N盐酸、100ml 1N氢氧化钠水溶液和100ml饱和氯化钠水溶液洗涤，用硫酸镁粉末干燥。蒸发溶剂，残余物用硅胶柱色谱法纯化，得到标题化合物。
得量：3.6g(8.6mmol)；收率：86％
步骤3
1-(2-氨基乙基)-4-(5H-二苯并[a，d]环庚烯-5-亚基)哌啶二盐酸盐的合成
将4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-(2-叔丁氧羰氨基)乙基)哌啶(8.47g，20.4mmol)溶解于100ml二氯甲烷中，向其中加入100ml 4N盐酸-二噁烷溶液，然后在室温下搅拌1小时。蒸发溶剂，得到标题化合物(8.56g)。
步骤4
1-叔丁氧羰基-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺的合成
将1-(2-氨基乙基)-4-(5H-二苯并[a，d]环庚烯-5-亚基)哌啶二盐酸盐(2.3g，6.0mmol)、1-叔丁氧羰基-4-哌啶甲酸(1.6g，7.2mmol)、三乙胺(3.0ml，21.6mmol)和1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(1.4g，7.2mmol)混合在一起，混合物于室温下搅拌过夜。蒸发溶剂后，将残余物溶解于100ml二氯甲烷中，用100ml 1N盐酸、100ml 1N氢氧化钠水溶液和50ml饱和氯化钠水溶液洗涤。蒸发溶剂，残余物用硅胶色谱法纯化，得到标题化合物。
得量：2.0g(3.8mmol)；收率：63％
步骤5
N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺二盐酸盐的合成
在1-叔丁氧羰基-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺(0.10g，0.185mmol)中加入10ml 4N盐酸-二噁烷溶液，混合物于室温下搅拌1小时。蒸发溶剂，得到标题化合物。
得量：0.093g(0.186mmol)；收率：100％
步骤6
1-甲氧羰基-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺盐酸盐的合成
将N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺二盐酸盐(0.59g，1.18mmol)和三乙胺(0.8ml，5.70mmol)溶解于50ml二氯甲烷中，加入氯甲酸甲酯(0.1ml，1.40mmol)。将混合物搅拌1小时，加入100ml二氯甲烷。混合物用70ml水、70ml 1N氢氧化钠水溶液和70ml饱和氯化钠水溶液洗涤，并用硅胶色谱法纯化。将所得产物转化为盐酸盐形式，得到标题化合物。
得量：0.39g(0.75mmol)；收率：63％
用与制备方法A中所述类似的方式制备表1所示的化合物。
Figure C9510419200152
Figure C9510419200161
Figure C9510419200162
Figure C9510419200171
Figure C9510419200172
制备方法B
1-(4-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基)丁基)吗啉的合成
步骤1
1-(4-氧-4-吗啉代丁酰基)-4-(5H-二苯并[a，d]环庚烯-5-亚基)哌啶的合成
在50ml二氯甲烷中，将4-(5H-二苯并[a，d]环庚烯-5-亚基)哌啶(0.27g，1.0mmol)、琥珀酸酐(0.12g，1.2mmol)、和三乙胺(0.17ml，1.2mmol)于室温下搅拌过夜。加入吗啉(0.14ml，1.6mmol)和1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(0.27g，1.4mmol)，将该混合物于室温下再搅拌8小时。反应混合物用30ml 1N盐酸、30ml 1N氢氧化钠水溶液和30ml饱和氯化钠水溶液洗涤，用硫酸镁粉末干燥，用硅胶色谱法纯化，得到标题化合物。
得量：0.44g(1.0mmol)；收率：100％
步骤2
1-(4-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基)丁基)吗啉二盐酸盐的合成
在四氢呋喃(60ml)中使1-(4-氧-4-吗啉代丁酰基)-4-(5H-二苯并[a，d]环庚烯-5-亚基)哌啶(0.44g，1.00mmol)与氢化铝锂(0.38g，10.0mol)于0℃下反应，并按常规方法进行进一步处理，得到标题化合物。
得量：0.32g(0.66mmol)；收率：66％
按照与制备方法B所述类似的方式制备表2所示的化合物。
Figure C9510419200191
测试例1
用牛大脑皮质膜样品评定与5-羟色胺2受体的结合亲合力。在200μl浓度已调至50mg(湿重)膜/ml的牛膜样品中，加入200μl 3nM [3H]-克丹西林(ketanserin)和200μl试验化合物溶液，试验化合物溶液的制备方法是：将试验化合物溶解于1.7％乙醇中，然后混合。将混合物于25℃下保温30分钟，然后用玻璃滤器过滤。用液体闪烁计数器测定滤器上捕集的放射性。非特异性结合由10-6M LY53857来定义。得出抑制50％[3H]-克丹西林特异性结合的试验化合物浓度(即IC50值)，按下列公式计算出Ki值。结果以Ki值的负对数(即pKi值)表示。 Ki = IC 50 1 + [ L ] Kd
该公式中，Ki表示解离常数，[L]表示]3H]-克丹西林的浓度。
由表1和表2的结果可见，本发明的哌啶衍生物对5-羟色胺2受体显示出强结合亲合力。
测试例2
用SD大鼠(体重：约300-400g，雄性)的血小板体外测定由5-羟色胺拮抗活性产生的抗血小板作用。由乙醚麻醉下的大鼠的腹主动脉取血，由含0.38％柠檬酸钠的血液制备富血小板血浆(PRP)和贫血小板血浆(PPP)。通过加入PPP将PRP的血小板浓度调至5×108个血小板/ml。然后加入溶解于0.4％乙醇水溶液中的试验化合物，将该混合物于37℃下保温3分钟。加入0.5μM或0.8μM腺苷二磷酸(ADP)+5-羟色胺诱导血小板聚集，并测定PRP透光度的增加。测定将不加试验化合物时5-羟色胺引起的血小板聚集增加抑制50％的试验化合物浓度，并计算出其负对数(pIC50)。结果示于表1和表2。由这些结果可见，本发明的哌啶类化合物强烈抑制由5-羟色胺引起的血小板聚集。
测试例3
用SD大鼠(体重：约210-330g，雄性)体内测定由5-羟色胺拮抗活性产生的抗血小板作用。将试验化合物溶解或悬浮于阿拉伯树胶中，以表3所示的剂量给大鼠口服。服用试验化合物2小时后，用乙醚麻醉大鼠，由大鼠腹主动脉取血，由含0.38％柠檬酸钠的血液制备富血小板血浆(PRP)和贫血小板血浆(PPP)。通过加入PPP将PRP的血小板浓度调至5×108个血小板/ml。然后将PRP于37℃下保温3分钟，加入0.7μM腺苷二磷酸(ADP)+5-羟色胺诱导血小板聚集，并测定PRP透光度的增加。测定每组中只加入ADP时发生的聚集与同时加入ADP和5-羟色胺时发生的最大聚集的比例，并计算出5-羟色胺引起的聚集增加。以服用阿拉伯树胶组中5-羟色胺引起的聚集增加为100％，用服用试验化合物组(n＝3)中5-羟色胺引起的聚集增加作为指标判断试验化合物的作用。结果示于表3中。
                      表3
试验化合物 服用量(mg/kg) 5-羟色胺引起的聚集增加(％)
阿拉伯树胶     -     100
 3号化合物     0.1     75.7
    0.3     57.3
    1     24.3
    3     27
    10     -2.7
 9号化合物     0.3     57.3
 17号化合物     0.3     50.7
 18号化合物     0.3     94.9
 38号化合物     0.3     82.4
 39号化合物     0.3     54.5
 41号化合物     0.3     91.5
由表3的结果可见，本发明的哌啶类化合物即使在口服情况下也强烈抑制由5-羟色胺引起的血小板聚集。
测试例4
通过测定对5-羟色氨酸(5HTP)诱导的小鼠头颤搐的抑制作用，评定中枢神经系统中的5-羟色胺拮抗活性。分别以1、3、10或30mg的量将试验化合物溶解于100ml水中，给前一天开始禁食的ICR小鼠(体重：27-32g，雄性)口服该溶液(10mg/kg体重)，90分钟后服用5HTP。对照组使用5％阿拉伯树胶。皮下施用甲基多巴肼(6mg/kg)，15分钟后腹膜内施用5HTP(180mg/kg)。从服用5HTP15分钟后开始计数2分钟内发生的头颤搐数。得到施用5％阿拉伯树胶组中抑制50％头颤搐数的试验化合物浓度。结果示于表4中。
                            表4
试验化合物                      ID50(mg/kg)
3号化合物                       0.39
cycloheptadin                   0.12
由表4的结果可见，本发明的哌啶类化合物对中枢神经系统的作用很低，是一种高度安全的化合物。

Claims (15)

1.通式(I)的哌啶衍生物或其可药用盐在制备用作为5-羟色胺拮抗剂用于预防由5-羟色胺所引起的一般疾病的药物中的应用：
Figure C9510419200021
其中A1代表取代的哌啶基或取代或未取代的哌啶子基、吗啉代、硫代吗啉代或哌嗪基、或含1-8个碳原子的烷氧基，
X1代表氢原子；
Y1代表下列有机基团之一：
-CONH-，-CONHCH2-，-CH2CH2-，或COO；
Z1代表下列有机基团之一：
-CH＝CH-，-CH2-CH2-，-S-，
其中A1具有一取代基，所述取代基是R1CO-，
其中R1是氢原子、具有1-6个碳原子的烷基或烷氧基、可以被烷基取代的氨基或酰氨基烷基。
2.权利要求1的应用，其中A1具有一取代基，所述取代基是甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、N，N-二甲基氨基甲酰基、N-乙酰基甘氨酰基。
3.权利要求1的应用，其中Y1是基团-CONH-。
4.权利要求1的应用，其中Z1是基团-CH＝CH-。
5.权利要求1的应用，其中所述哌啶衍生物是1-甲酰基-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺。
6.一种按照权利要求1-5中任一项的应用，其中所述疾病选自局部缺血性紊乱、血栓形成、动脉硬化、偏头痛或微循环衰竭。
7.通式(I)的哌啶衍生物或其可药用盐在制备用作为抗血小板剂用于预防因血小板聚集所引起的一般疾病的药物中的应用：
Figure C9510419200031
其中A1、X1、Y1和Z1的定义如权利要求1中所述。
8.权利要求7的应用，其中所述疾病选自局部缺血性紊乱、血栓形成、梗阻、脉管炎、糖尿病并发症、动脉硬化、肾病，以及由于慢性动脉阻塞造成的溃疡、疼痛、寒觉等，或在外科手术治疗局部缺血性心脏病后预防再狭窄、以及改善血液循环。
9.权利要求7的应用，其中所述哌啶衍生物是1-甲酰基-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺。
10.一种通式(II)所示的哌啶衍生物或其可药用盐：其中A2代表取代的哌啶基或未取代的或取代的哌啶子基、吗啉代、硫代吗啉代或哌嗪基、或含1-8个碳原子的烷氧基；
当A2带有取代基时，所述取代基是
            R4-CO-，其中R4代表含1-6个碳原子的烷基或烷氧基、可以被烷基取代的氨基或酰氨基烷基；和
X2、Y2和Z2的含义分别与权利要求1中的X1、Y1和Z1相同。
11.权利要求10的哌啶衍生物，其中A2带有取代基，所述取代基是甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、N，N-二甲基氨基甲酰基、N-乙酰基甘氨酰基。
12.权利要求10的哌啶衍生物，其中Y2是基团-CONH-。
13.权利要求10的哌啶衍生物，其中Z2是基团-CH＝CH-。
14.按照权利要求10的哌啶衍生物，其中所述化合物选自
1-乙酰基-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺，
1-叔丁氧羰基-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺，
1-(N，N-二甲基氨基甲酰基)-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺，
1-(N-乙酰基甘氨酰基)-N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺，
N-(2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-(N-乙酰基)-2-哌啶甲酰胺，
4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-(2-乙氧羰氨基)乙基)哌啶，
4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-(2-叔丁氧羰氨基)乙基)哌啶，
4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-(3-叔丁氧羰氨基丙基)哌啶，
4-(10，11-二氢-5H-二苯并[a，d]环庚烯-5-亚基)-1-(2-叔丁氧羰氨基)乙基)哌啶，
4-(9-噻吨亚基)-1-((2-叔丁氧羰氨基)乙基)哌啶，
1-(4-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基)丁基)吗啉，
1-(4-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基)丁基)硫代吗啉。
15.按照权利要求1的哌啶衍生物，其中所述化合物选自：
1-甲酰基-4-((2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基氨基甲酰基)哌嗪，
1-甲酰基-N-(3-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))丙基-4-哌啶甲酰胺，
1-甲酰基-4-哌啶甲酸2-(4-(5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基酯，
1-甲酰基-N-(2-(4-(10，11-二氢-5H-二苯并[a，d]环庚烯-5-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺，
1-甲酰基-N-(2-(4-(9-噻吨亚基)哌啶基))乙基-4-哌啶甲酰胺，
1-甲酰基-N-(2-(4-(11H-二苯并[b，e]硫杂环庚烷(thiepin)-2-氟-11-亚基)-1-哌啶基))乙基-4-哌啶甲酰胺。
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