CN100338062C - 作为c－Jun N－末端激酶抑制剂的氮杂吲哚类化合物 - Google Patents
作为c－Jun N－末端激酶抑制剂的氮杂吲哚类化合物 Download PDFInfo
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- CN100338062C CN100338062C CNB038095696A CN03809569A CN100338062C CN 100338062 C CN100338062 C CN 100338062C CN B038095696 A CNB038095696 A CN B038095696A CN 03809569 A CN03809569 A CN 03809569A CN 100338062 C CN100338062 C CN 100338062C
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Abstract
本发明涉及新的式(I)的5-取代的7-氮杂吲哚类化合物，其在抑制c-JunN-末端激酶中的用途，其在药物且特别是在细胞凋亡和/或炎症有关的神经变性疾病的预防或治疗中的用途。本发明还提供制造所述化合物的方法，含有该化合物的组合物以及制造该组合物的方法。
Description
本发明涉及新的5-取代的7-氮杂吲哚类化合物，其在抑制c-Jun N-末端激酶中的用途，其在药物、特别是在预防和/或治疗与细胞凋亡和/或炎症有关的神经变性疾病中的用途。本发明还提供制造上述化合物的方法，含有它们的组合物和制造所述组合物的方法。
c-Jun N-末端激酶(下文称作“JNK”)是促分裂原活化蛋白激酶(MAPK)家族的成员。JNK参与对多种刺激的响应，包括促炎细胞因子和环境应激。JNK，特别是JNK3，在细胞的程序死亡过程中起重要作用并且因此牵涉不同的疾病，包括中风、创伤性脑损伤和其它神经变性疾病例如帕金森氏病、阿耳茨海默氏病等。由于JNK活性是AP-1转录活性的生理调节物，因此预期JNK抑制剂可以减轻炎性反应。
细胞凋亡是细胞死亡的一种形式，其中细胞以包括一系列特定的由特定细胞死亡基因调控的生物化学和形态变化在内的程序积极参与其自身的破坏。凋亡性细胞死亡是一个在发育中的哺乳动物神经系统中观察到的过程。在小鼠中，编码促进细胞凋亡的蛋白如半胱氨酸蛋白酶-3或Bax蛋白的基因的同源重组可以防止发育性神经元细胞死亡。编码细胞死亡抑制剂的基因例如Bcl-x的破坏导致神经元细胞死亡增加。越来越多的证据显示，细胞凋亡在急性和慢性神经变性疾病的病理学中起重要作用。例如，在神经系统内过度表达抗细胞凋亡的Bcl-2蛋白的转基因小鼠中，脑部缺血后的梗塞体积减小。类似地，半胱氨酸蛋白酶抑制剂BAF的注射减少了新生大鼠中低氧症/局部缺血后的神经元细胞死亡。另一实例是脊柱肌肉萎缩(一种运动神经疾病)，其中SMN基因的功能突变的丧失与该疾病有关。最新的数据证实，野生型SMN蛋白结合Bcl-2并与其共同实现抑制细胞凋亡。这些结果提示了神经元细胞凋亡的抑制剂可能有利于人神经变性疾病的治疗。越来越多的证据表明神经元细胞凋亡是中风、创伤性脑部损伤和其它神经变性疾病的重要病理特征。因此，采用神经元细胞凋亡的抑制剂的药物治疗可以在神经变性病症中产生治疗效益。
许多研究小组利用体外细胞培养体系研究了神经元细胞死亡的机理并且结果揭示，在一些体系中转录因子c-Jun可以通过撤除存活信号而被激活并促进细胞死亡。
对c-Jun特异性的抗体可以保护NGF缺乏性大鼠交感神经元免于细胞凋亡。另外还证实，c-Jun显性失活突变体的表达具有类似的神经保护作用，而野生型c-Jun蛋白的过度表达在NGF的存在下足以诱发细胞凋亡。Estus及其同事最近证实，经历细胞凋亡的皮层神经元在用β-淀粉样肽处理后出现c-Jun RNA水平增高(Estus等，1997，J.Neurosci.17，7736-7745)。还证明在丧失存活信号的脑粒状神经元中细胞凋亡需要c-Jun。
c-Jun由JNK激活，它磷酸化其转录激活结构域。在人体中，存在3种JNK基因：JNK1、JNK2和JNK3。编码JNK1和JNK2的RNA在许多组织中表达，包括脑，但JNK3局限在神经系统并且在心脏和睾丸内的水平更小。
JNK在对多种应激的细胞反应中被强烈激活，例如UV辐射、心脏休克、渗透型休克、DNA损伤剂、促炎细胞因子如TNFα、IL-1β等。JNK途径的上游调节剂包括激酶例如SEK1、MKK7和MEKK1。有证据显示，体外神经元细胞凋亡需要Jun激酶活性。MEKK1在交感神经元中的过度表达使c-Jun蛋白水平和磷酸化作用增高并在NGF的存在下诱发细胞凋亡，表明Jun激酶途径的激活可以触发神经元细胞死亡。Jun激酶途径已被证实是丧失NGF的分化的PC12细胞死亡所需要的。此外，抑制c-Jun途径(Jun激酶的上游)的化合物CEP-1347可以保护运动神经元对抗由存活因子丧失引起的细胞死亡。
在JNK3纯合(-/-)敲除小鼠中，阻断了注射红藻氨酸引起的癫痫发作和海马CA3神经元的死亡。这表明JNK3参与某些形式的体内神经元细胞死亡。它还是GluR6介导的兴奋性毒性的决定性因素。此外，JNK3(-/-)小鼠可能正常发育并有活力，这揭示了JNK3不是发育或生存力所必需。
在急性低氧症患者的脑CA1神经元中的核JNK3免疫反应性强烈揭示了JNK3参与了与低氧症有关的神经变性。暂时性低氧症，也可以在发育的脑神经元中通过JNK信号途径触发细胞凋亡。
此外，JNK3免疫反应性局限在阿耳茨海默氏病感染的神经元。而且JNK3与阿耳茨海默氏病的神经元纤维化病变有关。具体地讲，JNK3诱发淀粉样前体蛋白(APP)的强磷酸化作用，由此影响其在疾病状态下的代谢。
本发明人提供了是c-Jun N-末端激酶的抑制剂的化合物。
本发明的第一方面涉及定义如下的式(I)化合物：
R表示碳环基、取代的碳环基、杂环基或取代的杂环基，其中任选取代的碳环基或任选取代的杂环基任选地稠合于不饱和、部分不饱和或完全饱和的含有0-3个杂原子的5-7元环，
R中、包括任选稠合的环中的各个可被取代的碳原子任选地且独立地被一个或多个C1-12烷基、C2-12链烯基、碳环基或杂环基、卤素、卤代烷基、OR2、SR2、NO2、CN、NR2R2、NR2COR2、NR2CONR2R2、NR2COR2、NR2CO2R2、CO2R2、COR2、CONR2R2、S(O)2R2、SONH2、S(O)R2、SO2NR2R2、NR2S(O)2R2取代，其中各R2可以相同或不同并且定义如下，且其中：
所述的C1-12烷基任选地掺有一个或两个选自-O-、-C(O)-、-N(R2)-、-S(O)-和-S(O2)-的插入基团，其中各R2可以相同或不同并且定义如下；
所述的C1-12烷基、碳环基或杂环基任选地被一个或多个卤素、卤代烷基、OR2、SR2、NO2、CN、NR2R2、NR2COR2、NR2CONR2R2、NR2COR2、NR2CO2R2、CO2R2、COR2、CONR2 2、S(O)2R2、SONH2、S(O)R2、SO2NR2R2、NR2S(O)2R2取代；其中各R2可以相同或不同并且定义如下；并且
所述的碳环基或杂环基任选地被一个或多个C1-12烷基取代，任选稠合的环中的各饱和的碳进一步任选地且独立地被＝O、＝S、＝NNHR8、NNR2R2、＝N-OR2、＝NNHCOR2、＝NNHCO2R2、＝NNSO2R2或＝NR2取代，其中各R2可以相同或不同并且定义如下；
R中的各个可被取代的氮原子任选地被R3、COR2、SO2R2或CO2R2取代，其中各R2和R3可以相同或不同并且定义如下；
R2是氢、C1-12烷基或芳基，任选地被一个或多个C1-4烷基、卤素、C1-4卤代烷基、OR4、SR4、NO2、CN、NR4R4、NR4COR4、NR4CONR4R4、NR4COR4、NR4CO2R4、CO2R4、COR4、CONR4 2、S(O)2R4、SONH2、S(O)R4、SO2NR4R4、NR4S(O)2R4取代，其中所述的C1-12烷基任选地掺有一个或两个选自-O-、-N(R4)-、-S(O)-和-S(O2)-的插入基团，其中各R4可以相同或不同并且定义如下；
R3为C1-12烷基或芳基，任选地被一个或多个C1-4烷基、卤素、C1-4卤代烷基、OR4、SR4、NO2、CN、NR4R4、NR4COR4、NR4CONR4R4、NR4COR4、NR4CO2R4、CO2R4、COR4、CONR4 2、S(O)2R4、SONH2、S(O)R4、SO2NR4R4、NR4S(O)2R4，其中所述的C1-12烷基任选地掺有一个或两个选自-O-、-N(R4)-、-S(O)-和-S(O2)-的插入基团，其中各R4可以相同或不同并且定义如下；
R4是氢、C1-4烷基或C1-4卤代烷基；条件是当R是被掺有两个插入基团-(CO)-和-NH-的支链C6-烷基(-CH(CH2-CH(CH3)(CH3))-CH2-)取代的苯基时，该C6-烷基不被-CN取代；
及其可药用盐和其它可药用的生物可水解的衍生物，包括其酯、酰胺、氨基甲酸酯、碳酸酯、酰脲、溶剂化物、水合物、亲和性试剂或前药。
为了避免疑惑，当上述定义的基团含有两个或多个基团例如基团R2时，例如在基团SO2NR2R2和NR2COR2中时，基团R2可以相同或不同。
对于本发明的目的，“烷基”是指1-12个碳原子的直链或支链烷基，优选1-6个碳原子且首选1-4个碳原子，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基等。术语“链烯基”是指2-12个碳原子并含有一个或多个碳碳双键的直链或支链链烯基，优选2-6个碳原子且首选2-4个碳原子，包括但不限于乙烯、正丙-1-烯、正丙-2-烯、异丙烯等。术语“链炔基”是指2-12个碳原子并含有一个或多个碳碳三键的直链或支链链炔基，优选2-6个碳原子且首选2-4个碳原子，并且包括但不限于乙炔基、2-甲基乙炔基等。术语“环烷基”是指饱和或不饱和的3-12元环状烷基并且包括但不限于环丙基、环丁基、环戊基、环己基等。环烷基可以任选地被取代或与一个或多个芳基、杂环基或环烷基稠合。“杂环烷基”是指含有一个或多个选自N、S和O的杂原子的3-12元饱和或部分不饱和环烷基。“卤代烷基”是指被一个或多个卤素原子取代的烷基，例如CH2CH2Br、CF3或CCl3。
“碳环基”是指饱和、部分不饱和或不饱和的3-10元烃环，包括环烷基和芳基。
“芳基”是指含有一个环或与一个或多个饱和或不饱和环稠合的芳香族3-10元烃，包括但不限于苯基、萘基、蒽基或菲基。
“杂芳基”是指含有一个或多个选自N、O或S的杂原子并含有一个环或与一个或多个饱和或不饱和环稠合的芳香族3-10元芳基。
“杂环基”是指含有一个或多个选自N、O或S的杂原子的3-10元环系并且包括杂芳基。杂环系可以含有一个环或可以与一个或多个饱和或不饱和的环稠合；该杂环基可以是完全饱和、部分饱和或不饱和的并且包括但不限于杂芳基和杂碳环基，例如环己基、苯基、吖啶、苯并咪唑、苯并呋喃、苯并噻吩、苯并唑、苯并噻唑、咔唑、噌啉、二英、二烷、二氧杂环戊环、二噻烷、二噻嗪、二噻唑、二硫杂环戊烷、呋喃、咪唑、咪唑啉、咪唑烷、吲哚、吲哚啉、吲嗪、吲唑、异吲哚、异喹啉、异唑、异噻唑、吗啉、萘啶、唑、二唑、氧杂噻唑、氧杂噻唑烷、嗪、二嗪、吩嗪、吩噻嗪、酚嗪、酞嗪、哌嗪、哌啶、蝶啶、嘌呤、吡喃、吡嗪、吡唑、吡唑啉、吡唑烷、哒嗪、吡啶、嘧啶、呲咯、吡咯烷、吡咯啉、喹啉、喹喔啉、喹唑啉、喹嗪、四氢呋喃、四嗪、四唑、噻吩、噻二嗪、噻二唑、噻三唑、噻嗪、噻唑、硫代吗啉、硫茚、噻喃、三嗪、三唑和三噻烷。
卤素是指F、Cl、Br或I，优选F。
R优选被一个或多个烷基(例如甲基、乙基或丙基)、卤代烷基(优选CF3)、卤素(例如F、Cl或Br，优选F)、OR8、SR8、SOR8、(NR8)2取代，其中R8独立地选自氢、C1-4烷基或卤代烷基，并且优选R是苯基或萘基。当R是苯基时，优选在4-(对)位被例如NR6R6取代，其中R6独立地表示H或C1-4烷基。
本发明第一方面的代表性化合物举例如下。
本发明的化合物可以作为盐提供，优选作为式(I)化合物的可药用盐。这些化合物的可药用盐的实例包括那些衍生自有机酸例如乙酸、苹果酸、酒石酸、柠檬酸、乳酸、草酸、琥珀酸、富马酸、马来酸、苯甲酸、水杨酸、苯基乙酸、扁桃酸、甲磺酸、苯磺酸和对甲苯磺酸，无机酸例如盐酸和硫酸等的盐，分别生成甲磺酸盐、对甲苯磺酸盐、盐酸盐和硫酸盐等，或者那些衍生自碱例如有机或无机碱的盐。适当无机碱的实例包括氨、锂、钠、钙、钾、铝、铁、镁、锌等的氢氧化物、碳酸盐和碳酸氢盐。也可以和适当的有机碱生成盐。适合于本发明的化合物生成可药用碱加成盐的碱包括无毒且强度足以形成盐的有机碱。此类有机碱是所属领域公知的并且可以包括氨基酸，例如精氨酸和赖氨酸、一-、二-或三羟基烷基胺例如一-、二-和三乙醇胺、胆碱、一-、二-和三烷基胺、例如甲基胺、二甲基胺和三甲基胺、胍；N-甲基葡糖胺；N-甲基哌嗪；吗啉；乙二胺；N-苄基苯乙胺；三(羟基甲基)氨基甲烷等。
盐可以利用所属领域公知的方法以常规方式制备。碱性化合物的酸加成盐可以通过将本发明第一方面或第二方面的游离碱化合物溶解在水或水醇溶液或其它含有所需酸的适当溶剂中来制备。当本发明的化合物含有酸性官能团时，该化合物的碱盐可以通过使该化合物与适当的碱反应来制成。酸或碱盐可以直接分离或者可以通过浓缩该溶液，例如通过蒸发来获得。本发明的化合物还可以以溶剂化物或水合物的形式存在。
本发明还涉及上述化合物的前药。前药是在生理条件下可以转化为或者通过溶剂分解生成本发明的化合物或者本发明化合物的可药用盐的化合物。前药可能无活性，当将其给予个体时在体内转化为本发明的活性化合物。
本发明的化合物可含有一个或多个不对称碳原子并且可以存在消旋形式和旋光形式。本发明的第一方面覆盖了所有这些化合物。
按照本发明的第二方面，通式(I)化合物：
可以通过氢化通式(II)的化合物来制备：
其中R定义如上并且hal代表卤素原子，主要是F或Cl，例如，在适当的金属催化剂例如活性炭载钯和适当的胺，例如三乙胺的存在下进行反应。可以利用化合物(II)在单一溶剂(例如醇，例如甲醇或乙醇)或包括例如醇、二氯甲烷、氯仿等的溶剂混合物中的溶液进行该反应。
通式(II)的化合物可以通过在通式(III)化合物的2位卤化来制备，例如：
其中R定义如上，例如使用P(O)Cl3高温下(约100℃)卤化。
通式(III)的化合物可以由7-氮杂吲哚按照本领域已知的方法制备，参见例如Glennon，K.C.等(WO00/56710)和Viaud，M.-C.等(EP0737685)和Cheung，M.等(WO99/21859)。制备通式(III)化合物的适当路线的实例为：
本发明的第三方面提供一种含有上述通式(I)化合物以及可药用载体、稀释剂或赋形剂的组合物。
所述的组合物还可以含有一种或多种其它活性剂，例如抗炎剂(例如p38抑制剂、谷氨酸受体拮抗剂或钙通道拮抗剂)、化疗药和/或抗增殖药。
适当的载体和/或稀释剂是本领域熟知的，并且包括药用级淀粉、甘露糖醇、乳糖、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖(或其它糖)、碳酸镁、明胶、油、醇、洗涤剂、乳化剂或水(优选无菌水)。所述的组合物可以是组合物的混合制剂，或者可以是用于同时、分开或顺序使用(包括给药)的联合制剂。
本发明用于上述适应症的组合物可以通过任何常规方法给药，例如通过口服(包括经吸入)、胃肠外、粘膜(例如颊、舌下、鼻)、直肠或透皮给药，并对组合物进行相应的改变。
对于口服给药，所述的组合物可以配制为液体或固体，例如溶液、糖浆、混悬剂或乳剂、片剂、胶囊和锭剂。
液体制剂一般包括所述化合物或其生理可接受盐在适当的水或非水液体载体中的混悬液或溶液，所述液体载体例如是水、乙醇、甘油、聚乙二醇或油。制剂还可以含有助悬剂、防腐剂、矫味剂或着色剂。
片剂形式的组合物可以利用制备固体制剂常用的适当药学载体来制备。此类载体的实例包括硬脂酸镁、淀粉、乳糖、蔗糖和微晶纤维素。
胶囊形式的组合物可以用常规包封方法制备。例如，可以利用标准载体制备含有活性成分的散剂、颗粒剂或丸剂并且随后填充到硬明胶胶囊中；或者，可以利用任何适当的药学载体例如含水树胶、纤维素、硅酸盐或油制备分散体或混悬剂，并随后将分散体或混悬剂填充到软明胶胶囊内。
口服给药的组合物可以设计为保护活性成分在其通过食道时不被降解，例如在片剂或胶囊上涂外包衣。
典型的胃肠外组合物由所述化合物或其生理可接受的盐在无菌含水或非水载体或胃肠外可接受的油例如聚乙二醇、聚乙烯吡咯烷酮、卵磷脂、花生油或芝麻油中的溶液或混悬液构成。或者，溶液剂可以冷冻干燥并且随后用适当溶剂在临给药之前重构。
经鼻或口服给药的组合物一般可以配制为气雾剂、滴剂、凝胶剂和散剂。气雾剂通常包括活性物质在生理可接受水或非水溶剂中的溶液或细混悬剂，并常常以单剂量或多剂量的量以灭菌形式存在于密封容器内，所述容器可以采取药筒或再填充的形式与雾化装置一起使用。或者，密封容器可以是单一的给药装置，例如单剂量鼻吸入器或安装有计量阀的气雾剂给药器，其可以在容器的内容物已经用尽时丢弃掉。当所述剂型包括气雾剂给药器时，它可以含有可药用抛射剂。气雾剂剂型也可以采取泵雾化器的形式。
适合经颊或舌下给药的组合物包括片剂、锭剂和软锭剂，其中活性成分与载体例如糖和阿拉伯胶、黄蓍胶或明胶和甘油一起配制。
用于直肠或阴道给药的组合物一般是栓剂(含有常规栓剂基质例如可可脂)、阴道环、阴道帽、泡沫剂或灌肠剂的形式。
适合经皮给药的组合物包括软膏剂、凝胶剂、贴剂和注射剂，包括粉末注射剂。
通常，组合物为单位剂型例如片剂、胶囊或安瓿。
此外，本发明提供一种制造本发明上述组合物的方法。可以利用所属领域熟知的标准技术进行制备，并且包括将本发明第一方面的化合物与可药用载体或稀释剂混合。该组合物可以是任何形式，包括片剂、液体、胶囊和散剂，或者是食品的形式，例如功能性食品。在后一种情况中，该食品本身可以充当可药用载体。
本发明提供用于治疗/药物的第一方面的化合物或第三方面的组合物。
本发明的第四方面涉及用于抑制JNK的以下所定义的通式I化合物或含有该化合物的组合物
其中：
R表示碳环基、取代的碳环基、杂环基或取代的杂环基，其中任选取代的碳环基或任选取代的杂环基任选地稠合于不饱和、部分不饱和或完全饱和的含有0-3个杂原子的5-7元环，
R中、包括任选稠合的环中的各个可被取代的碳原子任选地且独立地被一个或多个C1-12烷基、C2-12链烯基、碳环基或杂环基、卤素、卤代烷基、OR2、SR2、NO2、CN、NR2R2、NR2COR2、NR2CONR2R2、NR2COR2、NR2CO2R2、CO2R2、COR2、CONR2R2、S(O)2R2、SONH2、S(O)R2、SO2NR2R2、NR2S(O)2R2取代，其中各R2可以相同或不同并且定义如下，且其中：
所述的C1-12烷基任选地掺有一个或两个选自-O-、-C(O)-、-N(R2)-、-S(O)-和-S(O2)-的插入基团，其中各R2可以相同或不同并且定义如下；
所述的C1-12烷基、碳环基或杂环基任选地被一个或多个卤素、卤代烷基、OR2、SR2、NO2、CN、NR2R2、NR2COR2、NR2CONR2R2、NR2COR2、NR2CO2R2、CO2R2、COR2、CONR2 2、S(O)2R2、SONH2、S(O)R2、SO2NR2R2、NR2S(O)2R2取代；其中各R2可以相同或不同并且定义如下；并且
所述的碳环基或杂环基任选地被一个或多个C1-12烷基取代，任选稠合的环中的各饱和的碳进一步任选地且独立地被＝O、＝S、＝NNHR2、NNR2R2、＝N-OR2、＝NNHCOR2、＝NNHCO2R2、＝NNSO2R2或＝NR2取代，其中各R2可以相同或不同并且定义如下；
R中的各个可被取代的氮原子任选地被R3、COR2、SO2R2或CO2R2取代，其中各R2和R3可以相同或不同并且定义如下；
R2是氢、C1-12烷基或芳基，任选地被一个或多个C1-4烷基、卤素、C1-4卤代烷基、OR4、SR4、NO2、CN、NR4R4、NR4COR4、NR4CONR4R4、NR4COR4、NR4CO2R4、CO2R4、COR4、CONR4 2、S(O)2R4、SONH2、S(O)R4、SO2NR4R4、NR4S(O)2R4取代，其中所述的C1-12烷基任选地掺有一个或两个选自-O-、-N(R4)-、-S(O)-和-S(O2)-的插入基团，其中各R4可以相同或不同并且定义如下；
R3为C1-12烷基或芳基，任选地被一个或多个C1-4烷基、卤素、C1-4卤代烷基、OR4、SR4、NO2、CN、NR4R4、NR4COR4、NR4CONR4R4、S(O)R4、SO2NR4R4、NR4S(O)2R4，其中所述的C1-12烷基任选地掺有一个或两个选自-O-、-N(R4)-、-S(O)-和-S(O2)-的插入基团，其中各R4可以相同或不同并且定义如下；
R4是氢、C1-4烷基或C1-4卤代烷基；
及其可药用盐和其它可药用的生物可水解的衍生物，包括其酯、酰胺、氨基甲酸酯、碳酸酯、酰脲、溶剂化物、水合物、亲和性试剂或前药。
R、R2、R3和R4的所有优选的选项及其任何取代基和插入基团在本发明的第一方面中给出。第四方面的组合物的优选特征在第三方面中给出。
本发明的第四方面的化合物是JNK，例如JNK1、JNK2或JNK3的抑制剂。具体地讲，本发明的化合物是JNK3的抑制剂。优选地，本发明的化合物特异性地抑制JNK3。
本发明化合物的一个优点在于它们对肝脏微粒体具有良好的稳定性，至少在体外试验时如此，因此不会被机体快速代谢掉。
该化合物因此可用于那些得益于抑制JNK活性的病症。因此，优选地，这一方面提供了用于预防或治疗JNK介导的疾病的以上本发明的第四方面所定义的通式(I)化合物或含有式(I)化合物的组合物。因此，通式I的化合物可以用于抑制JNK，更优选用于抑制JNK3。
“JNK介导的疾病”是JNK在其中起作用的任何疾病或有害状况。其实例包括神经变性疾病(包括痴呆)、炎性疾病、与细胞凋亡、特别是神经元细胞凋亡有关的疾病、自身免疫性疾病、破坏性骨机能障碍、增殖性疾病、癌、感染性疾病、变态反应、局部缺血再灌注损伤、心脏病发作、血管生成性疾病、器官低氧症、血管增生、心脏肥大、凝血酶诱发的血小板聚集和任何与前列腺素内过氧化物酶合酶-2有关的病症。本发明的化合物可以用于任何这些由JNK介导的疾病。
本发明的第四方面的化合物特别适用于神经变性疾病的预防或治疗。具体地讲，所述的神经变性疾病是由细胞凋亡和/或炎症引起的。神经变性疾病的实例为：痴呆；阿耳茨海默氏病；帕金森氏病；肌萎缩性侧索硬化；杭廷顿氏舞蹈病；老年性舞蹈病；西登哈姆氏舞蹈病；低血糖；头部和脊髓创伤，包括创伤性头部损伤；急性和慢性疼痛；癫痫症和癫痫发作；橄榄体脑桥小脑痴呆；神经元细胞死亡；与低氧症有关的神经变性；急性低氧症；谷氨酸盐中毒，包括谷氨酸盐神经毒性；脑缺血；与脑膜炎和/或神经症有关的痴呆；脑血管痴呆；或HIV感染患者的痴呆。
神经变性疾病可以是外周性神经病，包括单神经病、复合型单神经病或多神经病。外周神经病的实例可以在糖尿病、莱姆病或尿毒症中发现；毒性剂引起的外周神经病；脱髓鞘疾病例如急性或慢性炎性多神经病、脑白质营养不良或格-巴二氏综合征；继发于胶原血管疾病(例如结节性多动脉炎、SLE、Sjgren氏综合征)的复合型单神经病；继发于肉样瘤的复合型单神经病；继发于代谢疾病(例如糖尿病或淀粉样变性)的复合型单神经病；或继发于感染性疾病(例如莱姆病或HIV感染)的复合型单神经病。
本发明的化合物还可以用于预防或治疗炎症导致的疾病。这些包括，例如，炎性肠病、支气管炎、哮喘、急性胰腺炎、慢性胰腺炎、各种类型的变态反应和阿耳茨海默氏病。可用本发明的化合物治疗或预防的自身免疫性疾病包括类风湿性关节炎、系统性红斑狼疮、肾小球肾炎、硬皮病、慢性甲状腺炎、格雷夫斯氏病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性中性白细胞减少、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化症、溃疡性结肠炎、节段性回肠炎、牛皮癣或移植物抗宿主疾病。
可以在给予本发明化合物的同时、之后或相继给予一种或多种其它活性剂，例如抗炎剂例如p38抑制剂、谷氨酸受体拮抗剂、钙通道拮抗剂、化学治疗剂或抗增殖药物。例如，对于急性治疗，p38抑制剂可以在本发明化合物给药之前给药。
本发明的化合物通常以如下每日剂量方案(用于成年患者)给药：例如，口服剂量为1mg-2000mg，优选30mg-1000mg，例如10-250mg，或者静脉内、皮下或肌肉内剂量为0.1mg-100mg，优选0.1mg-50mg，例如1-25mg的式(I)化合物或其生理可接受盐(基于游离碱计算)，所述的化合物每天给药1-4次。所述的化合物适宜在连续治疗的一段时期内给药，例如1周或更长时间。
因此，本发明的第五方面涉及治疗或预防个体中由JNK介导的疾病的方法，该方法包括给所述个体施用第四方面所定义的化合物或含有该化合物的组合物。活性化合物优选以累积有效量给药。个体可能需要治疗或预防。上述第四方面所列的任何JNK介导的疾病均可以是本发明第五方面治疗或预防的对象。可以在给予所述化合物的同时、之后或相继给予个体一种或多种其它活性剂。其它活性剂可以是抗炎剂例如p38抑制剂、谷氨酸受体拮抗剂、钙通道拮抗剂、化学治疗剂或抗增殖药物，但急性治疗优选p38抑制剂。
本发明的第六个方面提供本发明第四方面所定义的通式(I)化合物在制造用于预防或治疗JNK介导的疾病的药物中的应用。所述的药物可以用来治疗或预防本发明第四方面所列的任何由JNK介导的疾病。同样，本发明的化合物可以与一种或多种其它活性剂同时、相继或顺序给药，急性治疗优选p38抑制剂。
按照本发明的第七方面，还提供了一种测定本发明化合物的活性的分析方法，包括提供一种用于分析活性的系统并分析所述化合物的活性。优选该分析方法适用于分析所述化合物的JNK抑制活性、更优选适于分析所述化合物对JNK3的特异性抑制活性。本发明的化合物可以在体外、体内、in silico或在原代细胞培养物或细胞系中进行分析。体外分析包括测定对活化的JNK的激酶活性或ATP酶活性的抑制作用。或者，体外分析可以定量化合物结合JNK的能力并且可以通过在结合之前放射性标记该化合物来测定，随后分离抑制剂/JNK复合物并测定放射性标记结合的量或通过将新的抑制剂与结合已知放射性配体的JNK一起培养进行竞争性试验。可以采用的分析方法的实例是闪烁亲近测定法(SPA)，优选利用放射性标记的ATP。另一实例为ELISA。JNK的任意类型或同工型均可以用于这些分析。
在本发明的另一方面中，提供了一种抑制JNK、特别是JNK3的活性或功能的方法，该方法包括使JNK与本发明第一或第四方面的化合物或组合物接触。该方法可以在研究模型、体外、in silico或体内进行，例如在动物模型中进行。适当的动物模型可以是大鼠或小鼠的红藻氨酸模型、大鼠的创伤型脑损伤模型或小鼠的MPTP。
各个方面的全部特征均适用于所有细节上作必要修改的其它方面。
下面利用非限定性实例举例说明本发明。
实施例
5-取代的7-氮杂吲哚衍生物7的合成
路线1
3，3-二溴-1，3-二氢-吡咯并[2，3-b]吡啶-2-酮(2)
将工业级(90％)三溴化吡啶(220.4g，0.62mol)在30分钟内分批加入到7-氮杂吲哚(1，27.13g，0.23mol)在t-BuOH(1.36L)中的搅拌的混悬液内。将该混合物在室温下搅拌3小时，并且一次性加入更多的三溴化吡啶(73.3g，0.21mol)。继续在室温下搅拌2小时后，减压下蒸发溶剂。残余物在水∶AcOEt＝1∶1(4.2L)之间分离。水层用AcOEt(2×800mL)萃取。合并的有机溶液用水(2×500mL)、盐水洗涤，干燥(MgSO4)并真空浓缩。残余物用CH2Cl2(1500mL)研制20分钟。滤出固体，用CH2Cl2(250mL)洗涤并真空干燥得到2(49.85g，75％)，其为黄色粉末。1H NMR(400MHz，DMSO-d6)δ7.16(dd，J＝7.4，5.1Hz，1H)，7.98(dd，J＝7.4，1.5Hz，1H)，8.19(dd，J＝5.1，1.5Hz，1H)，11.97(bs，1H)。
3，3，5-三溴-1，3-二氢-吡咯并[2，3-b]吡啶-2-酮(3)
在30分钟内将溴(13.4mL，0.262mol)滴加到2(37.86g，0.131mol)在水∶t-BuOH＝1∶1(1500mL)中的冷的(冰浴)、搅拌中的混悬液内。撤去冷却浴并在室温下搅拌该混合物过夜。随后将该溶液冷却至15℃并加入NaHCO3的饱和水溶液(278mL)。将形成的黄色混悬液在真空中浓缩(浴温＜32℃)直至收集到约1000mL的浓缩物。滤出固体，用水洗涤(200mL)并真空干燥得到3(40.85g，85％)，为褐色粉末。
5-溴-1，3-二氢-吡咯并[2，3-b]吡啶-2-酮(4)
将锌粉(34.0g，0.52mol)以使温度保持在20-25℃之间的速率分小份加入到3(40.85g，0.111mol)在冰醋酸(1000mL)中的搅拌中的混悬液内(强放热反应；外部冰浴冷却)。加料耗时约20分钟。撤去冷却浴并在室温下继续搅拌2小时。过滤该固体，用甲苯(50mL)洗涤并用CH2Cl2∶MeOH＝4∶1(2.5L)研制。倾倒出溶液并用1.0M Na2CO3水溶液(170mL)处理。搅拌1后小时分离两层。有机层再次用1.0M Na2CO3水溶液(50mL)洗涤。合并的水层用CH2Cl2∶MeOH＝4∶1(10×100mL)萃取。合并的有机溶液用MgSO4(200g)干燥并浓缩。残余固体溶于THF(2000mL)并过滤不溶性物质。真空浓缩该滤液至干得到4(16.93g，72％)，其为褐色固体。1H NMR(400MHz，DMSO-d6)δ3.57(s，2H)，7.75(m，1H)，8.14(m，1H)，11.13(bs，1H)。
5-(3-氟-苯基)-1，3-二氢-吡咯并[2，3-b]吡啶-2-酮(5)
将4(16.63g，78.5mmol)、3-氟苯基硼酸(16.47g，117.7mmol)、Pd(PPh3)2Cl2(2.73g，6.60mmol)、LiCl(9.95g，0.23mol)、1.0M Na2CO3水溶液(196mL，0.196mol)在EtOH(470mL)-甲苯(470mL)中的混合物回流过夜。补加Pd(PPh3)2Cl2(1.30g，3.14mmol)并继续回流24小时。冷却该混合物，分离有机层并用盐水(100mL)洗涤。将洗涤液与水层合并并用AcOEt(4×400mL)萃取。合并的萃取液用盐水洗涤，加入到有机层中并用MgSO4干燥。真空浓缩该溶液至干得到26.98g的褐色半固体，将其用乙醚∶己烷＝1∶1(2×500mL)研制。将残余物真空干燥得到5(16.85g，94％)，其为褐色固体。将其直接用于下一步反应而无需进一步纯化。1H NMR(400MHz，CDCl3)δ3.66(s，2H)，7.08(dddd，J＝8.4，8.2，2.4，0.9Hz，1H)，7.22(ddd，J＝10.0，2.4，1.7Hz，1H)，7.30(ddd，J＝8.1，1.7，0.9Hz，1H)，7.43(ddd，J＝8.2，8.1，6.0Hz，1H)，7.69(s，1H)，8.36(d，J＝2.1Hz，1H)，8.98(bs，1H)。
2-氯-5-(3-氟-苯基)-1H-吡咯并[2，3-b]吡啶(6)
将5(16.52g，72.4mmol)在纯P(O)Cl3(21.5mL，0.231mol)中的混悬液在100-105℃下搅拌4小时。使该混合物冷却至室温，用对二甲苯(100mL)稀释并真空浓缩至干。将残余物在饱和NaHCO3水溶液-AcOEt之间分离。加入10％Na2CO3的水溶液碱化水层至pH9。分离有机相并将水层用AcOEt(8×300mL)萃取。合并的有机溶液用MgSO4干燥，浓缩，残余物通过硅胶色谱(SGC)纯化，用CH2Cl2∶AcOEt作为洗脱剂梯度洗脱得到回收的起始原料5(0.76g，5％)。所需产物随后用丙酮结晶得到6(10.06g，56％)，为细的褐色针状物。1H NMR(400MHz，CDCl3)δ6.47(s，1H)，7.08(tdd，J＝8.1，2.3，1.5Hz，1H)，7.33(ddd，J＝9.9，2.3，1.6Hz，1H)，7.38-7.48(m，2H)，8.03(d，J＝2.1Hz，1H)，8.53(d，J＝2.1Hz，1H)，11.46(bs，1H)。
5-(3-氟-苯基)-1H-吡咯并[2，3-b]吡啶(7)
将氯化物6(5.23g，21.3mmol)、10％Pd/C(2.7g)、Et3N(3.6mL，25.8mmol)在THF∶MeOH＝5∶1(180mL)中的混合物在H2下搅拌过夜。补加10％Pd/C(1.3g)并继续搅拌3小时。过滤除去催化剂，将该溶液真空浓缩至干。残余物通过SGC纯化，用CH2Cl2∶AcOEt作为洗脱剂梯度洗脱(最高至20％AcOEt)得到7(5.23g，88％)，为绿色粉末。1H NMR(400MHz，CDCl3)δ6.59(dd，J＝3.5，2.0Hz，1H)，7.04-7.10(m，1H)，7.33-7.37(m，1H)，7.40-7.48(m，3H)，8.14(d，J＝2.1Hz，1H)，8.57(d，J＝2.1Hz，1H)，9.91(bs，1H)。
JNK1，JNK2，JNK3-SPA分析实验
测试化合物对JNK1、JNK2和JNK3酶的抑制活性的典型试验如下所述：
1.将化合物溶于DMSO达到常规浓度并在10％DMSO中稀释至所需起始浓度的5倍浓度(常常1∶100)。
2.取10μl的500mM EDTA加入到Opti-平板行的交错的孔内，这些孔接受激酶反应物加DMSO。由此作为阴性对照。
3.对于JNK2和JNK3的分析，用水将化合物制备成6个2倍稀释液并且各浓度一式双份地进行试验。对于JNK1分析，用水将化合物制备成4个5倍稀释液并将其一式三份地进行试验。对照品进行同样的处理。
4.将一式两份20μl/孔的各化合物浓度转移到Opti平板中。
5.向各孔加入30μl(JNK2/3SPA)或50μl(JNK1SPA)的底物溶液(25mM HEPES pH7.5，10mM乙酸镁和3.33μM ATP(JNK2/3)或2μMATP(JNK1)，约7.5kBq[γ-33P]ATP，GST-c-Jun，在水中)。
6.向各孔内加入50μl(JNK2/3SPA)或30μl(JNK1SPA)的激酶溶液(JNK在25mM HEPES中，pH7.5，10mM乙酸镁)。
| 激酶 | 激酶/孔(μg) | GST-c-Jun/孔(μg) |
| JNK1 | 0.25 | 1 |
| JNK2 | 0.2 | 1.2 |
| JNK3 | 0.16 | 1.2 |
7.将平板在室温下温育30分钟。
8.取100μl珠/终止液加入到各孔内(5mg/ml谷胱甘肽-PVT-SPA珠，40mM ATP，在PBS中)。
9.密封平板并在室温下温育30分钟，在2500g下离心10分钟并计数。
10.IC50值计算为c-Jun的磷酸化作用减小到对照值的50％时被测试化合物的浓度。本发明化合物的示例IC50值如表1所示。
抗JNK3激酶的抑制功效的实例
表1.所选化合物对JNK3激酶的IC50值
Claims (41)
1.定义如下的式(I)化合物：
其中：
R表示其中碳原子可被一个或多个选自卤素和NR2R2的取代基任选取代的芳基或杂芳基，其中芳基是指含有一个环或与一个或多个饱和或不饱和环稠合的芳香族3-10元烃，其中杂芳基是指含有一个或多个选自N、O或S的杂原子并含有一个环或与一个或多个饱和或不饱和环稠合的芳香族3-10元芳基；
R2是氢、C1-12烷基；
及其可药用盐和其它可药用的生物可水解的衍生物。
2.权利要求1的化合物，其中所述的其它可药用的生物可水解的衍生物选自其酯、酰胺、氨基甲酸酯、碳酸酯、酰脲、溶剂化物或水合物。
3.权利要求1或2的化合物，其中R是芳基或杂芳基，其中的碳原子任选地被一个或多个卤素、N(R8)2取代，其中R8独立地选自氢或C1-4烷基。
4.权利要求1或2的化合物，其中R是苯基或萘基。
5.权利要求3的化合物，其中R是4-位取代的苯基。
6.权利要求1的化合物，其中R是被NR6R6取代的苯基，其中R6独立地表示H或C1-4烷基。
7.权利要求1的化合物，其中R是取代的芳基并且取代基是F、Cl或Br或C1-12烷基。
8.权利要求7的化合物，其中所述的取代基是F、甲基、乙基或丙基。
9.权利要求1的化合物，它是下列化合物：
10.制备一种或多种权利要求1-9任一项所述的化合物的方法，该方法包括氢化通式(II)的化合物：
其中R如权利要求1所定义并且hal表示卤素原子。
11.权利要求10的方法，其中使用氢和催化剂进行氢化。
12.权利要求11的方法，其中所述的催化剂是Pd-C。
13.权利要求10、11或12的方法，其中通式(II)的化合物是通过卤化通式(III)化合物的2位来制备的
其中R如权利要求1所定义且hal表示卤素。
14.权利要求13的方法，其采用P(O)Cl3在高温下进行卤化。
15.权利要求14的方法，其中所述的高温是100℃。
16.一种含有权利要求1-9任一项所定义的化合物和可药用载体、稀释剂或赋形剂的组合物。
17.权利要求16的组合物，进一步含有一种或多种其它活性剂，其中所述的活性剂选自抗炎剂、化疗药和抗增殖药。
18.权利要求16的组合物，其中该组合物进一步含有抗炎剂。
19.权利要求18的组合物，其中所述的抗炎剂是p38抑制剂。
20.一种制备权利要求16-19任一项所定义的组合物的方法，包括将权利要求1-9任一项所定义的化合物和任何附加的选自抗炎剂、化疗药和抗增殖药的活性剂与可药用的载体或稀释剂混和。
21.权利要求1-9任一项所定义的化合物在制备用于预防或治疗JNK介导的疾病的药物中的用途。
22.权利要求21所述的用途，其中所述的疾病是神经变性疾病、炎性疾病、与细胞凋亡有关的疾病、自身免疫性疾病、破坏性骨机能障碍、增殖性疾病、癌、感染性疾病、变态反应、局部缺血再灌注损伤、心脏病发作、血管生成性疾病、器官低氧症、血管增生、心脏肥大、凝血酶诱发的血小板聚集和/或任何与前列腺素内过氧化物酶合酶-2有关的病症。
23.权利要求22所述的用途，其中所述的神经变性疾病是痴呆。
24.权利要求22所述的用途，其中所述的与细胞凋亡有关的疾病是与神经元细胞凋亡有关的疾病。
25.权利要求22-24任一项所述的用途，其中所述的神经变性疾病是由细胞凋亡和/或炎症引起的。
26.权利要求22-24任一项所述的用途，其中所述的神经变性疾病是：痴呆；阿耳茨海默氏病；帕金森氏病；肌萎缩性侧索硬化；杭廷顿氏舞蹈病；老年性舞蹈病；西登哈姆氏舞蹈病；低血糖；头部和脊髓创伤；急性和慢性疼痛；癫痫症和癫痫发作；橄榄体脑桥小脑痴呆；神经元细胞死亡；与低氧症有关的神经变性；急性低氧症；谷氨酸盐中毒；脑缺血；与脑膜炎和/或神经症有关的痴呆；脑血管痴呆；或HIV感染患者中的痴呆。
27.权利要求26所述的用途，其中所述的头部和脊髓创伤是创伤性头部损伤。
28.权利要求26所述的用途，其中所述的谷氨酸盐中毒是谷氨酸盐神经毒性。
29.权利要求22-24任一项所述的用途，其中所述的神经变性疾病为外周神经病；脱髓鞘疾病；继发于胶原血管疾病的复合型单神经病；继发于肉样瘤的复合型单神经病；继发于代谢疾病的复合型单神经病；或继发于感染性疾病的复合型单神经病。
30.权利要求29所述的用途，其中所述的外周神经病是毒性剂引起的外周神经病。
31.权利要求29所述的用途，其中所述的外周神经病是单神经病、复合型单神经病或多神经病。
32.权利要求22所述的用途，其中所述的神经变性疾病是在糖尿病、莱姆病或尿毒症中发现的外周神经病、急性或慢性炎性多神经病、脑白质营养不良或格-巴二氏综合征、继发于结节性多动脉炎、SLE或Sjgren氏综合征的复合型单神经病、继发于糖尿病或淀粉样变性的复合型单神经病或继发于莱姆病或HIV感染的复合型单神经病。
33.权利要求21所述的用途，其中所述的疾病为炎性肠病；支气管炎；哮喘；急性胰腺炎；慢性胰腺炎；各种类型的变态反应；阿耳茨海默氏病；自身免疫性疾病、系统性红斑狼疮、肾小球肾炎、硬皮病、慢性甲状腺炎、格雷夫斯氏病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性中性白细胞减少、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化症、溃疡性结肠炎、节段性回肠炎、牛皮癣或移植物抗宿主疾病。
34.权利要求33所述的用途，其中所述的自身免疫性疾病是类风湿性关节炎。
35.权利要求21-24任一项所述的用途，其中所述的药物进一步含有一种或多种其它活性剂，所述的活性剂选自抗炎剂、化疗药和抗增殖药。
36.权利要求35所述的用途，其中所述的其它活性剂为抗炎剂。
37.权利要求36所述的用途，其中所述的抗炎剂是p38抑制剂。
38.一种测定权利要求1-9任一项所定义的化合物的活性的方法，包括提供用于分析活性的系统并分析权利要求1-9任一项所定义的化合物的活性。
39.权利要求38所述的测定方法，其中所述的分析是用于测定所述化合物的JNK抑制活性的。
40.权利要求39所述的测定方法，其中所述的分析是用于测定所述化合物的JNK3特异性抑制活性的。
41.权利要求38、39或40所述的测定法，其中所述的分析是利用放射性标记的ATP的闪烁亲近测定法或是ELISA。
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| GB0207488A GB0207488D0 (en) | 2002-03-28 | 2002-03-28 | Inhibitors |
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| GB0300400A GB0300400D0 (en) | 2003-01-08 | 2003-01-08 | JNK inhibitors |
| GB0300400.9 | 2003-01-08 | ||
| PCT/GB2003/001115 WO2003082869A1 (en) | 2002-03-28 | 2003-03-17 | Azaindoles as inhibitors of c-jun n-terminal kinases |
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| EP3148531A1 (en) | 2014-05-15 | 2017-04-05 | iTeos Therapeutics | Pyrrolidine-2,5-dione derivatives, pharmaceutical compositions and methods for use as ido1 inhibitors |
| CN107635990A (zh) | 2015-03-17 | 2018-01-26 | 辉瑞公司 | 新型3‑吲哚取代的衍生物、药物组合物及使用方法 |
| US10544095B2 (en) | 2015-08-10 | 2020-01-28 | Pfizer Inc. | 3-indol substituted derivatives, pharmaceutical compositions and methods for use |
| JP7132937B2 (ja) * | 2017-03-15 | 2022-09-07 | エフ・ホフマン－ラ・ロシュ・アクチェンゲゼルシャフト | Ｈｐｋ１の阻害剤としてのアザインドール |
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- 2003-03-17 US US10/509,127 patent/US7291630B2/en not_active Expired - Fee Related
- 2003-03-17 AT AT03709986T patent/ATE457312T1/de not_active IP Right Cessation
- 2003-03-17 EP EP03709986A patent/EP1490365B1/en not_active Expired - Lifetime
- 2003-03-17 DE DE60331219T patent/DE60331219D1/de not_active Expired - Fee Related
- 2003-03-17 JP JP2003580334A patent/JP2005534619A/ja active Pending
- 2003-03-17 CN CNB038095696A patent/CN100338062C/zh not_active Expired - Fee Related
- 2003-03-17 KR KR10-2004-7015414A patent/KR20050013534A/ko not_active Ceased
- 2003-03-17 WO PCT/GB2003/001115 patent/WO2003082869A1/en active Application Filing
- 2003-03-17 AU AU2003214414A patent/AU2003214414B2/en not_active Ceased
- 2003-03-17 CA CA002479205A patent/CA2479205A1/en not_active Abandoned
- 2003-03-17 IL IL16408203A patent/IL164082A0/xx unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| CA2479205A1 (en) | 2003-10-09 |
| US7291630B2 (en) | 2007-11-06 |
| DE60331219D1 (de) | 2010-03-25 |
| KR20050013534A (ko) | 2005-02-04 |
| JP2005534619A (ja) | 2005-11-17 |
| EP1490365A1 (en) | 2004-12-29 |
| ATE457312T1 (de) | 2010-02-15 |
| EP1490365B1 (en) | 2010-02-10 |
| US20060111390A1 (en) | 2006-05-25 |
| AU2003214414A1 (en) | 2003-10-13 |
| AU2003214414B2 (en) | 2008-10-09 |
| WO2003082869A1 (en) | 2003-10-09 |
| CN1649869A (zh) | 2005-08-03 |
| IL164082A0 (en) | 2005-12-18 |
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