CN105461608B - 二氢吲哚‑2‑酮类d3受体配体及其制备方法和用途 - Google Patents
二氢吲哚‑2‑酮类d3受体配体及其制备方法和用途 Download PDFInfo
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- CN105461608B CN105461608B CN201510818705.9A CN201510818705A CN105461608B CN 105461608 B CN105461608 B CN 105461608B CN 201510818705 A CN201510818705 A CN 201510818705A CN 105461608 B CN105461608 B CN 105461608B
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- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
本发明公开了一种二氢吲哚‑2‑酮类D3受体配体，如式I化合物所示：或其药用盐，其中，n＝2或3；R代表H、4‑CH3、2,3‑diCH3、2‑CH3、4‑OCF3、3‑OCH3、3,4‑di CH3或4‑Cl。相对于现有技术，本发明的化合物对多巴胺D3受体具有很强的活性，用于治疗或预防精神分裂症、帕金森病、药物依赖与复吸等中枢神经精神类疾病，也可用于神经保护，并作为工具药用于研究D3受体结构、功能以及与D3受体功能紊乱有关的疾病。
Description
技术领域
本发明涉及一种二氢吲哚-2-酮类D3受体配体及其制备方法和用途，属于药物合成技术领域。
背景技术
多巴胺是中枢神经系统内重要的神经递质，与帕金森病(PD)、亨廷顿症、精神分裂症(SCZD)等多种疾病有关。多巴胺受体分为D1、D2、D3、D4及D5共5种不同受体亚型，在跨膜区域具有高度的氨基酸序列同源性，使得开发兼具高亲和力及高选择性的多巴胺受体配体具有极其重要的意义。然而，多巴胺D3与D2受体跨膜单环内序列的高度一致性，尤其是这些受体内被推断为形成结合位点的残基的近乎同一性，使得开发具有类药性理化性质的D3受体选择性化合物非常艰难。
第二代非麦角碱类化合物普拉克索、罗匹尼罗通过单一或与左旋多巴联合用药，能有效治疗帕金森病。不过，与其它药物一样，D3受体配体在发挥治疗作用的同时，也有不同程度的副作用，产生诸如恶心、幻觉等药物副反应。临床上一般使用非典型抗精神分裂药物，如磺胺必利、氯氮平等药物治疗精神分裂症，取得了很好的效果。
长期以来药物成瘾的临床治疗显得步履维艰，一直没有找到特别有效的治疗方法。目前，国内外对药物成瘾进行治疗的主要方法是脱毒或控制戒毒症状，非药物治疗极少使用。近年来研究发现，BP897、NGB2904、S33138等D3受体部分激动剂和拮抗剂在治疗药物成瘾方面展示了一线希望，然而，要真正取得临床诊断和治疗方面的最终成功，仍然面临多重困难，可谓任重而道远。
发明内容
发明目的：为了解决上述技术问题，本发明提供了一种二氢吲哚-2-酮类D3受体配体及其制备方法和用途。
技术方案：为了实现上述发明目的，本发明公开了一种二氢吲哚-2-酮类D3受体配体，如式I化合物所示：
或其药用盐，
其中，n＝2或3；R代表H、4-CH3、2,3-diCH3、2-CH3、4-OCF3、3-OCH3、3,4-di CH3或4-Cl。
作为优选，所述n＝2时，R为3-OCH3、4-Cl、4-OCF3、H或3,4-di CH3；n＝3时，R为H、4-CH3、2,3-diCH3、2-CH3、4-OCF3、3-OCH3或3,4-di CH3。
优选的化合物，如表1所示：
表1化合物熔点及收率
a最后一步收率；b粘稠状物.
本发明还提供了所述的二氢吲哚-2-酮类D3受体配体或其药用盐在制备治疗或预防神经精神类疾病、保护神经、治疗与D3受体功能紊乱有关疾病的药物中的应用。
作为优选，所述神经精神类疾病为帕金森病、精神分裂症、药物依赖或不宁腿多动综合征；所述与D3受体功能紊乱有关疾病为精神分裂症、帕金森病、药物依赖或药物成瘾、各种形式的精神紧张、焦虑、睡眠障碍或者男性性功能障碍。
本发明另外还提供了所述的二氢吲哚-2-酮类D3受体配体或其药用盐在制备用于研究D3受体结构、功能以及与D3受体功能紊乱有关疾病的工具药中的应用。
本发明提供了一种药物组合物，含有至少一种所述二氢吲哚-2-酮类D3受体配体或其药用盐，以及药用载体或者赋形剂。
作为优选，所述药物组合物为针剂、输液剂、滴丸、片剂、胶囊剂、颗粒剂或口服液。
本发明最后提供了所述二氢吲哚-2-酮类D3受体配体的制备方法，所述二氢吲哚-2-酮类D3受体配体是由化合物3和化合物2反应所制成，反应式如下：
作为优选，所述化合物3是由化合物4经下列一系列反应所制成：
其中，化合物6中，R为H、4-CH3、2,3-diCH3、2-CH3、4-OCF3、3-OCH3、3,4-di CH3或4-Cl。
作为优选，所述化合物2是由化合物9经下列一系列反应，最后分离纯化或重结晶精制所制成：
上述优选化合物的合成方法如：
(1)中间体1i-1l的合成：
如以下反应流程式所示，化合物(6)为各种官能团取代的苯胺，R为各种取代基(团)，见表1。起始原料二乙醇胺经过一系列反应，得到各中间体1i-1l。其中各步骤试剂和条件为：(i)氯化亚砜,氯仿,1-8小时,室温,0.5-5小时,回流；80-95％；(ii)正丁醇,碳酸钾,40-100小时,回流,60-80％；(iii)氢氧化钠,水,pH＝12,90-97％；(iv)1-溴-3-氯丙烷,碳酸钾,丙酮,1-5小时,0-60℃,0.5-5小时,回流,50-70％；(v)1-溴-2-氯乙烷,碳酸钾,丙酮,1-5小时,0-50℃,0.5-3小时,回流,40-70％；(vi)碳酸钾,丙酮,2-7小时,0-55℃,0.5-4小时,回流,50-70％。
(2)中间体2的合成：
如以下反应流程式所示，由化合物(9)经过一系列反应，最后得到关键中间体(2)。最终产品可经柱层析分离纯化或有机溶剂重结晶精制。其中各步骤试剂和条件为：(i)氯化锌,苯甲酰氯,二氯甲烷,1-5小时,回流,85％-100％；(ii)二甲亚砜,碳酸氢钠,1-5小时,100-130℃,60-80％.(iii)硝基甲烷,正丁胺,乙酸,甲醇,10-25小时,0-50℃,53％-80％.(iv)三氯化铁,氯乙酰,二氯甲烷,1-3小时,-10-10℃,50％-70％；(v)水合肼,甲醇,10％钯炭,1-5h,回流；氢氧化钠,水,1-5小时,回流,64％-90％；(vi)对甲苯磺酰氯,吡啶,二氯甲烷,1-6小时,0-50℃,80％-96％；(vii)正丙胺,乙醇,50％-80％。
(3)目标化合物(3a-3l)的合成：
各种取代的化合物(1a-1l)与中间体(2)反应，生成目标化合物(3a-3l)，其中各步骤的试剂和条件为：试剂和条件:(i)KI,K2CO3,CH3CN,2.5h-12.5h,回流,34％-81％。
技术效果：相对于现有技术，本发明的化合物对多巴胺D3受体具有很强的活性，尤其是3a,3b,3g,用于治疗或预防精神分裂症、帕金森病、药物依赖与复吸等中枢神经精神类疾病，也可用于神经保护，并作为工具药用于研究D3受体结构、功能以及与D3受体功能紊乱有关的疾病。
附图说明
图1为各组大鼠在白箱中的停留时间对比；
具体实施方式
以下通过实施例说明本发明的具体步骤，但不受实施例限制。
在本发明中所使用的术语，除非另有说明，一般具有本领域普通技术人员通常理解的含义。
下面结合具体实施例并参照数据进一步详细描述本发明。应理解，这些实施例只是为了举例说明本发明，而非以任何方式限制本发明的范围。
在以下实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。
熔点用b形熔点管测定，温度计未校正；红外光谱仪为Nicolet Impact 410型，KBr压片；核磁共振仪为JEOL FX90Q型及Bruker-ACF-300型，TMS为内标；元素分析用CarloErba 1106型元素分析仪测定；质谱用Finnigan FTMS-2000型及HP1100LC/MSD型质谱仪测定。
实施例1 4-(2-((3-(4-苯基哌嗪-1-基)丙基)(丙基)氨基)乙基)二氢吲哚-2-酮的制备(3a)一、1-(3-氯丙基)-4-苯基哌嗪的制备(1a)
(1)双(2-氯乙基)胺盐酸盐的制备(5)
将氯化亚砜(128mL，1.76mol)加入80mL氯仿中，搅拌，于1h内缓缓滴加68mL氯仿稀释的二乙醇胺(40mL，0.417mol)。滴毕，室温下反应2-5h后，缓慢升温至70℃，回流0.5-1h后结束反应。冷却，抽滤，滤饼用二氯甲烷洗涤两次，干燥，得白色固体66g，收率89％，熔点214-215℃(文献207-209℃)。
(2)1-苯基哌嗪盐酸盐的制备(7)
将化合物5(30g，0.168mol)加入150mL正丁醇中，搅拌，缓缓滴加用10mL正丁醇稀释的苯胺(14.25g，0.153mol)，滴毕，回流反应30h，然后加入碳酸钾(23g，0.168mol)，继续回流40h后结束反应。趁热过滤，得深红色母液，冷却析晶，过滤，滤饼用少量正丁醇洗涤两次，干躁，最后得白色(微红)固体21.59g，收率71％。
(3)1-苯基哌嗪的制备(8)
将化合物7(26.0g，0.115mol)溶于250mL水中，用40％氢氧化钠溶液调节pH至12左右，乙酸乙酯萃取(2×200mL)，再用水、饱和食盐水分别洗涤一次，有机相用无水硫酸钠干燥过夜，过滤，减压浓缩得浅黄色油状物20.8g，收率95％。
(4)1-(3-氯丙基)-4-苯基哌嗪的制备(1a)
往50mL三口烧瓶里加入25mL丙酮，1.2g(7.40mmol)1-苯基哌嗪(8)，搅拌溶解，再加入2.56g(18.5mmol)碳酸钾。冰水浴下缓缓滴加1.75g(11.1mmol)1-溴-3-氯丙烷，然后缓慢加热至50℃反应3h，再缓缓加热，轻微回流8h，结束反应。冷却，过滤，滤液减压下旋转蒸发，残留物通过柱层析分离提纯，以石油醚：乙酸乙酯(体积比)＝2:1洗脱，最终得到浅黄色油状物1.04g，收率59％。
二、4-(2-(丙基氨基)乙基)二氢吲哚-2-酮的制备(2)
(1)苯甲酸(2-氯甲基)苯乙酯的制备(10)
将化合物9(65.0g,484mmol)加入120mL二氯甲烷中，搅拌，再加入氯化锌(1.95g,14.3mmol)。反应混合物加热至回流后，缓缓滴加苯甲酰氯(71.5g,509mmol)，滴毕，继续回流2.5h，原料9基本反应完。结束反应，冷却，水洗(3×200mL),无水硫酸钠干燥过夜。过滤，滤液减压浓缩，得棕色晶体产品132g，收率99％，熔点＜50℃。
1H NMR(300MHz,CDCl3),δH,ppm:3.23(t,J＝7.2Hz,2H),4.58(t,J＝7.2Hz,2H),4.72(s,2H),7.20-7.30(m,3H),7.38(d,J＝7.3Hz,1H),7.44(t,J＝7.7Hz,2H),7.56(t,J＝7.3Hz,1H),8.02(d,J＝7.3Hz,2H).
(2)苯甲酸(2-甲醛基)苯乙酯的制备(11)
将化合物10(2.70g,9.83mmol)投入35mL二甲亚砜中，搅拌，再加入碳酸氢钠(1.67g,19.9mmol)，加热升温至110℃。反应3h，原料10基本反应完毕，结束反应。过滤，减压浓缩得棕红色油状物，加水稀释，以二氯甲烷萃取(3×50mL)，水洗，减压去除溶剂，得粗产物。加入无水乙醇(9.2mL)，搅拌，再加入亚硫酸氢钠(8.64g,83.0mmol)与水(20mL)的混合物，20℃条件下充分搅拌30min，有白色固体析出。过滤，用冷的二氯甲烷洗至白色，干燥，得白色固体。将上述得到的固体加入碳酸氢钠(5.0g)、水(80mL)和二氯甲烷(45mL)的混合物中，常温下搅拌2h，静置分层，水层再用二氯甲烷萃取(2×40mL)。合并有机层，水洗(2×50mL)，再用饱和食盐水洗(50mL)，无水硫酸钠干燥过夜，减压浓缩得浅绿色油状物1.67g，收率67％。
1H NMR(300MHz,CDCl3),δH,ppm:3.53(t,J＝6.7Hz,2H),4.57(t,J＝6.7Hz,2H),7.37-7.48(m,4H),7.53(t,J＝7.3Hz,2H),7.84(d,J＝7.4Hz,1H),7.97(d,J＝7.3Hz,2H),10.26(s,1H).
(3)苯甲酸(2-β-硝基乙烯基)苯乙酯的制备(12)
称取9.33g(36.69mmol)化合物11，加入30mL甲醇中，搅拌溶解。冰水浴下依次缓缓滴加3.32g(54.39mmol)硝基甲烷、2.21g(36.80mmol)乙酸和2.73g(37.33mmol)正丁胺，滴加过程中体系温度控制在15℃以下。滴毕，于25℃左右反应14h，结束反应。将反应体系降温至-5℃，静置2h。过滤，用冷的异丙醇洗涤两次，40℃下真空干燥，得到黄色固体5.24g。收率：48％，熔点：65-67℃(文献值66-68℃)。
(4)4-(2-苯乙酸乙酯)3-氯-1,3-二氢-2H-吲哚-2-酮的制备(13)
将三氯化铁(15.9g,98.0mmol)加入80mL二氯甲烷中，搅拌，冰浴条件下缓慢滴加乙酰氯(7.69g,98.0mmol)，反应温度控制在5℃左右。滴毕，缓慢滴入溶于30mL二氯甲烷的化合物12(7.28g,24.5mmol)。5℃条件下反应3h，然后滴入100mL水，控制反应混合物的温度不超过30℃。滴毕，继续搅拌1h。静置分层，水层以二氯甲烷萃取(2×200mL)。合并有机层，水洗(3×200mL)，饱和食盐水洗(2×200mL)，无水硫酸钠干燥。过滤，减压浓缩至约100mL，加入55mL石油醚，0℃条件下冷却3h，有黄色固体颗粒析出。过滤，用40mL冷的混合液(二氯甲烷：石油醚＝4：1，体积比)洗涤，65℃真空干燥，得灰白色固体4.58g。收率59％，熔点154-155℃(文献值：154-155℃)。
1H NMR(300MHz,DMSO-d6),δH,ppm:3.15(m,2H),4.56(t,J＝6.7Hz,2H),5.69(s,1H),6.76(d,J＝7.7Hz,1H),6.99(d,J＝7.8Hz,1H),7.28(t,J＝7.8Hz,1H),7.52(t,J＝7.6Hz,2H),7.66(t,J＝7.4Hz,1H),7.94(d,J＝7.3Hz,2H),10.76(s,1H).
(5)4-(β-羟乙基)-1,3-二氢-2H-吲哚-2-酮的制备(14)
往15mL甲醇里加入中间体13(1.20g,3.80mmol)，搅拌，再加入10％Pd/C(0.075g,0.070mmol)，加热至回流。缓缓滴入水合肼(0.38g,7.59mmol)，滴毕，继续回流3h。滴加溶于26mL水的氢氧化钠(8.10g,202mmol)，再回流2h。称热过滤，减压浓缩除去大部分甲醇(溶液中刚开始有固体颗粒析出)，置于冰箱中冷却2h。过滤，冷水洗涤(2×15mL)，65℃真空干燥，得无色晶体0.48g。收率71％，熔点146-147℃(文献147-149℃)。
IR(KBr)δmax(cm-1):3261,3166,1682,1618,1608；1H NMR(300MHz,DMSO-d6),δH,ppm:2.64(t,J＝7.0Hz,2H),3.41(s,2H),3.59(t,J＝6.9Hz,2H),4.56(t,J＝5.2Hz,1H),6.64(d,J＝7.6Hz,1H),6.77(d,J＝7.7Hz,1H),7.07(t,J＝7.7Hz,1H),10.23(br,s,1H)；13CNMR(300MHz,DMSO-d6),δ:34.8,36.3,61.0,106.9,121.9,124.9,127.3,135.7,143.3,176.3。
(6)对甲苯磺酸2-(2-氧代二氢-4-吲哚)乙酯的制备(15)
往50mL反应瓶中加入化合物14(2.00g，11.29mmol)，13mL Py，搅拌，低于5℃下滴加以15mL二氯甲烷稀释的3.02g(15.84mmol)TsCl。滴毕，10℃下搅拌3h，反应完全。滴加20mL水，9mL二氯甲烷，15mL浓盐酸，搅拌2h后静置分层，水相以二氯甲烷萃取(40mL×2)，合并有机层，水洗，无水硫酸钠干燥过夜。滤液蒸至刚出现固体颗粒，冷却析晶，抽滤，干燥，得到淡黄色固体3.22g。收率86％，熔点：128-129℃。
(7)4-(2-(丙基氨基)乙基)二氢吲哚-2-酮的制备(2)
往反应瓶中加入65mL无水乙醇，9.08g(27.40mmol)化合物15，搅拌溶解，N2保护，冰水浴下加入85mL(1.03mol)正丙胺。滴毕，继续搅拌10min，然后缓缓加热，回流2.5h，结束反应。减压浓缩(<30℃)，往残留物中加150mL水，以40％NaOH调pH至11。以二氯甲烷萃取(250mL×3)，合并有机层，水洗，无水硫酸钠干燥过夜，过滤，浓缩。经柱层析提纯，以二氯甲烷：甲醇：三乙胺＝150:3:2作为洗脱液进行淋洗，得到棕色粘稠状化合物3.59g，收率60％。
1H NMR(300MHz,DMSO-d6),δH,ppm:0.85(t,J＝7.4Hz,3H),1.36-1.43(m,2H),2.45-2.51(m,3H),2.61(t,J＝6.81Hz,2H),2.68-2.74(m,2H),3.43(s,2H),6.64(d,J＝7.6Hz,1H),6.77(d,J＝7.7Hz,1H),7.08(t,J＝6.81Hz,1H),10.31(br,s,1H)；MS:219.1[M+H]+.
三、4-(2-((3-(4-苯基哌嗪-1-基)丙基)(丙基)氨基)乙基)二氢吲哚-2-酮的制备(3a)
冰水浴下往反应瓶中加入30mL乙腈，0.70g(3.21mmol)化合物2，0.77g(3.24mmol)化合物1a，搅拌溶解，再加入0.89g(6.44mmol)碳酸钾，0.54g(3.25mmol)碘化钾，缓缓升温至60℃，11h后原料基本反应完。趁热过滤，滤液减压浓缩，残留物以柱层析分离提纯，以二氯甲烷：甲醇：三乙胺＝200:0.5:1洗脱，得棕色粘稠状化合物0.86g，收率64％。
1H NMR(300MHz,CDCl3),δH,ppm:0.92(t,J＝7.2Hz,3H),1.54-1.59(m,2H),1.75-1.85(m,2H),2.45(t,J＝7.0Hz,2H),2.63-2.81(m,12H),3.22(s,4H),3.46(s,2H),6.81(d,J＝7.4Hz,1H),6.86(d,J＝7.4Hz,1H),6.91-6.94(m,3H),7.12(t,J＝7.7Hz,1H),7.23-7.30(m,2H),9.71(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.7,19.5,24.2,30.6,35.5,48.6,51.4,52.9,53.3,53.9,55.1,56.7,107.9,115.8,120.4,122.9,124.2,128.02,129.1,136.5,142.8,149.6,177.1；MS:421.3[M+H]+.
实施例2 3-(3-(4-(4-氯苯基)哌嗪-1-基)丙基)-10-甲氧基甲基-2,3,4,4a,5,6-六氢-1H-
吡嗪[1,2-a]并喹啉的制备(3b)
参照化合物3a的制备方法，制备化合物1b，投入中间体2(0.70g，3.21mmol)，反应结束后得到棕色粘稠状化合物0.93g，收率67％。
1H NMR(300MHz,CDCl3),δH,ppm:0.88(t,J＝7.2Hz,3H),1.41-1.53(m,2H),1.63-1.73(m,2H),2.26(s,3H),2.39(t,J＝7.4Hz,2H),2.46(t,J＝7.5Hz,2H),2.54(t,J＝7.3Hz,2H),2.60(s,4H),2.67(s,4H),3.15(s,4H),3.47(s,2H),6.71(d,J＝7.7Hz,1H),6.84(d,J＝7.9Hz,3H),7.06(d,J＝8.0Hz,2H),7.13(t,J＝7.7Hz,1H),9.28(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.9,20.3,20.3,24.5,30.9,35.1,49.6,52.1,53.2,54.3,56.1,56.6,107.5,116.3,122.7,124.0,127.9,129.1,129.5,137.1,142.5,149.2,177.6；IR(KBr,cm-1):3368,2954,2815,1687,1610,1577,1511,1459,1451,1237,811,720,651；MS:435.3[M+H]+.
实施例3 4-(2-((3-(4-(2,3-二甲基苯基)哌嗪-1-基)丙基)(丙基)氨基)乙基)二氢吲哚-2-酮的制备(3c)
参照化合物3a的制备方法，制备化合物1c，投入中间体2(0.70g，3.21mmol)，反应结束后得到棕色粘稠状化合物0.89g，收率62％。
1H NMR(300MHz,CDCl3),δH,ppm:0.89(t,J＝7.3Hz,3H),1.43-1.55(m,2H),1.65-1.75(m,2H),2.22(s,3H),2.27(s,3H),2.39-2.49(m,4H),2.53-2.69(m,10H),2.91-2.94(m,4H),3.48(s,2H),6.72(d,J＝7.7Hz,1H),6.83-6.93(m,3H),7.07(t,J＝7.7Hz,1H),7.15(t,J＝7.7Hz,1H),9.08(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.9,13.9,20.2,20.5,24.5,30.8,35.1,52.0,52.1,53.7,54.2,56.0,56.7,107.5,116.6,122.7,124.0,124.8,125.7,127.9,131.1,137.1,137.8,142.5,151.5,177.6；IR(KBr,cm-1):3440,3067,3025,2952,2872,1679,1619,1606,1581,1475,1460,1452,1376,1243,1145,1082,779,721,651；MS:449.4[M+H]+.
实施例4 4-(2-(丙基(3-(4-(邻甲苯基)哌嗪-1-基)丙基)氨基)乙基)二氢吲哚-2-酮的制备(3d)
参照化合物3a的制备方法，制备化合物1d，投入中间体2(0.70g，3.21mmol)，反应结束后得到棕色粘稠状化合物0.92g，收率66％。
1H NMR(300MHz,CDCl3),δH,ppm:0.89(t,J＝7.2Hz,3H),1.44-1.51(m,2H),1.64-1.74(m,2H),2.30(s,3H),2.41(t,J＝7.2Hz,2H),2.46(t,J＝7.3Hz,2H),2.54(t,J＝7.4Hz,2H),2.60(s,4H),2.68(s,4H),2.94(s,4H),3.48(s,2H),6.72(d,J＝7.6Hz,1H),6.84(d,J＝7.7Hz,1H),6.96(t,J＝7.3Hz,1H),7.02(d,J＝7.8Hz,1H),7.15-7.17(m,3H),9.31(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.9,17.8,20.3,24.6,30.9,35.1,51.6,52.1,53.7,54.3,56.0,56.7,107.5,118.9,122.7,123.0,124.0,126.5,127.9,130.9,132.5,137.1,142.5,151.4,177.7；IR(KBr,cm-1):3199,3066,3021,2954,2872,1687,1618,1607,1492,1458,1375,1266,1146,1084,777,722,650；MS:435.2[M+H]+.
实施例5 4-(2-(丙基(3-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)丙基)氨基)乙基)二氢吲哚-2-酮的制备(3e)
参照化合物3a的制备方法，制备化合物1e，投入中间体2(0.70g，3.21mmol)，反应结束后得到棕色粘稠状化合物1.13g，收率70％。
1H NMR(300MHz,CDCl3),δH,ppm:0.89(t,J＝7.2Hz,3H),1.43-1.54(m,2H),1.65-1.75(m,2H),2.40(t,J＝7.2Hz,2H),2.51(t,J＝7.5Hz,2H),2.58-2.71(m,10H),3.18(t,J＝4.5Hz,4H),3.45(s,2H),6.81-6.89(m,4H),7.08-7.14(m,3H),9.64(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.7,19.7,23.9,29.6,,30.3,35.1,49.0,51.8,52.8,53.0,54.0,55.7,56.2,108.0,116.4,121.8,122.4,124.0,127.9,136.1,141.8,142.9,149.9,177.1；IR(KBr,cm-1):3392,3079,2955,2874,2818,1697,1618,1607,1512,1457,1380,1264,1159,1085,1008,834,807,710,647；MS:505.2[M+H]+.
实施例6 4-(2–((3-(4-(3-甲氧基苯基)哌嗪-1-基)丙基)(丙基)氨基)乙基)二氢吲哚-2-酮的制备(3f)
参照化合物3a的制备方法，制备化合物1f，投入中间体2(0.70g，3.21mmol)，反应结束后得到棕色粘稠状化合物0.94g，收率65％。
1H NMR(300MHz,CDCl3),δH,ppm:0.89(t,J＝7.0Hz,3H),1.43-1.55(m,2H),1.66-1.76(m,2H),2.40(t,J＝7.1Hz,2H),2.51(t,J＝7.4Hz,2H),2.59-2.72(m,10H),3.20(s,4H),3.44(s,2H),3.78(s,3H),6.40(d,J＝7.9Hz,1H),6.46(s,1H),6.53(d,J＝8.0Hz,1H),6.81(d,J＝7.7Hz,1H),6.87(d,J＝7.6Hz,1H),7.11(t,J＝6.9Hz,1H),7.16(t,J＝7.8Hz,1H),9.71(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.8,19.9,24.1,30.5,35.1,48.8,51.8,52.9,54.1,55.1,55.8,56.3,102.3,104.3,108.0,108.7,122.3,123.9,127.9,129.6,136.3,142.9,152.5,160.4,177.0；IR(KBr,cm-1):3392,3079,2954,2871,2816,1683,1605,1576,1533,1496,1456,1255,1171,1050,1011,801,776,689,650；MS:451.3[M+H]+.
实施例7 4-(2-((3-(4-(3,4-二甲基苯基)哌嗪-1-基)丙基)(丙基)氨基)乙基)二氢吲哚-2-酮的制备(3g)
参照化合物3a的制备方法，制备化合物1g，投入中间体2(0.70g，3.21mmol)，反应结束后得到棕色粘稠状化合物0.91g，收率63％。
1H NMR(300MHz,CDCl3),δH,ppm:0.88(t,J＝7.3Hz,3H),1.41-1.53(m,2H),1.62-1.72(m,2H),2.17(s,3H),2.22(s,3H),2.39(t,J＝7.5Hz,2H),2.45(t,J＝7.5Hz,2H),2.53(t,J＝7.4Hz,2H),2.59(t,J＝4.6Hz,4H),2.67(s,4H),3.15(t,J＝4.5Hz,4H),3.47(s,2H),6.67-6.74(m,3H),6.83(d,J＝7.7Hz,1H),7.00(d,J＝8.2Hz,1H),7.12(t,J＝7.7Hz,1H),9.15(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.9,18.7,20.1,20.3,24.6,30.9,35.1,49.7,52.1,53.3,54.3,56.1,56.6,107.4,113.7,118.0,122.7,124.0,127.9,130.1,137.0,137.2,142.5,149.6,177.6；IR(KBr,cm-1):3195,3021,2954,2872,1695,1614,1572,1505,1455,1379,1149,1085,880,803,719,651；MS:449.3[M+H]+.
实施例8 4-(2-((2-(4-(3-甲氧基苯基)哌嗪-1-基)乙基)(丙基)氨基)乙基)二氢吲哚-2-酮的制备(3h)
参照化合物3a的制备方法，制备化合物1h，投入中间体2(0.70g，3.21mmol)，反应结束后得棕色粘稠状化合物0.91g，收率65％。
1H NMR(300MHz,CDCl3),δH,ppm:0.89(t,J＝7.3Hz,3H),1.43-1.52(m,2H),2.47-2.53(m,4H),2.62(t,J＝4.7Hz,4H),2.68-2.70(m,6H),3.19(t,J＝4.7Hz,4H),3.48(s,2H),3.78(s,3H),6.41(d,J＝8.0Hz,1H),6.46(s,1H),6.52(d,J＝8.3Hz,1H),6.71(d,J＝7.7Hz,1H),6.84(d,J＝7.7Hz,1H),7.11-7.18(q,J＝7.3Hz,2H),9.15(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.9,20.3,30.9,35.1,48.9,51.5,53.6,54.7,55.1,56.5,56.6,102.4,104.4,107.5,108.8,122.7,124.0,128.0,129.7,137.0,142.5,152.6,160.5,177.6；IR(KBr,cm-1):3200,3083,2950,2873,2822,1701,1604,1580,1497,1453,1299,1248,1204,1171,1055,774,759,719,687,650；MS:437.2[M+H]+.
实施例9 4-(2-((2-(4-(4-氯苯基)哌嗪-1-基)乙基)(丙基)氨基))乙基)二氢吲哚-2-酮的制备(3i)
参照化合物3a的制备方法，制备化合物1i，投入中间体2(0.70g，3.21mmol)，反应结束后得灰色固体0.96g，收率68％，熔点：136-137℃。
1H NMR(300MHz,CDCl3),δH,ppm:0.88(t,J＝7.2Hz,3H),1.44-1.52(m,2H),2.50-2.70(m,14H),3.15(s,4H),3.49(s,2H),6.72(d,J＝7.6Hz,1H),6.83(t,J＝8.3Hz,3H),7.11-7.19(m,3H),9.19(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.9,20.3,31.0,35.2,49.0,51.6,53.5,54.7,56.5,56.6,107.5,117.1,122.8,124.0,124.4,128.0,128.9,137.0,142.5,149.8,177.6；IR(KBr,cm-1):3211,3066,3039,3019,2948,2873,1669,1603,1498,1451,1299,1245,1128,1082,813,769,696,658；MS:441.2[M+H]+.
实施例10 4-(2-(丙基(2-(4-(4-(三氟甲氧基)苯基)哌嗪-1-基)乙基)氨基)乙基)二氢吲哚-2-酮的制备(3j)
参照化合物3a的制备方法，制备化合物1j，投入中间体2(0.70g，3.21mmol)，反应结束后得棕色粘稠状化合物0.93g，收率59％。
1H NMR(300MHz,CDCl3),δH,ppm:0.89(t,J＝7.3Hz,3H),1.45-1.52(m,2H),2.47-2.53(m,4H),2.63(t,J＝4.7Hz,4H),2.68-2.71(m,6H),3.17(t,J＝4.6Hz,4H),3.49(s,2H),6.73(d,J＝7.7Hz,1H),6.83-6.88(m,3H),7.08-7.16(m,3H),9.39(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.9,20.4,31.0,35.2,49.1,51.6,53.6,54.8,56.6,56.7,107.5,116.5,121.9,122.3,122.8,124.0,128.0,137.1,141.9,142.4,150.0,177.5；IR(KBr,cm-1):3166,3019,2955,2871,2819,1684,1605,1515,1458,1268,1238,1159,1003,832,718,646；MS:491.2[M+H]+.
实施例11 4-(2-((2-(4-苯基哌嗪-1-基)乙基)(丙基)氨基)乙基)二氢吲哚-2-酮的制备(3k)
参照化合物3a的制备方法，制备化合物1k，投入中间体2(0.70g，3.21mmol)，反应结束后得灰色固体0.93g。收率71％，熔点：113-114℃。
1H NMR(300MHz,CDCl3),δH,ppm:0.89(t,J＝7.2Hz,3H),1.44-1.56(m,2H),2.47-2.53(m,4H),2.64(t,J＝4.6Hz,4H),2.67-2.80(m,6H),3.12-3.27(m,4H),3.50(s,2H),6.71(d,J＝7.7Hz,1H),6.83-6.88(m,2H),6.92(d,J＝8.0Hz,2H),7.15(t,J＝7.7Hz,1H),7.26(t,J＝7.6Hz,2H),8.12(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.9,20.4,31.0,35.1,49.0,51.6,53.7,54.8,56.6,56.7,107.5,116.0,119.6,122.8,124.0,128.0,129.0,137.1,142.4,151.2,177.5；IR(KBr,cm-1):3183,3058,3039,3021,2957,2867,1664,1606,1577,1505,1456,1321,1301,1249,1140,1084,753,690,656；MS:407.3[M+H]+.
实施例12 4-(2-((2-(4-(3,4-二甲基苯基)哌嗪-1-基)乙基)(丙基)氨基)乙基)二氢吲哚-2-酮的制备(3l)
参照化合物3a的制备方法，制备化合物1l，投入中间体2(0.70g，3.21mmol)，反应结束后得棕色粘稠状化合物0.98g，收率70％。
1H NMR(300MHz,CDCl3),δH,ppm:0.88(t,J＝7.2Hz,3H),1.44-1.52(m,2H),2.17(s,3H),2.22(s,3H),2.47-2.53(m,4H),2.63-2.70(m,10H),3.14(s,4H),3.48(s,2H),6.66-6.74(m,3H),6.84(d,J＝7.7Hz,1H),7.00(d,J＝8.1Hz,1H),7.13(t,J＝7.7Hz,1H),9.22(s,1H)；13C-NMR(300MHz,CDCl3),δ:11.9,18.7,20.1,20.4,31.0,35.1,49.6,51.6,53.7,54.8,56.6,56.7,107.5,113.7,118.0,122.7,124.0,127.9,128.0,130.1,137.0,137.0,142.5,149.5,177.6；IR(KBr,cm-1):3186,3080,3025,2948,2856,1702,1605,1569,1505,1455,1307,1242,1140,1091,886,804,704,660；MS:435.3[M+H]+.
实验例生物活性研究
实验1化合物对多巴胺D3受体及D2受体的亲和力测试
对本发明所述化合物进行生物活性的研究，以稳定转染的D3R-HEK-293细胞株为载体，通过放射性配体[3H]Spiperone竞争结合实验，进行一系列受体结合浓度的试验，确定化合物对D3受体及D2受体的Ki值。
药品与试剂:
[3H]Spiperone(98Ci/mmol)均购自PE公司；(+)Butaclamol，购自RBI公司；GF/C玻璃纤维滤纸，购自Whatman公司；脂溶性闪烁液Tris,由吉泰科技有限公司分装。
实验方法:
D3R-HEK-293细胞，经48-72小时后受体蛋白在膜上大量表达，将细胞1000rpm离心5min后弃上清，将沉淀重悬于5mM Tris,5mM EDTA.2Na,5mM EGTA裂解液(pH＝7.4)中，冰上放置30min。斡旋震荡5-10次，4℃、40000g离心20min。弃上清，沉淀重悬于冰冷50mM Tris-HCl(pH＝7.4)缓冲液中，过针头5-10次，4℃、40000g离心20min。考马斯亮蓝G-250法测蛋白浓度。
将一定量待测化合物与放射性配基及受体蛋白加入反应试管中，30℃水浴孵育50min后，即刻移至冰浴终止其反应。然后，在Millipore细胞样品收集器上，经过GF/C玻璃纤维滤纸快速抽滤，并用洗脱液(50mM Tris-HCl,PH＝7.5)3ml×3次，用微波炉3～4min烘干，将滤纸移入0.5ml离心管中，加入500ul脂溶性闪烁液。避光静置30min以上，计数测定放射性强度。
各自取一定量被测试化合物样品，进行一系列受体结合浓度的试验，确定化合物对D3受体及D2受体的Ki值。化合物对多巴胺D3受体及D2受体的亲和力(Ki值)测定结果见表2。
表2化合物对多巴胺D3受体及D2受体的Ki值
*表示阳性对照
实验2条件性位置偏爱实验
优选上述化合物3g(代号ZBH-II-A-8)，研究其对吗啡诱导大鼠条件性位置偏爱的影响。
实验原理条件性位置偏爱实验(Conditioned Place Preference，CPP)是目前评价药物精神依赖性的经典实验，将实验动物(大鼠)置于条件性位置偏爱箱的白色观察区，注入精神依赖性药物吗啡，观察实验动物在条件性位置偏爱箱的黑色区和白色区的活动情况(白色区、黑色区以及其中的灰色区之间有小门可供动物自由通过)。因药物的精神依赖作用，动物每次处于给药区就会在药物奖赏效应的作用下对黑色和白色区域产生位置上的偏好。
仪器及材料大鼠条件性位置偏爱仪器；wistar大鼠，雄性，体重200±20g；
试剂：盐酸吗啡；化合物ZBH-II-A-8,由发明人合成。
实验过程分为四个阶段：药品准备，预测期，训练期，测试期。
1)药品准备
吗啡溶液：10mg/kg，称1mg吗啡溶于100mL双蒸水；化合物样品ZBH-II-A-8溶液：1.0mg/kg，称0.1mg化合物ZBH-II-A-8先溶于少量的DMSO，再加双蒸水至100mL；5.0mg/kg，称0.5mg化合物ZBH-II-A-8先溶于少量DMSO，再加双蒸水至100mL；10.0mg/kg，称1mg化合物ZBH-II-A-8先溶于少量的DMSO，再加双蒸水至100mL。
2)预测期
前3天，抽出箱之间的隔板，把大鼠放到中间箱，让其在三个箱内能够自由跑动15min。测定大鼠在各箱内的停留时间，判断大鼠对黑、白箱的偏爱情况。
3)训练期
第4-11天，插上隔板，阻止大鼠在箱间自由通过。每天上午9:00和下午14:00开始实验。每天用盐水和药物各训练1次，共连续8天时间。ZBH-II-A-8的3个剂量组，腹腔给ZBH-II-A-8各个剂量20分钟后，皮下注射吗啡10mg/kg，然后立即放入白箱(伴药箱)45min，皮下注射盐水后立即放入黑箱(非伴药箱)45min，每天循环一次。吗啡组腹腔给予溶剂30分钟后，皮下注射吗啡(10mg/kg)后立即放于白箱(伴药箱)45min，注射盐水后立即放入黑箱(非伴药箱)45min，每天循环一次。溶剂组腹腔给予盐水30分钟后，皮下注射溶剂后立即放入白箱45min，注射盐水后放入黑箱中45min，每天循环一次。
4)测试期
第12天，抽出隔板，把大鼠放到中间箱位置，让其在三个箱子内自由跑动15min，用计算机记大鼠在白箱(伴药箱)内的停留时间。
整个实验分为五组：(a)溶剂+生理盐水(NS)；(b)吗啡+溶剂(Mor-10mg/kg)；(c)吗啡+ZBH-II-A-8(1.0mg/kg)；(d)吗啡+ZBH-II-A-8(5.0mg/kg)；(e)吗啡+ZBH-II-A-8(10.0mg/kg)。
实验结果：根据单因素多水平方差分析数据统计分析，对比各组大鼠在伴药箱中的停留时间。实验结果表明，在吗啡诱导的大鼠条件性位置偏爱实验中，ZBH-II-A-8在5.0mg/kg和10.0mg/kg两个剂量时能明显减少吗啡诱导的条件性位置偏爱的发生。结果见说明书附图1。
在以上条件性位置偏爱试验中，本发明其它实施例的化合物都具有与ZBH-II-A-8基本相似的试验结果，在一定剂量时都能明显减少吗啡诱导的条件性位置偏爱的发生。
Claims (10)
1.二氢吲哚-2-酮类D3受体配体，如式I化合物所示：
或其药用盐，
其中，n＝2或3；R代表H、4-CH3、2,3-diCH3、2-CH3、4-OCF3、3-OCH3、3,4-di CH3或4-Cl。
2.根据权利要求1所述的二氢吲哚-2-酮类D3受体配体，其特征在于，所述n＝2时，R为3-OCH3、4-Cl、4-OCF3、H或3,4-di CH3；n＝3时，R为H、4-CH3、2,3-diCH3、2-CH3、4-OCF3、3-OCH3或3,4-di CH3。
3.权利要求1-2任一项所述的二氢吲哚-2-酮类D3受体配体或其药用盐在制备治疗或预防神经精神类疾病、保护神经、治疗与D3受体功能紊乱有关疾病的药物中的应用。
4.根据权利要求3所述的二氢吲哚-2-酮类D3受体配体或其药用盐的应用，其特征在于，所述神经精神类疾病为帕金森病、精神分裂症、药物依赖或不宁腿多动综合征；所述与D3受体功能紊乱有关疾病为精神分裂症、帕金森病、药物依赖或药物成瘾、各种形式的精神紧张、焦虑、睡眠障碍或者男性性功能障碍。
5.权利要求1-2任一项所述的二氢吲哚-2-酮类D3受体配体或其药用盐在制备用于研究D3受体结构、功能以及与D3受体功能紊乱有关疾病的工具药中的应用。
6.一种药物组合物，其特征在于，含有至少一种权利要求1-2任一项所述二氢吲哚-2-酮类D3受体配体或其药用盐，以及药用载体或者赋形剂。
7.根据权利要求6所述的药物组合物，其特征在于，所述药物组合物为针剂、输液剂、滴丸、片剂、胶囊剂、颗粒剂或口服液。
8.权利要求1-2任一项所述二氢吲哚-2-酮类D3受体配体的制备方法，其特征在于，所述二氢吲哚-2-酮类D3受体配体是由化合物3和化合物2反应所制成，反应式如下：
9.根据权利要求8所述二氢吲哚-2-酮类D3受体配体的制备方法，其特征在于，所述化合物3是由化合物4经下列一系列反应所制成：
其中，化合物6中，R为H、4-CH3、2,3-diCH3、2-CH3、4-OCF3、3-OCH3、3,4-diCH3或4-Cl。
10.根据权利要求8所述二氢吲哚-2-酮类D3受体配体的制备方法，其特征在于，所述化合物2是由化合物9经下列一系列反应，最后分离纯化所制成：
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