CN100358867C - 糖原合酶激酶gsk-3的杂环抑制剂 - Google Patents
糖原合酶激酶gsk-3的杂环抑制剂 Download PDFInfo
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Abstract
A,E,G,X,Y和——-键代表各种含义的化学式(I)化合物在制备一种药物制剂中的应用所述药物制剂用于例如治疗涉及GSK-3的疾病包括阿尔海默氏病或者非胰岛素依赖型糖尿病,或者过增生性疾病例如癌症,组织的displasias或者化生,牛皮癣,动脉硬化或者再狭窄。
Description
发明领域
本发明涉及酶抑制剂,更具体而言,涉及糖原合酶激酶3β,GSK-3的杂环抑制剂。
发明背景
阿尔海默氏病(AD)是-种神经变性过程,其特征为与胆碱能功能渐进退化相关的认知紊乱,和由原纤β-淀粉状蛋白形成的神经病理学损伤如老年斑,和由成对的螺旋纤丝的维管束形成的神经原纤维缠结。通常而言,AD限制在60岁或者60岁以上的年龄组,而且通常是老龄人群痴呆的最普遍的原因。如今,AD在世界范围内侵袭了二千三百万人。随着寿命的增加,据估计到2050年,AD患者的数量将超过现在的3倍。[Amaduci,L.;Fratiglioni,L.“Epidemiology of AD:Impact on thetreatment”,in Alzheimer Disease:Therapeutic Strategies,E.Giacobini和R.Becker,Eds.,Birh_user,EEUU,1994,pp.8]。
在AD患者的大脑中发现了两种主要的、与神经元缺失相关的组织学损伤:分别在细胞内和细胞外水平的神经原纤维缠结和老年斑[“AlzheimerDisease:From molecular biology to therapy”,E.Giacobini和R.Becker,Eds.,Birh_user,EEUU,1996]。
神经原纤维缠结是由成对的螺旋纤丝(PHFs)形成的结构。它们主要是由在异常过磷酸化状态下的微管相关蛋白(MAP)tau组成的。[Grundke-Iqbal,I.;Iqbal,K.;Tung,Y.C.;Quinlan,M.;Wisniewski,H.M.;Binder,L.I.,“Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology”,Proc.Natl.Acad.Sci.USA,1986,83,4913-4917;Grundke-Iqbal,I.;Iqbal,K.;Quinlan,M.;Tung,Y.C.;Zaidi,M.S.;Wisniewski,H.M.,“Microtubule-associatedprotein tau.A component of the Alzheimer paired helical filaments”,J.Biol.Chem.,1986,261,6084-6089;Greenberg,S.G.;Davies,P.;Schein,J.D.;Binder,L.I.,“Hydrofluoric acid-treated tau PHF proteins display thesame biochemical properties as normal tau.”,J.Biol.Chem.,1992,267,564-569]。这种由不同蛋白激酶和磷酸酶的作用所决定的tau的异常磷酸化作用似乎对它结合并稳定微管的能力造成损害而且这可能对AD病理学有作用[Moreno,F.J.;Medina,M.;Perez,M.;Montejo de Garcini,E.;Avila,J.,“Glycogen sintase kinase 3 phosphorylation of different residuesin the presence of different factors:Analysis on tau protein”,FEBS Lett.,1995,372,65-68]。因此,对这个过磷酸化步骤的阻断,可以是中断致病级联的一个重要目标。tau激酶的选择性抑制剂可能会成为治疗AD的新的有效药物。
对tau激酶抑制剂的研究是一个非常感兴趣的领域。Tau可以被几种脯氨酸指导的蛋白激酶(PDKs)和非PDKs磷酸化。但是,在AD中,仍不清楚这些激酶中的任何一种在tau的异常过磷酸化中的确切作用,而且迄今为止,没有发现这些酶的活性被上调。毫无疑问,在大脑中,糖原合酶激酶3β(GSK-3β)是一种体内的tau激酶[Lovestone,S.;Hartley,C.L.;Pearce,J.;Anderton,B.H.,“Phosphorylation of tau by glycogensynthase-3 in intact mammalian cells:the effects on the organization andstability of microtubules”,Neuroscience,1996,73,1145-1157;Wagner,U.;Utton,M.;Gallo,J.M.;Miller,C.C.,“Cellular phosphorylation oftau by GSK-3βinfluences tau binding to microtubules and microtubuleorganisation”,J.Cell.Sci.,1996,109,1537-1543;Ledesma,M.;Moreno,F.J.;Perez,M.M.;Avila,J.,“Binding of apolipoprotein E3 totau protein:effects on tau glycation,tau phosphorylafion and tau-microtubulebinding,in vitro”,Alzheiiner Res.,1996,2,85-88]。这些发现为将GSK-B抑制剂用作AD治疗中的治疗剂敞开了大门。此时,只有很少的化合物已知具有这种酶抑制剂的特性。在体外和完整细胞中,锂相当于蛋白激酶GSK-3家族的一种特异抑制剂。[Mu
oz-Monta
o,J.R.;Moreno,F.J.;Avila,J.;Diaz-Nido,J.,“Lithium inhibits Alzheimer’sdisease-like tau protein phosphorylation in neurons”,FEBS Lett.,1997,411,183-188]。
最后,研究发现,胰岛素钝化GSK-3,而且研究表明由于这种酶的活化发展了非胰岛素依赖型糖尿病。因此,GSK-3抑制剂将会是一种治疗非胰岛素依赖型糖尿病的新疗法。
我们研究组最近发现了一种在微摩尔水平具有GSK-3β抑制性能的小合成杂环分子新家族。
发明内容
本发明涉及以通式I表示的化合物
其中
A 是-C(R1)2-, -O-或者-NR1-;
E 是-NR1-或者-CR1R2-,而且如果---是E和G之间的第二个键,则取代基R2不存在;
G 是-S-,-NR1-或者-CR1R2-,而且如果---是E和G之间的第二个键,则取代基R2不存在;
--- 可以是E和G之间的第二个键,这是E和G的特性允许的,和E与G随后任选地形成稠芳基。
R1和R2 独立地选自氢,烷基,环烷基,卤代烷基,芳基,-(Z)n-芳基,杂芳基-OR3,-C(O)R3,-C(O)OR3,-(Z)n-C(O)OR3和-S(O)t-或者如同所指出的那样,R2可以是使得E与G随后形成稠芳基的基团。
Z 独立地选自-C(R3)(R4)-,-C(O)-,-O-,-C(=NR3)-,-S(O)t-,N(R3)-;
n 是0,1或者2;
t 是0,1或者2;
R3和R4独立地选自氢,烷基,芳香基和杂环;和
X和Y 独立地选自=O,=S,=N(R3) 和=C(R1) (R2)。
发明详述
除非相反地限定,在本说明书和附加权利要求中使用的下面的术语具有下面的含义:
“烷基”指的是直或支化的烃链自由基,这些自由基由碳原子和氢原子组成,包含未饱和,具有1-8个碳原子,而且通过单键连接到其它分子上,例如甲基,乙基,正丙基,异丙基,正丁基,叔丁基,正戊基等等。烷基自由基可以任选地被一种或者多种取代基取代,所述取代基独立选自卤素,羟基,烷氧基,羧基,氰基,羰基,酰基,烷氧羰基,氨基,硝基,巯基,和烷基硫基(alkylthio)。“烷氧基”指的是化学式为-ORa的自由基,其中Ra是一种上面定义的烷基自由基,例如甲氧基,乙氧基,丙氧基等等
“烷氧羰基”指的是化学式为-C(O)ORa的自由基,其中Ra是上面定义的烷基自由基,例如甲氧羰基,乙氧羰基,丙氧羰基等等。
“烷基硫基”指的是化学式为-SRa的自由基,其中Ra是上面定义的烷基自由基,例如甲基硫基,乙基硫基,丙基硫基等等。
“氨基”指的是化学式为-NH2的自由基。
“芳基”指的是苯基或者萘基自由基,优选苯基自由基。此处定义的芳基自由基可以任选地被一种或多种取代基取代,所述取代基选自羟基,巯基,卤素,烷基,苯基,烷氧基,卤代烷基,硝基,氰基,二烷基氨基,氨基烷基,酰基和烷氧羰基。
“芳烷基”指的是连接到烷基的芳基。优选的实例包括苄基和苯乙基。
“酰基”指的是化学式为-C(O)-Rc和-C(O)-Rd的自由基,其中Rc是上述定义的烷基自由基,Rd是上述定义的芳基自由基,例如乙酰基,丙酰,苯甲酰基等等。
“芳酰基烷基”指的是被-C(O)-Rd取代的烷基。优选的实例包括苯甲酰基甲基。
“羰基”指的是化学式为-C(O)OH的自由基。
“氰基”指的是化学式为-CN的自由基。
“环烷基”指的是稳定的、3-10元的单环或者双环自由基,该自由基是饱和的或者部分饱和的,并且仅由碳原子和氢原子组成。除非在说明书中另外具体说明,术语“环烷基”意图包括环烷基自由基,所述环烷基自由基任选地被一种或者多种自由基取代,所述自由基独立选自烷基,卤素,羟基,氨基,氰基,硝基,烷氧基,羧基和烷氧羰基。
“稠芳基”指的是稠化到五元环的一种芳基,特别是苯基或者杂环芳基。
“卤素”指的是溴,氯,碘,或者氟。
“卤代烷基”指的是被一种或者多种上述定义的卤代自由基取代的上述定义的烷基自由基,例如三氟甲基,三氯甲基,2,2,2-三氟乙基,1-氟甲基-2-氟乙基等等。
“杂环”指的是杂环自由基。该杂环指的是一种稳定的3-15元环,该3-15元环由碳原子和1-5个选自氮,氧和硫的杂原子组成,优选具有一个或者多个杂原子的4-8元环,更优选具有一个或者多个杂原子的5元环或者6元环。对于本发明而言,所述杂环可以是单环,双环或者三环体系,该体系可以包括稠合环体系;而且杂环自由基中的氮,碳或者硫原子可以任选地被氧化;氮原子可以任选地被季铵化;而且杂环自由基可以是部分或者完全饱和的或者可以是芳族的。这些杂环的实例包括但不限于氮杂,苯并咪唑,苯并噻唑,呋喃,异噻唑,咪唑,吲哚,哌啶,哌嗪,嘌呤,喹啉,噻重氮,四氢呋喃。杂环可以任选地被上述发明概述中定义的R3和R4取代。
“杂芳基”指的是芳族杂环。
“巯基”指的是化学式为-SH的自由基。
“硝基”指的是化学式为-NO2的自由基。
本发明特别涉及针对通式I化合物的激酶的酶活性。
A优选选自-C(R1)2-和-NR1-。
优选地R1选自氢,烷基,环烷基,芳基(任选地被选自烷基,卤素和烷氧基的基团取代),-C(R3)(R4)-芳基(该芳基部分任选地被选自烷基,卤素和烷氧基的基团取代),-OR3,-C(O)OR3和-C(R3)(R4)-C(O)OR3,而且R3和R4独立地选自氢和烷基。
下标n优选0或者1,而且将顾及已知化学的可能基团来选择n。
X和Y优选氧或者硫,X和Y至少一个优选是氧。
尤其优选的一类化合物具有化学式(II)。
其中Ra和Rb独立地选自氢,烷基,环烷基,卤代烷基,芳基,-(Z)n-芳基,杂芳基,-OR3,-C(O)R3,-C(O)OR3,-(Z)n-C(O)OR3和-S(O)t-,并且Z,n,t,R3,R4,X和Y如上述定义。
在化学式(II)中,X和Y优选选自氧,硫和-NR3-,其中R3是杂环,特别是含有1个为氮的杂原子的6元杂环,任选是芳族的并且任选地被氧化或者被季铵化。更优选地,X和Y都是氧。
优选地,Ra和Rb独立地选自氢,烷基,环烷基,芳基(任选地被选自烷基,卤素和烷氧基的基团取代),-C(R3)(R4)-芳基(该芳基部分任选地被选自烷基,卤素和烷氧基的基团取代),-OR3,-C(O)OR3和-C(R3)(R4)-C(O)OR3,而且R3和R4独立地选自氢,烷基和杂环。
更优选地,Ra和Rb独立选自烷基,芳基(任选地被选自烷基,卤素和烷氧基的基团取代),-CH2-芳基(该芳基部分任选地被选自烷基,卤素和烷氧基的基团取代),和-CH2-C(O)OR3,其中R3是氢或者烷基。
更更优选,Ra和Rb独立选自甲基,乙基,丙基,苄基,苯基(任选地被选自甲基,氟,氯,溴和甲氧基的基团取代)和-CH2-C(O)O-乙基。
最优选的化学式(II)的化合物列于下表1中。
表1
R<sup>a</sup> | R<sup>b</sup> | X | Y |
CH<sub>2</sub>Ph | Me | O | O |
Et | Me | O | O |
Ph | Me | O | O |
CH<sub>2</sub>CO<sub>2</sub>Et | Me | O | O |
4-OMePh | Me | O | O |
4-MePh | Me | O | O |
4-BrPh | Me | O | O |
4-FPh | Me | O | O |
4-ClPh | Me | O | O |
CH<sub>2</sub>Ph | CH<sub>2</sub>Ph | O | S |
Ph | Ph | O | S |
本发明的另一类优选的化合物是化学式(III)的那些化合物:
其中,
B是-NR7-或者C(R7)(R8)-(其中R7和R8独立地选自氢,烷基,芳基,CH2-W-芳基,和-W-CO2H,和W是单键,CH2或者CO);R5和R6独立地选自氢,烷基,芳基和-CH2-芳基;并且X和Y独立地选自=O和=S。
在化学式(III)中,B优选-NR7-,其中R7选自氢,烷基和-CH2-芳基,特别是氢,甲基或者苄基。
R5和R6优选是氢。
X和Y优选是氧。
最优选的化学式(III)的化合物列于下表2中。
表2
B | X | Y | R<sup>5</sup> | R<sup>6</sup> |
NH | O | O | H | H |
N-CH<sub>2</sub>Ph | O | O | H | H |
NMe | O | O | H | H |
CH<sub>2</sub> | O | O | H | H |
化学式I的化合物的其它类别的实例包括:
a)A是-CH2-;E是-CR1R2-,优选-CH2-;G是-CR1R2-,优选-CH2-;
b)A是-CH2-;E是-CR1-,优选-CH-;G是-CR1-,优选-CH-;和----是G和E之间的第二个键;
c)A是-O-;E是-CR1-,优选-CH-;G是-CR1-,优选-CR-;和----是G和E之间的第二个键;
d)A是-NR1-,其中R1优选氢,烷基或者芳烷基;E是-CR1-,优选-CH-;G是-CR1-,优选-CH-;和----是G和E之间的第二个键;
e)A是-NR1-,其中R1是优选氢或者芳烷基;E是-CR1R2-,优选-CH2-;G是-CR1R2-,优选-CH2-;
f)A是-NR1-,其中R1优选氢或者芳烷基;E是-CR1-;G是-CR1-;----是E和G之间的第二个键;而且E与G形成稠合的芳基,优选苯基;
g)A是-NR1-,其中R1是优选氢,烷基,羧基烷基,芳酰基烷基或者芳烷基;E是-S;G是-C(R1)2-,优选-CH2-;
h)A是-NR1,其中R1优选芳基;E是-NR1-,其中R1优选氢或者烷基;G是-NR1-,其中R1是优选氢或者烷基。
在这些类别的化合物中,尽管对于类别(g),X可以是O和Y可以是S,但是X和Y优选都是O。当E与G形成稠合的苯基时,所得到的化合物是苯二酰亚氨基衍生物。
本发明化合物的合成
可以通过能够利用的程序来合成本发明的化合物。
对于优选的化学式(II)的化合物,可以使用通用程序[Martinez,A.;Castro,A.;Cardelús,I.;Llenas,J.;Palacios,J.M.Bioorg.Med.Chem.,1997,5,1275-1283]。
具体地,按照流程1中描述的合成步骤,并且利用N-烷基-S-[N’-氯氨基甲酰基)氨基]异硫代氨基甲酰氯与不同的烷基异氰酸酯之间的反应性,来制备化学式(II)中的化合物和收集在表1中的化合物。通过在-15℃,向上述异硫氰酸酯的己烷溶液中加入等分子量的氯气来执行异硫氰酸酯的氯化。在惰性气氛下,形成的亚氨基氯烷基亚磺酰氯与烷基或异氰酸芳基酯之间的反应和随后的水解产生表1中描述的噻二唑烷二酮。
流程1
本发明的典型化合物选择性抑制GSK-3β而不抑制其它蛋白激酶例如PKA,PKC,CK-2和CdK2,对其它蛋白激酶的抑制可能消除普遍作用。AD的病因发病机理(aetiopathogenesis)涉及GSK-3β而且GSK-3β是造成tau蛋白的异常过磷酸化的原因。本发明公开的选择性抑制剂可成为治疗与tau蛋白的病理学相关的神经变性疾病,尤其是AD的有用的治疗制剂,所述选择性抑制剂形成本发明的一部分。这些化合物对GSK-3β的抑制作用引导着药物的设计,所述药物能够阻止神经原纤维缠结的形成,所述神经原纤维缠结是存在于该神经变性过程的标志之一。这些化合物可用于涉及GSK-3β的其它病理例如非胰岛素依赖型糖尿病的治疗。
此外,由于这些化合物对细胞周期的抑制作用,这些化合物可用于过增生性疾病例如不同组织的发育不良和化生,牛皮癣,动脉硬化(artherioschlerosis),再狭窄和癌症的治疗。
因此,本发明还提供了包含本发明的一种化合物与药用载体或稀释剂的药物组合物。依照常规的实践,可以设计并采用合适的剂型和剂量给药比。
实施例
实施例1-本发明组合物的酶抑制作用
GSK-3β抑制:在存在或者不存在相应的测试化合物的情况下,通过培育GSK-3酶(Sigma),磷酸盐(酯)源和GSK-3底物的混合物,并且通过测定该混合物的GSK-3活性来确定GSK-3活性。
具体地,在补充了作为底物的15μM(终浓度)合成肽GS1[Woodgett,J.R.“Use of peptides for affinity purification of protein-serinekinases”,Anal.Biochem.,1989,180,237-241],15μM ATP,0.2μCj[γ-32P]ATP和不同浓度测试化合物的终体积为12μl的缓冲液(50mM tris,pH=7.5,1mM EDTA,1mM EGTA,1mM DTT,10mM Cl2Mg)中,通过将酶在37℃温育20分钟来确定GSK-3活性。通过在磷酸纤维素p81纸中加入等分部分的反应混合物来终止反应。将这些纸用1%的磷酸清洗三次,并且在液体闪烁计数器中测定结合入GS1肽中的放射性。
表1中所示的化合物表示本发明的GSK-3抑制活性物质。IC50(显示出50%的酶抑制作用时的浓度)值集中在下表3中。
表3
GSK-3抑制作用:在可变的ATP浓度(一直到50μM)下同样进行抑制实验,而且在所有情况下都得到了相同的IC50值。因此推测噻二唑烷二酮不与ATP竞争结合GSK-3。
分析前四种化合物对其它酶的抑制作用。
蛋白激酶A(PKA)抑制作用:通过确定蛋白激酶A(PKA)的esthatmine磷酸化作用来评价该酶的潜在抑制作用。按照Belmont和Mitchinson描述的程序纯化esthatmine(Belmont,L.D.;Mitchinson,T.J.“Identification ofa protein that interact with tubulin dimers and increases the catastrophe rate ofmicrotubule”,Cell,1996,84,623-631)。
具体地,在总体积为25μl的、含有20μM(γ-32P)ATP的缓冲液中,使用纯化的PKA(Sigma,catalytic subunit from bovine heart(p2645))和10-15μg底物(esthatmine)。在50μl的25mM hepes,pH 7.4,20mMMgCl2,2mM EGTA,2mM二硫苏糖醇,0.5mM Na3VO4中加入cAMP激酶蛋白(100ng/反应)。反应发生后,加入终止缓冲液,将反应物在100℃下煮沸5分钟,用凝胶电泳表征磷酸化的蛋白,用放射自显影定量。
在这些条件下,没有一种被分析的化合物显示出对PKA的任何抑制作用。
蛋白激酶C(PKC)抑制作用:将磷脂酰丝氨酸作为刺激剂,通过确定蛋白激酶C(PKC)对肽PANKTPPKSPGEPAK的磷酸化作用,来评价该酶的潜在抑制作用(Woodgett,J.R.“Use of peptides for affinitypurification of protein-serine kinases”,Anal.Biochem.,1989,180,237-241)。下面的方法与上述的用于GSK-3的方法相同。
具体地,在总体积为25μl的含10μM(γ-32P)ATP的足够的(adecuated)缓冲液中使用按照Walsh描述的方法(Walsh,M.P.;Valentine,K.A.;Nagi,P.K.;Corruthers,C.A.;Hollenberg,M.D.Biochem.J.,1984,224,117-127)从大鼠脑中纯化的PKC和1-10mM的底物。在这些条件下,没有一种被分析的化合物显示出对PKC的任何抑制作用。
酪蛋白激酶2(CK-2)抑制作用:在总体积为25μl的足够的、含有20μM(γ-32P)ATP的缓冲液中使用按照Alcazar描述的方法(Alcazar,A.;Marín,E.;Lopez-Fando,J.;Salina,M.“An improved purification procedureand properties of casein kinase II from brain”,Neurochem.Res.,1988,13,829-836)从牛脑纯化的CK-2和3.6μM的底物。在50μl的25mM hepes,pH 7.4,20mM MgCl2,2mM EGTA,2mM二硫苏糖醇,0.5mM Na3VO4和100ng纯化的CK-2中用esthatmine作为底物(参见PKA测定)进行CK-2测定。反应发生以后,下面的步骤与PKA中描述的方法相同。
在这些条件下,没有一种被分析的化合物显示出对CK-2的任何抑制作用。
细胞周期蛋白依赖的蛋白激酶2(Cdc2)抑制作用:在总体积为25μl的足够的、含有20μM(γ-32P)ATP的缓冲液中,使用按照Kobayashi描述的方法(Kobayashi,H.;Stewart,E.;Poon,R.Y.;Hunt,T.“Cyclin A andcyclin B dissociate from p34cdc2 with half-times of 4 and 15h,respectively,regardless of the phase of the cell cycle”,J.Biol.Chem.,1994,269,29153-29160)得到的Cdc2(Calbiochem)和1μg/μl的底物测定该酶针对组蛋白H1的磷酸化活性。在50μl的pH 7.5,50mM Tris-HCl,10mMCl2Mg,1mM DTT,1mM EGTA,100μM ATP,0.01%BRIJ-35缓冲液中,用组蛋白1作为底物进行Cdc2分析(参见PKA测定)。反应发生以后,下面的步骤与PKA中描述的方法相同。
在这些条件下,没有一种被分析的化合物显示出对Cdc2的任何抑制作用。
实施例2-药物处理后对神经突生长的分析
将细胞保持在含有10%胎牛血清,谷氨酰胺(2mM)和抗生素的Dulbecco培养基(DEMEM)中。为了分析在体内的潜在的GSK-3抑制作用,使用小鼠成神经细胞瘤(neuroblastoms)N2A培养物(Garcia-Perez,J.;Avila,J.;Diaz-Nido,J.“Lithium induces morphological differentiationof mouse neuroblastoma”,J.Neurol.Res.,1999,57,261-270)。将测试化合物添加到这些细胞培养物中。在添加了氯化锂(10mM),一种已知的GSK-3抑制剂以后,该细胞系具有表达某种神经元表型(轴突(neuritic)延长)的特性。培养2-3天后,检测那些收集在表1中的被测试化合物的作用。结果发现,轴突延长的产生比在加入锂时的延长要多。这个事实证实了本发明的化合物在体内对GSK-3的抑制作用。
实施例3.细胞周期阻断
平行地,在N2A细胞上研究这些化合物对细胞周期的潜在干扰作用。将该细胞培养物保持在含有10%胎牛血清,谷氨酰胺(2mM)和抗生素的Dulbecco培养基(DEMEM)中。
在描述的条件下,分析收集于表3中的具有通式(I)的前4种化合物,结果显示在100nM和1μM的抑制剂浓度下能够抑制细胞周期。在100-200nM的浓度下最初观察到细胞阻断,在1μM的浓度下完全有效。
在与抑制剂持续接触10天后,所测试的化合物在静止的成纤维细胞培养物MRC-5中是无毒的。
实施例4-其它化合物的GSK-3抑制作用
GSK-3抑制数据
表4
GSK-3抑制剂:对于属于家族D的化合物,在可变的ATP浓度下(一直到50μM)下同样进行GSK-3抑制作用实验,而且在所有情况下都得到了相同的IC50值。因此可推测这些化合物不与ATP竞争结合GSK-3。
实施例5.-细胞周期阻断
表5中收集了一些在N2A细胞培养物中测试的化合物的IC50。
表5
R<sup>a</sup> | R<sup>b</sup> | X | Y | IC<sub>50</sub>(μM) |
CH<sub>2</sub>Ph | Me | O | O | 4-8 |
Et | Me | O | O | 40-100 |
Et | nPr | O | O | 5-10 |
Et | 环己烷 | O | O | 6-9 |
Ph | Me | O | O | 4-7 |
CH<sub>2</sub>CO<sub>2</sub>Et | Me | O | O | 1-2 |
4-OMePh | Me | O | O | 1-2 |
CH<sub>2</sub>Ph | Et | O | O | 4-7 |
CH<sub>2</sub>Ph | CH<sub>2</sub>Ph | O | O | 2-3 |
Et | Et | O | O | 30-80 |
CH<sub>2</sub>Ph | CH<sub>2</sub>Ph | O | S | 1-2 |
Ph | Ph | O | S | 4-8 |
Claims (20)
1.一种具有通式(II)的化合物在制备用于涉及GSK-3的疾病的治疗的药物组合物中的应用:
其中:
Ra和Rb独立地选自
氢,
未取代的或被一个或多个取代基所取代的C-1-8烷基,所述取代基独立选自卤素,羟基,C-1-8烷氧基,羧基,氰基,羰基,酰基,C-1-8烷氧羰基,氨基,硝基,巯基,和C-1-8烷硫基,
未取代的或被一个或多个取代基所取代的C-3-10环烷基,所述取代基独立选自C-1-8烷基,卤素,羟基,氨基,氰基,硝基,C-1-8烷氧基,羧基和C-1-8烷氧羰基,
卤代C-1-8烷基,
未取代的或被一个或多个取代基所取代的芳基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
未取代的或被一个或多个取代基所取代的-(Z)n-芳基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
杂芳基,-OR3,-C(O)R3,-C(O)OR3,和-(Z)n-C(O)OR3;
Z独立地选自-C(R3)(R4)-,-C(O)-,-O-,-C(=NR3)-,-S(O)t-,和N(R3)-;
n是0,1或者2;
t是0,1或者2;
R3和R4独立地选自氢,C-1-8烷基,芳基和杂环;和
X和Y独立地选自=O,=S,=N(R3)和=C(R1)(R2),
R1和R2独立地选自氢,C-1-8烷基,C-3-10环烷基,卤代C-1-8烷基,芳基,-(Z)n-芳基,杂芳基,-OR3,-C(O)R3,-C(O)OR3,和-(Z)n-C(O)OR3,
其中所述芳基是苯基或萘基,所述杂环是由碳原子和1-5个选自氮、氧和硫的杂原子组成的稳定的3-15元环,和所述杂芳基是芳族杂环。
2.根据权利要求1的应用,其中所述的疾病是阿尔海默氏病。
3.根据权利要求1的应用,其中所述的疾病是非胰岛素依赖型糖尿病。
4.根据权利要求1的应用,其中所述的疾病是过增生性疾病。
5.根据权利要求4的应用,其中所述的过增生性疾病选自癌症,组织的发育不良或者化生,牛皮癣,动脉硬化或者再狭窄。
6.根据权利要求1-5中任一项的应用,其中在式(II)的化合物中,Ra和Rb独立地选自:
氢,C-1-8烷基,C-3-10环烷基,
未取代的或被一个或多个取代基所取代的芳基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
未取代的或被一个或多个取代基所取代的-C(R3)(R4)-芳基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
-OR3,-C(O)OR3和-C(R3)(R4)-C(O)OR3,
而且R3和R4独立地选自氢,C-1-8烷基和杂环。
7.根据权利要求6的应用,其中在式(II)的化合物中,Ra和Rb独立地选自
C-1-8烷基,
未取代的或被一个或多个取代基所取代的芳基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
未取代的或被一个或多个取代基所取代的-CH2-芳基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
-CH2-C(O)OR3,
而且R3是氢或者C-1-8烷基。
8.根据权利要求6和7中任何一项的应用,其中芳基或芳基部分被选自C-1-8烷基、卤素和C-1-8烷氧基的基团取代。
9.根据权利要求7的应用,其中在式(II)的化合物中,Ra和Rb独立地选自
甲基,乙基,丙基,苄基,
未取代的或被一个或多个取代基所取代的苯基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
和-CH2-C(O)O-乙基。
10.根据权利要求9的应用,其中苯基被选自甲基、氟、氯、溴和甲氧基的基团取代。
11.根据权利要求1-5中任何一项的应用,其中在式(II)的化合物中,X和Y独立地选自=O,=S和=NR3,其中R3是杂环。
12.根据权利要求11的应用,其中在式(II)的化合物中,X是=O。
13.根据权利要求12的应用,其中在式(II)的化合物中,X是=O和Y是=O。
14.根据权利要求1-5中任何一项的应用,其中:
Ra和Rb独立地选自:
氢,C-1-8烷基,C-3-10环烷基,
未取代的或被一个或多个取代基所取代的芳基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
未取代的或被一个或多个取代基所取代的-C(R3)(R4)-芳基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
-OR3,-C(O)OR3和-C(R3)(R4)-C(O)OR3;
R3和R4独立地选自氢,C-1-8烷基和杂环;和
X和Y独立地选自=O,=S和=NR3。
15.根据权利要求14的应用,其中:
Ra和Rb独立地选自
氢,C-1-8烷基,C-3-10环烷基,
未取代的或被一个或多个取代基所取代的芳基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
未取代的或被一个或多个取代基所取代的-C(R3)(R4)-芳基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
-OR3,-C(O)OR3和-C(R3)(R4)-C(O)OR3;
R3和R4独立地选自氢和C-1-8烷基;和
X是=O。
16.根据权利要求14和15中任何一项的应用,其中芳基或芳基部分被选自C-1-8烷基、卤素和C-1-8烷氧基的基团取代。
17.根据权利要求15的应用,其中:
Ra和Rb独立地选自
甲基,乙基,丙基,苄基,
未取代的或被一个或多个取代基所取代的苯基,所述取代基独立选自羟基,巯基,卤素,C-1-8烷基,苯基,C-1-8烷氧基,卤代C-1-8烷基,硝基,氰基,二C-1-8烷基氨基,氨基C-1-8烷基,酰基和C-1-8烷氧羰基,
和-CH2-C(O)O-乙基;
X是=O;和
Y是=O。
18.根据权利要求17的应用,其中苯基被选自甲基、氟、氯、溴和甲氧基的基团取代。
19.根据权利要求1至5任何一项的应用,其中式(II)的化合物符合下面的可能性之一:
20.根据权利要求19的应用,其中式(II)的化合物符合下面的可能性之一:
。
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CZ296087B6 (cs) | 2006-01-11 |
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US20080033012A1 (en) | 2008-02-07 |
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DK1286964T3 (da) | 2007-10-01 |
IL152721A0 (en) | 2003-06-24 |
CZ20023692A3 (cs) | 2003-06-18 |
AU5498101A (en) | 2001-11-20 |
BR0110734A (pt) | 2003-02-04 |
ATE366238T1 (de) | 2007-07-15 |
US7781463B2 (en) | 2010-08-24 |
CA2408747C (en) | 2011-04-05 |
US7666885B2 (en) | 2010-02-23 |
EP1286964B1 (en) | 2007-07-04 |
HUP0302002A3 (en) | 2007-02-28 |
WO2001085685A1 (en) | 2001-11-15 |
KR20030025919A (ko) | 2003-03-29 |
US6872737B2 (en) | 2005-03-29 |
EP1286964A1 (en) | 2003-03-05 |
US20030195238A1 (en) | 2003-10-16 |
CA2408747A1 (en) | 2001-11-15 |
US20050014803A1 (en) | 2005-01-20 |
CY1106826T1 (el) | 2012-05-23 |
PL209780B1 (pl) | 2011-10-31 |
ES2288948T3 (es) | 2008-02-01 |
AU783615B2 (en) | 2005-11-17 |
DE60129222D1 (de) | 2007-08-16 |
DE60129222T2 (de) | 2008-03-06 |
HUP0302002A2 (hu) | 2003-09-29 |
PL359671A1 (en) | 2004-09-06 |
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