CN105949120B - 一种四齿螯合型单喹啉衍生物及其制备方法和作为神经退行性疾病的金属离子调节剂的应用 - Google Patents
一种四齿螯合型单喹啉衍生物及其制备方法和作为神经退行性疾病的金属离子调节剂的应用 Download PDFInfo
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Abstract
本发明提供了一种四齿螯合型单喹啉衍生物,所述衍生物结构式如式(I)所示:本发明所提供的衍生物能够特异性螯合与神经退行性疾病(阿尔茨海默病,帕金森病,肌萎缩侧索硬化)代谢紊乱或铜蓄积病(威尔逊氏病)相关的氧化还原活性金属离子,如铜离子。所述衍生物对锌离子的络合常数比与铜离子的络合常数低6~12个数量级,且显示较强的抗氧化应激的能力。所述衍生物制备方法简单,在作为制备治疗神经退行性疾病药物及铜离子紊乱等相关疾病药物中具有潜在的应用前景。
Description
技术领域
本发明涉及药物与有机合成技术领域,具体地,涉及一种四齿螯合型单喹啉衍生物及其制备方法和作为神经退行性疾病的金属离子调节剂的应用。
背景技术
大量研究表明,许多复杂的进行性神经退行疾病都与金属离子失调及过度积聚相关,一些单病因疾病也有类似的情况。例如,在阿尔茨海默症中,由于患者脑内铜离子稳态调节失衡,导致铜离子在患者大脑中的淀粉样斑块中大量积聚,引起的氧化应激可能诱导神经元死亡。
大量科技论文报导了,具有氧化还原活性的金属离子(铜离子、铁离子)参与蛋白质的错误折叠和聚集,导致各种严重的疾病,如阿尔茨海默症,帕金森病,亨廷顿病,肌萎缩侧索硬化,海绵状脑病等。在这些病症中,具氧化还原活性的金属离子的稳态平衡很容易遭各种内源性还原剂(或其它外来电子源)的破坏,从而产生金属介导的氧分子的还原反应,导致生成活性氧族(ROS),如过氧化氢和羟基自由基(P.Faller,C.Hureau,Chem.Eur.J.,012,18,15910‐15920;M.A.Telpoukhovskaia,C.Orvig,Chem.Soc.Rev.,2013,42,1836‐1846).
在各种金属离子螯合剂中,氯碘羟喹和PBT2这两种单喹啉衍生物已经做为潜在的治疗药物用于阿尔茨海默病的治疗研究(R.A.Cherny et al.Neuron,2001,30,665-676;K.J.Barnham and A.I.Bush,Chem.Soc.Rev.,2014,43,6727‐6749)。然而,氯碘羟喹和PBT2这类单喹啉化合物仅作为双齿配体,不易清除淀粉样蛋白内的铜离子。最近的研究表明,这类型双齿配体形成的是“淀粉样蛋白-铜离子-氯碘羟喹”三元复合物(M.Nguyen et al.,ChemistryOpen,2014,20,6771-6785)。该研究同时报导了四齿配体有效从淀粉样蛋白中剔除出铜离子。
相关的最新的综述性文章可参考:Barnham and Bush,Chem.Soc.Rev.,2014,43,6727-6749,Perez and Franz,Dalton Trans.,2010,39,2177-2187,Rowinska-Zyrek etal.,Coord.Chem.Rev.,2015,284,298-312,Robert et al.,Acc.Chem.Res.2015,48,1332-1339,Bandmann et al.,Lancet Neurol.,2015,14,103-113.
但目前,关于单喹啉化合物中能够特异性提取淀粉样蛋白内铜离子的报道较少。
发明内容
本发明的目的在于提供一类能够高选择性螯合铜离子,具备调节神经退行性疾病(如阿尔茨海默病、亨廷顿氏病、帕金森氏病、唐氏综合征、肌萎缩侧索硬化)及铜离子聚集病(威尔逊氏病)中的铜离子稳态失衡能力的单8-氨基喹啉类四齿配体化合物。在本发明中提供的单氨基喹啉衍生物据有合适的疏水性、良好的口服活性及穿透血脑屏障能力。这些新型配体统称为“四配位单喹啉衍生物”,并以TDMQ做为简称。
更确切地说,根据本发明的化合物是金属配位化合物,能够特异性螯合氧化还原活性的金属离子,如铜离子(其在阿尔茨海默症患者的淀粉样斑块中大为过量)。在本专利文本中,AD代表阿尔茨海默症。本发明的化合物也可用于其它金属离子调节障碍有关的其他神经退行性疾病如帕金森病(PD)和肌萎缩性侧索硬化症(ALS)。此外,威尔逊氏病(WD)导致血液循环和其他器官中铜离子的过负荷,也是本发明螯合配位化合物的应用领域。
本发明的另一目的在于提供上述衍生物的制备方法和应用。
为了获得具有良好生物利用度的小分子四齿配体化合物,本发明基于单氨基喹啉骨架设计新系列药物。
本发明报道了化合物的合成,金属螯合能力和抗氧化应激的能力,作为一个实施例,本发明报导了化合物降低铜离子-淀粉样蛋白复合物在还原剂存在下介导产生过氧化氢的作用。
为实现上述目的,本发明采用的技术方案为:
本发明提供了一种四齿螯合型单喹啉衍生物,所述衍生物结构式如式(I)所示:
其中:X为-OR,-NRR',-OCOR或-OCOOR;
Y为-(CH2)n-NR6-(CH2)m-NR7R8;
R和R'相同或不同,分别为一个氢原子,或者为被烷氧基(-OR)、胺基(-NRR')、卤素、氰基(-CN)、三氟甲基(-CF3)、酯基(-COOR或-OCOOR)、酰胺基(-CONRR'或-NRCOOR')中的任意一个或多个基团所取代的环烷基或烷基;
R1,R2,R3,R4,R5,R6,R7,R8相同或不同,分别代表氢原子、烷氧基、胺基、卤素原子、氰基、三氟甲基、酯基、酰胺基;或者代表被烷氧基(-OR)、胺基(-NRR')、卤素原子、氰基(-CN)、三氟甲基(-CF3)、酯基(-COOR或-OCOOR)、酰胺基(-CONRR'或-NRCOOR')中的任意一个或多个基团所取代的烷基;
n为1、2、3、4、5或6;m为1、2、3、4、5或6。
优选地,式(I)所示四齿螯合型单喹啉衍生物中X为-OR,-NRR',-OCOR或-OCOOR;Y为-(CH2)n-NR6-(CH2)m-NR7R8;
R和R'相同或不同,分别为一个氢原子,或者为被胺基(-NRR')、卤素原子、氰基(-CN)或三氟甲基(-CF3)中的任意一个或多个基团所取代的环烷基或烷基;
R1,R2,R3,R4,R5,R6,R7,R8相同或不同,分别代表氢原子、烷氧基、胺基、卤素原子、氰基、三氟甲基,或者代表被烷氧基(-OR)、胺基(-NRR')、卤素原子、氰基(-CN)或三氟甲基(-CF3)中的任意一个或多个基团所取代的烷基。
更优选地,式(I)所示四齿螯合型单喹啉衍生物中X为-NRR',R和R'相同或不同,分别代表氢原子、或者代表被胺基(-NRR')、卤素原子、氰基(-CN)或三氟甲基(-CF3)中的任意一个或多个基团所取代的烷基;
R1,R2,R3,R4,R5,R6,R7,R8相同或不同,分别代表氢原子、烷氧基、胺基、卤素原子、氰基或三氟甲基。
最优选地,式(I)所示四齿螯合型单喹啉衍生物中X为-NH2。
术语解释:
本发明涉及的化合物还包括生理上可接受的立体异构体或立体异构体混合物,互变异构体形式,水合物,溶剂化物,成盐化合物(包括盐酸盐,氢溴酸盐,硫酸盐,硫酸氢盐,磷酸盐,硝酸盐,醋酸盐,苯甲酸盐,甲基苯磺酸盐,柠檬酸盐,酒石酸盐,马来酸盐,等等),自由形式和各种成酯衍生物等。
本发明提到的烷基指线性或含支链的饱和烷基,包含1到20个碳原子,优选1到6个碳原子。
甲基,乙基,丙基,丁基,戊基,己基,辛基,壬基,癸基,十二烷基,十六烷基和十八烷基是线性烷基。
异丙基,叔丁基,2-乙基己基,2-甲基丁基,2-甲基戊基,1-甲基戊基和3-甲基庚基是含支链的烷基。
烷氧基是指-O-烷基(-OR)形式的基团,其中烷基R跟本发明前面定义一致。
本发明提到的卤素原子是指氟原子,氯原子,溴原子,碘原子。
烯基可以是线性或含支链的包含一个或多个碳碳双键的烯烃基团。烯基也可以是线性或含支链含一个或多个碳碳三键的炔烃基团。
环烷基可以是饱和或不饱和的单环、双环或三环烷烃,可以包含3到11个碳原子,例如环丙烷基、环戊烷基、环已烷基或金刚烷基及相应的含有一个或多个不饱和键的环烷烃基团。
芳香基团指的是含有6个至10个碳原子的单环或双环碳氢不饱和芳香基团,例如,苯基或萘基(可以含有或不含卤素原子取代)。
杂芳基指的是含有一个或多个杂原子,4个至11个碳原子的单环或双环芳香环基团,杂原子可以是氮原子、氧原子或硫原;例如,吡嗪基,噻吩基,噁唑基,噁二唑基,吡咯基,1,2,4-噻二唑基,吲唑基,苯并咪唑基,呋喃基,咪唑基,吲哚基,四唑基,吡唑基,异喹啉基,喹啉基,噻唑基等。
术语“生理上可接受的成盐物”指的是相对无毒的本发明化合物的无机酸盐或有机酸盐。这些成盐形式的化合物可以在化合物最终分离时原位制备或纯化后制备得到。可以与本发明化合物成盐的酸有溴化氢,氯化氢,硫酸,磷酸,硝酸,醋酸,草酸,硼酸,对甲苯磺酸,柠檬酸,马来酸,富马酸,甲磺酸,磺酸等,且不限于上述这些酸。
优选地,式(I)所示四齿螯合型单喹啉衍生物的制备方法,反应式如下,包括如下步骤:
S1.对化合物I-1的X基团进行保护,生成化合物I-2;
S2.将化合物I-2与进行氧化官能团化后,与NH2R7反应生成化合物I-3;
S3.将化合物I-3去保护,得到所述衍生物I。
R0为X基团的保护基团,R0包括但不限于叔丁氧羰基、乙酰基。
本发明设计合成的四齿螯合型单喹啉衍生物显示出了较好的特异性金属螯合能力和抗氧化应激的能力。特别地,具有四齿配体从而能够强烈螯合铜离子,并有合适的疏水性从而具有良好的口服活性及具有穿透血脑屏障能力。通过对本发明所述衍生物与铜、锌离子进行配位反应,并计算其亲和常数,发现本发明对铜离子的结合常数Log KCu 2+达到10以上,而对锌离子的结合常数Log KZn 2+为4.5左右,表明本发明所述衍生物具有强烈的特异性螯合铜离子能力,同时,是作为制备治疗许多进行性神经退行性疾病药物中良好的配体。通过对淀粉样多肽Aβ在铜离子及还原性试剂条件下诱导生成过氧化氢试验中发现,本发明提供的衍生物能够特异性结合淀粉样蛋白,显示出其较强的降低氧化应激的能力。
因此,需要保护本发明所述四齿螯合型单喹啉衍生物在制备金属配合物中的应用。所述衍生物特异性螯合金属铜离子制备得到金属配合物。
需要保护本发明所述四齿螯合型单喹啉衍生物在作为神经退行性疾病的金属离子调节剂的应用,同时也包括在制备治疗神经退行性疾病和铜离子代谢紊乱疾病药物中的应用。
优选地,所述衍生物还包括生理上可接受的立体异构体或立体异构体的混合物,异构体、水合物、溶剂化物、成盐物、自由的形式或酯;成盐物包括硫酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、乙酸盐、苯甲酸盐、对甲苯磺酸盐、柠檬酸盐、马来酸盐、酒石酸盐。
优选地,所述神经退行性疾病包括阿尔茨海默病、亨廷顿氏病、帕金森氏病、唐氏综合征或肌萎缩侧索硬化,铜离子代谢紊乱疾病包括威尔逊氏病。
与现有技术相比,本发明具有以下优点及有益效果:
本发明所提供的衍生物能够选择性螯合铜离子,所述衍生物与铜离子的络合常数比与锌离子的络合常数高达6~12个数量级,且具备较强的抗氧化应激的能力。所述衍生物制备方法简单,在作为制备治疗多种进行性神经退行性疾病药物中具备极大的应用前景。
附图说明
图1为化合物TDMQ-5、其它竞争性配体与铜离子的紫外-可见光谱图。
图2为化合物TDMQ-5、TDMQ-10与铜离子、抗坏血酸钠诱导产生过氧化氢含量图。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,本发明所用试剂和材料均为市购。
实施例1:化合物TDMQ‐5的制备,合成路线如下所示,具体步骤如下:
2-甲基-5,7-二氯-喹啉(1):在0℃不断搅拌下,向溶有3,5-二氯苯胺(3.24g,20mmol)的浓盐酸溶液(12mL)中逐滴加入35wt.%乙醛水溶液(12.8mL,80mmol)。反应混合液在0摄氏度下搅拌15分钟后,逐步升温至75℃,并在该温度下反应4个小时。反应物冷却至室温后,倒入冰水中,滴加25%氨水溶液中和,使呈碱性,用二氯甲烷萃取3次。有机相分离后经无水硫酸钠干燥、过滤、减压浓缩。粗产物经硅胶柱层析(乙酸乙酯/石油醚,1:20)分离纯化得2.93g淡黄色固体化合物1,收率69%。1H NMR(400MHz,CDCl3):δ8.40(d,J=8.0Hz,1H),7.96(d,J=2.0Hz,1H),7.55(d,J=2.0Hz,1H),7.37(d,J=8.0Hz,1H),2.76(s,3H)。
2-甲基-5,7-二氯-8-硝基喹啉(2):常温下,向溶有化合物1(2.12g,10mmol)的浓硫酸溶液(10mL)中逐滴加入发烟硝酸(2.0mL),一小时滴加完毕后继续反应1个小时。反应物倒入冰水中,滴加25%氨水溶液中和,使呈碱性,用二氯甲烷萃取3次。有机相分离后经无水硫酸钠干燥、过滤、减压浓缩。粗产物经硅胶柱层析(乙酸乙酯/石油醚,1:10)分离纯化得2.34g淡黄色固体化合物2,收率91%。1H NMR(400MHz,CDCl3):δ8.43(d,J=8.0Hz,1H),7.64(s,1H),7.50(d,J=8.0Hz,1H),2.76(s,3H)。
2-甲基-5,7-二氯-8-氨基喹啉(3):常温下将还原铁粉(1.34g,24mmol)和冰醋酸(18mL)加入化合物2(2.06g,8mmol)的乙醇溶液(50mL)中。回流反应4个小时后,将反应体系冷却到常温,向反应体系中逐滴加入饱和NaHCO3水溶液(400mL)。用二氯甲烷萃取3次,有机相分离后经无水硫酸钠干燥、过滤、减压浓缩。粗产物经硅胶柱层析(乙酸乙酯/石油醚,1:10)分离纯化得1.62g淡黄色固体化合物3,收率89%。1H NMR(400MHz,CDCl3):δ8.31(d,J=8.0Hz,1H),7.42(s,1H),7.35(d,J=8.0Hz,1H),5.36(brs,2H),2.76(s,3H)。
2-甲基-5,7-二氯-8-(N,N-二乙酰基)氨基喹啉(4):在0℃下,向溶有化合物3(1.29g,5mmol)的二氯甲烷溶液(10mL)中逐滴分别加入乙酰氯(1.1mL)和N,N-二异丙基乙胺(5mL)。反应体系在0℃下搅拌15分钟后,逐步升温至回流。继续反应4小时后,减压除去溶剂。粗产物经硅胶柱层析(乙酸乙酯/石油醚,1:20)分离纯化得1.09g淡黄色固体化合物4,收率70%.1H NMR(400MHz,CDCl3):δ8.41(d,J=8.0Hz,1H),7.70(s,1H),7.42(d,J=8.0Hz,1H),2.71(s,3H),2.29(s,6H)。
2-醛基-5,7-二氯-8-(N,N-二乙酰基)氨基喹啉(5):向化合物4(0.93g,3mmol)的二氧六环溶液(7mL)中,加入氧化硒(0.5g,4.5mmol),反应在85℃下搅拌12小时,反应体系用硅藻土过滤并用二氯甲烷洗涤滤饼。合并有机相并减压浓缩。粗产物经硅胶柱层析(乙酸乙酯/石油醚,1:20)分离纯化得0.69g淡黄色固体化合物5,收率71%.1H NMR(400MHz,CDCl3):δ10.13(s,1H),8.76(d,J=8.0Hz,1H),8.18(d,J=8.0Hz,1H),7.92(s,1H),2.32(s,6H)。
2-(N,N-二甲基乙二胺基)甲基-5,7-二氯-8-氨基喹啉(TDMQ-5):在氩气保护下,向化合物5(622mg,2mmol)的1,2-二氯乙烷溶液(30mL)中加入N,N-二甲基乙二胺(352mg,4mmol),反应混合物在室温下搅拌1个小时,向反应体系中加入NaBH(OAc)3(848mg,4mmol),继续反应12小时。向反应体系中分别加入100mL二氯甲烷和饱和NaHCO3水溶液(40mL),分离有机相后,向水相加入2mL氨水,再用二氯甲烷萃取3次。合并后的有机相减压浓缩。粗产物溶于5mL二氯甲烷,加入6N HCl(2mL),在室温下搅拌反应4小时。向反应体系中加入50mL水并用氨水中和至碱性。二氯甲烷萃取3次。合并后的有机相经无水硫酸钠干燥、过滤、减压浓缩。粗产物经硅胶柱层析(乙酸乙酯/异丙醇/25%氨水,8:2:0.5)分离纯化得488mg淡黄色固体化合物TDMQ-5,收率78%。
化合物TDMQ-5的结构式如下:
核磁共振氢谱:1H NMR(400MHz,CDCl3)δ8.35(d,J=8.8Hz,1H),7.49(d,J=8.8Hz,1H),7.43(s,1H),5.38(brs,2H),4.10(s,2H),2.75(t,J=6.0Hz,2H),2.55(brs,1H),2.48(t,J=6.0Hz,2H),2.22(s,6H).
质谱:ESI+-MS:m/z(relative intensity)313.1(MH+,100),314.1(18),315.1(65),316.1(11),317.1(11),318.1(2).Minor peaks due to fragmentation in themass spectrometer were detected at m/z 268.0{M’=[M–(CH3)2N]+,9},224.9{M”=[M–(CH3)2N-(CH2)2-NH]+,15},190.0(M”–Cl,5),155.0(M”–2Cl,3).Isotopic patterns areconsistent.HRMS(ESI+)for C14H19N4Cl2:Calcd,313.0987;Found,313.0987.
油水分配系数:Calculated logP=2.42(ChemDraw Pro,v.14.0)。
实施例2:化合物TDMQ‐9的制备,合成路线如下所示,具体步骤如下:
2-甲基-6-氟-8-硝基喹啉(6):参照化合物1的制备方法,合成化合物6的产率为73%,为淡黄色固体。1H NMR(400MHz,CDCl3)δ8.00(d,J=8.4Hz,1H),7.70(dd,J=8.0,2.8Hz,1H),7.55(dd,J=8.0,2.8Hz,1H),7.40(d,J=8.4Hz,1H),2.69(s,3H)。
2-甲基-6-氟-8-氨基喹啉(7):参照化合物3的制备方法,合成化合物7的产率为92%,为淡黄色固体。1H NMR(400MHz,CDCl3)δ7.87(d,J=8.4Hz,1H),7.25(d,J=8.4Hz,1H),6.95(dd,J=10.8,2.8Hz,1H),6.63(dd,J=10.8,2.8Hz,1H),5.13(brs,2H),2.69(s,3H)。
2-甲基-6-氟-8-(N-Boc)氨基喹啉(8):向化合物7(1.76g,10mmol)的二氧六环溶液(20mL)中加入二碳酸二叔丁酯(3.27g,15mmol).回流反应12小时。减压除去溶剂后,粗产物经硅胶柱层析(乙酸乙酯/石油醚,1:20)分离纯化得2.58g淡黄色固体化合物8,收率89%.1H NMR(400MHz,CDCl3)δ9.08(s,1H),8.21(d,J=10.4Hz,1H),7.94(d,J=8.4Hz,1H),7.31(d,J=8.4Hz,1H),6.97(dd,J=8.8,2.8Hz,1H),2.72(s,3H),1.59(s,9H)。
2-醛基-6-氟-8-(N-Boc)氨基喹啉(9):参照化合物5的合成方法,合成化合物9为淡黄色固体,收率50%.1H NMR(400MHz,CDCl3):δ10.23(s,H),9.04(s,1H),8.36(d,J=10.8Hz,1H),8.23(d,J=8.4Hz,1H),8.07(d,J=8.4Hz,1H),7.11(dd,J=8.4,2.4Hz,1H),1.62(s,9H)。
2-(N,N-二甲基乙二胺基)甲基-6-氟-8-(N-Boc)氨基喹啉(10):氩气保护下,向化合物9(580mg,2mmol)的1,2-二氯乙烷溶液(30mL)中加入N,N-二甲基乙二胺(352mg,4mmol),反应混合物在室温下搅拌1个小时,向反应体系中加入NaBH(OAc)3(848mg,4mmol),继续反应12小时。向反应体系中分别加入100mL二氯甲烷和饱和NaHCO3水溶液(40mL),分离有机相后,向水相加入2mL氨水,再用二氯甲烷萃取3次。合并后的有机相无水硫酸钠干燥、过滤、减压浓缩。粗产物经硅胶柱层析(乙酸乙酯/异丙醇/25%氨水,8:2:0.5)分离纯化得660mg淡黄色固体化合物10,收率91%.1H NMR(400MHz,CDCl3):δ9.07(s,1H),8.25(d,J=10.0Hz,1H),8.02(d,J=8.8Hz,1H),7.49(d,J=8.8Hz,1H),7.0(dd,J=8.8,2.8Hz,1H),4.11(s,2H),2.76(t,J=6.0Hz,2H2),2.49(t,J=6.0Hz,2H),2.24(s,6H),1.60(s,9H)。
2-(N,N-二甲基乙二胺基)甲基-6-氟-8-氨基喹啉(TDMQ-9):向溶有化合物10(725mg,2mmol)的二氯甲烷溶液(10mL)中滴加5mL三氟乙酸,并在室温下搅拌4小时。减压出去过量的三氟乙酸后,向反应体系中加入50mL水并用氨水中和至碱性。二氯甲烷萃取3次。合并后的有机相经无水硫酸钠干燥、过滤、减压浓缩。粗产物经硅胶柱层析(乙酸乙酯/异丙醇/25%氨水,8:2:0.5)分离纯化得451mg淡黄色固体化合物TDMQ-9,产率86%.1H NMR(400MHz,CDCl3)δ7.93(d,J=8.4Hz,1H),7.39(d,J=8.4Hz,1H),6.71(dd,J=10.4,2.8Hz,1H),6.64(dd,J=10.4,2.8Hz,1H),5.20(brs,2H),4.07(s,2H),2.85(brs,1H),2.78(t,J=6.0Hz,2H),2.49(t,J=6.0Hz,2H),2.23(s,6H)。
实施例3:化合物TDMQ‐10的制备,合成路线如下所示,具体步骤如下:
2-甲基-5,6-二氯-8-硝基喹啉(11):参照化合物1的制备方法,合成化合物11为淡黄色固体,收率为54%.1H NMR(400MHz,CDCl3)δ8.51(d,J=8.8Hz,1H),8.03(s,1H),8.16(d,J=8.8Hz,1H),2.79(s,3H)。
2-甲基-5,6-二氯-8-胺基喹啉(12):参照化合物3的制备方法,合成化合物12为淡黄色固体,收率为86%.1H NMR(400MHz,CDCl3)δ10.25(s,H),8.91(s,1H),8.34(d,J=8.8Hz,1H),7.37(d,J=8.8Hz,1H),6.93(s,1H),2.71(s,3H)。
2-甲基-5,6-二氯-8-(N-Boc)氨基喹啉(13):参照化合物8的制备方法,合成化合物13为白色固体,收率为84%.1H NMR(400MHz,CDCl3)δ8.98(s,1H),8.50(s,1H),8.40(d,J=8.4Hz,1H),7.42(d,J=8.4Hz,1H),2.75(s,3H),1.59(s,9H)。
2-醛基-5,6-二氯-8-(N-Boc)氨基喹啉(14):参照化合物5的制备方法,合成化合物14为淡黄色固体,收率为56%.1H NMR(400MHz,CDCl3)δ10.25(s,1H),8.91(s,1H),8.69(d,J=8.4Hz,1H),8.65(s,1H),8.16(d,J=8.4Hz,1H),1.62(s,9H)。
2-(N,N-二甲基乙二胺基)甲基-5,6-二氯-8-(N-Boc)氨基喹啉(15):参照化合物10的制备方法,合成化合物15为淡黄色固体,收率为92%.1H NMR(400MHz,CDCl3):δ8.97(s,1H),8.54(s,1H),8.48(d,J=8.8Hz,1H),7.60(d,J=8.8Hz,1H),4.14(s,2H),2.75(d,J=6.0Hz,2H),2.48(d,J=6.0Hz,2H),2.24(s,6H),1.59(s,9H)。
2-(N,N-二甲基乙二胺基)甲基-5,6-二氯-8-氨基喹啉(TDQM-10):参照化合物TDMQ-9的制备方法,合成化合物TDMQ-10为淡黄色固体,收率为92%;
化合物TDMQ-10的结构式如下:
核磁共振氢谱:1H NMR(400MHz,CDCl3)δ8.41(d,J=8.8Hz,1H),7.54(d,J=8.8Hz,1H),6.94(s,1H),5.06(s,2H),4.10(s,2H),2.76(d,J=6.0Hz,2H),2.48(d,J=6.0Hz,2H),2.23(s,6H).
质谱:ESI+-MS:m/z ESI+-MS:m/z(relative intensity)313.1(MH+,100),314.1(18),315.1(65),316.1(11),317.1(11),318.1(2).Minor peaks due to fragmentationin the mass spectrometer were detected at m/z 268.0{M’=[M–(CH3)2N]+,10},224.9{M”=[M–(CH3)2N-(CH2)2-NH]+,18},190.0(M”–Cl,6),155.0(M”–2Cl,3).Isotopicpatterns are consistent.HRMS(ESI+)for C14H19N4Cl2:Calcd,313.0987;Found,313.0990.
油水分配系数:Calculated logP=2.42(ChemDraw Pro,v.14.0)。
实施例4:化合物TDMQ‐12的制备,合成路线如下所示,具体步骤如下:
2-甲基-6-氯-8-硝基喹啉(16):参照化合物1的制备方法,合成化合物16为淡黄色固体,收率为54%.1H NMR(400MHz,CDCl3):δ8.04(d,J=8.4Hz,1H),7.94(d,J=2.1Hz,1H),7.92(d,J=2.2Hz,1H),7.44(d,J=8.4Hz,1H),2.76(s,3H)。
2-甲基-6-氯-8-胺基喹啉(17):参照化合物3的制备方法,合成化合物17为淡黄色固体,收率为81%.1H NMR(400MHz,CDCl3):δ7.84(d,J=8.4Hz,1H),7.24(d,J=8.4Hz,1H),7.06(d,J=2.0Hz,1H),6.83(d,J=2.0Hz,1H),5.05(brs,2H),2.68(s,3H)。
2-甲基-6-氯-8-(N-乙酰基)氨基喹啉(18):参照化合物8的制备方法,合成化合物18为淡黄色固体,收率为81%.1H NMR(400MHz,CDCl3):δ9.79(s,1H),8.75(s,1H),7.94(d,J=8.0Hz,1H),7.43(s,1H),7.34(d,J=8.0Hz,1H,),2.73(s,3H),2.36(s,3H)。
2-醛基-6-氯-8-(N-乙酰基)氨基喹啉(19):参照化合物5的制备方法,合成化合物19为淡黄色固体,收率为45%.1H NMR(400MHz,CDCl3):δ10.23(s,1H),9.71(s,1H),8.90(s,1H),8.24(d,J=8.0Hz,1H),8.10(d,J=8.0Hz,1H),7.57(s,1H),2.42(s,3H)。
2-(N,N-二甲基乙二胺基)甲基-6-氯-8-氨基喹啉(TDMQ-12):参照化合物TDMQ-5的制备方法,合成化合物TDMQ-12为淡黄色固体,收率为91%.1H NMR(400MHz,CDCl3)δ7.89(d,J=8.4Hz,1H),7.39(d,J=8.4Hz,1H),7.07(d,J=2.0Hz,1H),6.83(d,J=2.0Hz,1H),5.14(brs,2H),4.06(s,2H),2.81(brs,1H),2.77(t,J=6.0Hz,2H),2.48(t,J=6.0Hz,2H),2.22(s,6H)。
实施例5:化合物TDMQ‐13的制备,合成路线如下所示,具体步骤如下:
2-甲基-7-氯-8-硝基喹啉(20):参照化合物1的制备方法,合成化合物20为淡黄色固体,收率为80%.1H NMR(400MHz,CDCl3)δ8.08(d,J=8.5Hz,1H),7.83(d,J=8.8Hz,1H),7.52(d,J=8.8Hz,1H),7.40(d,J=8.5Hz,1H),2.74(s,3H)。
2-甲基-7-氯-8-胺基喹啉(21):参照化合物3的制备方法,合成化合物21为淡黄色固体,收率为86%.1H NMR(400MHz,CDCl3):δ7.84(d,J=8.0Hz,1H),7.24(d,J=8.0Hz,1H),7.06(s,1H),6.83(s,1H),5.05(brs,2H),2.68(s,3H)。
2-甲基-7-氯-8-(N-乙酰基)胺基喹啉(22):参照化合物8的制备方法,合成化合物22为淡黄色固体,收率为42%.1H NMR(400MHz,CDCl3):δ8.04(d,J=8.4Hz,1H),7.79(d,J=8.8Hz,1H),7.57(d,J=8.8Hz,1H),7.32(d,J=8.4Hz,1H),2.688(s,3H),2.298(s,6H)。
2-醛基-7-氯-8-(N-乙酰基)胺基喹啉(23):参照化合物5的制备方法,合成化合物23为淡黄色固体,收率为64%.1H NMR(400MHz,CDCl3):δ10.13(s,1H),8.39(d,J=8.8Hz,1H),8.10(d,J=8.8Hz,1H),7.96(d,J=8.8Hz,1H),7.81(d,J=8.8Hz,1H),2.330(s,6H)。
2-(N,N-二甲基乙二胺基)甲基-7-氯-8-(N-乙酰基)氨基喹啉(24):参照化合物10的制备方法,合成化合物24为淡黄色固体,收率为94%.1H NMR(400MHz,CDCl3):δ8.08(d,J=8.4Hz,1H),7.62(d,J=8.8Hz,1H),7.54(d,J=8.8Hz,1H),7.43(d,J=8.4Hz,1H),4.11(s,2H),2.79(t,J=6.0Hz,2H),2.50(t,J=6.0Hz,2H),2.239(s,6H)。
2-(N,N-二甲基乙二胺基)甲基-7-氯-8-氨基喹啉(TDMQ-13):参照化合物TDMQ-5的制备方法,合成化合物TDMQ-13为淡黄色固体,收率为97%.TDMQ-13:1H NMR(400MHz,CDCl3)δ7.99(d,J=8.4Hz,1H),7.39(d,J=8.4Hz,1H),7.34(d,J=8.7Hz,1H),7.05(d,J=8.7Hz,1H),5.35(brs,2H),4.09(s,2H),2.76(t,J=6.0Hz,2H),2.48(t,J=6.0Hz,2H),2.46(brs,1H),2.23(s,6H)。
实施例6:化合物TDMQ‐16的制备,合成路线如下所示,具体步骤如下:
2-甲基-6-三氟甲基-8-硝基喹啉(25):参照化合物5的制备方法,合成化合物25为淡黄色固体,收率为59%.1H NMR(400MHz,CDCl3)δ8.28(s,1H),8.22(d,J=8.4Hz,1H),8.12(s,1H),7.54(d,J=8.4Hz,1H),2.81(s,3H)。
2-甲基-6-三氟甲基-8-胺基喹啉(26):参照化合物3的制备方法,合成化合物26为淡黄色固体,收率为74%.1H NMR(400MHz,CDCl3):δ8.02(d,J=8.4Hz,1H),7.39(s,1H),7.33(d,J=8.4Hz,1H),7.01(s,1H),5.15(brs,2H),2.74(s,3H)。
2-甲基-6-三氟甲基-8-(N-乙酰基)胺基喹啉(27):参照化合物8的制备方法,合成化合物27为淡黄色固体,收率为78%.1H NMR(400MHz,CDCl3):δ9.85(s,1H),8.97(s,1H),8.12(d,J=8.4Hz,1H),7.76(s,1H),7.42(d,J=8.4Hz,1H),2.79(s,3H),2.38(s,3H)。
2-醛基-6-三氟甲基-8-(N-乙酰基)胺基喹啉(28):参照化合物5的制备方法,合成化合物21为淡黄色固体,收率为50%.1H NMR(400MHz,CDCl3):δ10.28(s,1H),9.77(s,1H),9.12(s,1H),8.45(d,J=8.0Hz,1H),8.18(d,J=8.0Hz,1H),7.90(s,1H),2.43(s,3H)。
2-(N,N-二甲基乙二胺基)甲基-6-三氟甲基-8-(N-乙酰基)氨基喹啉(29):参照化合物10的制备方法,合成化合物29为淡黄色固体,收率为96%.1H NMR(400MHz,CDCl3):δ9.92(s,1H),9.00(s,1H),8.20(d,J=8.0Hz,1H),7.79(s,1H),7.61(d,J=8.0Hz,1H),4.17(s,2H),2.77(t,J=6.0Hz,2H),2.50(t,J=6.0Hz,2H),2.36(s,3H),2.24(s,6H)。
2-(N,N-二甲基乙二胺基)甲基-6-三氟甲基-8-氨基喹啉(TDMQ-16):参照化合物TDMQ-5的制备方法,合成化合物TDMQ-16为淡黄色固体,收率为99%.TDMQ‐16:1H NMR(400MHz,CDCl3)δ8.07(d,J=8.4Hz,1H),7.48(d,J=8.4Hz,1H),7.39(s,1H),7.01(s,1H),5.23(brs,2H),4.11(s,2H),2.77(t,J=6.0Hz,2H),2.55(brs,1H),2.48(t,J=6.0Hz,2H),2.23(s,6H)。
实施例7:化合物TDMQ‐19的制备,合成路线如下所示,具体步骤如下:
2-(N,N-二甲基丙二胺基)甲基-5,7-二氯-8-氨基喹啉(TDMQ-19):参照化合物TDMQ-5的制备方法,合成化合物TDMQ-19为淡黄色固体,收率为87%.1H NMR(400MHz,D2O):δ8.49(d,J=8.8Hz,1H),7.58(s,1H),7.49(d,J=8.8Hz,1H),4.58(s,2H),3.25(t,J=8.0Hz,2H),3.19(t,J=8.0Hz,2H),2.82(s,6H),2.23-2.15(m,2H)。
实施例8:化合物TDMQ‐20的制备,合成路线如下所示,具体步骤如下:
2-乙烯基-5,7-二氯-8-硝基喹啉(30):将化合物2(102.8mg,0.4mmol)溶于DMA(2mL)后,分别加入FeCl3(6.4mg,0.04mmol)和TBHP(0.8mmol,70%aqueous solution),在140℃搅拌反应4小时。反应体系冷却到室温后,用水稀释,二氯甲烷萃取。有机相经无水硫酸钠干燥、过滤、减压浓缩。粗产物用硅胶柱层析(二氯甲烷/石油醚,1:10)分离纯化得35.6mg白色固体化合物30,产率33%(回收原料41%).1H NMR(400MHz,CDCl3)δ8.52(d,J=8.8Hz,1H),7.73(d,J=8.8Hz,1H),7.65(s,1H),6.97(dd,J=17.6,10.8Hz,1H),6.46(d,J=17.6Hz,1H),5.79(d,J=10.8Hz,1H)。
2-(2’-(N,N-二甲基乙二胺基))乙基-5,7-二氯-8-硝基喹啉(31):化合物30(1.08g,4mmol),N,N-二甲基乙二胺(352mg,4mmol),乙酸(4mmol)溶于15mL甲醇中回流反应12小时。减压除去有机溶剂后,粗产物溶于30mL二氯甲烷中。有机相经10%的NaOH水溶液洗涤后,用K2CO3干燥。过滤K2CO3后有机相减压浓缩。粗产物经硅胶柱层析(乙酸乙酯/异丙醇/25%氨水,8:2:0.5)分离纯化得1.07g淡黄色固体化合物31,收率75%.1H NMR(400MHz,CDCl3):δ8.46(d,J=8.8Hz,1H),7.66(s,1H),7.54(d,J=8.8Hz,1H),3.22(t,J=6.0Hz,2H),3.12(t,J=6.0Hz,2H),2.74(t,J=6.4Hz,2H),2.43(t,J=6.4Hz,2H),2.23(s,6H)。
2-(2’-(N,N-二甲基乙二胺基))乙基-5,7-二氯-8-氨基喹啉(TDMQ-20):参照化合物3的制备方法,合成化合物TDMQ-20为淡黄色固体,收率为90%.1H NMR(400MHz,CDCl3):δ8.33(d,J=8.8Hz,1H),7.43(s,1H),7.37(d,J=8.8Hz,1H),5.40(brs,2H),3.19-3.12(m,4H),2.77(t,J=6.0Hz,2H),2.44(t,J=6.0Hz,2H),2.22(s,6H)。
实施例9:本发明衍生物特异性螯合金属铜离子试验:
通式(I)中化合物与金属离子亲和常数的估算:
与铜离子亲和常数的估算,配制如下各种溶液:(A)待测配体[L]:将化合物TDMQ-n溶于20mM Tris-HCl/150mM NaCl,pH为7.4的缓冲体系中,初始浓度为300μM;(B)竞争性配体[Lc]:分别将已知结合常数的配体(EDTA,EDDA,EGTA,CDTA等)溶于20mM Tris-HCl/150mMNaCl,pH为7.4的缓冲体系中,浓度为300μM;(C)铜离子溶液[Cu]:将氯化铜溶于去离子水中,初始浓度为15mM。在紫外-可见光比色槽中,依次加入100μL溶液(A),100μL溶液(B),1800mL(20mM Tris-HCl/150mM NaCl,pH为7.4)的缓冲溶液及2μL溶液(C),如此可知测定时比色槽中待测配体[L],竞争性配体(LC)及铜离子[Cu]的浓度均为15μM。记录在室温下从波长250nm至600nm进行光谱扫描的图谱,得到竞争性螯合配体谱图,如图1所示。
根据以上条件,用2μL去离子水代替2μL铜离子溶液(C),记录光谱扫描图谱,得到待测化合物谱图;用100μL(20mM Tris-HCl/150mM NaCl,pH为7.4的缓冲溶液)代替100μL溶液(B),记录光谱扫描图谱,得到待测化合物与铜离子螯合配合物[Cu2+-L]的谱图。在上面这些实验中,所有研究的配体及螯合物都可以满足比尔-朗伯定律。根据以上条件,所形成的配合物满足下列平衡方程:
可以推导出:
通过紫外-可见光吸收光谱记录383nm处下竞争性螯合配合物(Amix)的吸收光谱值,无铜离子时待测化合物(AL)的吸收光谱值,无竞争性配体时待测化合物与铜离子螯合物(ACu―L)的吸收光谱值。铜离子与待测化合物L螯合的比例可通过下式计算:x=(AL―Amix)/(AL―ACu―L),实验重复三次。
另外,与锌离子亲和常数的估算:当待测化合物与锌离子(1/1)形成的配合物显示出非常低的亲和力时,在相同的反应条件下的溶液中有如下平衡:
根据紫外-可见光滴定实验,与铜离子滴定实验比较,TDMQs化合物与锌离子均表现出弱得多的亲和性。在实验中,滴加锌离子溶液至浓度为10~20mM,在溶液中没有参与配位的自由配体L、形成的L-Zn配合物(化学计量比L/Zn=1/1)达到平衡。因此,亲和常数Kapp[Zn‐L]可以通过往待测配体L溶液中不断滴加锌离子溶液至平衡来计算。
表1.不同配体化合物在pH为7.4时,与铜离子、锌离子的结合常数
表1的结果显示,对本发明所述衍生物与铜、锌离子进行配位能力测试,并计算其络合常数,发现本发明涉及的衍生物,对铜离子的络合常数Log KCu 2+达10~16左右,对锌离子的结合常数Log KZn 2+为4左右。如:TDMQ-19对锌离子的络合常数接近0,几乎不络合锌离子,对铜离子的络合常数为10.2,两者相差10个数量级;TDMQ20对铜、锌离子的络合常数分别为16.5和4.2,相差12个数量级。表明本发明所述衍生物具有特异性螯合铜离子能力,可用于开发制备治疗神经退行性疾病药物和铜离子紊乱相关疾病药物。
实施例10:定量分析待测化合物配体对淀粉样多肽Aβ在铜离子及还原性试剂条件下诱导生成过氧化氢的影响:
通过荧光定量法测定过氧化氢的产生,实验所用过氧化氢测定试剂盒来自Enzo生命科学公司(试剂盒编号:ENZ-51004Lot No.10231415)。所用荧光光谱仪型号为Edinburgh仪器公司的FLSP9220,激发和发射带宽为2nm,激发波长λex=540nm,发射波长λem=584nm,采集范围550-700nm。每个实验重复三次。配制母液为:氯化铜水溶液,10μM;淀粉样多肽Aβ1‐16水溶液,10μM;化合物TDMQ-5盐酸盐水溶液,10μM;化合物TDMQ-10盐酸盐水溶液,10μM及20μM;抗坏血酸钠水溶液,100μM;pH为7.4的0.1M的Hepes缓冲溶液。
具体实验操作流程如下:分别取50μL Hepes缓冲溶液,10μL氯化铜水溶液,10μL淀粉样多肽Aβ1‐16水溶液,充分混合孵化30分钟以形成Cu2+-Aβ1‐16配合物。然后加入化合物TDMQ溶液(所加体积为10L或20L,相当于1当量或2当量的铜离子),加完后混合孵化30分钟;然后,加入10μL抗坏血酸钠水溶液,并加水至总体积为100L,继续孵化30分钟。铜离子、Aβ1‐16、化合物TDMQ、抗坏血酸钠、缓冲溶液的最终浓度分别为1μM、1μM、1μM或2μM、10μM、50mM。然后通过过氧化氢试剂盒在荧光光谱仪上检测(激发波长λex=540nm,发射波长λem=550~700nm),并计算所产生过氧化氢的量。反应混合物避光孵化30分钟后进行测量。对照实验,在相同条件下进行如下测定:Cu2+-Aβ1‐16配合物±抗坏血酸钠,氯化铜±抗坏血酸钠,仅有淀粉样多肽Aβ1-16,仅有铜离子,结果如图2所示。
通过对淀粉样多肽Aβ在铜离子及还原性试剂条件下诱导生成过氧化氢试验中发现,本发明提供的衍生物能够特异性结合淀粉样蛋白,显示出其较强的抗氧化应激的能力。
Claims (8)
1.一种四齿螯合型单喹啉衍生物,其特征在于,所述衍生物结构式如式()所示:
式();
其中:X 为-NH2;
Y 为-(CH2)n-NR6-(CH2)m-NR7R8;
R1,R2,R3,R4,R5相同或不同,分别代表氢原子、C1-6烷氧基、胺基、卤素原子、氰基或三氟甲基;或者代表被C1-6烷氧基、胺基、氰基、三氟甲基中的任意一个或多个基团所取代的C1-6烷基;R6、R7、R8分别代表氢原子或被C1-6烷氧基、胺基、氰基、三氟甲基中的任意一个或多个基团所取代的C1-6烷基;
n为1、2、3、4、5或6;m为1、2、3、4、5或6。
2.根据权利要求1所述的四齿螯合型单喹啉衍生物,其特征在于,R1,R2,R3,R4,R5相同或不同,分别代表氢原子、卤素原子或三氟甲基。
3.一种权利要求1所述的四齿螯合型单喹啉衍生物的制备方法,其特征在于,包括如下步骤:
S1. 对化合物I-1 的X基团进行保护,生成化合物I-2 ;
S2. 将化合物I-2 中C2位的甲基氧化成醛基或乙烯基后,与NH2R6(CH2)mNR7R8反应生成化合物I-3 ;其中,n为1或2;
S3. 将化合物I-3 去保护,得到所述四齿螯合型单喹啉衍生物;
R0为X基团的保护基团,R0选自叔丁氧羰基或乙酰基。
4.一种权利要求1或2任意一项权利要求所述的四齿螯合型单喹啉衍生物在制备金属配合物中的应用,所述四齿螯合型单喹啉衍生物特异性螯合金属铜离子制备得到金属配合物。
5.权利要求1或2任意一项权利要求所述的衍生物在制备神经退行性疾病的金属离子调节剂药物中的应用。
6.权利要求1或2任意一项权利要求所述的衍生物在制备铜离子代谢紊乱疾病药物中的应用,所述铜离子代谢紊乱疾病为威尔逊氏病。
7.根据权利要求4所述的应用,其特征在于,所述衍生物还包括生理上可接受的成盐物;成盐物包括硫酸盐、盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、乙酸盐、苯甲酸盐、对甲苯磺酸盐、柠檬酸盐、马来酸盐或酒石酸盐。
8.根据权利要求5所述的应用,其特征在于,所述神经退行性疾病包括阿尔茨海默病、亨廷顿氏病、帕金森氏病、唐氏综合征或肌萎缩侧索硬化。
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CN107987016B (zh) * | 2016-10-27 | 2022-05-27 | 广州威尔曼新药研发有限公司 | 化合物n-丁基-2,2’-亚氨基-双(8-喹啉胺)的晶体、药物组合物及其应用 |
CN106674102A (zh) * | 2016-12-26 | 2017-05-17 | 广东工业大学 | 一种卤代喹啉类化合物及其制备方法 |
CN112867728B (zh) * | 2018-07-20 | 2024-04-05 | 冷泉港实验室 | 与铜螯合的(吡啶基亚甲基)丁二胺衍生物 |
CN113318116B (zh) * | 2021-06-17 | 2023-08-25 | 成都奥睿药业有限公司 | 姜黄素二氟硼及其衍生物的用途 |
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FR2724171B1 (fr) * | 1994-09-05 | 1997-01-03 | Synthelabo | Derives de 3,3a,4,5-tetrahydro-1h-oxazolo(3,4-a)quinolein-1-one, leur preparation et leur application en therapeutique |
US6277841B1 (en) * | 2000-03-02 | 2001-08-21 | Mallinckrodt Inc. | Quinoline ligands and metal complexes for diagnosis and therapy |
US7589209B2 (en) * | 2004-03-23 | 2009-09-15 | New York University | 8-hydroxyquinoline tripodal metal ion probes |
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EP3466931A1 (en) | 2019-04-10 |
CN105949120A (zh) | 2016-09-21 |
HRP20240476T1 (hr) | 2024-08-30 |
US10807957B2 (en) | 2020-10-20 |
US20190092730A1 (en) | 2019-03-28 |
EP3466931B1 (en) | 2024-01-10 |
EP3466931A4 (en) | 2019-11-27 |
WO2017202360A1 (zh) | 2017-11-30 |
JP6889825B2 (ja) | 2021-06-18 |
ES2974620T3 (es) | 2024-06-28 |
EP3466931C0 (en) | 2024-01-10 |
HUE066677T2 (hu) | 2024-08-28 |
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