CN102675300A - 硫辛酸-阿朴菲共轭化合物、其药物组合物及其用途 - Google Patents
硫辛酸-阿朴菲共轭化合物、其药物组合物及其用途 Download PDFInfo
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- CN102675300A CN102675300A CN2011100668230A CN201110066823A CN102675300A CN 102675300 A CN102675300 A CN 102675300A CN 2011100668230 A CN2011100668230 A CN 2011100668230A CN 201110066823 A CN201110066823 A CN 201110066823A CN 102675300 A CN102675300 A CN 102675300A
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Abstract
本发明涉及一类硫辛酸-阿朴菲共轭化合物、其药物组合物及其用途。具体地,涉及一类由如下通式I表示的硫辛酸-阿朴菲共轭化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物、其药物组合物及其在制备治疗中枢神经系统疾病的药物中的用途,所述中枢神经系统疾病包括帕金森氏症、精神分裂症、抑郁症、药物成瘾等。
Description
技术领域
本发明属于药剂学领域,涉及一类硫辛酸-阿朴菲共轭化合物、其药物组合物及其用途。具体地,涉及一类由如下通式I表示的新型阿朴菲类化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物、其药物组合物和用于制备治疗中枢神经系统疾病的药物,所述中枢神经系统疾病包括:精神分裂症、抑郁症、焦虑症、帕金森氏症以及抗帕金森氏病/精神分裂症药物引起的运动障碍等。
通式I
背景技术
1、多巴胺受体
多巴胺是哺乳动物体内重要的儿茶酚胺类神经递质,对多种生理功能均有调控作用。外周多巴胺系统对调控心血管系统功能、控制儿茶酚胺释放和激素分泌、消化功能及胃肠道运动有着重要的功能。中枢多巴胺系统则被认为与一系列的中枢退行性疾病(如帕金森氏症,亨廷顿舞蹈病,精神分裂症等)和精神紊乱有关。
多巴胺是通过多巴胺受体(D1、D2、D3、D4、D5)发挥作用的。多巴胺受体属于G-蛋白偶联受体家族,分为D1和D2两个大类。D1类包括D1和D5两种亚型,它们被激活后提高腺苷酸环化酶的活性,引起cAMP的升高。D2类包括D2,D3,D4三种亚型,它们被激活后抑制腺苷酸环化酶的活性,降低cAMP水平。
2、5-羟色胺受体
5-羟色胺(5-HT)也是一种重要的中枢神经递质,在一系列的生理功能中发挥了重要的作用,被认为与痛觉、摄食行为、性行为、情感、睡眠、记忆等有关。5-HT的合成、储存、膜摄取及代谢与5-HT受体共同构成5-HT神经系统。根据氨基酸序列、基因结构、与其偶连的第二信使和药理学表征,5-HT受体至少可以分为7类,16种亚型。除了5-HT3受体是属于配基-门控离子通受体外,其余属于G-蛋白偶联受体家族。其中5-HT1受体包括5种亚型(5-HT1A、5-HT1B、5-HT1D、5-HT1E、5-HT1F),5-HT2受体包括3种亚型(5-HT2A、5-HT2B、5-HT2C)。
3、硫辛酸
α-硫辛酸(lipoic acid),于1951年被L.J.Reed等首次分离成晶体,为含硫八碳脂酸,在6,8位上有二硫键相连(C6和C8上的氢原子被二硫键取代),故又称6,8-二硫辛酸,有氧化、还原二型。天然的LA为R构型,它虽然不属于维生素,但其可作为辅酶,参与机体内物质代谢过程中酰基转移,起到递氢和转移酰基的作用(即作为氢载体和酰基载体),具有与维生素相似的功能(类维生素)。
α-硫辛酸含有双硫五元环结构,电子密度很高,具有显著的亲电子性和与自由基反应的能力,因此它具有抗氧化性,具有极高的保健功能和医用价值(如抗脂肪肝和降低血浆胆固醇的作用)。此外,硫辛酸的巯基很容易进行氧化还原反应,故可保护巯基酶免受重金属离子的毒害。因此,硫辛酸可以作为强效抗氧化剂、神经保护剂和铁离子螯合剂。
4、多巴胺受体、5-羟色胺受体、硫辛酸和帕金森氏症、精神分裂症
帕金森氏症(Parkinson’s disease,PD)又名震颤麻痹(paralysis agitans),是一种常见的中老年人神经系统退行性疾病。临床表现为静止性震颤、动作迟缓、运动减少、肌强直和姿势平衡障碍4大主要特征,起病年龄多见于50~60岁。研究表明多巴胺受体激动剂,尤其是多巴胺D1和D2受体激动剂是治疗帕金森氏症的有效手段之一。
另外,5-HT1A受体激动剂也已被证明能有效缓解多巴胺受体激动剂左旋多巴诱导的异动症。同时具有多巴胺和5-羟色胺活性的药物是目前抗抑郁药的主要选择,如丁螺环酮(Buspirone)、坦度螺酮(Tandospirone)、吉哌隆(Gepirone)、扎螺酮(Zalospirone)等。不仅如此,同时作用于多巴胺和5-羟色胺受体的药物还在其他精神障碍疾病的治疗中起着重要的作用。
鉴于α-硫辛酸具有抗氧化作用,它被广泛的应用在病因多元化疾病研究中,如神经退行性疾病(如帕金森氏症和老年痴呆症等)、高血压、糖尿病和癌症等。如,L-Dopa与(R)-α-硫辛酸轭合(J.Med.Chem,2006,49,1486-1493)、他可宁与α-硫辛酸轭合(J.Med.Chem,2005,48,360-363)、哌唑嗪片段和α-硫辛酸轭合(J.Med.Chem,2005,48,28-31)、罗格列酮片段与α-硫辛酸或二氢硫辛酸轭合(J.Med.Chem,2006,49,4072-4084)、EGFR抑制剂PD153035骨架与α-硫辛酸轭合(J.Med.Chem,2006,49,6642-6645),都产生了良好的药理效果。
因此,本发明主要是基于阿朴菲这一经典多巴胺受体激动剂的结构以及硫辛酸的抗氧化作用,通过合理的结构修饰来引入α-硫辛酸及其类似物的片段,从而获得一类具有阿朴菲骨架的多巴胺受体和五羟色胺受体多靶点药物,这些化合物将用于帕金森氏症或精神分裂病的治疗药物研究。
发明内容
本发明的一个目的是提供通式I表示的一类硫辛酸-阿朴菲共轭化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物。
本发明的另一目的是提供包含通式I化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物的药物组合物。
本发明的又一目的是提供上述化合物在制备治疗中枢神经系统疾病的药物中的用途。本发明的阿朴菲类化合物不仅具有多巴胺D2受体活性,同时还具有5-HT1A受体活性。因此,本发明的化合物可用于制备治疗中枢神经系统疾病的药物,尤其是精神分裂症、抑郁症、焦虑症、帕金森氏症以及抗帕金森氏病/精神分裂症药物引起的运动障碍。
本发明提供由通式I表示的硫辛酸-阿朴菲共轭化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物。
通式I
其中,
R1为C1-C12烷基、烯丙基、顺或反式-3-碘-烯丙基、炔丙基、环丙基、环丁基、环丙甲基、环丁甲基、苄基、苯乙基、苯乙烯基、2-氟乙基、3-氟丙基、2-甲氧基乙基、3,4-二氯-苯基乙基、3-呋喃甲基、2-呋喃甲基、3-四氢呋喃甲基或2-四氢呋喃甲基;
R2为氢、C1-C12烷氧基、烯丙氧基、顺或反式-3-碘-烯丙氧基、炔丙氧基、环丙氧基、环丁氧基、环丙甲氧基、环丁甲氧基、苄氧基、苯乙氧基、苯乙烯氧基、2-氟乙氧基、3-氟丙氧基、2-甲氧基乙氧基、3,4-二氯-苯基乙氧基、3-呋喃甲氧基、2-呋喃甲氧基、3-四氢呋喃甲氧基或2-四氢呋喃甲氧基;
m为1-5的整数;
n为0-12的整数;
r为0-6的整数;
A为
其中,k为1-8的整数;
R3、R4、R5各自独立地为氢、C1-C6烷氧基、卤素、硝基、三氟甲基、氰基、羟基、胺甲酰基或C1-C6酰基。
在优选的实施方案中,通式1的化合物中:
R1为C1-C6烷基、烯丙基、炔丙基、环丙基、环丁基、环丙甲基、环丁甲基、苄基;
R2为氢、C1-C6烷氧基、烯丙氧基、炔丙氧基、环丙氧基、环丁氧基、环丙甲氧基、环丁甲氧基、苄氧基;
m为1-2的整数;
n为0-4的整数;
r为0-2的整数;
A为
其中,k为1-8的整数;R3、R4、R5各自独立地为氢、C1-C6烷氧基、卤素、硝基、三氟甲基、氰基、羟基、胺甲酰基或C1-C6酰基。
在更优选的实施方案中,通式1的化合物中:R1为C1-C4烷基,R2为氢或C1-C6烷氧基,
m为1,n为3或4,r为0或1,
最优选地,通式I化合物选自下列化合物中:
通式I化合物含有二个手性中心,因此可存在4个非对映立体异构体。本发明包括通式I表示的化合物的4个非对映立体异构体及它们的混合物。
本发明也包括通式I表示的化合物的药学上可接受的盐。例如与无机酸或有机酸形成的盐,具体而言,所述无机酸为盐酸、氢溴酸、硫酸或磷酸,所述有机酸为有机羧酸,如柠檬酸(枸橼酸)、乳酸、苹果酸、葡糖酸、酒石酸、己二酸、醋酸、琥珀酸、富马酸、抗坏血酸或衣康酸,或者为有机磺酸,如甲磺酸或苯磺酸。
通式I表示的化合物的药学上可接受的溶剂合物非限制性地包括通式I表示的化合物与水、乙醇、异丙醇、乙醚、丙酮等形成的溶剂合物。
本发明还提供了包含治疗有效量的通式I化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物作为有效成分的药物组合物。本发明还提供了通式I化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物及其药物组合物在用于制备预防或治疗与多巴胺D1受体、多巴胺D2受体、5-羟色胺1A受体和/或5-羟色胺2A受体相关的疾病的药物中的用途,尤其是在制备治疗中枢神经系统疾病,例如精神分裂症、抑郁症、焦虑症,帕金森氏症以及抗帕金森氏病/精神分裂症药物引起的运动障碍等的药物中的用途。
附图说明
图1显示了对化合物I12-1进行的D2和5-HT1A受体功能试验的结果。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但这些实施例并不限制本发明的范围。
一、制备实施例
1H-NMR用Varian MercuryAMX300型仪测定;MS用VG ZAB-HS或VG-7070型仪测定,除注明外均为EI源(70ev);所有溶剂在使用前均经过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得;除注明外,所有反应均是在氮气保护下进行并进行TLC跟踪,后处理时均经饱和氯化钠水溶液洗涤和无水硫酸钠干燥过程;产品的纯化除说明外均使用硅胶(200~300目)柱色谱法;其中硅胶(200~300目)由青岛海洋化工厂生产,GF254薄层硅胶板由烟台江友硅胶开发有限公司生产。
化合物I1的合成
化合物1根据文献方法(Neumeyer,J.L.;Granchelli,F.E.J.Med.Chem.1974,17(10),1090-5.)制备。化合物2和3的制备可参考文献方法(Zhang,A.;Neumeyer,J.L.Org.Lett.2003,5,201-3;Koufaki,M.;Kiziridi,C.;Alexi,X.;Alexis,M.N.Bioorg.Med.Chem.2009,17,6432-41.)。
其中,Tf2O为三氟甲磺酸酐,Py为吡啶,DCM为二氯甲烷,Zn(CN)2为氰化锌,Pd(PPh3)4为四三苯基磷钯,DMF为N,N-二甲基甲酰胺,NH2OH·HCl为盐酸羟胺,Et3N为三乙胺,EtOH为乙醇,DCC为1,3-二环己基碳二亚胺,lipoic acid为(DL)-α-硫辛酸,TBAF为四丁基氟化铵,THF为四氢呋喃。
11-羟基-N-丙基阿朴菲1(900mg,3.22mmol)溶于80ml无水二氯甲烷中,加入1ml吡啶,置于-60℃中,于氮气保护下,缓慢滴加三氟甲磺酸酐(0.83ml,4.83mmol)的10ml二氯甲烷溶液,滴毕,继续于该温度搅拌反应1h,逐渐升温至室温反应过夜。于冰浴下,加入饱和的碳酸钠溶液搅拌30min,分出二氯甲烷层,用饱和食盐水洗、干燥、旋干、柱层析得到灰色固体2。(1.3g,97.7%)
将灰色固体2(240mg,0.58mmol)、氰化锌(136mg,1.16mmol)、四苯基磷钯(54mg,0.046mmol)加入到30ml反应管中,加入无水15mL DMF,快速抽真空氮气置换3次,置于微波反应器中,升温至150℃反应30min,快速降温至室温。打开反应管,转移到分液漏斗中,加入饱和碳酸钠溶液和水,混合物用乙酸乙酯萃取。合并提取液,用饱和食盐水洗、干燥、浓缩、柱层析得到黄色固体3(165mg,98%)。1SH-NMR(300MHz,CDCl3):δ8.07(d,1H J=7.8Hz),7.64(d,1H,J=7.8Hz),7.48(d,1H,J=7.2Hz),7.29(m,2H),7.17(d,1H,J=7.8Hz),3.33(dd,1H,J=3.0,13.8Hz),3.14(m,3H),2.82(m,1H),2.50(d,1H,J=17.1Hz),2.49(m,3H),1.67(m,2H),0.97(t,3H,J=7.2,7.5Hz).13C-NMR(100MHz,CDCl3):δ137.9,137.4,135.7,133.8,133.7,132.5,130.4,129.7,127.1,126.5,124.5,119.8,107.8,58.9,56.3,48.8,34.6,29.0,19.6,12.0.MS(EI)m/z288[M+];HR-MS理论值C20H20N2:288.1626,实测值:288.1622。
将黄色固体3(80mg,0.28mmol)溶于6ml的无水乙醇中,加入NH2OH·HCl(97mg,1.39mmol)和Et3N(0.20mL,1.44mmol),然后升温至回流反应2d。向反应液中加入乙酸乙酯和饱和食盐水,有机层干燥并旋干,柱层析得到黄色固体(88mg,98%)。然后将得到的黄色固体溶于8ml无水二氯甲烷中,加入(DL)-α-硫辛酸(58mg,0.28mmol)和DCC(68mg,0.33mmol),混合液于室温下搅拌24小时。加入二氯甲烷和饱和食盐水稀释,分出有机层,干燥并浓缩进行柱层析得到黄绿色固体(55mg,40%)。
将上一步制备好的黄绿色固体(55mg,0.11mmol)溶于3mL无水THF中,加入TBAF(29mg,0.11mmol),在室温下搅拌反应30min,旋干反应液,残留物用乙酸乙酯溶液,用饱和食盐水洗、无水硫酸钠干燥然后浓缩后柱层析得到黄灰色固体I1(35mg,67%)。1H-NMR(300MHz,CDCl3):δ7.52(d,1H,J=7.8Hz),7.42(d,1H,J=7.2Hz),7.31(t,1H,J=7.5Hz),7.02(d,1H,J=7.8Hz),6.93(t,1H,J=7.8Hz),6.72(d,1H,J=7.8Hz),3.54(m,2H),3.14(m,5H),2.91(m,3H),2.77(d,1H,J=16.8Hz),2.57(m,2H),2.46(m,2H),1.85(m,3H),1.67(m,4H),1.51(m,2H),0.99(t,3H,J=7.2,7.5Hz).13C-NMR(100MHz,CDCl3):δ179.4,170.5,138.0,135.9,134.6,133.4,131.8,130.4,130.3,128.2,127.1,126.0,125.4,124.0,59.0,56.6,56.1,48.7,40.1,38.4,35.1,34.4,34.3,29.2,28.5,28.4,26.4,26.3,19.5,12.0.MS(EI)m/z 491[M+];HR-MS理论值C28H33ON3S2:491.2065,实测值:491.2073.
化合物I2的合成
化合物4的制备可参考文献方法(Jeremiah J.Harnett;Michel Auguet;Isabelle Viossat;Christine Dolo;Dennis Bigg;Pierre-E.Chabrier.Bioorg.Med.Chem.Lett.,12(2002),1439-1442;Gillespie,R.J.;Bamford,S.J.;Botting,R.;Comer,M.;Denny,S.;Gaur,S.;Griffin,M.;Jordan,A.M.;Knight,A.R.;Ruston,V.;Upton,R.;Weiss,S.M.J.Med.Chem.2009,52,33-47.)。
其中,Raney Ni为雷尼镍,NH4OH为浓氨水,EDCI为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐,HOBt为1-羟基苯并三唑。
将化合物3(80mg,0.28mmol)和浓氨水(1mL)溶解在15ml乙醇中,加入催化量的Raney Ni,抽真空氢气置换3次,于室温下反应24h。抽滤除去镍,并浓缩后柱层析得到无色油状物4(70mg,86%)。1H-NMR(300MHz,CDCl3):δ8.07(d,1H,J=7.8Hz),7.64(d,1H,J=7.8Hz),7.48(d,1H,J=7.2Hz),7.29(m,2H),7.17(d,1H,J=7.8Hz),4.23(d,1H,J=13.8Hz),4.07(d,1H,J=13.8Hz),3.33(d,1H,J=13.5Hz),3.16(m,3H),2.92(m,1H),2.78(d,1H,J=16.2Hz),2.49(m,3H),1.67(m,2H),0.97(t,3H,J=7.2Hz);13C-NMR(100MHz,CDCl3):δ139.2,137.4,136.4,133.7,133.3,132.9,128.4,127.7,127.1,126.5,125.8,125.7,59.6,56.5,48.7,44.8,35.7,29.3,19.7,12.0.MS(EI)m/z 292[M+];HR-MS理论值C20H24N2:292.1939,实测值:292.1939.
将无色油状物4(50mg,0.17mmol)、Et3N(0.03mL,0.22mmol)、HOBt(33mg,0.24mmol)和EDCI(94mg,0.49mmol)依次加入到(DL)-α-硫辛酸(39mg,0.19mmol)的二氯甲烷溶液(10ml)中,然后搅拌反应过夜,加入水稀释,用二氯甲烷萃取3次,油相用食盐水洗,干燥浓缩后柱层析得到黄色固体I2。(62mg,76%).1H-NMR(300MHz,CDCl3):δ7.25(m,5H),7.09(d,1H,J=6.9Hz),5.84(s,1H),4.91(dd,1H,J=6.6,14.7Hz),4.52(d,1H,J=14.7Hz),3.53(m,1H),3.41(d,1H,J=13.2Hz),3.13(m,5H),2.89(m,1H),2.76(d,1H,J=15.6Hz),2.45(m,4H),2.19(m,3H),1.88(m,1H),1.64(m,5H),1.44(m,2H),0.96(dt,3H,J=2.1,7.2Hz).13C-NMR(100MHz,CDCl3):δ172.5,137.6,136.4,134.2,134.0,133.5,132.2,128.5,127.9,127.3,127.1,125.9,125.7,59.6,56.5,56.3,48.7,42.2,40.1,38.4,36.3,35.6,34.5,29.2,28.8,25.3,19.6,12.0.MS(EI)m/z 480[M+];HR-MS理论值C28H36ON2S2:480.2269,实测值:480.2263.
化合物I3的合成
将I2(118mg,0.25mmol)溶于8mL的THF中,加入劳森试剂(韶远化学科技(上海)有限公司)(101mg,0.25mmol),然后加热至回流反应过夜。减压除去溶剂、柱层析得到黄色油状物I3(50mg,41%)。1H-NMR(300MHz,CDCl3):δ7.46(s,1H),7.28(m,3H),7.20(m,2H),7.09(d,1H,J=7.2Hz),5.29(dd,1H,J=4.8,15.0Hz),4.86(dd,1H,J=3.0,15.0Hz),3.52(m,1H),3.28(dd,1H,J=3.0,13.2Hz),3.01-3.22(m,5H),2.89(m,1H),2.77(d,1H,J=16.2Hz),2.61(m,2H),2.35-2.54(m,4H),1.88(m,1H),1.74(m,2H),1.63(m,4H),1.43(m,2H),0.96(t,3H,J=7.2,7.5Hz).13C-NMR(100MHz,CDCl3):δ204.6,137.9,136.3,134.5,133.6,131.9,129.1,128.1,127.8,127.4,126.1,125.4,59.5,56.4,56.2,49.2,48.7,46.4,40.1,38.3,35.5,34.4,29.2,28.8,28.3,19.6,12.0.MS(EI)m/z 494[M+];HR-MS理论值C28H36N2S3:494.2041,实测值:494.2026.
化合物I4的合成
其中,TMSN3为三甲基硅叠氮,DIAD为偶氮二异丙酯,PPh3为三苯基磷。
将化合物I3(0.034g,0.07mmol)溶解于0.5ml无水四氢呋喃中,缓慢滴加DIAD(0.02ml,0.11mmol)和PPh3(0.029g,0.11mmol),搅拌5min后,滴加TMSN3(0.02ml,0.11mmol),滴毕,于室温下搅拌反应5h,蒸除溶剂,柱层析得灰白色固体I4(12mg,35%)。1H-NMR(300MHz,CDCl3):δ7.46(s,1H),7.28(m,3H),7.20(m,2H),7.09(d,1H,J=7.2Hz),5.65(d,1H,J=15.0Hz),5.05(d,1H,J=15.0Hz),3.52(m,1H),3.28(dd,1H,J=3.0,13.2Hz),3.01-3.22(m,5H),2.89(m,1H),2.77(d,1H,J=16.2Hz),2.61(m,4H),2.35-2.54(m,4H),1.88(m,1H),1.74(m,2H),1.63(m,2H),1.43(m,2H),0.96(t,3H,J=7.2,7.5Hz).13C-NMR(100MHz,CDCl3):δ153.1,137.9,136.3,134.5,133.6,131.9,129.1,128.1,127.8,127.4,126.1,125.4,59.5,56.4,56.2,49.2,48.7,40.1,38.3,35.5,34.4,29.2,28.8,28.3,26.0,19.6,12.0.MS(EI)m/z 505[M+];HR-MS理论值C28H35N5S2:505.2334,实测值:505.2330.
化合物I5的合成
化合物5的制备可参考文献方法(J.Med.Chem.,1996,31(6),1818-822);化合物6的制备可参考文献方法(J.Org.Chem.,42(3),512-517)。
其中,AcOH为冰醋酸,70%H2SO4为70%(V/V)的硫酸,DMAP为4-二甲氨基吡啶。
将化合物3(80mg,0.28mmol)溶于4ml冰醋酸和70%硫酸的1∶1溶液中,加热至回流反应过夜,将该混合液倒入冰水中,用碳酸钠固体使产品沉淀,过滤,滤饼用水洗,用乙酸重结晶得化合物5(30mg,35%)。1H NMR(300MHz,CDCl3):δ8.7(s,1H),7.50(m,2H),7.05-7.36(m,4H),3.43(m,1H),3.18(m,3H),2.82(m,2H),2.50(m,3H),1.67(m,2H),0.97(t,J=7.8Hz,3H).13C NMR(100MHz,CDCl3)δ167.3,137.7,135.7,133.6,133.4,132.2,131.4,129.9,128.5,127.7,127.4,126.2,125.8,59.1,56.5,48.8,35.0,29.2,19.6,12.0.MS(EI)m/z307[M+];HR-MS:m/z[M+]理论值C20H21NO2:307.3862,实测值:307.3862.
将化合物5(30mg,0.1mmol)、化合物6(25mg,0.13mmol)和催化量的DMAP溶解在无水二氯甲烷中,于氮气保护下加入EDCI(38.4mg,0.2mmol),在室温下搅拌反应24h。反应液加入水和二氯甲烷稀释,分出二氯甲烷层,用食盐水洗,无水硫酸钠干燥,浓缩后柱层析得到淡黄色油状物I5(35mg,73%),之后在氯化氢的乙醚溶液的作用下转化成相应的盐酸盐。1H-NMR(300MHz,CDCl3):δ7.72(d,1H,J=8.1Hz),7.21(m,3H),7.06(d,1H,J=7.5Hz),7.00(d,1H,J=8.4Hz),4.30(t,2H,J=8.1Hz),3.54(m,1H),3.41(dd,1H,J=16.2,2.7Hz),3.16(m,5H),2.90(m,1H),2.76(dd,1H,J=16.2,4.5Hz),2.51(m,6H),1.89(m,1H),1.70(m,8H),0.97(t,3H,J=7.2Hz).13C-NMR(100MHz,CDCl3):161.6,147.1,138.6,135.8,133.6,130.6,128.1,127.7,127.3,125.9,124.6,122.0,64.8,59.1,56.4,56.2,48.7,40.1,38.4,34.9,34.5,34.3,29.2,28.7,24.3,19.5,12.0.MS(EI):m/z 481(M+);HR-MS理论值C28H35NO2S2:481.2109,实测值:481.2107.
化合物I6的合成
化合物7的制备可参考文献方法(J.Am.Chem.Soc.2000,122,2850-2859)。
将化合物5(30mg,0.10mmol)、化合物7(25mg,0.13mmol)和催化量的DMAP溶液加入无水二氯甲烷中,于氮气保护下加入EDCI(38.4mg,0.2mmol),在室温下搅拌反应24h。反应液加入水和二氯甲烷稀释,分出二氯甲烷层,用食盐水洗,无水硫酸钠干燥,浓缩后柱层析得到淡黄色油状物I6(24mg,50%)。1H-NMR(300MHz,CDCl3):δ7.72(d,1H,J=8.1Hz),7.21(m,3H),7.06(d,1H,J=7.5Hz),7.00(d,1H,J=8.4Hz),6.45(s,1H),3.54(m,1H),3.41(dd,1H,J=16.2,2.7Hz),3.30(t,2H,J=8.1Hz),3.16(m,5H),2.90(m,1H),2.76(dd,1H,J=16.2,4.5Hz),2.51(m,6H),1.89(m,1H),1.70(m,8H),0.97(t,3H,J=7.2Hz).13C-NMR(100MHz,CDCl3):161.6,147.1,138.6,135.8,133.6,130.6,128.1,127.7,127.3,125.9,124.6,122.0,64.8,59.1,56.4,56.2,48.7,40.1,38.4,34.9,34.5,34.3,29.2,28.7,24.3,19.5,12.0.MS(EI):m/z 480(M+);HR-MS理论值C28H35NO2S2:480.2269,实测值:480.2268.
化合物I7的合成
将I6(118mg,0.25mmol)溶于8mL的THF中,加入劳森试剂(101mg,0.25mmol),然后加热至回流反应过夜。减压除去溶剂、柱层析得到黄色油状物I7(43mg,35%)。1H-NMR(300MHz,CDCl3):δ7.72(d,1H,J=8.1Hz),7.21(m,3H),7.06(d,1H,J=7.5Hz),7.00(d,1H,J=8.4Hz),6.45(s,1H),3.54(m,1H),3.41(dd,1H,J=16.2,2.7Hz),3.30(t,2H,J=8.1Hz),3.16(m,5H),2.90(m,1H),2.76(dd,1H,J=16.2,4.5Hz),2.51(m,6H),1.89(m,1H),1.70(m,8H),0.97(t,3H,J=7.2Hz).13C-NMR(100MHz,CDCl3):198.7,145.1,138.6,135.8,133.6,130.6,128.1,127.7,127.3,125.9,124.6,122.0,64.8,59.1,56.4,56.2,48.7,40.1,38.4,34.9,34.5,34.3,29.2,28.7,24.3,19.5,12.0.MS(EI):m/z 496(M+);HR-MS理论值C28H36N2S3:496.2041,实测值:496.2043.
化合物I8的合成
将化合物I7(0.034g,0.07mmol)溶解于0.5ml无水四氢呋喃中,缓慢滴加DIAD(0.02ml,0.11mmol)和PPh3(0.029g,0.11mmol),搅拌5min后,滴加TMSN3(0.02ml,0.11mmol),滴毕,于室温下搅拌反应5h,蒸除溶剂,柱层析得灰白色固体I8(10mg,29%)。1H-NMR(300MHz,CDCl3):δ7.46(s,1H),7.28(m,3H),7.20(m,2H),7.09(d,1H,J=7.2Hz),3.52(m,1H),3.38(t,2H,J=8.1Hz),3.28(dd,1H,J=3.0,13.2Hz),3.01-3.22(m,5H),2.89(m,1H),2.77(d,1H,J=16.2Hz),2.61(m,4H),2.35-2.54(m,4H),1.88(m,1H),1.74(m,2H),1.63(m,2H),1.43(m,2H),0.96(t,3H,J=7.2,7.5Hz).13C-NMR(100MHz,CDCl3):δ153.1,137.9,136.3,134.5,133.6,131.9,129.1,128.1,127.8,127.4,126.1,125.4,59.5,56.4,56.2,49.2,48.7,40.1,38.3,35.5,34.4,29.2,28.8,28.3,26.0,19.6,12.0.MS(EI)m/z 505[M+];HR-MS理论值C28H35N5S2:505.2334,实测值:505.2330.
化合物I9的合成
化合物8的制备可参考文献方法(Alexi,X.;Alexis,M.N.Bioorg.Med.Chem.2009,17,6432-41.)。
其中,BOP为苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐,又称卡特缩合剂;POCl3为三氯氧磷。
将酸5(35mg,0.113mmol)溶于4ml无水DMF中,置于冰浴中滴加三乙胺(0.1ml),搅拌30min后,依次滴入BOP(50mg,0.113mmol)的二氯甲烷溶液和8(25mg,0.113mmol)的DCM溶液,于室温下搅拌反应过夜。反应完毕后,加入乙酸乙酯,然后用饱和食盐水洗、干燥、浓缩、柱层析得到黄灰色固体。(23mg,40%)1H-NMR(300MHz,CDCl3):δ8.12(s,2H),8.07(d,1H,J=8.1Hz),7.54(d,2H,J=7.2Hz),7.23(d,1H,J=8.1Hz),7.11(t,2H,J=7.8,8.1Hz),3.57(m,1H),3.30(d,1H,J=12.6Hz),3.14(m,5H),2.91(m,1H),2.78(d,1H,J=15.9Hz),2.43(m,6H),1.92(m,1H),1.74(m,4H),1.58(m,4H),0.97(t,3H,J=6.9,7.5Hz).
上步得到的黄灰色固体和三氯氧磷(0.2ml)的混合物加热到100℃,反应1h。之后加入向反应液中加入冷水,用二氯甲烷萃取。合并二氯甲烷层,用饱和食盐水洗,干燥浓缩后柱层析得化合物I9(15mg,67%)。1H-NMR(300MHz,CDCl3):δ8.03(d,1H,J=8.1Hz),7.50(d,2H,J=7.2Hz),7.21(d,1H,J=8.1Hz),7.11(t,2H,J=7.8,8.1Hz),3.57(m,1H),3.30(d,1H,J=12.6Hz),3.14(m,5H),2.89(m,1H),2.78(d,1H,J=15.9Hz),2.43(m,6H),1.92(m,1H),1.74(m,4H),1.58(m,4H),0.97(t,3H,J=6.9,7.5Hz).13C-NMR(100MHz,CDCl3):δ163.7,163.2,137.7,134.7,133.4,131.3,128.2,127.9,126.3,124.4,123.6,122.0,59.6,56.5,56.3,48.7,40.2,38.5,37.6,35.4,34.7,29.3,28.9,28.8,25.1,19.7,12.0.MS(EI)m/z 491[M+];HR-MS理论值C28H33N3OS2:491.2065,实测值:491.2062.
化合物I10的合成
化合物9的制备可参考文献方法(Alexi,X.;Alexis,M.N.Bioorg.Med.Chem.2009,17,6432-41.)。
然后将9(77mg,0.33mmol)溶于8ml无水二氯甲烷中,加入酸5(58mg,0.28mmol)和DCC(68mg,0.33mmol),混合液于室温下搅拌24小时。加入二氯甲烷和饱和食盐水稀释,分出有机层,干燥并浓缩进行柱层析得到黄绿色固体(55mg,40%).
将上一步制备好的黄绿色固体(55mg,0.11mmol)溶于3mL无水THF中,加入TBAF(29mg,0.11mmol),在室温下搅拌反应30min,旋干反应液,残留物用乙酸乙酯溶液,用饱和食盐水洗、无水硫酸钠干燥然后浓缩后柱层析得到黄灰色固体I10(35mg,67%)。1H-NMR(300MHz,CDCl3):δ7.52(d,1H,J=7.8Hz),7.42(d,1H,J=7.2Hz),7.31(t,1H,J=7.5Hz),7.02(d,1H,J=7.8Hz),6.93(t,1H,J=7.8Hz),6.72(d,1H,J=7.8Hz),3.54(m,2H),3.14(m,5H),2.91(m,3H),2.87(t,2H,J=6.9Hz),2.77(d,1H,J=16.8Hz),2.57(m,2H),2.46(m,2H),1.85(m,3H),1.67(m,4H),1.51(m,2H),0.99(t,3H,J=7.2,7.5Hz).13C-NMR(100MHz,CDCl3):δ175.4,169.5,138.0,135.9,134.6,133.4,131.8,130.4,130.3,128.2,127.1,126.0,125.4,124.0,59.0,56.6,56.1,48.7,40.1,38.4,35.1,34.4,34.3,29.2,28.7,28.5,28.4,26.4,26.3,19.5,12.0.MS(EI)m/z 505[M+];HR-MS理论值C29H35N3OS2:505.2222,实测值:505.2223.
化合物I11的合成
化合物11和10的制备可参考文献方法(Alexi,X.;Alexis,M.N.Bioorg.Med.Chem.2009,17,6432-41;Zhili Liu;Hai Zhang;Na Ye;Jing Zhang;QianQian Wu;Peihua Sun;Linyong Li;Xuechu Zhen;Ao Zhang.J.Med.Chem.2010,53,1319-1328.)。
将化合物10(63mg,0.20mmol)溶于4ml正丁醇和水的2∶1的混合溶液中,依次加入11(54mg,0.25mmol)的正丁醇∶水=2∶1的溶液、五水硫酸铜(20mg)、抗坏血酸钠(10mg),之后于室温下反应24h。向反应液中加入乙酸乙酯和氨水溶液,乙酸乙酯层用饱和食盐水洗、干燥、浓缩、柱层析得I11(43mg,40%)。1H-NMR(300MHz,CDCl3):δ8.07(d,1H,J=8.1Hz),7.54(d,2H,J=7.2Hz),7.23(d,1H,J=8.1Hz),7.11(t,2H,J=7.8,8.1Hz),5.23(dd,J=12.6Hz & 27.9Hz,2H),4.46(t,J=6.9Hz,2H),3.57(m,1H),3.30(d,1H,J=12.6Hz),3.14(m,5H),2.91(m,1H),2.78(d,1H,J=15.9Hz),2.43(m,6H),1.92(m,1H),1.74(m,4H),1.58(m,4H),0.97(t,3H,J=6.9,7.5Hz).13C-NMR(100MHz,CDCl3):δ143.1,137.7,134.7,133.4,131.3,128.6,128.2,127.9,126.3,124.4,123.6,122.0,69.8,59.6,56.5,56.3,52.4,48.7,40.2,38.5,37.6,35.4,34.7,29.3,28.9,28.8,25.1,19.7,12.0.MS(EI)m/z 534[M+];HR-MS理论值C30H38N4OS2:534.2487,实测值:534.2487.
化合物I12的合成
其中酸分别为(DL)-α-硫辛酸、(D)-α-硫辛酸或(L)-α-硫辛酸。
将(R)-11-羟基-N-丙基阿朴菲1(30mg,0.11mmol)(参考文献制备:Liu,Z.;Zhang,H.;Ye,N.;Zhang,J.;Wu,Q.;Sun,P.;Li,L.;Zhen,X.;Zhang,A.J.Med.Chem.2010,53(3),1319-28.)、硫辛酸(0.13mmol)和催化量的DMAP溶液在无水二氯甲烷中,于氮气保护下加入EDCI,在室温下搅拌反应24h。反应液加入水和二氯甲烷稀释,分出二氯甲烷层,用食盐水洗,无水硫酸钠干燥,浓缩后柱层析得到淡黄色油状物I12-1(35mg,70%),之后在氯化氢的乙醚溶液的作用下转化成相应的盐酸盐。同样操作得到I12-2和I12-3。1H-NMR(300MHz,CDCl3):δ7.72(d,1H,J=8.1Hz),7.21(m,3H),7.06(d,1H,J=7.5Hz),7.00(d,1H,J=8.4Hz),3.54(m,1H),3.41(dd,1H,J=16.2,2.7Hz),3.16(m,5H),2.90(m,1H),2.76(dd,1H,J=16.2,4.5Hz),2.51(m,6H),1.89(m,1H),1.70(m,8H),0.97(t,3H,J=7.2Hz).13C-NMR(100MHz,CDCl3):171.6,147.1,138.6,135.8,133.6,130.6,128.1,127.7,127.3,125.9,124.6,122.0,59.1,56.4,56.2,48.7,40.1,38.4,34.9,34.5,34.3,29.2,28.7,24.3,19.5,12.0.MS(EI):m/z 467(M+);元素分析C24H33NO2S2·0.9 HCl·0.1H2O:C,64.33;H,6.86;N,2.78;实测值:C,64.36;H,6.86;N,2.60.
化合物I13的合成
化合物12的制备可参考文献方法(Liu,Z.;Chen,X.;Yu,L.;Zhen,X.;Zhang,A.Bioorg.Med.Chem.2008,16,6675-81.)。
其中,Pd(OAc)2为醋酸钯,BINAP为(RS)-1,1-联萘二苯基磷,Cs2CO3为碳酸铯,NaOAc为乙酸钠,MeOH为甲醇。
将化合物2(0.102g,0.25mmol)溶于10ml无水四氢呋喃中,在氮气保护下依次加入BINAP(25mg)、碳酸铯(122mg)、18-冠-6(20mg)、醋酸钯(20mg)、二苯亚酮胺(69μL,0.37mmol),然后升温至70℃,反应24h。减压除去溶剂,加入二氯甲烷和水,二氯甲烷层用饱和食盐水洗,干燥、旋干、柱层析得到粗品胺。将粗品胺溶于10mL的甲醇中,加入NH2OH·HCl(35mg,0.50mmol)和无水NaOAc(61mg,0.75mmol),然后于室温下搅拌反应过夜。减压除去溶剂,用0.1M NaOH稀释,并用二氯甲烷萃取,合并有机相,用饱和食盐水洗、干燥、旋干、柱层析得黄色油状物12(31mg,两步46%)。1H-MR(300MHz,CDCl3):δ7.89(d,1H,J=7.8Hz),7.23(t,1H,J=8.1Hz),7.04(t,2H,J=7.8,9.3Hz),6.71(dd,2H,J=7.5,10.8Hz),4.06(s,2H),3.33(dd,1H,J=2.1,11.1Hz),3.18(m,3H),2.91(m,1H),2.77(d,1H,J=17.1Hz),2.48(m,3H),1.62(m,2H),0.98(t,3H,J=7.2Hz).13C-MR(100MHz,CDCl3):δ143.2,138.0,136.0,133.9,132.7,127.9,127.1,126.0,123.0,120.3,118.5,115.8,59.8,56.6,48.9,35.5,29.3,19.6,12.1.MS(EI,[M+])m/z 278;HR-MS(EI)理论值C19H22N2:278.1783,实测值:278.1774.
将胺12(29mg,0.1mmol)、硫辛酸(0.12mmol)和催化量的DMAP溶于无水CH2Cl2(8mL)中,氮气保护下,加入EDC(38mg,0.2mmol),于室温下反应过夜。向反应液中加入CH2Cl2(20mL)和H2O(10mL),分出有机层,用饱和食盐水洗,无水硫酸钠干燥、蒸去溶剂、柱层析得到黄色油状物I13(17mg,37%)。1H-NMR(300MHz,CDCl3):δ8.07(d,1H,J=8.1Hz),7.54(d,2H,J=7.2Hz),7.23(d,1H,J=8.1Hz),7.11(t,2H,J=7.8,8.1Hz),3.57(m,1H),3.30(d,1H,J=12.6Hz),3.14(m,5H),2.91(m,1H),2.78(d,1H,J=15.9Hz),2.43(m,6H),1.92(m,1H),1.74(m,4H),1.58(m,4H),0.97(t,3H,J=6.9,7.5Hz).13C-NMR(100MHz,CDCl3):δ170.8,137.7,134.7,133.4,131.3,128.2,127.9,126.3,124.4,123.6,122.0,59.6,56.5,56.3,48.7,40.2,38.5,37.6,35.4,34.7,29.3,28.9,28.8,25.1,19.7,12.0.MS(EI)m/z 466[M+];HR-MS理论值C27H34ON2S2:466.2112,实测值:466.2106.
化合物I14的合成
将I13(118mg,0.25mmol)溶于8mL的THF中,加入劳森试剂(101mg,0.25mmol),然后加热至回流反应过夜。减压除去溶剂、柱层析得到黄色油状物I14(48mg,40%)。1H-NMR(300MHz,CDCl3):δ8.07(d,1H,J=8.1Hz),7.54(d,2H,J=7.2Hz),7.23(d,1H,J=8.1Hz),7.11(t,2H,J=7.8,8.1Hz),3.57(m,1H),3.30(d,1H,J=12.6Hz),3.14(m,5H),2.91(m,1H),2.78(d,1H,J=15.9Hz),2.43(m,6H),1.92(m,1H),1.58-1.74(m,8H),0.97(t,3H,J=6.9,7.5Hz).13C-NMR(100MHz,CDCl3):δ202.1,137.7,134.7,133.4,131.3,128.2,127.9,126.3,124.4,123.6,122.0,59.6,56.5,56.3,48.7,40.2,38.5,37.6,35.4,34.7,29.3,28.9,28.8,25.1,19.7,12.0.MS(EI)m/z 482[M+];HR-MS理论值C27H34N2S3:482.1884,实测值:482.1882.
化合物I15的合成
将化合物I14(0.034g,0.07mmol)溶解于0.5ml无水四氢呋喃中,缓慢滴加DIAD(0.02ml,0.11mmol)和PPh3(0.029g,0.11mmol),搅拌5min后,滴加TMSN3(0.02ml,0.11mmol),滴毕,于室温下搅拌反应5h,蒸除溶剂,柱层析得灰白色固体I15(10mg,30%)。1H-NMR(300MHz,CDCl3):δ8.07(d,1H,J=8.1Hz),7.54(d,2H,J=7.2Hz),7.23(d,1H,J=8.1Hz),7.11(t,2H,J=7.8,8.1Hz),3.57(m,1H),3.30(d,1H,J=12.6Hz),3.14(m,5H),2.91(m,1H),2.86(d,1H,J=15.9Hz),2.50(m,6H),1.92(m,1H),1.58-1.74(m,8H),0.97(t,3H,J=6.9,7.5Hz).13C-NMR(100MHz,CDCl3):δ153.2,137.7,134.7,133.4,131.3,128.2,127.9,126.3,124.4,123.6,122.0,59.6,56.5,56.3,48.7,40.2,38.5,37.6,35.4,34.7,29.3,28.9,28.8,25.1,19.7,12.0.MS(EI)m/z 491[M+];HR-MS理论值C27H33N5S2:491.2177,实测值:491.2175.
二、试验实施例
通过下面的药理试验测试本发明的化合物对多巴胺D1和D2受体,5-羟色胺1A受体,5-羟色胺2A受体的活性,进而提供其在制备治疗中枢神经系统疾病药物中的应用。
1、多巴胺D1、D2受体
(1)药物配制:
D1受体阳性药物SCH-23390和本发明的受试化合物,参考化合物SKF38393和SKF83959均用DMSO溶解至0.01mol/L,用去离子水稀释至100μmol/L;
D2受体阳性药物螺哌隆(spiperone)和本发明的受试化合物用DMSO溶解至0.01mol/L,用去离子水稀释至100μmol/L;
(2)实验材料:
a.受体构建及细胞培养材料
大肠杆菌E.coli.DH5α菌株;昆虫病毒转移载体pVL1393质粒;BaculoGold线性化杆状病毒DNA,购自PharMingen公司;mkD1R cDNA;rD2RcDNA,购自UMR cDNA资源中心(Rolla,MO,USA);Lipofectamine2000(Invitrogen)试剂;HEK293细胞,购自中科院细胞库;草地夜蛾离体细胞SF9(Spodoptetra Frugiperda 9);各种限制性内切酶、Taq DNA聚合酶、T4连接酶,购自TakaRa公司;LB培养基;昆虫细胞培养基TNM-FH;质粒纯化、胶回收、PCR产物纯化试剂盒,购自上海华舜生物技术有限公司。
b.受体结合实验材料
D1受体同位素配基[3H]SCH23390和D2受体同位素配基[3H]Spiperone(118.0Ci/mmol)均购自Amersham公司;(+)布他拉莫(Butaclamol),购自RBI公司;GF/B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。
(3)实验方法
a.D1R、D2R重组病毒的构建
设计引物,对mkD1R和Rd2R基因分别进行PCR扩增,通过酶切、连接、质粒转化等反应构建昆虫病毒转移载体PVL1393-mkD1R及PVL1393-rD2R。并通过酶切及测序鉴定。采用磷酸钙沉淀方法,BaculoGold线性化杆状病毒DNA和PVL1393-mkD1R及PVL1393-rD2R共转染SF9细胞。转染7天后,通过观察细胞形态及生长状况确定重组病毒的产生,收集含重组病毒的培养液,4℃保存。
b.D1R、D2R重组病毒产生的鉴定
用倒置显微镜观察被转染的SF9细胞,如出现如下迹象则表示转染后的细胞有重组病毒产生;
(i)转染后细胞生成速度变慢或基本停止生长;
(ii)细胞变大,一般直径增加25%-50%;
(iii)细胞折光率增大,部分细胞内部出现空泡;
(iv)感染6-7天后细胞开始裂解。
c.D1R、D2R受体竞争结合实验
用含以上各种基因的重组病毒分别感染HEK-293细胞,48-72小时后受体蛋白在膜上大量表达,将细胞1000rpm离心5min后弃培养液,收集胞体,保存于-20℃冰箱内备用。实验时用Tris-HCl反应缓冲液(pH 7.7)重新混悬。
受体竞争结合实验:将待测化合物与同位素配基各20μl及160μl受体蛋白加入反应试管中,使待测化合物及阳性药物终浓度均为10μmol/L,30℃水浴孵育50min后,即刻移至冰浴终止其反应;在微孔细胞样品收集器上,经过GF/B玻璃纤维滤纸快速抽滤,并用洗脱液(50mM Tris-HCl,pH 7.4)3ml×3次,用微波炉8~9min烘干,将滤纸移入0.5ml离心管中,加入500μl脂溶性闪烁液。避光静置30min以上,计数测定放射性强度。按以下公式计算各化合物对同位素配基结合的抑制率百分率:其中,cpm为每分钟同位素计数。
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
每浓度测定两副管,每个化合物进行两次独立试验。
粗筛抑制率高于80%的化合物进行一系列浓度的受体结合试验,确定半数抑制量(IC50与各受体结合所需化合物浓度)和抑制率常数(Ki)。抑制率和抑制率常数结果见表1。
2、5-羟色胺1A受体
(1)药物配制:
5-HT1A受体阳性药物5-羟色胺(5-hydroxytryptamine)用去离子水溶解至0.01mol/L;受试药物用DMSO溶解至0.01mol/L,然后均用去离子水稀释至100μmol/L。
(2)实验材料:
5-HT1A受体同位素配基[3H]8-OH-DPAT;GF/B玻璃纤维滤纸;脂溶性闪烁液;HEK-293细胞表达的5-HT1A受体蛋白、Beckman LS-6500型多功能液体闪烁计数仪。
(3)实验方法:
用含有5-HT1A受体蛋白基因的质粒载体转染HEK-293细胞,使用磷酸钙转染法,并从转染后的细胞中,通过含G418的培养液培养,以及挑选细胞单克隆和放射性培基结合实验,最终获得能稳定表达5-HT1A受体蛋白的稳定细胞株。
将能稳定表达5-HT1A受体蛋白的稳定细胞株,1000rpm离心5min后弃培养液,收集胞体,保存于-20℃冰箱内备用。实验时用Tris-HCl反应缓冲液(pH 7.7)重新混悬。
受体竞争结合实验:将待测化合物与同位素配基各10μl及80μl受体蛋白加入反应试管中,使待测化合物及阳性药物终浓度均为10μmol/L,37℃水浴孵育15min后,即刻移至冰浴终止其反应;在微孔细胞样品收集器上,经过GF/B玻璃纤维滤纸快速抽滤,并用洗脱液(50mM Tris-HCl,pH 7.7)3ml×3次,用微波炉8~9min烘干,将滤纸移入0.5ml离心管中,加入500μl脂溶性闪烁液。避光静置30min以上,计数测定放射性强度。按以下公式计算各化合物对同位素配基结合的抑制率百分率:
抑制率(I%)=总结合管cpm-化合物cpm/总结合管cpm-非特异结合管cpm×100%
每浓度测定两副管,每个化合物进行两次独立试验。
抑制率高于80%的化合物进行一系列浓度的受体结合试验,确定半数抑制量(IC50,抑制50%[3H]8-OH-DPAT与5-HT1A受体结合所需化合物浓度)和抑制率常数(Ki)。抑制率和抑制率常数结果见表1。
3、5-羟色胺2A受体
(1)药物配制:
阳性药物spiperone和受试化合物均用DMSO溶解至0.01mol/L,然后用去离子水稀释至100μmol/L。
(2)实验材料:
a、5-HT2A细胞转染:
本实验用含有5-HT2A受体蛋白基因的质粒载体转染HEK-293细胞,使用磷酸钙转染法,并从转染后的细胞中,通过含G418的培养液培养,以及挑选细胞单克隆和放射性培基结合实验,最终获得能稳定表达5-HT2A受体蛋白的稳定细胞株。
b、受体结合实验材料:
同位素配基[3H]Ketanserin(酮色林)(67.0Ci/mmol),购自PerkinElmer公司;(+)spiperone,购自RBI公司;GF/C玻璃纤维滤纸,购自Whatman公司;Tris进口分装;PPO、POPOP购自上海试剂一厂;脂溶性闪烁液。BeckmanLS-6500型多功能液体闪烁计数仪。
(3)实验方法:
将能稳定表达5-HT2A受体蛋白的稳定细胞株,1000rpm离心5min后弃培养液,收集胞体,保存于-20℃冰箱内备用。实验时用Tris-HCl反应缓冲液(pH 7.7)重新混悬。
受体竞争结合实验:将待测化合物与同位素配基各10μl及80μl受体蛋白加入反应试管中,使受试化合物及阳性药物终浓度均为10μmol/L,37℃水浴孵育15min后,即刻移至冰浴终止其反应;在微孔细胞样品收集器上,经过GF/C玻璃纤维滤纸快速抽滤,并用洗脱液(50mM Tris-HCl,pH 7.7)3ml×3次,用微波炉8~9min烘干,将滤纸移入0.5ml离心管中,加入500μl脂溶性闪烁液。避光静置30min以上,计数测定放射性强度。按以下公式计算各化合物对同位素配基结合的抑制率百分率:
抑制率(I%)=(总结合管cpm-化合物cpm)/(总结合管cpm-非特异结合管cpm)×100%
化合物每次实验做两副管,进行三次单独实验。
抑制率高于80%的化合物进行一系列浓度的受体结合试验,确定半数抑制量(IC50,抑制50%[3H]8-OH-DPAT与5-HT1A受体结合所需化合物浓度)和抑制率常数(Ki)。抑制率和抑制率常数结果见表1。
试验结果
表1、化合物I1-I15的抑制率或Ki值
此外,代表性化合物I12-1还进行了D2和5-HT1A受体功能试验:
(1)实验材料
[35S]GTPγS;GF/C玻璃纤维滤纸;脂溶性闪烁液;CHO细胞表达的5-HT1A受体蛋白;CHO细胞表达的D2受体蛋白;Gpp(NH)p(三磷酸鸟嘌呤的非水解类似物),GDP,悬浮缓冲液(RB缓冲液)。
(2)实验方法
细胞用50mM Tris,pH7.4,破细胞,1000×g,4℃离心10分钟,上清再36000×g,4℃离心30分钟,保留沉淀(即细胞膜),用50Mm Tris(pH 7.4)悬浮,BCA法测蛋白浓度。
GTPγS结合实验在100μl缓冲体系中进行,每管10μg蛋白,反应缓冲液为50mM Tris(ph 7,4),5mM MgCl2,1mM EDTA,100mM NaCl,1mMDTT(pH7.5)。反应体系含40μM GDP,非特异管加入100μM Gpp(NH)p,测试管加入不同浓度受试药物。各管加入0.1nM[35S]GTPγS,置于30℃水浴反应30分钟。取出置冰中中止反应,经GF/C膜过滤,烘干后置于0.5ml EP管中,加入500μl脂溶性闪烁液,用MicroBeta液闪仪测放射强度。每个浓度三复管,进行至少2次独立实验。
计算公式为:[35S]GTPγS结合率(%高于基础值)=100×(样品放射强度-基础放射强度)/(基础放射强度-非特异放射强度)%
用软件拟合浓度-效应曲线并得到EC50或IC50值。其结果见附图1。
通过5-HT1A受体功能试验发明人发现代表性化合物I5、I6、I9、I12、I13和I14均为5-HT1A受体激动剂,其EC50约为100-900nm;通过D2受体功能试验发明人发现这些化合物同时还是D2受体激动剂,其EC50约为300-2000nm。
由表1可以看出,大部分化合物对5-HT1A受体均显示中到高的活性;同时,部分化合物对多巴胺D2受体呈现出中等到高等活性,特别是化合物I5、I6、I9、I12、I13和I14,不仅显示了对5-HT1A受体的高亲和力,还显示了对D2受体的高亲和力。更有意义的是,功能试验结果显示它们为5-HT1A和D2受体的双重激动剂,有别于此前文献报道的所有阿朴啡类似物,其对5-HT1A和D2受体的双靶向性使得它们作为治疗中枢神经系统疾病(如抑郁症,焦虑症、帕金森氏症以及抗帕金森氏病/精神分裂症药物引起的运动障碍等)的新型先导药物或临床药物时,显示出较好的安全性和治疗指数。
Claims (8)
1.一种由如下通式I表示的硫辛酸-阿朴菲共轭化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物,
通式I
其中,
R1为C1-C12烷基、烯丙基、顺或反式-3-碘-烯丙基、炔丙基、环丙基、环丁基、环丙甲基、环丁甲基、苄基、苯乙基、苯乙烯基、2-氟乙基、3-氟丙基、2-甲氧基乙基、3,4-二氯-苯基乙基、3-呋喃甲基、2-呋喃甲基、3-四氢呋喃甲基或2-四氢呋喃甲基;
R2为氢、C1-C12烷氧基、烯丙氧基、顺或反式-3-碘-烯丙氧基、炔丙氧基、环丙氧基、环丁氧基、环丙甲氧基、环丁甲氧基、苄氧基、苯乙氧基、苯乙烯氧基、2-氟乙氧基、3-氟丙氧基、2-甲氧基乙氧基、3,4-二氯-苯基乙氧基、3-呋喃甲氧基、2-呋喃甲氧基、3-四氢呋喃甲氧基或2-四氢呋喃甲氧基;
m为1-5的整数;
n为0-12的整数;
r为0-6的整数;
A为
其中,k为1-8的整数;
R3、R4、R5各自独立地为氢、C1-C6烷氧基、卤素、硝基、三氟甲基、氰基、羟基、胺甲酰基或C1-C6酰基。
5.根据权利要求1至4中任一项所述的硫辛酸-阿朴菲共轭化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物,
其中,所述立体异构体为非对映立体异构体及它们的混合物;
所述药学上可接受的盐为通式I化合物与为盐酸、氢溴酸、硫酸或磷酸的无机酸或者与为柠檬酸、乳酸、苹果酸、葡糖酸、酒石酸、己二酸、醋酸、琥珀酸、富马酸、抗坏血酸或衣康酸的有机酸或者与为甲磺酸或苯磺酸的有机磺酸形成的盐;
所述药学上可接受的溶剂合物为通式I化合物与水、乙醇、异丙醇、乙醚或丙酮形成的溶剂合物。
6.一种药物组合物,其包含治疗有效量的如权利要求1-4中任一项所述的硫辛酸-阿朴菲共轭化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物作为有效成分。
7.如权利要求1-4中任一项所述的硫辛酸-阿朴菲共轭化合物、其立体异构体、药学上可接受的盐或药学上可接受的溶剂合物及其药物组合物在用于制备预防或治疗与多巴胺D1受体、多巴胺D2受体、5-羟色胺1A受体和/或5-羟色胺2A受体相关的疾病的药物中的用途。
8.如权利要求7所述的用途,其中,所述疾病为精神分裂症、抑郁症、焦虑症,帕金森氏症的中枢神经类疾病;或者由帕金森氏病或精神分裂症引起的运动障碍。
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