CN1306428A - 转录因子nf－κb的抑制剂 - Google Patents
转录因子nf－κb的抑制剂 Download PDFInfo
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- CN1306428A CN1306428A CN99807572A CN99807572A CN1306428A CN 1306428 A CN1306428 A CN 1306428A CN 99807572 A CN99807572 A CN 99807572A CN 99807572 A CN99807572 A CN 99807572A CN 1306428 A CN1306428 A CN 1306428A
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- indenone
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Abstract
本发明提供转录因子NF－ΚB的氨基二氢茚酮抑制剂及其可药用盐、水合物和溶剂化物,这些化合物的药物组合物,以及治疗其中涉及NF－ΚB活化的疾病的方法。更具体地说,本发明通过对需此治疗的患者施用本发明的化合物提供了各种与NF－ΚB活化有关的疾病的治疗方法,它们包括炎症性疾病;尤其是类风湿关节炎、炎症性肠病和哮喘;皮肤病,包括牛皮癣和急性皮炎;自身免疫性疾病;组织和器官排斥反应;阿尔茨海默氏病;中风;动脉粥样硬化;再狭窄;癌症,包括何杰金氏病;和某些病毒性感染,包括AIDS;骨关节炎;骨质疏松;以及AtaxiaTelangiestasia。
Description
发明领域
本发明主要涉及使用氨基二氢茚酮抑制转录因子NF-κB的方法。这类化合物尤其可用于治疗其中涉及NF-κB活化的疾病。更具体地说，这些化合物抑制IκB磷酸化和随后的降解。这类化合物可用于治疗各种与NF-κB活化有关的疾病，包括炎症性疾病；尤其是类风湿关节炎、炎症性肠病和哮喘；皮肤病，包括牛皮癣和特应性皮炎；自身免疫性疾病；组织和器官排斥反应；阿尔茨海默氏病；中风；动脉粥样硬化；再狭窄；癌症，包括何杰金氏病；和某些病毒性感染，包括AIDS；骨关节炎；骨质疏松；以及Ataxia Telangiestasia。
发明背景
最近有关急慢性炎症性疾病和癌症的介质的科学研究进展导致了探索有效治疗的新战略。传统的方法包括直接靶向介入治疗，例如使用特异性抗原、受体拮抗剂或酶抑制剂。最近有关各种介质的转录和翻译的调节机制的突破性阐述提高了人们对涉及基因转录水平的治疗方法的兴趣。
NF-κB属于与由Rel/NF-κB族多肽的各种结合物构成的二聚转录因子复合物密切相关的一族物质。该族物质包括哺乳动物中的五种独特的基因产物，RelA(p65)、NF-κB1(p50/p105)、NF-κB2(p49/p100)、c-Rel和RelB，所有这些都可形成杂聚或均聚的二聚体。这些蛋白都拥有高同源性的300个氨基酸的“Rel同源结构域”，该结构域包含DNA结合和二聚化结构域。在Rel同源结构域的C端是在NF-κB从胞浆中转运到细胞核中具有重要意义的细胞核易位序列。另外，p65和cRel在它们的C末端具有有效反式激活结构域。
NF-κB的活性通过其与一类IκB族蛋白抑制剂的相互作用来调节。该相互作用有效地阻断NF-κB蛋白上细胞核定位序列，由此阻止二聚体向细胞核的迁移。种类众多的刺激物通过可能是多信号传导途径活化NF-κB。包括有细菌产物(LPS)、某些病毒(HIV-1、HTLV-1)、炎症性细胞因子(TNFα、IL-1)和环境应力。对于所有刺激物明显相同的是磷酸化和随后的IκB降解。IκB通过最近鉴别的IκB激酶(IKK-α和IKK-B)在其两个N末端丝氨酸上被磷酸化。与位点有关的诱变研究表明这些磷酸化对随后的NF-κB活化具有重要意义，即，一旦被磷酸化蛋白就通过遍在蛋白-蛋白激酶途径被标记降解。从IκB上游离出来，活性NF-κB复合物可易位至细胞核，在这里它们选择性地与优选的基因特异性增强子序列结合。通过NF-κB调节的基因包括各种细胞因子、细胞粘附分子和急性期蛋白。
众所周知，NF-κB在调节众多促炎性介体的表达中起着关键作用，所述介体包括细胞因子，例如IL-6和IL-8；细胞粘附分子，如ICAM和VCAM；以及一氧化氮合成诱导酶(iNOS)。这些介体已知在炎症部位的白细胞募集中起作用，并且在某些炎症和自身免疫疾病中，iNOS可导致器官的破坏。
通过对包括哮喘在内的呼吸道炎症的研究，更增强了NF-κB在炎症中的重要性，据显示在哮喘中NF-κB被活化。这种活化作用可能是这些疾病中细胞因子产生增加和白细胞浸润的基础。另外，已知吸入类甾醇(steroids)可减弱呼吸道的过度反应性并抑制哮喘呼吸道的炎症反应。鉴于最近有关糖皮质激素对NF-κB的抑制作用的发现，人们可能会想到这些作用是通过抑制NF-κB介导的。
其它有关NF-κB在炎症性疾病中的作用的证据来自类风湿性滑膜的研究。虽然NF-κB一般以没有活性的复合物形式存在于胞浆中，但最近的免疫组织化学研究表明在包含类风湿性滑膜的细胞中，NF-κB存在于细胞核中，因此是有活性的。此外，据显示在对TNF-K敏感的人滑膜细胞中NF-κB是活化形式的。这种分布可能是该组织特征性细胞因子和类花生酸产生增加的基础机制。参见Roshak,A.K.等，J.Biol.Chem.,271,31496-31501(1996)。
NF-κB/Rel和IκB蛋白可能还在肿瘤的转化中起作用。作为过度表达、基因扩增、基因重排或易位的结果，家族成员与体外或体内细胞转化有关。另外，在20-25％的某些人类淋巴肿瘤中可观察到编码这些蛋白的基因的重排和/或扩增。再者，据报道，NF-κB在调节细胞程序死亡中的作用增强了该转录因子在控制细胞增殖中的作用。
下列文献中记载了数种NF-κB抑制剂：C.Wahl等，J.Clin.Invest.101(5),1163-1174(1998)；R.W.Sullivan等，J.Med.Chem.41,413-419(1998)；J.W.Pierce等，J.Biol.Chem.272,21096-21103(1997)。
已知海洋天然产物hymenialdisine抑制NF-κB。Roshak,A.等，JPET,283,955-961(1997)。Breton,J.J.和Chabot-Fletcher,M.C.,JPET,282,459-466(1997)。
氨基二氢茚酮是已知化合物。氨基二氢茚酮类似物的通用制备方法记载于G.Maury,E.-M.Wu.N.H.Cromwell,J.Org.Chem.1968,33,1900-1907。3-溴中间体的合成记载于B.D.Pearson,R.P.Ayer.N.H.Cromwell,J.Org.Chem.1962,27,3038-3044。2-亚苄基二氢茚酮的合成记载于A.Hassner,N.H.Cromwell,J.Org.Chem1958,80,893-900。
现在我们发现了一种使用氨基二氢茚酮抑制转录因子NF-κB活化的新方法。
发明简述
本发明的目的是提供一种治疗可通过改变转录因子NF-κB的活性治疗缓和的疾病的方法。
因此，一方面，本发明提供一种含有式Ⅰ化合物和可药用载体、稀释剂或赋形剂的药物组合物。
另一方面，本发明提供一种治疗疾病的方法，其中所述疾病的病理学可通过抑制NF-κB得以治疗缓和。
特别是，本发明提供治疗与NF-κB活化有关的各种疾病的方法，所述疾病包括炎症性疾病；尤其是类风湿关节炎、炎症性肠病和哮喘；皮肤病，包括牛皮癣和特应性皮炎；自身免疫性疾病；组织和器官排斥反应；阿尔茨海默氏病；中风；动脉粥样硬化；再狭窄；癌症，包括何杰金氏病；和某些病毒性感染，包括AIDS；骨关节炎；骨质疏松；以及Ataxia Telangiestasia。
发明详述
本发明提供一种治疗与NF-κB活化有关的疾病的方法，包括给需此治疗的动物，优选哺乳动物，最优选人施用式Ⅰ化合物及其可药用盐、水合物和溶剂化物：
其中：
R1是芳基；
R2选自：H、C1-6烷基和芳基；
R3选自：C1-6烷基和C3-8环烷基；并且
R2和R3可一起形成一个5-7个原子的杂环，所示原子选自：C、N、O和S。
本发明优选提供一种治疗下列疾病的方法：炎症性疾病；尤其是类风湿关节炎、炎症性肠病和哮喘；皮肤病，包括牛皮癣和特应性皮炎；自身免疫性疾病；组织和器官排斥反应；阿尔茨海默氏病；中风；动脉粥样硬化；再狭窄；癌症，包括何杰金氏病；和某些病毒性感染，包括AIDS；骨关节炎；骨质疏松；以及Ataxia Telangiestasia。
优选将选自下面组的式Ⅰ化合物用于本发明的方法：
3-[(N-丁基)氨基]-2-亚苄基二氢茚酮；
3-[(N-环己基)氨基]-2-亚苄基二氢茚酮；
3-吗啉基-2-亚苄基二氢茚酮；和
3-哌啶基-2-亚苄基二氢茚酮。
定义
本发明包括本发明化合物的所有水合物、溶剂化物、复合物和前药的应用。前药是在体内释放式Ⅰ的活性母体药物的任何共价键合的化合物。如果在本发明的化合物中存在一个手性中心或另一种形式的异构体中心，则本发明包括所有形式的这类异构体，包括对映体和非对映体。包含一个手性中心的本发明化合物可以外消旋混合物形式使用，富含一种对映体的混合物或外消旋混合物可采用熟知的技术分离，也可单独使用对映体。在化合物具有不饱和碳-碳双键的情况下，顺式(Z)和反式(E)异构体均包括在本发明范围内。在其中化合物可以互变异构体形式存在的情况下，例如酮-烯醇式互变异构体，无论是平衡还是一种形式占主导存在的各种互变异构体形式均应包括在本
发明范围内。
式Ⅰ或其亚结构式中存在的任何取代基的含义是彼此独立的，除非另有说明，在任何其它情况下，才具有任何其它取代基的含义。
本文的“C1-6烷基”是指包括取代和未取代的甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基、戊基、正戊基、异戊基、新戊基和己基及其简单的脂族异构体。任何C1-6烷基可任选独立地被一或两个卤素、SR’、OR’、N(R’)2、C(O)N(R’)2、氨基甲酰基或C1-4烷基取代，其中R’是C1-6烷基。
本文的“C3-8环烷基”是指包括取代和未取代的环丙基、环丁基、环戊基、环辛基、环庚基和环辛基及其简单的脂族异构体。任何C3-8环烷基可任选独立地被一个或两个卤素、SR’、OR’、N(R’)2、C(O)N(R’)2、氨基甲酰基或C1-4烷基取代，其中R’是C1-6烷基。
本文的“卤素”包括F、Cl、Br和I。
本文的“Ar”或“芳基”包括苯基或萘基，它们可任选独立地被一个或多个下述的基团取代：Ph-C0-6烷基、Het-C0-6烷基、C1-6烷基、C1-6烷氧基、Ph-C0-6烷氧基、Het-C0-6烷氧基、OH、CN、CO2R’或卤素。C0烷基是指在所述结构部分不存在烷基。因此，Ar-C0烷基相当于Ar。两个C1-6烷基可联合形成5-7元环，该环可以是饱和的或不饱和的、与Ar环稠合的。Ph可任选地被一个或多个C1-6烷基、C1-6烷氧基、OH、CO2R’或卤素取代。
本文采用的“Het”或“杂环”表示稳定的5-7元单环，该环可以是饱和的或不饱和的，其由碳原子和选自N、O和S的一至三个杂原子构成并且其中的氮杂原子和硫杂原子可任选地被氧化，氮杂原子还可任选地被季铵化；以及包括上面定义的任何杂环与苯环稠合的任何双环基团。所述杂环可在任何杂原子或碳原子处进行连接，其结果是产生一个稳定的结构，并且可任选地被选自下列的一个或多个基团取代：Ph-C0-6烷基、Het-C0-6烷基、C1-6烷基、C1-6烷氧基、Ph-C0-6烷氧基、Het-C0-6烷氧基、OH或CN。两个C1-6烷基可联合形成5-7元环，该环可以是饱和的或不饱和的、与Het环稠合的。Ph可任选地被一个或多个C1-6烷基、C1-6烷氧基、OH、CO2R’或卤素取代。这类杂环的实例包括哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代吖庚因基、吖庚因基、吡咯基、4-吡啶酮基、吡咯烷基、吡唑基、吡唑烷基、咪唑基、吡啶基、吡嗪基、噁唑烷基、噁唑啉基、噁唑基、异噁唑基、吗啉基、噻唑烷基、噻唑啉基、噻唑基、奎宁啶基、吲哚基、喹啉基、异喹啉基、苯并咪唑基、苯并吡喃基、苯并噁唑基、呋喃基、吡喃基、四氢呋喃基、四氢吡喃基、噻吩基、苯并噁唑基、硫代吗啉基亚砜、硫代吗啉基砜和噁二唑基环。
制备方法
在本发明方法中使用的化合物可通过下面的反应路线图1所示的方法方便地制备。
氨基二氢茚酮类似物的通用制备方法记载于G.Maury,E.-M.Wu.N.H.Cromwell,J.Org.Chem.1968,33,1900-1907。3-溴中间体的合成记载于B.D.Pearson,R.P.Ayer.N.H.Cromwell,J.Org.Chem.1962,27,3038-3044。2-亚苄基二氢茚酮的合成记载于A.Hassner,N.H.Cromwell,J.Org.Chem 1958,80,893-900。通用制备方法：
反应路线图1中显示了通用制备方法。在碱中，用苯甲醛处理二氢茚酮得到2-亚苄基二氢茚酮。在CCl4中用NBS溴化2-亚苄基二氢茚酮，得到3-溴-2-亚苄基二氢茚酮。在苯中，用烷基伯胺或仲胺处理3-溴-2-亚苄基二氢茚酮，得到3-烷基氨基-2-亚苄基二氢茚酮。
反应路线图1
有关上面反应路线图1中所示的制备式Ⅰ化合物的方法，本领域普通技术人员都清楚，本发明应包括制备式Ⅰ化合物所需的所有新的中间体。
本文使用的原料是市售的或者可通过本领域普通技术人员熟知的常规方法制备，参见普通参考书，例如COMPENDIUM OF ORGANICSYNTHETIC METHODS,Vol.Ⅰ-Ⅵ(Wiley-Interscience出版)。
式Ⅰ化合物的酸加成盐可在适宜的溶剂中，由母体化合物和过量的酸以标准方法制备，所述酸是，例如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、乙酸、三氟乙酸、马来酸、琥珀酸或甲磺酸。某些化合物形成内盐或两性离子也是可接受的。阳离子盐通过用包含适合阳离子的过量的碱性试剂(例如氢氧化物、碳酸盐或醇化物)；或用适合的有机胺处理母体化合物来制备。存在于可药用盐中的阳离子实例是，例如Li+、Na+、K+、Ca++、Mg++和NH4 +。存在于可药用盐中的阴离子实例是卤离子、硫酸根、磷酸根、链烷酸根(例如乙酸根和三氟乙酸根)、苯甲酸根和磺酸根(例如甲磺酸根)。
本发明提供一种药物组合物，该组合物含有式Ⅰ的化合物和可药用载体、稀释剂或赋形剂。因此，式Ⅰ化合物可用于制备药物。如上文所述制备的式Ⅰ化合物的药物组合物可配制成用于非胃肠给药的溶液或冻干粉末。粉末可在临用前通过加入适宜的稀释剂或其它可药用载体重新配制。液体制剂可以是缓冲的等渗水溶液。适宜稀释剂的实例是生理等渗盐水溶液、标准的5％葡萄糖水溶液或缓冲的乙酸钠或乙酸铵溶液。这类制剂尤其适于非胃肠给药，但也可用于口服或盛于计量剂量的吸入器或雾化器中用于吹入给药。加入赋形剂，例如聚乙烯吡咯烷酮、明胶、羟基纤维素、阿拉伯胶、聚乙二醇、甘露醇、氯化钠或柠檬酸钠也是可取的。
或者，可将这些化合物制成口服给药的胶囊、片剂或者制备成乳液或糖浆形式。可加入可药用的固体或液体载体以增强或提高组合物的稳定性或有助于该组合物的制备。固体栽体包括淀粉、乳糖、二水合硫酸钙、石膏、硬脂酸镁或硬脂酸、滑石、果胶、阿拉伯胶、琼脂或明胶。液体载体包括糖浆、花生油、橄榄油、盐水和水。载体还包括缓释材料，例如甘油一硬脂酸酯或甘油二硬脂酸酯，或者它们与蜡的混合物。固体载体的用量可以变化，但每剂量单位优选含约20mg至约1g固体载体。药物制剂由常规的制药技术制备，制备片剂，需要时，包括研磨、混合、制粒和压制；制备硬明胶胶囊，包括研磨、混合和填充。当使用液体载体时，制剂可以是糖浆、酏剂、乳液或水性或非水性悬浮液形式的。这类液体制剂可直接口服给药(p.o.)或填充到软明胶胶囊中。
为了直肠给药，本发明的化合物也可与赋形剂，例如椰子油、甘油、明胶或聚乙二醇混合并铸模为栓剂。
本发明的方法包括局部施用式Ⅰ化合物。局部给药是指非系统给药，包括对表皮外用、对颊口腔施用本发明的化合物和将这类化合物滴注到耳、眼和鼻中，其中化合物剂量不明显进入血流。系统给药是指口服、静脉内、腹膜内和肌内给药。通过局部给药产生治疗或预防作用所需的式Ⅰ化合物(下文称为活性化合物)的量随所选择的化合物、所治疗适应症的性质和严重程度及进行治疗的动物而变化，当然最终是由医师决定。
虽然活性成分可以化学原料形式给药，但优选以药物制剂形式给药。用于局部给药时，活性成分可占制剂的0.01％-5.0％。
无论是兽用还是人用，本发明的局部制剂都含有活性成分与一种或多种可接受的载体，以及可任选的其它治疗性成分。载体须是“可接受的”，即意为可与制剂中的其它成分相容并且对接受者不产生危害。
适于局部给药的制剂包括适于渗透通过皮肤进入所需治疗部位的液体或半固体制剂，例如搽剂、洗剂、霜剂、软膏或糊剂，以及适于眼、耳或鼻给药的滴剂。
本发明的滴剂可含有无菌的水性或油性溶液或者悬浮液，它们可通过将活性成分溶于适合的杀菌和/或杀真菌和/或任何其它适宜的防腐剂的水溶液中来制备，该水溶液中优选含有表面活性剂。然后通过过滤使所得溶液澄明，转移至适合的容器中，然后密封并用高压釜或者在90-100℃保持1.5小时进行灭菌。或者，可通过过滤进行灭菌，然后采用无菌技术转移至容器中。适于包括在滴剂中的杀菌剂或杀真菌剂的例子包括硝酸苯汞或乙酸苯汞(0.002％)、苯扎氯铵(0.01％)和醋酸洗必太(0.01％)。制备油性溶液的适宜溶剂包括甘油、稀乙醇和丙二醇。
本发明的洗剂包括适用于皮肤或眼的那些。洗眼剂可包含可任选地含有杀菌剂的无菌水溶液，它可通过类似于制备滴剂的方法进行制备。应用于皮肤的洗剂或搽剂也可包括加速干燥和使皮肤凉爽的物质，例如乙醇或丙酮；和/或保温剂，例如甘油或油(例如蓖麻油和花生油)。
本发明的霜剂、软膏或糊剂是外用的活性成分的半固体制剂。可借助适宜的机器，通过将活性成分以细粉形式本身地或者以其在水性或非水性液体中的溶液或悬浮液形式与油性或非油性基质混合来制备半固体制剂。基质可包括烃类，例如硬的、软的或液体石蜡，甘油、蜂蜡、金属皂；粘浆；天然来源的油，例如杏仁、玉米、花生、蓖麻或橄榄油；羊毛脂或其衍生物，或者脂肪酸(如硬脂酸或油酸)与醇(例如丙二醇或聚乙二醇)的混合物。该制剂可掺入任何适宜的表面活性剂，例如阴离子性、阳离子性或非离子性表面活性剂，例如脱水山梨醇酯或其聚氧化乙烯衍生物。也可包含悬浮剂，例如天然的树胶、纤维素衍生物或无机材料，如含硅的硅石，以及其它成分，例如羊毛脂。
本发明实用性
式Ⅰ化合物是有用的NF-κB抑制剂。本发明提供所述化合物的有用组合物和制剂，包括所述化合物的药物组合物和制剂。
本发明还提供与NF-κB活化有关的疾病的治疗方法，该方法包括给需此治疗的动物，尤其是哺乳动物，最优选是人施用式Ⅰ的化合物。本发明优选提供包括下列疾病的治疗方法：炎症性疾病；尤其是类风湿关节炎、炎症性肠病和哮喘；皮肤病，包括牛皮癣和特应性皮炎；自身免疫性疾病；组织和器官排斥反应；阿尔茨海默氏病；中风；动脉粥样硬化；再狭窄；癌症，包括何杰金氏病；和某些病毒性感染，包括AIDS；骨关节炎；骨质疏松；以及Ataxia Telangiestaisa。
对于急性治疗，优选将式Ⅰ化合物通过非胃肠给药。本发明化合物在5％葡萄糖水溶液或5％葡萄糖的生理盐水溶液中的静脉输液是最有效的，当然肌内快速浓注也有效。非胃肠给药剂量典型地是约0.01-50mg/kg；优选0.1-20mg/kg，以使药物的血浆浓度维持在有效抑制NF-κB活化的浓度。为获得约0.4-80mg/kg/日的每日总剂量，化合物可每日给药一至四次。治疗有效的本发明化合物的精确剂量和最佳给药途径很容易由本领域普通技术人员通过将所述化合物的血液水平与产生治疗效果所需的浓度进行比较来确定。
式Ⅰ化合物还可以足以抑制NF-κB或者治疗本文所公开的任何其它适应症的药物浓度口服给药于患者。含有所述化合物的药物组合物一般以约0.1-50mg/kg的口服剂量给药(以与患者的适应症相一致)。口服剂量优选为约0.5-20mg/kg。
式Ⅰ化合物也可以足以抑制NF-κB或者治疗本文所公开的任何其它适应症的药物浓度局部给药于患者。含有所述化合物的药物组合物一般以约0.01％-5％w/w的局部制剂给药。
当本发明的化合物按照本发明给药时，预期没有不可接受的毒副作用。
本文所述的化合物抑制NF-κB活化的能力可由其抑制驱动(driven)NF-κB的报道基因的能力清楚地证明(见表1)。本发明的NF-κB抑制剂在治疗疾病中的实用性前提是NF-κB活化在各种疾病中具有重要意义。
表1对NF-κB驱动报道基因活性的抑制
NF-κB在调节众多炎症性介体的表达中起着关键作用，所述介质包括细胞因子，例如IL-6和IL-8(Mukaida等，1990；Liberman和Baltimore,1990；Matsusaka等，1993)；细胞粘附分子，如ICAM和VCAM(Marui等，1993；Kawai等，1995；Ledebur和Parks,1995)；以及一氧化氮合成诱导酶(iNOS)(Xie等，1994；Adcock等，1994)。(所有这些文献均附在该部分的最后)。这些介体已知在炎症部位的白细胞募集中起作用，并且在某些炎症和自身免疫疾病中，iNOS可导致器官的破坏(McCartney-Francis等，1993；Kleemann等，1993)。重要的是，本文所述的化合物抑制IL-8合成和一氧化氮(一种iNOS活性产物)的产生(见表2)。
表2表1中化合物2的抗炎活性
| 体外 | |
| RSF中IL-1诱导的PGE2的产生 | IC50=1μM |
| 体内 | |
| 佛波酯诱发的耳部炎症耳肿胀炎症性细胞浸润 | 85％抑制@1mg/耳29％抑制@1mg/耳 |
对哮喘患者的研究获得了NF-κB在炎症性疾病中的重要作用的证据。与取自正常的非变应性对照相比，取自轻微变应性哮喘的支气管活检显示粘膜下层染色活化的NF-κB、总NF-κB和NF-κB调节的细胞因子，例如GM-CSF和TNF-α的细胞数量明显增多(Wilson等，1998)。另外，表达NF-κB载体的免疫反应性百分数同活检样品的表皮中的IL-8免疫反应性一样增高(Wilson等，1998)。因此，正如预期这些化合物对呼吸道炎症具有有益效果所证实的那样，通过抑制NF-κB来抑制IL-8的产生。
最近的研究表明NF-κB在炎症性肠病(BID)的发病机理中也起着关键作用。在取自节段性回肠炎(Chron’s disease)和溃疡性结肠炎患者的结肠活检样品中观察到了活化的NF-κB(Ardite等，1998；Rogler等，1998；Schreiber等，1998)。活化在发炎的粘膜中明显；在不发炎的粘膜中则不明显(Ardite等，1998；Rogler等，1998)，并与这些相同部位IL-8 mRNA表达的增高有关(Ardite等，1998)。再者，皮质类固醇的处理强烈地抑制肠的NF-κB活化并减弱了结肠炎症(Ardite等，1998；Rogler等，1998；Schreiber等，1998)。另外，正如预期这些化合物在炎症性肠病中具有有益效果所证实的那样，通过抑制NF-κB来抑制IL-8的产生。
胃肠道炎症的动物模型进一步支持了NF-κB是结肠炎症的关键调节剂的观点。在带有活化复合物的主要成分p65的小鼠中，以2,4,6-三硝基苯磺酸(TNBS)引发的结肠炎，在其巨噬细胞固有层中观察到了NF-κB活性的提高(Neurath等，1996；Neurath和Pettersson,1997)。局部施与p65反义物消除了被治疗动物中建立的结肠炎的信号，同时没有出现毒性信号(Neurath等，1996；Neurath和Pettersson,1997)。因此，可以预言小分子NF-κB抑制剂可用于治疗IBD。
关于NF-κB在炎症性疾病中的作用的进一步的证据来自类风湿性滑膜的研究。虽然NF-κB通常以没有活性的胞浆复合物形式存在，但最近的免疫组织化学研究表明NF-κB还存在于包括人类风湿性滑膜的细胞中的细胞核内，因而是活性的(Handel等，1995；Marok等，1996；Sioud等，1998)，另外它还存在于该疾病的动物模型中的细胞核内并因而是有活性的(Tsao等，1997)。染色与A型滑膜细胞和血管内皮有关(Marok等，1996)。另外，在培养的滑膜细胞(Roshak等，1996；Miyazawa等，1998)和用IL-1β或TNF-α刺激的滑膜细胞培养物中(Roshak等，1996；Fujkawa等，1996；Roshak等，1997)，观察到了NF-κB的组成活化。因此，NF-κB活化可成为细胞因子产生增加和炎症性滑膜的特征性白细胞浸润的基础。可以预言这些化合物抑制NF-κB的能力并由此抑制这些细胞产生类花生酸将对类风湿性关节炎产生有益效果(见表2)。
Mukaida N,MaheY,Mataushima K(1990)在通过促炎性细胞因子活化的白介素-8基因中，核因子-κB和类似于顺式调节增强子结合蛋白的因子结合单元的协同相互作用，J.Biol Chem265:21128~21133。
Libennan TA,Baltimore(1990)通过NF-κB转录因子的白介素-6基因表达的活化，Mol Cell Biol 10:2327-2334。
Matsusaka T,Fujikawa K,Nishio Y,Mukaida N,MatsushimaK,Kishimoto T,Akira S(1993)转录因子NF-IL6和NF-κB协同活化炎性细胞因子白介素6和白介素8的转录，Proc Natl Acad SciUSA 90:10193-10197。
Marui N,Offerman MK,Swerlick,R,Kunsch C,Rosen CA,Ahmad M,Alexander RW,Medford RM(1993)在人血管内皮细胞中通过抗氧剂敏感性机理调节血管细胞粘附分子-1(VCAM-1)的基因转录和表达，J Clin Invest 92:1866-1874。
Kawai M,Nishikomori R,Jung E-Y,Tai G,YamanakC,MayumiM,Heike T(1995)吡咯烷二硫代氨基甲酸酯抑制由人成纤维细胞中的细胞因子诱导的细胞间粘附分子-1的生物合成，J Immunol 154:2333-2341。
Ledebur HC,Parks TP(1995)通过人内皮细胞中的炎性细胞因子调节细胞间粘附分子-1基因的转录，J Biol Chem 270:933-943。
Xie Q,Kashiwabara Y,Nathan C(1994)转录因子NF-κB/Rel在诱导一氧化氮合成酶中的作用，J BiOl Chem 269:4705-4708。
Adcock IM,Brown CR,Kwon O,Barnes PJ(1994)氧化应力在人内皮细胞中诱导NF-κB DNA结合和诱导NOS mRNA,BiochemBiophys Res Commun 199:1518-1524。
McCartney-Francis N,Allen JB,Mizel DE,Albina JE,XieQ,Nathan CF,Wahl SM(1993)通过一氧化氮合成酶的抑制剂抑制关节炎，J Exp Med 178:749-754。
Kleemann R,Rothe H,Kolb-Bachofen V,Xie Q,Nathan C,Matin S,Kolb H(1993)在前驱糖尿病BB大鼠的胰腺中一氧化氮合成诱导酶的转录和翻译，FEBS Lett 328:9-12。
Wil son SJ,Wallin A,Sandstrom T,Howarth PH,Holgate ST(1998)在轻微哮喘和正常对照中的NF-κB和相关性粘附分子的表达，J Allergy Clin Innunol 101:616。
Ardite E,Panes J,Miranda M,Salas A,Elizalde JI,SansM,Arce Y,Bordas JM,Fernandz-Checa JC,Pique JM(1998)炎症性肠病患者中类固醇治疗对核因子κB的活化的影响，Br JPharmacol 124:431-433。
Rogler G,Brand K,Vogl D,Page S,Hofmeister R,Andus T,Knuechel R,Baeuerle PA,Scholmerich J.Gross V(1998)在发炎性肠粘膜的巨噬细胞和表皮细胞中核因子κB被活化，Gastroenterol 115:357-369。
Schreiber S,Nikolaus S,Hampe S(1998)炎症性肠病中核因子κB的活化，Gut 42:477-484。
Neurath MF,Pettersson S,Meyer zum Buschenfelde K-H,Strober W(1996)对NF-κB的p65亚基局部施用反义硫代磷酸酯寡核苷酸消除了小鼠中已建立的实验性结肠炎，Nature Med 2:998-1004。
Neurath MF,Pettersson S(1997)NF-κB p65在慢性肠炎的发病机理中的主导作用，Immunolbiol 198:91-98。Handel ME,McMorrow LB,Gravallese EM(1995)类风湿性滑膜中的核因子-κB；p50和p65的定位，Arthritis Rheumatism 38:1762-1770。
Marok R,Winyard PG,Coumbe A,Kus ML,Gaffney K,BladesS,Mapp PI,Morris CJ,Blake DR,Kaltschmidt C,BaeuerlePA(1996)人发炎性滑膜组织中转录因子核因子-κB的活化，ArthritisRheumatism 39:583-591。
Sioud M,Mellbye O,Forre O(1998)RA滑膜和多关节JRA中NF-κBp65亚基、Fas抗原、Fas配体和Bcl-2相关的蛋白的分析，ClinExpRheumatol 16:125-134。
Tsao PW,Suzuki T,Totsuka R,Murata T,Takagi T,OhmachiY,Fjimura H,Takata I(1997)地塞米松对佐剂性关节炎中活化的NF-κB的表达的影响，Clin Immunol Immunopathol 83:173-178。
Roshak AK,Jackson JR,McGough K,Chabot-Fletcher M,Mochan E,Marchall L(1996)不同NF-κB蛋白的处理改变白介素-1β-诱发的人类风湿滑膜的成纤维细胞的前列腺素E2的形成，J Biol Chem271:31496-31501。
Miyazawa K,Mori A,Yamamoto K,Okudaira H(1998)通过类风湿性滑膜细胞的人白介素-6基因的组成转录；NF-κB和CBF1的自发活化，Am J Pathol 152,793-803
Fujisawa K,Aono H,Sasunuma T,Yamamoto K,Mita S,Ni shiola K(1996)对肿瘤坏死因子α应答的人滑膜细胞中转录因子NF-κB的活化，Aathritis Rheumatism 39:197-203。
Roshak AK,Jackson JR,Chabot-Fletcher M,Marshall L(1997)海洋天然产物hymenialdisine对NF-κB介导的白介素-1β-刺激的前列腺素E2形成的抑制，J Pharmacol Exp Therapeut 283:955-961。
生物学分析
用数种生物学分析方法之一测试本发明的化合物以确定产生给定药理学作用所需的化合物浓度。
如Breton,J.J和Chabot-Fletcher,M.C.,JPET,282,459-466(1997)中所述，用细胞基荧光素酶报告分析分析NF-κB活性。概括地说，在加有250μg/ml遗传霉素(硫酸G418,LifeTechnologies,Grand Island,NY)的上述培养基中培养用NF-κB报道质粒(见下)永久转染的U937人组织细胞性淋巴细胞系。在转染的U937克隆细胞中进行荧光素酶报告分析。在300xg下离心两次(每次5分钟)后，再悬浮于含10％FBS的RPMI 1640中至1×106个细胞/毫升。将每份1毫升的该悬浮液等份试样加到24孔板的孔中。将化合物或二甲基亚砜(DMSO)载体(1μl)加到该适合的孔中，将培养板在37℃、5％CO2下保温30分钟。加入刺激物(5ng/ml TNFα,100ng/mlLPS或0.1μM PMA)，将该样品在37℃、5％CO2下保温5分钟，转移至1.9ml的聚丙烯管中，并于200xg下离心5分钟。细胞沉淀物用不合Ca2+和Mg2+的1ml PBS洗涤两次，并如上所示进行离心。将所得细胞沉淀物在50μl1×裂解缓冲液(Promega Corporation,Madison,WI)中裂解、涡旋并在室温保温15分钟。将每份20μl的裂解物转移至不透明的白底96孔培养板(Wallac Inc.,Gaithersburg,MD)中并在Micro Lumant LB 96 P发光计(EG&G Berthold,Bad Wilbad,Germany)中分析荧光素酶的产生。发光计将100μl的荧光素酶分析试剂(Promega Corporation,Madison,WI)分配到每个孔中并记录整体发出的光20秒。以相对光单位(RLUs)测量发出的光量。
也可采用电泳迁移率变动分析(EMSA)测定NF-κB的活性来估测核中存在的NF-κB蛋白。将被分析细胞以1×106/ml进行培养。通过离心捕获细胞，用不含Ca2+和Mg2+的PBS洗涤后，再以1×107个细胞/毫升的密度悬浮于含Ca2+和Mg2+的PBS。为测定化合物对NF-κB活化的影响，在37℃下用不同浓度的药物或载体(DMSO,0.1％)将细胞悬浮液处理30分钟，然后用TNFα(5.0ng/ml)刺激15分钟。如下制备细胞和核的提取物。概括地说是，在处理结束时，将细胞(1×107个细胞)用不含Ca2+和Mg2+的PBS洗涤两次。将所得细胞沉淀物再悬浮于20μl缓冲液A(10mM Hepes(pH7.9),10mM KCl,1.5mM MgCl2,0.5mM二硫苏糖醇(DTT)和0.1％NP-40)并在冰中保温10分钟。在4℃下通过以3500rpm微量离心10分钟使核沉淀。收集上清液作为细胞提取物，将核沉淀物再悬浮于15μl缓冲液C(20mM Hepes(pH7.9),0.42MNaCl,1.5mM MgCl2,25％甘油，0.2mM EDTA,0.5MM DTT和0.5mM苯甲基磺酰氟(PMSF))中。将该悬浮液在4℃轻轻搅拌20分钟后，在4℃以14000rpm微量离心10分钟。收集上清液并用缓冲液D(20mM Hepes(pH7.9),50mM KCl,20％甘油，0.2mM EDTA,0.5MM DTT和0.5mM PMSF)稀释至60μl。将所有的样品在保存在-80℃直至分析时。按照Bradford(Bradford,1976)的方法，用BioRad试剂测定提取物的蛋白浓度。
采用电泳迁移率变动分析(EMSA)用上述的处理过细胞的核提取物估测化合物对转录因子活化的影响。用T4多核苷酸激酶和[g-32P]ATP标记双链NF-κB共有的寡核苷酸(5’-AGTTGAGGGGACTTTCCCAGGC-3’)。结合的混合物(25μl)含有10mMHepes-NaOH(pH7.9),4mM Tris-HCl(pH7.9),60mM KCl,1mM EDTA,1mM二硫苏糖醇，10％甘油，0.3mg/ml胎牛血清白蛋白和1μg多(dI-dC)·多(dI-dC)。在室温下，在有或没有未标记的竞争物的存在下，将该结合的混合物(10μg核提取蛋白)与0.5ng32P-标记的寡核苷酸(50000-100000cpm)保温20分钟，之后将该混合物加载到在1XTris硼酸盐/EDTA中制备的4％聚丙烯酰胺凝胶上，在200伏下电泳2小时。电泳凝胶之后，进行干燥并与测定结合反应的膜接触。
可用蛋白印迹法监测化合物对IκB磷酸化的影响。使细胞提取物在10％凝胶(BioRad,Hercules,CA)上进行月桂基硫酸钠-聚丙烯酰胺凝胶电泳(SDS-PAGE)并将蛋白转移至硝酸纤维素膜(Hybond1m-ECL,Amersham Corp.,Arlington Heights,IL)。用直接抗IκBα或IκBβ的多克隆兔抗体，然后用过氧化物酶结合的驴抗兔第二代抗体(Amersham Corp.,Arlington Heights,IL)进行免疫印迹分析。用增强化学荧光(ECL)分析系统(Amersham Corp.,Arlington Heights,IL)监测免疫反应带。
用人RSF的原代培养物评价人滑膜成纤维细胞(RSF)对类花生酸产生的影响。通过酶消化取自成人类风湿患者的滑膜得到RSF。在37℃和5％CO2下，在Earl氏最低必需培养基(EMEM)中培养细胞，该培养基中还含有10％胎牛血清(FBS)、100单位/毫升青霉素和100微克/毫升链霉素(GIBCO,Grand Island,NY)。为获得更均匀的I型成纤维细胞群，使用在第4-9传代细胞的培养物，对于某些研究，将成纤维细胞以5×104个细胞/ml密度加到直径为16mm的24孔培养板(Costar,Cambridge,MA)。使细胞与最佳剂量的IL-1β(1ng/ml；Roshak等，1996a)(Genzyme,Cambridge,MA)接触指定的时间。在加入IL-1之前15分钟，往细胞培养物中加入DMSO载体中的药物(1％)。用购自Cayman Chemcial Co.(Ann Arbor,MI)的酶免疫分析(EIA)试剂盒直接测定在培养结束时汇集在不含细胞的培养基中的前列腺素E2水平。用实验培养基制备样品和标准稀释液。
用佛波酯诱发的小鼠耳部炎症模型评价体内抗炎活性。将乙酸肉桂酸佛波酯(PMA)(4μg/20μl丙酮)施用于雄性Balb/c小鼠(6只/组)(Charles River Breeding Laboratories,Wilmington,MA)左耳的内表面和外表面4小时后，将溶解在25μl丙酮中的化合物施用在同一耳朵上。20小时后用刻度式测微计(Mitutoyo,Japan)测量两只耳朵的厚度，并局部施用第二次剂量的化合物。24小时后，测量耳部的厚度，数据以治疗耳和未治疗耳的厚度变化(×10-3cm)表示。然后切下发炎的左耳并贮存于-70℃直至分析用于分析髓过氧化物酶(MPO)的活性，该酶活性是一种炎症细胞浸润的量度。
通过测量发炎耳组织中存在的髓过氧化物酶活性评价炎症细胞的浸润。将部分融化的耳组织切碎，然后用Tissumizer匀浆器(Tekmar Co.,Cincinnati,OH)在含0.5％HTAB的50mM磷酸盐缓冲液(pH 6)中匀化(10％w/v)。对组织匀化物进行三次冷冻-融化循环，然后进行短暂超声(10秒)。如下测定匀化物中的MPO活性。在460nm用分光光度法测定邻二甲氧基苯胺(0.167mg/加ml,SigmaChemical,St.Louis,MO)和过氧化氢(0.0005％)的MPO-依赖性反应的有色产物的出现。用Bechman DU-7分光光度计和动力学分析设备(Beckman Instruments,Inc.,Sommerset,NJ)动力学定量上清液的MPO活性(以15秒的间隔取样，测量3分钟的吸收变化)。一单位的MPO活性被定义为25℃下每分钟分解一微摩尔的过氧化物。
在体外软骨分离块系统中测定对炎症介导的软骨破裂的影响。在该模型中，在有或没有试验化合物的存在下，将牛关节软骨分离块或该分离块和rHuIL-1α一起保温4天/96小时，以促进软骨破裂。取出上清液用于进行一氧化氮分析。用Greiss反应并以分光光度计读取530nm处的数据测定一氧化氮。该反应测定二氧化氮(NO2)，它是一氧化氮的稳定终产物。
通述
在250、300或400Mhz下，分别使用Bruker AM 250、Bruker 300或Bruker AC 400光谱仪测定核磁共振谱。CDCl3是氘代氯仿，DMSO-d6是六氘代二甲基亚砜，CD3OD是四氘代甲醇。化学位移值以与内标四甲基硅烷相比的低场位移(downfield)的百万分之一为单位报告。NMR数据中的缩写如下：s=单峰，d=双重蜂，t=三重峰，q=四重峰，m=多重峰，dd=双重双峰，dt=双三重峰，app=清晰可见的峰，br=宽峰。J表示在Hertz中测量的NMR偶合常数。在Perkin Elmer683红外光谱仪上记录连续波红外光谱(IR)，在Nicolet Impact 400D红外光谱仪上记录傅立叶变换红外光谱(FTIR)。以传输方式记录IR和FTIR，以反波数为单位(cm-1)记录谱带的位置。在VG 70 FE、PESyx API Ⅲ或VG ZAB HF仪上，使用快速原子轰击(FAB)或电喷(ES)离子化技术测定质谱。用Perkin-Elmer 240C元素分析仪进行元素分析。在Thomas-Hoover熔点仪上测定熔点，但没有校正。所有的温度均以摄氏度报告。
用Analtech Silica Gel GF和E.Merck Silica Gel 60F-254薄层板进行薄层色谱。用E.Merck Kieselgel 60(230-400目)硅胶进行快速色谱和重力色谱。
如下面所示，某些原料购自Aldrich Chemical Co.,Milwaukee,Wisconsin。
实施例
在下列合成实施例中，温度以摄氏度(℃)表示。除非另有说明，所有原料均从市场获得。无需进一步的阐述，相信本领域普通技术人员可以通过前面的描述最大程度的实现本发明。这些实施例用于说明本发明，而非限制其范围。发明者要求保护的是下面提到的权利要求书。
实施例1
3-[(N-丁基)氨基]-2-亚苄基二氢茚酮的制备
a)2-亚苄基二氢茚酮
按照A.Hassner,N.H.Cromwell,J.Org.Chem.1958,80,893-900的方法，在0℃下，将苯甲醛(6.05ml,53.6mmol)加到二氢茚酮(Aldrich,7.08g,53.6mmol)的乙醇溶液和KOH(600mg,10.6mmol)中，将该反应物放置在冰箱中过夜。将反应混合物过滤，用50％乙醇水溶液洗涤，然后在热乙醇中重结晶，得到5.84g 2-亚苄基二氢茚酮。1H NMR(300MHz,CDCl3)δ7.93(d,1H,J=7.7),7.75-7.35(m,8H),4.08(s,2H)。
b)3-溴-2-亚-苄基二氢茚酮
按照B.D.Pearson,R.P.Ayer,N.H.Cromwell,J.Org.Chem.1962,27,3038-3044的方法，在四氯化碳(15ml)中，将实施例1(a)得到的化合物(1.0g,4.55mmol)用NBS(810mg,4.55mmol)和过氧化苯甲酰(50mg)处理，并将该混合物用热灯加热回流1小时。将反应物冷却，过滤并蒸发滤液，得到3-溴-2-亚苄基二氢茚酮，该产物无需纯化即可使用。1H NMR(300MHz,CDCl3)δ8.1-7.2(m,10H),6.40(s,2H)。
c)3-[(N-丁基)氨基]-2-亚苄基二氢茚酮
按照G.Maury,E.-M.Wu.N.H.Cromwell,J.Org.Chem.1968,33,1900-1907的方法，在苯中将实施例1(b)得到的化合物用正丁基胺(300μl,3.04mmol)处理并将该溶液在室温下搅拌24小时。蒸发反应物，残余物经快速色谱(硅胶，10％乙酸乙酯的己烷溶液)纯化，得到353mg 3-[(N-丁基)氨基]-2-亚苄基二氢茚酮。在乙醚中，将一部分游离碱用1N盐酸的乙醚溶液处理，得到固体状的盐酸盐。ES-MS(M+H)+m/e 292；H NMR(300MHz,CDCl)δ8.2(d,1H,J=7.0Hz),9.03(s,1H),7.98(d,1H,J=6Hz),7.84(t,1H,J=6Hz),7.75-7.50(m,7H),6.7(brs,1H),2.48(brs,1H),2.28(brs,1H),1.6-1.3(m,2H),0.95-0.8(m,2H),0.65(t,3H,J=6.5Hz)。
上述说明书和实施例充分公开了如何制备和使用本发明的化合物。但本发明不限于上文描述的特定实施方案，而是包括本发明范围内其所有的改变。本文引述的各种期刊、专利和其它出版物文献包括了现有技术的描述，将它们全文结合到本文中以供参考。
Claims (18)
1、一种药物组合物，含有式Ⅰ化合物
其中：
R1是芳基；
R2选自：H、C1-6烷基和芳基；
R3选自：C1-6烷基和C3-8环烷基；并且
R2和R3可一起形成一个5-7个原子的杂环，所示原子选自：C、N、O和S；
以及可药用载体、稀释剂或赋形剂。
2、权利要求1的药物组合物，其中R2是H。
3、权利要求2的药物组合物，其中R3选自：丁基和环己基。
4、权利要求1的药物组合物，其中R2和R3可一起联合形成5-7个原子的杂环，所述原子选自C、N、O和S。
5、权利要求4的药物组合物，其中R3选自吗啉基和哌啶基。
6、权利要求1的药物组合物，其中所述化合物选自：
3-[(N-丁基)氨基]-2-亚苄基二氢茚酮；
3-[(N-环己基)氨基]-2-亚苄基二氢茚酮；
3-吗啉基-2-亚苄基二氢茚酮；和
3-哌啶基-2-亚苄基二氢茚酮。
7、一种抑制NF-κB的方法，包括对需此抑制的患者施用有效量的式Ⅰ化合物：其中：
R1是芳基；
R2选自：H、C1-6烷基和芳基；
R3选自：C1-6烷基和C3-8环烷基；并且
R2和R3可一起形成一个5-7个原子的杂环，所示原子选自：C、N、O和S。
8、权利要求7的方法，其中所述化合物选自：
3-[(N-丁基)氨基]-2-亚苄基二氢茚酮；
3-[(N-环己基)氨基]-2-亚苄基二氢茚酮；
3-吗啉基-2-亚苄基二氢茚酮；和
3-哌啶基-2-亚苄基二氢茚酮。
9、一种以NF-κB过度活化为特征的疾病的治疗方法，包括通过对需此治疗的患者施用有效量的式Ⅰ化合物及其可药用盐、水合物和溶剂化物抑制所述过度活化其中：
R1是芳基；
R2选自：H、C1-6烷基和芳基；
R3选自：C1-6烷基和C3-8环烷基；并且
R2和R3可一起形成一个5-7个原子的杂环，所示原子选自：C、N、O和S。
10、权利要求9的方法，其中所述化合物选自：
3-[(N-丁基)氨基]-2-亚苄基二氢茚酮；
3-[(N-环己基)氨基]-2-亚苄基二氢茚酮；
3-吗啉基-2-亚苄基二氢茚酮；和
3-哌啶基-2-亚苄基二氢茚酮。
11、权利要求9和10的方法，其中所述疾病是炎症性疾病。
12、权利要求14的方法，其中所述疾病选自类风湿关节炎、炎症性肠病和哮喘。
13、权利要求9和10的方法，其中所述疾病是皮肤病。
14、权利要求13的方法，其中所述疾病选自牛皮癣和特应性皮炎。
15、权利要求9和10的方法，其中所述疾病选自：自身免疫性疾病；组织和器官排斥反应；阿尔茨海默氏病；中风；动脉粥样硬化；再狭窄；骨关节炎；骨质疏松；和Ataxia Telangiestaisa。
16、权利要求9和10的方法，其中所述疾病是癌症。
17、权利要求16的方法，其中所述癌症是何杰金氏病。
18、权利要求9和10的方法，其中所述疾病是AIDS。
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| US9001698P | 1998-06-19 | 1998-06-19 | |
| US60/090,016 | 1998-06-19 |
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| AU713473B2 (en) | 1996-12-23 | 1999-12-02 | Immunex Corporation | Receptor activator of NF-kappa B, receptor is member of TNF receptor superfamily |
| US6316408B1 (en) | 1997-04-16 | 2001-11-13 | Amgen Inc. | Methods of use for osetoprotegerin binding protein receptors |
| EP1076699B1 (en) | 1998-05-14 | 2008-10-29 | Immunex Corporation | Method of inhibiting osteoclast activity |
| EP1250137B1 (en) * | 2000-01-24 | 2007-08-15 | Genzyme Corporation | Jak/stat pathway inhibitors and the use thereof for the treatment of primary generalized osteoarthritis |
| US20060148732A1 (en) * | 2000-11-17 | 2006-07-06 | Gutterman Jordan U | Inhibition of NF-kappaB by triterpene compositions |
| US7425580B2 (en) | 2004-05-19 | 2008-09-16 | Wyeth | (Diaryl-methyl)-malononitriles and their use as estrogen receptor ligands |
| JP2009526855A (ja) | 2006-02-16 | 2009-07-23 | ミレニアム・ファーマシューティカルズ・インコーポレイテッド | アルファカルボリンおよびその使用 |
| ES2431368T3 (es) | 2008-10-02 | 2013-11-26 | Asahi Kasei Pharma Corporation | Derivado de isoquinolina substituido en posición 8 y su utilización |
| US9127016B2 (en) | 2009-03-20 | 2015-09-08 | University of Pittsburgh—of the Commonwealth System of Higher Education | Small molecule inhibitors of Dusp6 and uses therefor |
| US9186365B2 (en) * | 2009-07-31 | 2015-11-17 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Antiangiogenic small molecules and methods of use |
| WO2012109527A2 (en) | 2011-02-10 | 2012-08-16 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Class of hdac inhibitors expands the renal progenitor cells population and improves the rate of recovery from acute kidney injury |
| US9670236B2 (en) | 2012-10-31 | 2017-06-06 | University of Pittsburgh—of the Commonwealth System of Higher Education | Class of HDAC inhibitors expands the renal progenitor cells population and improves the rate of recovery from acute kidney injury |
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| Publication number | Publication date |
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| EP1085872A1 (en) | 2001-03-28 |
| NO20006452D0 (no) | 2000-12-18 |
| NO20006452L (no) | 2001-02-16 |
| CZ20004760A3 (cs) | 2001-08-15 |
| JP2002518333A (ja) | 2002-06-25 |
| EP1085872A4 (en) | 2003-04-16 |
| TR200003779T2 (tr) | 2001-06-21 |
| KR20010052990A (ko) | 2001-06-25 |
| HUP0102492A2 (hu) | 2001-11-28 |
| CA2335293A1 (en) | 1999-12-23 |
| ZA200007448B (en) | 2001-12-12 |
| PL345577A1 (en) | 2001-12-17 |
| AU4699699A (en) | 2000-01-05 |
| WO1999065495A1 (en) | 1999-12-23 |
| CO5080752A1 (es) | 2001-09-25 |
| IL140324A0 (en) | 2002-02-10 |
| BR9911151A (pt) | 2001-03-06 |
| AR019871A1 (es) | 2002-03-20 |
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