CN102985407A - 8-羟基-喹啉衍生物 - Google Patents
8-羟基-喹啉衍生物 Download PDFInfo
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- CN102985407A CN102985407A CN2011800335245A CN201180033524A CN102985407A CN 102985407 A CN102985407 A CN 102985407A CN 2011800335245 A CN2011800335245 A CN 2011800335245A CN 201180033524 A CN201180033524 A CN 201180033524A CN 102985407 A CN102985407 A CN 102985407A
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- Prior art keywords
- methyl
- quinoline
- amino
- group
- alcohol
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Abstract
本发明涉及通式(I)的化合物及其药学上可接受的盐(其中R1表示氢原子、低级烷基、低级烯基、低级环烷基、芳基、芳烷基或杂环基,其中上述基团任选在邻位、间位和/或对位上被1、2、3或4个吸电子基团或供电子基团取代;R2表示氢原子、低级烷基、芳基、芳烷基或杂环基,其中上述基团任选被一个或多个卤原子取代;R3表示低级烷基、芳基、芳烷基或杂环基,其中上述基团任选在邻位、间位和/或对位上被1、2、3或4个吸电子基团或供电子基团取代;R4表示氢原子、低级烷基或任一酸官能基;n是1或2)。本发明的化合物可主要用于治疗与神经学和/或氧化性应激相关的疾病的药物。
Description
本发明涉及新颖的喹啉衍生物、这些化合物的合成、含有这些化合物的药物组合物、这些药物组合物的制备,也涉及本发明的新颖的8-羟基-喹啉衍生物在治疗和预防不同疾病方面的用途,主要是与神经学和/或氧化性应激相关的那些疾病。
本发明公开了细胞保护剂和金属螯合形成剂及其医疗用途。而且,本发明的目的是治疗缺血、再灌注损伤、心血管疾病、神经变性疾病(包括阿尔茨海默病和亨廷顿病)和创伤。而且,本发明的目的是治疗抑郁及其它神经精神疾病,包括焦虑症。本发明的另一目的是治疗肝、肾或肺损伤。本发明的化合物可用作神经保护性和心脏保护性药物,并用于治疗神经精神疾病。
本专利说明书中提及的出版物和所引用的专利作为参考包含于说明书中。
各种病原学细胞损伤和细胞死亡是许多心血管、神经学和炎症疾病的主要特征。细胞损伤可作为细胞低氧或缺血、各种氧化剂或自由基的形成和/或不同生物调节剂(细胞因子、趋化因子、脂质调节剂)的过度生成的结果而出现。这些过程经常是相互依赖的;因此这些过程作为自身放大(“自杀性”)细胞内循环的一部分而出现,并形成许多人类疾病的决定性基础。虽然细胞死亡一般被描述为细胞凋亡或坏死,但这两种形式仅表示细胞损伤形式的范围的两端。参与上述细胞死亡过程的细胞间机理是复杂的,但经常激活称为半胱氨酸天冬氨酸蛋白酶的细胞死亡效应器家族,并刺激线粒体功能障碍、活性氧的产生以及使线粒体组分释放到胞液中(综合性文献:Szabó,2005;Duprez等,2009;Degterevés Yuan,2008;Wang等,2009)。细胞死亡的路径包括聚(ADP-核糖)聚合酶(PARP)的活化。后一种酶在细胞核中表达(综合性文献:Jagtap and Szabó,2005)。
预防细胞损伤和细胞死亡的化合物一般称为“细胞保护性”化合物。可通过许多药理学和生物化学方法得到细胞保护。本文提到了它们的下述实例:氧化剂和自由基的清除剂、某些“死亡效应器路径”的抑制剂、细胞膜的稳定等。在缺血或几个相关疾病过程中,由组织释放的铁和铜阳离子以Haber-Weiss路径通过已知方式催化羟基自由基的形成从而引起细胞损伤。这些金属阳离子的失活或螯合物的形成可产生细胞保护作用。因此以给药形成铁载体(如去铁胺)的铁螯合物的形式进行试验,以减缓铁和铜阳离子的催化效率(Lewen等,2000;Britton等,2002)。
已知的是,谷氨酸盐与锌阳离子一起由神经系统细胞的突触体利用谷氨酸盐作为化学信使进行释放。通常,在神经联会处释放的锌很快再次在突触体中建立。由于缺血、持久攻击和大脑损伤,由突触体释放的锌在环绕神经元的细胞外液体中蓄积。当过量的锌进入细胞体,锌可通过细胞凋亡和坏死引起细胞死亡。通过该机理形成的锌螯合物可形成神经性保护并影响不同神经精神性疾病的结果(Regland等,2001;Koh等,1996)。
因此,锌螯合剂也可用于治疗阿尔茨海默病,所述治疗通过结合出现在斑块中的锌,因而削弱了斑块的结构(Frederickson等,2005;等,2007)。锌螯合剂也可用于治疗亨廷顿病(Nguyen等,2005)。
根据细胞保护的另一方式,诱导了调节保护效应的细胞内路径。该方法的原型是所谓的“缺血预适应”,其中使细胞或器官短时间缺血以诱导细胞保护基因(如抗氧化酶、热休克蛋白及其他的基因)的过调节。酶(HO-1)的血红素氧化酶表达已经在几个试验体系中证实了细胞保护作用(如Li等,2007;Idris等,2008)。
涉及细胞保护方法的先前的专利申请与下述相关:不同细胞凋亡路径或效应器的抑制剂(如US6,949,516;US6,737,511;US6,544,972;US6,521,617;US6,495,522;US7,604,989;US7,601,846;US7,533,852);在细胞损伤期间维持线粒体功能(如US6,552,076;US6,511,966;US7,550,439;US7,528;174);PARP酶催化活性的直接抑制(如US6,476,048;US6,531,464;US7,601,719;US7,595,406;US7,550,603;US7,449,464;US7,217,709;US6,956,053;US6,534,651);细胞保护基因(包括血红素氧化酶)的过调节(如US7,524,819;US7,364,757)。
用于内质网应激抑制的化合物已经公开于美国专利申请公开号2008/293699中。
最近已经进行了基于细胞的筛选测试以用于细胞保护作用化合物的系统鉴定。在该测试中,模拟某种形式的细胞损伤并筛选化学库以鉴定预防或延缓细胞损伤的化合物(如Gero等,2007)。该筛选测试没有鉴定所述效果的机理,然而,其能通过辅助测试的方式进行鉴定。
通过基于细胞筛选方法的方式,我们已经发现并确定了新颖的羟基-喹啉衍生物。这些化合物保护细胞免遭由氧化性应激诱导的损伤,因此其可能用于治疗许多疾病。本发明的化合物发挥了多种细胞效果如铁螯合、PARP活化的抑制、线粒体功能障碍的抑制、血红素氧化酶的活化和与铁离子形成的螯合物。在实现本发明的过程中,以不含铁、锌和铜阳离子的形式添加螯合剂,因此当与生理学体系接触时,这些化合物与上述阳离子形成络合物。
本发明的药物组合物包含作为活化剂的螯合剂,其不与铁、铜或锌阳离子形成络合物键。
本发明的另一目的是针对患有与细胞死亡相关症状患者的神经保护和/或心脏保护方法。根据本发明,以向有此需要的患者给药本发明化合物的方式获得神经保护和/或心脏保护,所述化合物能保护细胞免于细胞毒性攻击。
一方面,本发明的目的是通式(I)的化合物及其药学上可接受的盐
在该式中
R1表示氢原子、低级烷基、低级烯基、低级环烷基、芳基、芳烷基或杂环基,其中上述基团任选在邻位、间位和/或对位上被1、2、3或4个吸电子基团或供电子基团取代;
R2表示氢原子、低级烷基、芳基、芳烷基或杂环基,其中上述基团任选被一个或多个卤原子取代;
R3表示低级烷基、芳基、芳烷基或杂环基,其中上述基团任选在邻位、间位和/或对位上被1、2、3或4个吸电子基团或供电子基团取代;
R4表示氢原子、低级烷基或任一酸官能基;
n是1或2。
优选的一组通式(I)的化合物是衍生物,其中
R1表示在对位上被吸电子基取代的基团,或在间位上被吸电子基取代的基团,或在邻位、间位或对位上被供电子基取代的上述基团;或R1表示在间位和对位上被吸电子基双取代的基团;或R1表示在邻位和对位上被吸电子基双取代的基团;或R1表示取代或未取代的杂环基;
R3表示在对位上被吸电子基取代的芳香基;或R3表示未取代的或在邻位、间位或对位上被烷基和/或吸电子基取代的杂芳基或脂环基;
R2和R4表示氢原子;和
n是1。
在通式(I)的本发明化合物的特别优选衍生物中,
R1表示任选被硝基、三氟甲基、羟基、氟原子、异丙氧基单取代或双取代的苯基;或吡啶基;
R2表示氢原子;
R4表示氢原子;和
n是1。
特别优选的是作为实施例的标题化合物提及的8-羟基-喹啉衍生物。
附图说明
图1a、1b和1c说明了心脏移植之后,实施例1的化合物再灌注损伤减少的效果;
图2说明了在体外肝细胞中,本发明的几种化合物对过氧化氢引起的细胞死亡的效果;
图3说明了在体外混合神经元和星形细胞中,本发明的几种化合物对过氧化氢引起的细胞死亡的效果;
图4说明了实施例1化合物在高架十字迷宫试验中的效果;和
图5说明了实施例1化合物在强迫游泳试验中的效果。
说明书中使用的术语应如下述解释:
“低级烷基”指的是具有1-4个碳原子的支链或非支链烷基(如甲基、乙基、异丙基等)。
术语“低级烯基”指的是具有2-4个碳原子的支链或非支链烯基(如烯丙基或丙烯基)。
术语“环烷基”指的是具有3-8个碳原子的环状基团(如环丙基、环丁基、环己基等)。
术语“芳基”指的是单环或双环芳香烃基(如苯基、萘基等)。
术语“芳烷基”指的是被满足上述定义的上述芳基单取代或双取代的烷基(如苄基、β苯乙基等)。
术语“卤原子”指的是溴、氟、氯或碘原子;优选氟和氯原子。
术语“吸电子基团”取代基优选卤原子、三氟甲基或硝基。
在“供电子”取代基中,可提及低级烷基(如甲基)。
“酸官能基”可以是任一酯基(低级烷氧羰基,优选甲氧基羰基)或腈或酰胺基。
通式(I)的化合物与碱在羟基上或与酸在氮原子上形成盐。对于盐的形成,可使用药学上可接受的碱(例如碱金属氢氧化物,如氢氧化钠或氢氧化钾)或药学上可接受的无机或有机酸(例如盐酸、氢溴酸、乙酸、富马酸、马来酸、苹果酸、琥珀酸、酒石酸、苯磺酸、对甲苯磺酸、甲磺酸等)。
本发明的另一目的是通式(I)的化合物及其药学上可接受盐的制备方法,其特征在于将通式(II)的8-羟基喹啉衍生物
与通式(III)的氧代化合物
和通式(IV)的胺反应
R3-NH-R3' IV
(式中的取代基如上述所定义,R3′独立地选自R3的可能含义,且R3′也可为氢原子;且R3和R3'可相互连接形成环仲胺),接着得到的式(I)化合物任选转化成其药学上可接受的盐或由其盐释放出。
利用改良的Betti反应(其为已知的方法)进行所述反应(Betti,1900;Betti,1903;Phillips等,1954;Phillips等,1956;Phillips,1956)。
反应在溶剂中进行。水或有机溶剂(如乙腈)可用作反应媒介。任选地,反应在酸性催化剂(如甲酸)存在下进行。
对于本发明化合物的制备,取决于起始原料,使用下述方法A或B:
方法A:
将1mmol的醛悬浮或溶解于2倍体积的水中并向反应混合物中添加1.1当量的伯胺。在60°C保持1小时,并向热混合物中滴加溶解于体积为水两倍的乙腈或丙酮中的0.6当量的8-羟基-喹啉溶液。接着将反应混合物冷却到室温并搅拌直到出现沉淀。通过HPLC和TLC的方式监测反应。过滤沉淀,用乙腈洗涤并干燥。
方法B:
将1mmol的醛溶解于3倍体积的乙腈中并向反应混合物中添加1当量的胺、0.6当量的8-羟基-喹啉和1V/V%的甲酸。搅拌混合物直到出现沉淀或起始喹啉点消失。通过过滤、用乙腈洗涤来处理混合物,利用己烷(异构体混合物)/乙酸乙酯的混合物进行色谱分离并由醇或乙腈重结晶。
反应完成,利用一般方法(如过滤或离心)从反应混合物分离所需产物并且如果需要的话,通过已知方法纯化(重结晶或色谱法)。
本发明的另一目的是含有作为活化剂的通式(I)的化合物或其药学上可接受的盐和惰性固体或液体药物载体和/或赋形剂的药物组合物。
本发明的药物组合物可为固体(如片剂、胶囊)、半固体(如栓剂)或液体(如可注射溶液)制剂。所述制剂可通过口服、直肠给药或胃肠外给药。本发明的组合物可包含通常适合治疗的载体和/或赋形剂(如淀粉、纤维素或纤维素衍生物、乳糖、甘露醇、氯化钠、碳酸钠、蔗糖、麦芽糖、碳酸钙等)。
本发明的药物组合物可用于治疗与神经学和/或氧化性应激相关的疾病,其中向有此需要的患者给药治疗有效量的通式(I)的化合物或其药学上可接受的盐。根据本发明的优选实施方式,与神经学或氧化性应激相关的疾病选自下述疾病:缺血、再灌注损伤、心血管疾病、神经变性疾病(特别是包括阿尔茨海默病和亨廷顿病)、创伤、神经精神疾病(特别是包括抑郁和焦虑症)以及肝、肾和肺损伤。
根据上述,本发明的药物组合物在肝、肾和肺损伤情况下可用作神经保护和心脏保护试剂,并可用于治疗或预防抑郁、焦虑症、阿尔茨海默病和亨廷顿病。
本发明的其它细节以下述实施例公开,并非将保护范围限于实施例中。
化学实施例
实施例1:7-((6-甲基吡啶-2-基氨基)(4-硝基苯基)甲基)喹啉-8-醇
方法A:
向10.lg(18.5mmol,Sigma)的4-硝基-苯甲醛中,滴加水(20ml),接着在强烈搅拌下向该柠檬黄色悬浮液中加入2-氨基-6-甲基吡啶(7.95g,1.1当量,Aldrich)。颜色变化后(从柠檬黄到橙黄),将5.82g的8-羟基-喹啉(0.6当量,Sigma)与20mL丙酮(Molar)的溶液加入到该悬浮液中,且反应容器在60°C加热4小时,接着将该溶液冷却到室温。过滤黄色粉末沉淀(7.87g50.8%),用少量丙酮洗涤;其纯度通过HPLC检测(≥99.5%)。
方法B:
将4-硝基-苯甲醛(2.8g,18.5mmol,Sigma)溶于无水乙腈(15ml,Molar)中,且在搅拌下向该柠檬黄色溶液中加入2-氨基-6-甲基吡啶(2g,1当量,Aldrich)。将1.61g的8-羟基-喹啉(0.6当量,Sigma)加入到混合物中并在室温搅拌四天。过滤沉淀出的产物(4.2g,27.1%),通过质谱确定产物的分子量,其结构通过NMR确定(MW:386.1),纯度通过HPLC检测(≥99.6%)。
C22H18N4O3(MW:386.1);熔点:157-160℃;HPLC(CH3CN/H2O70:30Phenomenex C18282nm):Tr=7.14分钟1H NMR1(DMSO)δ2.2(3H,s,CH 3),6.37(1H,d,J=7.0Hz),6.49(1H,d,J=7.9Hz),6.98(1H,d,J=8.8Hz,NHCH),7.28(1H,t,J=7.9Hz),7.40(2H,t,J=7.9和8.8Hz),7.50-7.55(1H,m),7.59-7.66(3H,m),8.16(2H,d,J=8.8Hz),8.28(1H,d,J=7.9Hz),10.1(1H,宽s,OH)13C NMR1(DMSO)δ24.2(CH3),51.5(CH),105.6(CH),111.6(CH),117.7(CH),121.9(CH),123.5(2xCH),124.5(Cq),126.7(CH),127.7(Cq),128.2(2xCH),136.1(CH),137.3(CH),138.2(Cq),146.2(Cq),148.4(CH),149.8(Cq),152.0,155.7和157.3(Cq)。
实施例2:4-((8-羟基喹啉-7-基)(4-硝基苯基)甲基氨基)苯甲酸乙酯
以用于实施例1化合物的方法A和方法B制备标题化合物,其中所用起始原料改变为苯佐卡因(Sigma)、4-硝基-苯甲醛(Sigma)和8-羟基喹啉。通过柱色谱纯化产物:C25H21N3O5;(MW:443.2);产率:50mg(30.9%,方法A)。HPLC(CH3CN/H2O70:30Phenomenex C-18254nm):Tr=8.82分钟。
实施例3:4-{[(8-羟基喹啉-7-基)-苯基-甲基]-氨基}-苯甲酸乙酯
C25H22N2O3;(MW:398.1)
以实施例1的方法A制备。
实施例4:7-(苯基氨基-吡啶-2-基-甲基)-喹啉-8-醇
C21H17N3O;(MW:327.1)
以实施例1的方法A制备。
实施例5:7-[吡啶-2-基-(4-三氟甲基-苯基氨基)-甲基]-喹啉-8-醇
以用于实施例1化合物的方法A和方法B制备实施例5的标题化合物,改变在于:将吡啶-2-甲醛(Molar)用作起始醛,并将4-三氟甲基-苯胺(Sigma)用作伯胺。产物通过柱色谱纯化:C22H16F3N3O(MW:395.1);产率:151mg,(42.1%,方法B);熔点:158-161°C;HPLC(CH3CN/H2O70:30PhenomenexC18254nm):Tr=10.39分钟。
1H NMR5(DMSO)δ6.31(1H,d,J=7.1Hz),6.79(1H,d,J=7.6Hz),7.27(1H,t,J=5.1Hz),7.29-7.37(4H,m),7.47-7.54(3H,m),7.75(1H,t,J=7.2Hz),7.74(1H,d,J=8.5Hz),8.24(1H,d,J=8.3Hz),8.55(1H,d,J=4.1Hz),8.85(1H,d,J=3.2Hz),10.24(1H,宽s)。
实施例6:7-[(3-甲基-吡啶-2-基氨基)-(4-硝基-苯基)-甲基]-喹啉-8-醇
C22H18N4O3;(MW+1:386,1)
以实施例1的方法A制备。
实施例7:7-[(6-甲基-吡啶-2-基氨基)-(4-三氟甲基-苯基)-甲基]-喹啉-8-醇
以用于实施例1化合物的方法A和方法B制备标题化合物,其中所用起始原料改变为4-三氟甲基苯甲醛(Sigma)、2-氨基-6-甲基吡啶和8-羟基-喹啉。所得产物(方法B):C23H18F3N3O(MW:409.1);(229mg,32.5%);熔点:136-138°C;HPLC(CH3CN/H2O70:30Phenomenex C18254nm):Tr=10.18分钟。
实施例8:7-[(4-甲基-吡啶-2-基氨基)-(4-三氟甲基苯基)-甲基]-喹啉-8-醇
以用于实施例1化合物的方法B制备标题化合物,其中所用起始原料改变为2-氨基-4-甲基-吡啶(Molar)、4-三氟甲基-苯甲醛(Sigma)和8-羟基-喹啉(Sigma)。所得产物:C23H18F3N3O;(MW:409.1);产率:230mg,(29.6%)熔点:104-107°C;HPLC(CH3CN/H2O70:30Phenomenex C18282nm):Tr=7.61分钟。1H NMR8(DMSO)δ2.18(3H,s,CH 3),6.41(1H,d,J=5.1Hz),6.44(1H,s,NH),6.49(1H,d,J=4.9Hz),7.07(1H,d,J=9.2Hz),7.39(1H,d,J=8.9Hz),7.49-7.54(1H,m),7.58(2H,d,J=7.9Hz),7.63(2H,d,J=8.3Hz),7.73(1H,d,J=7.9Hz),7.85(2H,d,J=7.9Hz),8.03-8.08(1H,m),8.12(2H,d,J=8.5Hz),8.27(1H,d,J=8.2Hz),8.81-8.86(1H,m);13C-NMR8(DMSO)δ23.5(CH3),51.8(NHCH),109.5(CH),117.6(CH),121.8(CH),124.5(Cq),125.1(CH),125.6(2xCH),126.8(CH),127.7(2xCH),127.8(Cq),130.1(CH),134.7(Cq),136.1(CH),138.1(Cq),148.2(Cq),148.5(CH),149.6(Cq),157.7(CH),161.6(Cq),166.3(Cq)。
实施例9:2-((4-甲基嘧啶-2-基氨基)(4-硝基苯基)甲基)苯酚
以用于实施例1化合物的方法B制备标题化合物,其中所用起始原料改变为2-氨基-4-甲基-嘧啶(Sigma)、4-硝基-苯甲醛和8-羟基-喹啉。所得产物:C21H17N5O3,(MW:387.1);产率:344mg,(49.6%);熔点:136-145°C;HPLC(CH3CN/H2O70:30Phenomenex C18282nm):Tr=5.21分钟。1HNMR9(DMSO)δ2.14(3H,s,CH3),6.35(1H,d,J=5.8Hz),6.55(1H,s),7.00(1H,d,J=8.0Hz),7.36-7.43(2H,m],7.50-7.55(1H,m),7.56(1H,d,J=7.5Hz),7.60(1H,d,J=8.5Hz),7.79(1H,d,J=5.5Hz),8.15(2H,d,J=8.5Hz),8.28(1H,d,J=8.5Hz),8.84(s,1H),10.1(s,1H);13C NMR9(DMSO)δ20.6(CH3),51.6(NHCH),109.0(CH),114.2(CH),117.7(CH),121.9(CH),123.5(2xCH),124.6(Cq),126.7(CH),127.7(Cq),128.2(2xCH),136.1(CH),138.2(Cq),146.2(Cq),147.1(Cq),147.2(CH),148.5(CH),149.8,152.0和157.9(3Cq)。
实施例10:7-((4-甲基嘧啶-2-基氨基)(4-(三氟甲基)苯基)甲基)喹啉-8-醇
以用于实施例1化合物的方法A和方法B制备标题化合物,改变在于将4-三氟甲基-苯甲醛和2-氨基-4-甲基-嘧啶用作醛和氨源(Molar)。所得产物(方法B),产率:1.7g,(34.8%);C22H17F3N4O;(MW:410.1),熔点:144-147°C;HPLC(CH3CN/H2O70:30Phenomenex C18254nm):Tr=7.75分钟。1H NMR10(DMSO)δ2.24(3H,s,CH3),6.49(1H,d,J=5.1Hz),7.07(1H,d,J=9.0Hz,NHCH)),7.39(1H,d,J=8.5Hz),7.49-7.55(1H,m),7.58(2H,d,J=7.7Hz),7.64(2H,d,J=7.9Hz),7.74(1H,d,J=8.5Hz),8.07(1H,d,J=8.9Hz),8.14(1H,d,J=4.9Hz),8.28(1H,d,J=7.7Hz),8.83(1H,s),10.08(1H,宽s)。
13C NMR10(DMSO)δ23.6(CH3),51.7(NHCH),110.4(CH),117.6(CH),121.8(CH),124.6(Cq),125.2(2xCH),126.8(CH),127.2(Cq),127.4(Cq),127.7(Cq),127.8(2xCH),136.1(CH),138.1(Cq),148.2(Cq),148.4(CH),149.8,149.6,161.6和167.6(4Cq)。
实施例11:7-[(2-羟基苯基)-(4-甲基-嘧啶-2-基氨基)-甲基]-喹啉-8-醇
以用于实施例1化合物的方法B制备标题化合物,其中所用起始原料改变为2-羟基-苯甲醛(Molar)和2-氨基-4-甲基-嘧啶(Sigma)。沉淀出的产物,产率:45mg;C2IH18N4O2;(MW:358.1)。
1H NMR11(DMSO)δ2.21(3H,s,CH3),6.39-6.46(2H,m),6.69(1H,t,J=6.4Hz),6.75(1H,d,J=7.7Hz),7.23(1H,d,J=7.0Hz),7.32(1H,d,J=8.4Hz),7.44-7.51(2H,m),7.57(2H,d,J=8.0Hz),8.09(1H,d,J=5.4Hz),8.25(1H,d,J=8.0Hz),8.79(1H,宽s),9.47(1H,宽s,OH),9.80(1H,宽s,OH)。
实施例12:7-[(4-异丙氧基苯基)-(6-甲基-吡啶-2-基氨基)-甲基]-喹啉-8-醇
以用于实施例1化合物的方法B制备标题化合物,其中所用醛成分改变为4-异丙基-氧基-苯甲醛(Molar)。产物通过柱色谱纯化,C25H25N3O2;(MW+1:399.2),产率135mg,(63.1%),熔点:132-134°C;HPLC(CH3CN/H2O70:30Phenomenex C18282nm):Tr=9.23分钟。
实施例13:7-[(2-羟基苯基)-(6-甲基-吡啶-2-基氨基)-甲基]-喹啉-8-醇
以用于实施例1化合物的方法B制备标题化合物,其中所用起始原料改变为水杨醛(Molar)、2-氨基-6-甲基吡啶(1当量)和8-羟基-喹啉(0.6当量)来进行反应。沉淀产物:C22H19N3O2;(MW:357.1),产率1.6g,(50.9%);熔点:189-191°C;HPLC(CH3CN/H2O70:30Phenomenex C18282nm):Tr=5.05分钟。
1H NMR13(DMSO)δ2.23(3H,s),6.34(1H,d,J=6.0Hz),6.38(1H,d,J=7.1Hz),6.69(1H,t,J=7.2Hz),6.80(2H,m),7.02(2H,m),7.18(1H,d,J=6.2Hz),7.25(1H,d,J=6.8Hz),7.36(1H,d,J=7.4Hz),7.42-7.54(1H,m),7.64(1H,d,J=7.9Hz),8.25(1H,d,J=7.1Hz),8.80(1H,s),9.85(1H,s)
13C NMR13(DMSO)δ23.9(CH3),47.8(CHNH),111.1(CH),115.7(CH),116.7(CH),118.7(CH),121.5(CH),125.3(Cq),127.2(CH),127.4(Cq),127.8(CH),128.3(CH),129.2(Cq),135.9(CH),137.5(CH),138.2(Cq),148.1(CH),149.7,155.1,155.6和157.6(4x Cq)。
实施例14:7-[(4-氟苯基)-(吡咯烷-1-基)-甲基]-喹啉-8-醇
C20H19FN2O;(MW:322.2)
以实施例1的方法A制备标题化合物。
实施例15:7{[(5-甲基-1,2-唑-3-基)氨基](3-硝基苯基)甲基}喹啉-8-醇
C20H16N4O4;(MW:376.1)
以实施例1的方法A制备标题化合物。
实施例16:7-((6-甲基吡啶-2-基氨基)(3,4-二氟苯基)甲基)喹啉-8-醇
以用于实施例1化合物的方法B制备标题化合物,改变为:将3,4-二氟苯甲醛与2-氨基-6-甲基吡啶和8-羟基-喹啉反应。沉淀出白色粉末:C22H17F2N3O,(MW:377.1);产率:275mg(53.3%)。熔点:162-165°C;HPLC(CH3CN/H2O70:30Phenomenex C18282nm):7.97分钟。
实施例17:7-((6-甲基吡啶-2-基氨基)(3-(三氟甲基苯基)甲基)喹啉-8-醇
以实施例1化合物提供的具有更高产率的方法B制备标题化合物。沉淀出白色粉末:C23H18F3N3O(MW:409.1);产率:356mg,57.3%。熔点:140-143°C,HPLC(MeOH/H2O80:20Phenomenex C18254nm):10.21分钟。
实施例18:7-[(4,6-二甲基-嘧啶-2-基氨基)-(4-三氟甲基-苯基)-甲基]-喹啉-8-醇
以实施例1化合物提供的具有更高产率的方法B制备标题化合物。沉淀出白色粉末:C23H19F3N4O;(MW:424.2);产率:255mg,(54.6%)。
实施例19:7-[(6-甲基-吡啶-2-基氨基)-吡啶-2-基-甲基]-喹啉-8-醇
以用于实施例1化合物的方法B制备标题化合物。沉淀出淡黄白色粉末:C21H18N4O(MW:342.2);产率:1.2g,(70.5%)。熔点:155-157°C。
实施例20:7-[(5-氟-吡啶-2-基氨基)-吡啶-2-基-甲基]-喹啉-8-醇
以用于实施例1化合物的方法B制备标题化合物。骨色粉末,通过柱色谱纯化。C20H15FN4O;(MS:346,1),产率45mg,(18.4%)。熔点:165-168°C,HPLC(CH3CN/H2O70:30Phenomenex C18282nm):4.44分钟。
实施例21:7-[(5-氯-吡啶-2-基氨基)-吡啶-2-基-甲基]-喹啉-8-醇
以用于实施例1化合物的方法B制备标题化合物;2-氨基-5-氯-吡啶、2-吡啶-甲醛和8-羟基-喹啉用于反应中;反应混合物在60°C加热3天。灰白色粉末,产物通过柱色谱纯化。C20H15ClN4O;(MW:362.1);产率:55mg,(23.7%)。熔点:160-162°C,HPLC(CH3CN/H2O70:30Phenomenex C18282nm):5.69分钟。
实施例22:7-[(5-甲基-6-硝基-吡啶-2-基氨基)-(4-三氟甲基-苯基)-甲基]-喹啉-8-醇
以用于实施例1化合物的方法B制备标题化合物,改变在于使用2-氨基-5-甲基-6-硝基-吡啶、4-三氟甲基-苯甲醛和8-羟基-喹啉,且反应混合物在60°C加热7天。淡黄白色粉末。C23H17F3N4O3;(MW:454.1),产率:26mg,(10%)。熔点≥300°C,HPLC(CH3CN/H2O70:30Phenomenex C18282nm):Tr=5.60分钟。
实施例23:7-[(3-羟基-苯基)-(6-甲基-吡啶-2-基氨基)-甲基]-喹啉-8-醇
以用于实施例1化合物的方法B制备标题化合物,改变在于3-羟基-苯甲醛与2-甲基-6-甲基吡啶和8-羟基-喹啉反应。白色粉末,通过柱色谱纯化。C22H19N3O2;(MW:357.2),产率:211mg,(80.2%)。熔点:187-189°C,HPLC(CH3CN/H2O70:30Phenomenex C18282nm):Tr=3.97分钟。
生物学实施例
实施例24:7-((6-甲基吡啶-2-基氨基)(4-硝基苯基)甲基)喹啉-8-醇对基质金属蛋白酶2(MMP-2,72kDa明胶酶)和基质金属蛋白酶9(MMP-9,92kDa明胶酶)的活性抑制
将H9c2大鼠胚胎心肌细胞(来自ATCC,Rockville,MD,USA)在含有10%牛血清、4mM L-谷氨酰胺(Sigma-Aldrich,Hungary)、100IU/ml青霉素和100ug/ml链霉素的Dulbecco改良Eagle培养基中培养。电泳前,向H9c2上清液样品中,加入来自含30mM DMSO(1000倍稀释)的30uM的实施例1化合物(7-((6-甲基吡啶-2-基氨基)(4-硝基苯基)甲基)喹啉-8-醇)的储备溶液。向对照组中,加入不含实施例1化合物的DMSO。电泳后,将凝胶切成两份随后复性;一份以最终浓度向其中加入30uM的实施例1化合物进行孵育,而第二份(对照组)在无该化合物的情况下进行孵育。如果在孵育过程中存在底物,则实施例1的化合物完全抑制72kDa明胶酶(MMP-2)。其也抑制92kDa明胶酶(MMP-9),但与72kDa明胶酶相比抑制的程度更小。
在缺氧再充氧后,MMP-9和MMP-2通过破坏细胞基质相互作用和稳态整联蛋白信号,促成了半胱氨酸天冬氨酸蛋白酶介导的内皮细胞死亡。MMP-2和MMP-9抑制剂显著减少了半胱氨酸天冬氨酸蛋白酶-3的活性并减少了内皮细胞死亡(Lee等,2004)。
实施例25:实施例1化合物(7-((6-甲基吡啶-2-基氨基)(4-硝基苯基)甲基)喹啉-8-醇)在心脏移植后减少再灌注损伤。
以早期公开的方法(聚(ADP-核糖)建立异向心脏移植试验模型;聚合酶的抑制减少了心脏移植之后出现的再灌注损伤(Szabó等,2002)。简言之:供体心脏从Lewis大鼠移植。在4°C进行缺血保护1小时之后,通过使受体大鼠的腹主动脉或腔静脉的供体心脏的主动脉和肺动脉吻合而在腹内植入心脏。按照“Principles of Laboratory Animal Care”;National Society of MedicalResearch and the Guide for the Care and Use of Laboratory Animals prepared bythe National Academy of Sciences;publisher:National Institutes of Health(NIHPublication No.86-23,revised1996)的要求饲养所有动物。
按如下方式进行移植的功能性测评:通过Millar微压计(MillarInstruments,Inc.),使用心室内球对不同左心室(LV)测量左心室心脏收缩压(LVSP)、左心室舒张末期压(LVEDP)、血压变化率(dP/dt)和弛豫时间常数(TE)。用血管周围超声流量样品在供体主动脉上测量总冠状动脉血流量(CBF)。确定基线之后,将内皮依赖性血管舒张剂乙酰胆碱(ACH,1nmol/l,0.2ml)和缓激肽(BK0.1nmol/l,0.2ml),和内皮非依赖性血管舒张剂硝普钠(SNP,10nmol/l,0.2ml)通过供体主动脉直接加入到移植的冠状动脉中。在灌注之间,使CBF回到基线水平。血管舒张剂响应表示为由基线的CBF最大百分数变化。
研究了两个移植组(n=6/每组中)。在即将松开主动脉钳之前,开始缓慢注射普通盐溶液(对照组)或实施例1化合物(3mg/kg),并在再灌注期间的头5分钟期间继续进行。
再灌注之后1小时,在组A(对照)和组B(实施例1的化合物)中进行心脏收缩和舒张功能以及CBF的测量。
再灌注60分钟之后,确定血液动力学参数和心肌血流量。每组中受体的心率和主动脉压相同。与对照值相比,用实施例1化合物处理的组心脏收缩功能的恢复显著更好。在用实施例1化合物处理的组中,LVSP和峰正值dP/dt显著更高(P=0.05)。
与用载体处理的组相比,用实施例1化合物处理的组中心脏收缩心功能曲线向左表现出显著位移(图1a和图1b)。在组间,LVEDP没有显示出改变值。心脏舒张协同曲线(舒张末期压体积关系)在每组中是相似的(图1c)。
实施例26:用通式(I)的化合物进行处理,预防了由过氧化氢在体外心脏、神经元和肝细胞中引起的细胞死亡
将H9c2大鼠胚胎心肌细胞(来自ATCC,Rockville,MD,USA)在含有10%牛血清、4mM L-谷氨酰胺(Sigma-Aldrich,Hungary)、100IU/ml青霉素和100ug/ml链霉素的Dulbecco改良Eagle培养基中培养。将细胞置于96孔微量滴定板中(10000细胞/孔),24小时之后,用1%H2O2(Sigma)溶液(0.2mM最终浓度)处理。处理30分钟之后,将通式(I)的不同化合物以不同浓度置于其上,在3和24小时之后,通过MTT(3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2H-溴化四唑)试验的方式确定细胞活性。
实施例27:用通式(I)的不同化合物处理,预防了由过氧化氢在体外肝细胞中引起的细胞死亡
将10%的Hep3B人血肿细胞(ATCC,Rockville,MD,USA)在含有10%牛血清、4mM L-谷氨酰胺(Sigma-Aldrich,Hungary)、100IU/ml青霉素和100ug/ml链霉素的Dulbecco改良Eagle培养基中培养。在含潮湿空气和5%CO2的37°C空间的孵育器中,将细胞放置在100mm TC皿(OrangeScientific,Belgium)中。
将细胞置于96孔E-plate(Roche)微量滴定板中,该滴定板用明胶(10000细胞/孔)预处理,并培养16小时。处理30分钟之后,将不同浓度的通式(I)的不同化合物置于其上,并利用Excelligence设备通过RT-CES方法(Roche),每2分钟测量确定细胞指数以持续测量细胞活性。结果示于图2中。曲线"A"表示未处理的对照,曲线"I"表示化合物PJ34(一种已知的PARP抑制剂),而曲线"J″表示用过氧化物处理的对照。
在该试验中,测试通式(I)的下述化合物(其中图2中的曲线表示给定化合物对正常细胞指数的影响):
7-((4-硝基苯基氨基)(苯基)甲基)喹啉-8-醇(曲线"B"),
4-{[(8-羟基喹啉-7-基)-苯基-甲基]-氨基}-苯甲酸乙酯(曲线"C",实施例3),
7-((4-苯基哌嗪-1-基)(噻吩-2-基)甲基)喹啉-8-醇(曲线"D"),
7-((6-甲基吡啶-2-基氨基)(4-(三氟甲基)苯基)甲基)喹啉-8-醇(曲线"E"),
7-((4-氟苯基)(噻唑-2-基氨基)甲基)喹啉-8-醇(曲线"F"),
7-(苯基氨基-吡啶-2-基-甲基)-喹啉-8-醇(曲线"G",实施例4)和
7-[(4-氟苯基)-(吡咯烷-1-基)-甲基]-喹啉-8-醇(曲线"H",14)。
进行测试以确定H2O2处理30分钟之后,对Hep3B人血肿细胞的细胞保护作用。将250uM的过氧化氢用于这些细胞中。在施用过氧化氢的过程中,细胞生长是线性的。用本发明的通式(I)的不同化合物处理30分钟之后,细胞指数曲线的斜率显著改变,基于此建立了本发明化合物的不同细胞保护效果。
实施例28:用通式(I)的不同化合物处理,预防了由过氧化氢在体外对混合的主要神经元和星形细胞上引起的细胞死亡
在含潮湿空气和5%二氧化碳的37°C空间的孵育器中,将细胞放置在100mm TC皿(Orange Scientific,Belgium)中。按照Griffin S等(Griffin等,2005)的方法制备大脑神经元和星形细胞的联合培养物。将细胞培养物放置在含有10%胎牛血清和1%非必需氨基酸溶液(Sigma-Aldrich,Hungary)的Eagle最低必需培养基中。结果示于图3中。曲线"K"表示未处理的对照,曲线"P″表示用PJ34处理的对照,曲线"Q"表示用过氧化氢处理的对照。
将细胞置于96孔E-plate(Roche)微量滴定板中,其用明胶(10000细胞/孔)预处理,并培养16小时。在处理前5分钟,将通式(I)的本发明下述化合物以5um的浓度置于其上:
7-((6-甲基吡啶-2-基氨基)(4-硝基苯基)甲基)喹啉-8-醇(曲线"L",实施例1),
7-[(6-甲基-吡啶-2-基氨基)-(4-三氟甲基-苯基)-甲基]-喹啉-8-醇(曲线"M",实施例7),
4-((8-羟基喹啉-7-基)(4-硝基苯基)甲基氨基)苯甲酸乙酯(曲线"N",实施例2)和
7-((4-甲基嘧啶-2-基氨基)(4-(三氟甲基)苯基)甲基)喹啉-8-醇(曲线"O",实施例10)。
然后利用Excelligence设备通过RT-CES方法(Roche),每2分钟测量确定细胞指数以连续测量细胞活性。处理以加入100uM H2O2开始,其引起不含通式(I)化合物的对照孔中总细胞的90%的破坏。
实施例29:实施例1化合物(7-((6-甲基吡啶-2-基氨基)(4-硝基苯基)甲基)喹啉-8-醇)对大鼠行为的影响
测试动物
将来自Charles River Laboratories(Budapest,Hungary)的Wistar大鼠用作测试动物。使用约2个月的大鼠(体重200-300g)。饲养动物约1周。动物接受标准实验室食物(Charles River Laboratories,Budapest,Hungary)并自由饮用自来水。温度和湿度分别保持在22±2°C和60±10%。大鼠以每组5只放置于45x35x25cm的Makrolon笼中。使用12小时的日/夜循环;在19:00时切断光。在白昼期间进行试验。根据1986年11月24日的EuropeanCommunities Council Directive(86/609/EEC,根据Animal Welfare Committeeof the Institute of Experimental Medicine的管理和批准)进行试验。
实施例29.1:通过高架十字迷宫测试确认实施例1化合物的抑制焦虑效果
高架十字迷宫测试
将黑色金属盒用于高架十字迷宫测试。设备的尺寸按照如下所述:臂长:40cm,臂宽:12cm,壁高:30cm和台高:70cm。开放的臂以0.5cm的突出环绕。根据下述出版物进行测试:Pellow等,1985。
在白昼阶段的较早几小时,用载体、实施例1化合物(2mg/kg)、实施例1化合物(8mg/kg)和氯氮(8mg/kg)(每组中n=10)处理大鼠。在该测试的早期,氯氮剂量减轻了焦虑。处理2小时之后,将动物置于设备中心,它们的头直接朝向闭合臂。暴露时间是5分钟。进入到闭合臂是运动活力的指示,而开放臂的使用是焦虑程度的指示。开放臂的使用以两个变量为特征:开放臂中花费时间的百分比分额和进入开放臂的百分比频率(100x开放臂的进入/臂的总进入)(Pellow等,1985;Hogg,1996).
实施例29.2:实施例1化合物对抑郁的效果
强迫游泳试验
如下述出版物:Porsolt等,1978所述,强迫大鼠游泳两次。在第一天,将每只大鼠置于15cm宽,35cm高的玻璃圆筒中,其中注入水到30cm。在该水深度,大鼠尾没有接触到圆筒底部。水温是24±0.5°C。在接下来的一天,用载体、2mg/kg实施例1化合物、8mg/kg实施例1化合物和30mg/kg丙咪嗪处理动物。该剂量的丙咪嗪在以前的试验中可靠地减少了漂浮;在该试验中,其为抑郁样行为的主要特征。休息2小时之后,强迫大鼠再游泳5分钟。在距圆筒2米处设置摄像机记录动物行为。记录下述行为因素:挣扎(动物通过攀爬壁试图离开圆筒);游泳(在圆筒中巡回游泳)和漂浮(动物仅仅做出必须的移动以保持其头在水面之上)。在该测试中,漂浮的时间指示似抑郁行为的程度。
结果示于图5中。在该图中,“图1”指的是实施例1的化合物。
实施例30:本发明化合物对不同肿瘤细胞株的细胞毒性效果
在我们的试验中,使用HepG2和Hep3B(人类肝细胞癌)、SUM149PT(人类乳腺癌)、K562(人类红细胞白血病)、U87(人类神经胶质瘤)、CCRF-CEM(人类白血病)细胞培养物;将这些培养于下述培养基中:
U87、CCRF-CEM:Dulbecco改良Eagle培养基(D-MEM)(高葡萄糖)(Gibco BRL,Carlsbad,CA,USA)、青霉素(50IU/ml)-链霉素(50mg/ml)、10%胎牛血清。
HepG2、Hep3B、SUM149PT的1:1混合物:Dulbecco改良Eagle培养基(D-MEM)(高葡萄糖)(Gibco BRL,Carlsbad,CA,USA)和营养混合物F-12Ham(Sigma,St.Louis,MO,USA)、青霉素(50IU/ml)-链霉素(50mg/ml)、10%胎牛血清。
CCRF-CEM:RPMI1640培养基(Gibco BRL,Carlsbad,CA,USA)、青霉素(50IU/ml)-链霉素(50mg/ml)、10%胎牛血清。
将细胞置于96-孔微量滴定板中(10000细胞/孔),24小时之后,利用不同的底物孵育细胞。孵育后,以0.5mg/ml的最终浓度将(3-(4,5-二甲基噻唑-2-基)-5-(3-羧甲氧苯基)-2-(4-磺苯基)-2H-四唑)(Promega,Madison,Wi,USA)加入到细胞中进行MTS试验,接着在37°C孵育1小时。用PBS洗涤细胞,将甲染料溶解于异丙醇中。用Powerwave读数器(Biotek,Winooski,VT)在570nm测量甲染料的转化量;背景测量690nm。测量细胞的系列稀释液转化MTT的能力并利用Gen5软件计算活细胞数,得到校准曲线。
利用不同细胞的试验结果示于表1中。在该表中,提供了每种底物的EC50值(基于MTS测试的结果,使一半细胞死亡的浓度)。
可以很好地看出本发明的化合物对不同肿瘤细胞株显示出细胞毒性效应。
表1:不同喹啉衍生物对不同人类肿瘤细胞株的抑制细胞效应
(表1,续)
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Claims (9)
2.根据权利要求1所述的通式(I)的化合物,其中
R1表示在对位上被吸电子基取代的基团,或在间位上被吸电子基取代的基团,或在邻位、间位或对位上被供电子基取代的上述基团;或R1表示在间位和对位上被吸电子基双取代的基团;或R1表示在邻位和对位上被吸电子基双取代的基团;或R1表示取代或未取代的杂环基;
R3表示在对位上被吸电子基取代的芳香基;或R3表示未取代的或在邻位、间位或对位上被烷基和/或吸电子基取代的杂芳基或脂环基;
R2和R4表示氢原子;和
n是1。
4.通式(I)的下述化合物:
7-((6-甲基吡啶-2-基氨基)(4-硝基苯基)甲基)喹啉-8-醇;
4-((8-羟基喹啉-7-基)(4-硝基苯基)甲基氨基)苯甲酸乙酯;
4-{[(8-羟基喹啉-7-基)-苯基-甲基]-氨基}-苯甲酸乙酯;
7-(苯基氨基-吡啶-2-基-甲基)-喹啉-8-醇;
7-[吡啶-2-基-(4-三氟甲基-苯基氨基)-甲基]-喹啉-8-醇;
7-[(3-甲基-吡啶-2-基氨基)-(4-硝基-苯基)-甲基]-喹啉-8-醇;
7-[(6-甲基-吡啶-2-基氨基)-(4-三氟甲基-苯基)-甲基]-喹啉-8-醇;
7-[(4-甲基-吡啶-2-基氨基)-(4-三氟甲基苯基)-甲基]-喹啉-8-醇;
2-((4-甲基嘧啶-2-基氨基)(4-硝基苯基)甲基)苯酚;
7-((4-甲基嘧啶-2-基氨基)(4-(三氟甲基)苯基)甲基)喹啉-8-醇;
7-[(2-羟基苯基)-(4-甲基-嘧啶-2-基氨基)-甲基]-喹啉-8-醇;
7-[(4-异丙氧基苯基)-(6-甲基-吡啶-2-基氨基)-甲基]-喹啉-8-醇;
7-[(2-羟基苯基)-(6-甲基-吡啶-2-基氨基)-甲基]-喹啉-8-醇;
7-[(4-氟苯基)-(吡咯烷-1-基)-甲基]-喹啉-8-醇;
7-((6-甲基吡啶-2-基氨基)(3,4-二氟苯基)甲基)喹啉-8-醇;
7-((6-甲基吡啶-2-基氨基)(3-(三氟甲基苯基)甲基)喹啉-8-醇;
7-[(4,6-二甲基-嘧啶-2-基氨基)-(4-三氟甲基-苯基)-甲基]-喹啉-8-醇;
7-[(6-甲基-吡啶-2-基氨基)-吡啶-2-基-甲基]-喹啉-8-醇;
7-[(5-氟-吡啶-2-基氨基)-吡啶-2-基-甲基]-喹啉-8-醇;
7-[(5-氯-吡啶-2-基氨基)-吡啶-2-基-甲基]-喹啉-8-醇;
7-[(5-甲基-6-硝基-吡啶-2-基氨基)-(4-三氟甲基-苯基)-甲基]-喹啉-8-醇;和
7-[(3-羟基-苯基)-(6-甲基-吡啶-2-基氨基)-甲基]-喹啉-8-醇。
5.制备通式(I)的化合物的方法,
其中
R1表示氢原子、低级烷基、低级烯基、低级环烷基、芳基、芳烷基或杂环基,其中上述基团任选在邻位、间位和/或对位上被1、2、3或4个吸电子基团或供电子基团取代;
R2表示氢原子、低级烷基、芳基、芳烷基或杂环基,其中上述基团任选被一个或多个卤原子取代;
R3表示低级烷基、芳基、芳烷基或杂环基,其中上述基团任选在邻位、间位或对位上被1、2、3或4个吸电子基团或供电子基团取代;
R4表示氢原子、低级烷基或任一酸官能基;
n是1或2,
其特征在于
通式(II)的8-羟基喹啉衍生物
与通式(III)的氧代化合物
和通式(IV)的胺反应
R3-NH-R3'
IV
(其中取代基如上述所定义,R3'独立地选自R3的含义,且R3′也可为氢原子;且R3和R3'可相互连接形成环仲胺),所得到的通式(I)的化合物任选转化成药学上可接受的酸加成盐或由其盐释放。
6.药物组合物,其含有通式(I)的化合物或其与药学上可接受的酸或碱形成的盐,和药学上可接受的固体或液体载体和/或赋形剂。
7.权利要求6所述药物组合物的制备方法,其特征在于通式(I)的化合物或其药学上可接受的盐与药学上可接受的惰性固体或液体载体和/或赋形剂混合。
8.一种治疗与神经学和/或氧化性应激相关的疾病的方法,其特征在于向有此需要的患者给药治疗有效量的通式(I)的化合物或其药学上可接受的盐。
9.根据权利要求8所述的方法,其中所述与神经学和/或氧化性应激相关的疾病选自下述疾病:缺血、再灌注损伤、心血管疾病、神经变性疾病(特别是包括阿尔茨海默病和亨廷顿病)、创伤、神经精神疾病(特别是包括抑郁和焦虑症)以及肝、肾和肺损伤。
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CN108137540A (zh) * | 2015-03-09 | 2018-06-08 | 艾维丁股份有限公司 | 8-羟基喹啉衍生物的对映异构体及其合成 |
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KR20130029772A (ko) | 2013-03-25 |
CA2798419C (en) | 2021-01-05 |
HUE050886T2 (hu) | 2021-01-28 |
MX2012012883A (es) | 2013-03-20 |
AU2011256989A1 (en) | 2013-01-10 |
EA201270787A1 (ru) | 2013-04-30 |
SI2566849T1 (sl) | 2020-02-28 |
MX337999B (es) | 2016-03-30 |
RS59678B1 (sr) | 2020-01-31 |
NZ603967A (en) | 2014-06-27 |
EP2566849B1 (en) | 2019-09-18 |
ES2761832T3 (es) | 2020-05-21 |
PT2566849T (pt) | 2020-01-06 |
US8871937B2 (en) | 2014-10-28 |
JP5812541B2 (ja) | 2015-11-17 |
AU2011256989B2 (en) | 2014-08-21 |
EP2566849A1 (en) | 2013-03-13 |
CY1122426T1 (el) | 2021-01-27 |
HRP20192278T1 (hr) | 2020-03-06 |
JP2013525473A (ja) | 2013-06-20 |
PL2566849T3 (pl) | 2020-03-31 |
CA2798419A1 (en) | 2011-12-01 |
CN102985407B (zh) | 2015-09-09 |
HU1000243D0 (en) | 2010-06-28 |
EA021026B1 (ru) | 2015-03-31 |
KR101837974B1 (ko) | 2018-03-13 |
DK2566849T3 (da) | 2020-01-02 |
WO2011148208A1 (en) | 2011-12-01 |
US20130131096A1 (en) | 2013-05-23 |
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