CN1589137A - 神经退化性及心血管疾病之治疗方法 - Google Patents
神经退化性及心血管疾病之治疗方法 Download PDFInfo
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- CN1589137A CN1589137A CNA02823183XA CN02823183A CN1589137A CN 1589137 A CN1589137 A CN 1589137A CN A02823183X A CNA02823183X A CN A02823183XA CN 02823183 A CN02823183 A CN 02823183A CN 1589137 A CN1589137 A CN 1589137A
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Abstract
一种以如下列化学式(I)所示的化合物治疗神经退化性或心血管疾病的方法。其中，该化合物中的X、Y、A1、A2、R1和R2都在说明书中定义。
Description
发明背景
由一氧化氮所引发(Nitric Oxide(NO)-induced)以及与硫胱氨酸蛋白酶1有关(caspase 1-related)的神经元丧失(neuronal loss)会导致神经退化性疾病，如：新生儿与成人的中风(neonatal and adult stroke)、帕金森氏症(Parkinson’s disease)、亨丁顿氏舞蹈症(Huntington’sdisease)、阿滋海默氏症(Alzheimer’s disease)、肌萎缩侧索硬化症(amyothrophic lateral sclerosis)、中风(stroke)、脊柱损伤(spinal injury)、移植(transplantation)、多发性硬化症(multiple sclerosis)和听力丧失(hearing loss)。目前尚无任何神经保护药物(neuroprotective drug)能有效治疗这些疾病。有一些药物藉由增加剩余神经元的功能而治疗这些疾病。然而，没有一种药物能非常成功地减缓这些疾病的恶化，有些药物甚至会产生不好的副作用，例如，帕金森氏症病人会产生运动症状波动(motor fluctuations)和乱动症(dyskinesias)(参考Quinn，et al.，Neurology，1998，51，S25-29)。此外，由一氧化氮引发及与硫胱氨酸蛋白酶1有关的心脏细胞丧失(heart cell loss)会导致心脏血管疾病，包括：心脏衰竭(heart failure)、动脉硬化(arteriosclerosis)、心肌炎(myocarditis)和心肌病(cardiomyopathy)。
发明内容
本发明是有关于一种治疗神经退化性和心血管疾病，以及其他由一氧化氮引发或与硫胱氨酸蛋白酶1有关的细胞死亡所造成的疾病的方法。上述方法包括为一个需要治疗的个体投予一个或更多的如下式所代表的化合物(I)：
其中，R1和R2分别是碳数1～8的次烷基(alkylene)，碳数2～8的次烯烃基(alkenylene)，或将其删除；A1和A2分别是芳基(aryl)或异芳基(heteroaryl)，可以卤素(halogen)，-CN、-NO2、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4、-C(O)R3、-S(O)R3、-S(O)2R3、-NR4R5、-C(O)OR3、-C(O)NR4R5、-O(O)CR4、或-NR4(O)CR5任意地单一取代或多取代(例如：双取代或三取代)，而X和Y分别是氧(O)、硫(S)或NR6，其中R3是碳数1～4的烷基(C1-4 alkyl)，R4、R5和R6则分别是氢(H)或碳数1～4的烷基。
“烷基”是单价的烃基(hydrocarbon radical)，该烃基为直链或分支链(例如：-CH2CH2CH3或-CH(CH3)2)。“次烷基”是双价的烃基，该烃基为直链或分支链(例如：-CH2CH2-或-CH2CH(CH3)-CH3)。“次烯烃基”是双价的烃基，该烃基为直链或分支链，并且包含一个或多个双键(例如：-CH2CH＝CH-CH2-或-CH2CH(CH3)CH＝CH-CH2-)。“芳基”是碳数6～12的单环(monocyclic)或多环(multicyclic)(稠合的或分离的)芳香系统(aromatic system)，其中每个环上有高达4个原子会被取代。芳基族的例子包括苯基(phenyl)和萘基(naphthyl)。“异芳基(heteroaryl)”是5-8元单环，8-12元双环，或11-14元三环的芳环系统。若该系统为单环系统，则包含1-3个异原子；若为双环系统，则包含1-6个异原子；若为三环系统，则包含1-9个异原子(这些异原子包括氧、氮或硫)。异芳基族的例子包括吡啶基(pyridyl)、呋喃基(furyl)、咪唑基(imidazolyl)、苯并咪唑基(benzimidazolyl)、嘧啶基(pyrimidinyl)、喹啉基(quinolinyl)、吲哚(indolyl)或噻唑(thiazolyl)。
接着讨论(I)式化合物。能够用以实行本发明方法的化合物当中，其中一子集的X与Y各自为氧。另一子集中，R1是碳数2～8的次烯烃基，而R2是碳数1～8的次烷基。另一子集中，A1和A2各自为芳基(例如：苯基)，并可以卤素，-CN、-OH、-SH，、OR3、-SR3、-R3、-R3-OR4、或-NR4R5任意地取代。再另一子集中，R1是碳数2～3的次烯烃基(例如：-CH＝CH-)，而R2是碳数1～3的次烷基(例如：-CH2-CH2-)。该等化合物的其中一例为咖啡酸苯乙酯(caffeic acid phenethyl ester)：
可用本发明方法治疗神经退化性及心血管疾病的起因是由一氧化氮引发或与硫胱氨酸蛋白酶1有关的细胞丧失(cell loss)，以及多巴胺(dopamine)或多巴胺能神经细胞(dopaminergic neurons)的数量减少。此类疾病与一些疾病有关联，例如：新生儿与成人的中风、帕金森氏症、亨丁顿氏舞蹈症、阿滋海默氏症、肌萎缩侧索硬化症、中风、脊柱损伤、移植、多发性硬化症、听力丧失、心脏衰竭、动脉硬化、心肌炎、心肌病和糖尿病。因此，在本发明的范围内，可利用一个或更多上述化合物作为治疗这些疾病的药物。
在为一个需要治疗神经退化性或心血管疾病的病人投予一个或更多上述化合物之前，需先将该化合物配制成药学组合物(pharmaceuticalcomposition)。因此，本发明也有关于一药学组合物，该药学组合物包含药学上可接受的载体以及一有效量的上述一个或更多用以治疗神经退化性或心血管疾病的化合物。另一方面，进一步讲，本发明是有关于一种制品，该制品包括：I)容器；II)药学组合物，该药学组合物包含了药学上可接受的载体以及一有效量的一个或更多上述化合物；III)标签，该标签配置于容器上，并且标示用以治疗神经退化性或心血管疾病的药学组合物的用法说明。该用法说明可以提供病人药学组合物的使用指示，例如：硬膜(epidural)注射、鞘内(intrathecal)注射、非口服给药(parenteral)，或局部用药。
同时，在本发明范畴之内，也包括使用一个或以上的上述化合物的药剂制品，用于治疗上述神经退化性及心血管疾病。
在适当情况下，上述化合物也包括其盐类及前驱药物(prodrug)。举例来说，该盐类可经由上述化合物中的正价取代基(例如：胺基(amino))与阴离子(anion)结合而成。适当的阴离子包括：氯化物(chloride)、溴化物(bromide)、碘化物(iodide)、硫酸盐(sulfate)、硝酸盐(nitrate)、磷酸盐(phosphate)、柠檬酸盐(citrate)、甲磺酸(methanesulfonate)、三氟乙酯(trifluoroacetate)、和乙酯(acetate)，但不只限于此。同样地，上述化合物中的负价取代基(例如：羧酸盐(carboxylate))可以和阳离子(cation)形成盐类。适当的阳离子包括：钠离子、钾离子、镁离子、钙离子和阳离子铵(ammonium cation)(例如：四甲基铵离子(tetramethylammonium ion))。前驱药物的例子包括：酯类(esters)和其他药学上可接受的衍生物。在为病人投予药物的过程中，该前驱药物能供给上述化合物。
本发明的详细实施例会在下列实施方式中提及。本发明的其他特色、目的和优点将列于实施方式与申请专利范围之中。
发明详述
本发明是有关于一种治疗神经退化性和心血管疾病，以及其他由一氧化氮引发或与硫胱氨酸蛋白酶1有关的细胞死亡所造成的疾病的方法。该方法是使用一个或以上的下式化合物：
其中，A1、A2、R1、R2、X和Y已于先前定义。
通过已知技术可合成这些化合物。例如：将分子式A1-R1-C(＝X)-OH的前驱物(precursor)与分子式A2-R2-YH(Y是O、S或NH)的前驱物反应可得到X是氧或硫的化合物。参考：Loudon，OrganicChemistry，3rd Ed.，1995，Benjamin/Cummings Publishing Company，Inc.，Redwood，City，CA.。由此得到的化合物与氨(ammonia)或胺(amine)反应后可任意地转变成亚胺(imine)(即X为NH或氮(烷基)(N(alkyl)))。参考：Verardo et al.，Synth Commun，1998，18，1501；andFarrar，Rec.Chem.Prog.1968，29，85-101.。
举例来说，将咖啡酸与过量的苯乙醇(phenethyl alcohol)以及酸催化剂(acid catalyst)(例如：甲苯磺酸(p-toluene sulfonic acid)在适当溶剂(例如：苯(benzene))中，经回流(reflux)反应一段长时间(例如：3或4天)后，可合成咖啡酸苯乙酯。利用蒸馏法除去过多的苯乙醇即可获得纯咖啡酸苯乙酯(熔点126-128℃，针晶)。见Grunberger etal.，Experientia，1988，44，23-232.。
一适当、有效量的(I)式化合物或其盐类需要先以药学上可接受的载体将其配制成药学组合物，才能将该化合物或其盐类投与需治疗神经退化性和心血管疾病、以及其他由一氧化氮引发或与硫胱氨酸蛋白酶1有关的细胞死亡(cell death)所造成疾病的病人。“有效量(an effectiveamount)”是指能给予被治疗个体治疗效果的化合物量，该有效量则是根据动物和临床研究而确立的。动物与人类之间剂量的相互关系(以每平方米体表面积的毫克数为根据)可参考Freireich et al.，CancerChemother Rep，1966，50，219的叙述。由病人的身高与体重可大致确定体表面积(body surface)(参考：Scientific Tables，Geigy Pharmaceuticals，Ardley，New York，1970，537.)。根据已知技术，有效剂量会随着给药途径、赋形剂用法(excipient usage)和选择性地并用其他疗法而改变。药学上可接受的载体包括胶态二氧化矽(colloidal silicon dioxide)、硬脂酸镁(magnesium stearate)、纤维素(cellulose)、硫酸月桂酸钠(sodium laurylsulfate)和D&C 10号黄色素(D&C Yellow #10)等。
药学组合物可以通过非口服途径(parenteral route)给予，例如：腹膜腔内(intraperitoneally)给药和静脉内(intravenously)给药。非口服剂量形式的例子包括：将活性化合物溶于磷酸盐缓冲液生理食盐水(phosphate buffer saline，PBS)中，或利用其他药学上可接受的载体混合。已知技术中常用的溶解剂(solubilizing agents)(例如：环糊精(cyclodextrins)或其他溶解剂)也可以包含在药学组合物中。
利用已知技术中的体外和体内分析(in vitro and in vivo assays)，可评估(I)式化合物治疗神经退化性或心血管疾病的效能。见以下提供的三个实例。
即使没有更进一步的详细说明，一般相信熟悉此技术的人士能以此处的说明为基础，将本发明使用至极致。所有在此引用的出版品全部并入参考文献。因此，下列特定的范例描述一种(I)式化合物——咖啡酸苯乙酯——的生物检定(biological testing)，而该范例只以图式说明，并且不以任何方式局限于揭露的其余部分。
实施例1
根据Du，et al.，Proc Natl Acad Sci，2001，98，14669-14674.一文中所描述的方法，欲评估咖啡酸苯乙酯对于治疗神经退化性疾病和其他由一氧化氮引发细胞死亡所造成疾病的效能，可在培养的神经元上测试咖啡酸苯乙酯阻碍由一氧化氮引发的细胞死亡的能力。
从小脑颗粒状神经元(cerebellar granule neurons，CGN)培养物中发现，由一氧化氮所引发的显著的神经元细胞死亡现象会被咖啡酸苯乙酯以浓度依赖(concentration-dependent)方式(半数抑制浓度(IC50)～1微摩尔(μM))阻断。当使用6-羟基多巴胺(6-hydroxydopamine)诱导神经毒性(neurotoxicity)时，也会观察到咖啡酸苯乙酯的神经保护作用。
实施例2
利用小鼠来评估咖啡酸苯乙酯治疗神经元退化性疾病的效能。使用三组8周大的C57B1/6雄性小鼠(Taconic Farms Inc.，Germantown，NY)，每组5-7只。一组小鼠给予咖啡酸苯乙酯(将咖啡酸苯乙酯溶于10％乙醇，再以胃管经口灌食5或20毫克/公斤/天(mg/kg/day)，或者经由腹膜腔内给药40毫克/公斤/天)9天。第二组小鼠为对照组，只给予10％乙醇，而不给予咖啡酸苯乙酯。然后，这两组小鼠在一天之内每隔两小时一次，经由腹膜腔内给予4次以生理食盐水溶解的1-甲基-4-苯基-1，2，3，6-四氢吡啶盐酸盐(1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine(“MPTP”)-HCl)(20毫克/公斤，不含碱(base))(见Liberatore，et al.，Nat Med，1999，5，1403-1409的描述)。
在最后一次给予1-甲基-4-苯基-1，2，3，6-四氢吡啶7天之后，以哈药仙吸入剂(halothane inhalation)麻醉小鼠，然后取出小鼠的脑，以含有4％三聚甲醛(paraformaldehyde)的0.1摩尔磷酸盐缓冲液(pH7.4)灌注固定。经过固定以及随后以30％蔗糖/磷酸盐缓冲液低温保护(cryoprotection)之后，将脑置于液态氮中冷冻，并且将其中脑连续切片成40微米。该组织切片以含有0.1％非离子性界面活性剂Triton X-100的0.1摩尔磷酸盐缓冲液生理食盐水冲洗三次，每次5分钟。然后将该切片置于多株兔抗酪氨酸羟化酶抗体(rabbit polyclonal anti-tyrosinehydroxylase(anti-TH)antibody)(1：2，500，CALBIOCHEM，La Jolla，CA)、生物素化结合的多株羊抗兔抗体(goat biotinylated-conjugatedpolyclonal anti-rabbit antibody)(1：250；Vector Laboratories，Burlingame，CA)与马萝卜过氧化物酶结合的卵白素/生物素复合体(horseradish-peroxidase conjugated avidin/biotin complex)(VECTASTAIN ABC Reagent，Vector Laboratories)中，接着将其曝于二氨基联苯胺(diaminobenzidine)以进行酪酸胺羟化酶免疫组织化学(TH-immunohistochemistry)分析和酪氨酸羟化酶阳性神经元(TH-positive neurons)的体视学定量(stereological quantification)。用以计算酪氨酸羟化酶阳性神经元数量的体视学方法可参考Triarhou，etal.，J Neurocytol，1988，17，221-232.的叙述。
第三组小鼠为另一组对照组，只给予生理食盐水，而不给予咖啡酸苯乙酯和1-甲基-4-苯基-1，2，3，6-四氢吡啶。
第二组小鼠的黑质致密区(substantia nigra pars compacta，SNpc)中的酪氨酸羟化酶阳性神经元数量大约为第三组小鼠的49％。第一组小鼠的酪氨酸羟化酶阳性神经元数量(达100％)比第二组小鼠高。只给予咖啡酸苯乙酯9天的小鼠的酪氨酸羟化酶阳性神经元数量无显著改变。
通过高效液相层析仪(HPLC)结合电化学侦测器(electrochemicaldetector)，可确定纹状体(striatal)内的多巴胺及其代谢物二羟苯乙酸(dihydroxyphenylacetic acid，DOPAC)与高香草酸(homovanillic acid，HVA)的含量(参考Du，et al.，Proc Natl Acad Sci，2001，98，14669-14674)。比较第二组小鼠与第三组小鼠的数据，其结果显示，在给予1-甲基-4-苯基-1，2，3，6四氢吡啶而未以予咖啡酸苯乙酯48小时以后，第二组小鼠纹状体的多巴胺、二羟苯乙酸和高香草酸含量分别减少了62％、46％和35％。在第一组小鼠当中，咖啡酸苯乙酯(腹膜腔内给药40毫克/公斤)明显地阻断在纹状体中由1-甲基-4-苯基-1，2，3，6四氢吡啶所引发的多巴胺及其代谢物的减少。更具体地说，给予咖啡酸苯乙酯的结果是使得纹状体中由1-甲基-4-苯基-1，2，3，6四氢吡啶所引发的多巴胺、二羟苯乙酸和高香草酸的减少分别只有3％、-2％和16％。
这些结果意外地显示咖啡酸苯乙酯能有效保护神经元不至于因1-甲基-4-苯基-1，2，3，6四氢吡啶而造成死亡。
实施例3
根据Choong，et al.，J Cardiovasc Surg(Torino)，1993 Oct.，34(5)：423-433.文章中所描述的方法，采用兔离体工作心脏模型(isolatedworking rabbit heart model)说明局部缺血(ischaemia)时咖啡酸苯乙酯的心脏保护作用(cardioprotective effects)(功能、新陈代谢和超微结构(ultrastructure))。更具体地来说，在局部缺血期间，使心脏(每组7个样本)停搏并回输(45分钟)冰的(4℃)心脏冷冻液(cardioplegicsolution)。咖啡酸苯乙酯(腹膜腔内给药30毫克/公斤)在一个小时之内显著地(p＜0.05)提升局部缺血后心输出量(cardiac output)的恢复百分比，从71.48+/-9.66％增加至90.83+/-3.2％。在40分钟的局部缺血停搏(ischaemic arrest)期间(对照组与处理组分别以55.14+/-8.65与19.33+/-7.4免疫单位/升(IU/L)灌注，p＞0.05)，乳酸去氢酶(lactatedehydrogenase)的释出量减少。见Ersahin et al.，J Cardiovasc Pharmacol，1999 Oct；34(4)：604-611.。其结果显示咖啡酸苯乙酯保护心肌(myocardium)免于局部缺血的伤害，因此能用以治疗心跳停止(cardiacarrest)。
虽然本发明比较有效的实施案例已如上文所述，但是本发明并非仅限于这些案例。任何熟习此技术的人士，在不脱离本发明的精神和范围内，可以进行各种变更和润饰，因此本发明的保护范围应按后附权利要求书所界定的内容为准。
Claims (21)
1.一种用于治疗神经退化性或心血管疾病的方法，包括为一需要治疗个体投予一有效量的下式化合物：
其中
R1和R2分别是碳数1～8的次烷基，碳数2～8的次烯烃基，或将其删除；
A1和A2分别是芳基或异芳基，并且可以卤素，-CN、-NO2、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4、-C(O)R3、-S(O)R3、-S(O)2R3、-NR4R5、-C(O)OR3、-C(O)NR4R5、-O(O)CR4、或-NR4(O)CR5任意地取代；以及
X和Y分别是氧、硫或NR6，其中R3是碳数1～4的烷基，以及R4、R5和R6则分别是氢或碳数1～4的烷基。
2.如权利要求1所述的方法，其中X和Y分别是氧。
3.如权利要求2所述的方法，其中R1是碳数2～8的次烯烃基，以及R2是碳数1～8的次烷基。
4.如权利要求3所述的方法，其中R1是碳数2～3的次烯烃基，以及R2是碳数1～3的次烷基。
5.如权利要求4所述的方法，其中A1是和A2各自为芳基，并且可以卤素，-CN、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4、或-NR4R5任意地取代。
6.如权利要求4所述的方法，其中R1是-CH＝CH-，以及R2是-CH2-CH2-。
7.如权利要求6所述的方法，其中A1是和A2各自为芳基，并且可以卤素，-CN、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4或-NR4R5任意地取代。
8.如权利要求7所述的方法，其中A1是和A2各自为苯基，并可以任意地以-OH或-SH取代。
9.如权利要求2所述的方法，其中A1是和A2各自为芳基，并且可以卤素，-CN、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4或-NR4R5任意地取代。
10.如权利要求9所述的方法，其中A1是和A2各自为苯基，并可以任意地以-OH或-SH取代。
11.如权利要求1所述的方法，其中R1是碳数2～8的次烯烃基，以及R2是碳数1～8的次烷基。
12.如权利要求11所述的方法，R1是碳数2～3的次烯烃基；以及R2是碳数1～3的次烷基。
13.如权利要求12所述的方法，其中R1是-CH＝CH-，以及R2是-CH2-CH2-。
14.如权利要求12所述的方法，其中A1和A2各自为芳基，并且可以卤素，-CN、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4或-NR4R5任意地取代。
15.如权利要求14所述的方法，其中A1是3，4-二羟基苯基(3，4-dihydroxyphenyl)，A2是苯基。
16.如权利要求15所述的方法，其中R1是-CH＝CH-，R2是-CH2-CH2-；以及X和Y分别为氧。
17.如权利要求1所述的方法，其中A1和A2各自为芳基，并且可以卤素，-CN、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4或-NR4R5任意地取代。
18.如权利要求17所述的方法，其中A1是和A2各自为苯基，并可以任意地以-OH或-SH取代。
19.一种制品，该制品包括：
i)一个容器；
ii)一种有效剂量的化合物，该化合物置于容器之内，且其分子式如下：
其中
R1和R2分别是碳数1～8的次烷基，碳数2～8的次烯烃基，或将其删除；
A1和A2分别是芳基或异芳基，并且可以卤素，-CN、-NO2、-OH、-SH、-OR3、-SR3、-R3、-R3-OR4、-C(O)R3、-S(O)R3、-S(O)2R3、-NR4R5、-C(O)OR3、-C(O)NR4R5、-O(O)CR4或-NR4(O)CR5任意地取代；以及
X和Y分别是氧、硫或NR6，其中R3是碳数1～4的烷基，以及R4、R5和R6则分别是氢或碳数1～4的烷基；以及
iii)一标签，该标签位于容器之上，并且具有治疗神经退化性或心血管疾病的使用说明。
20.如权利要求19所述的制品，其中X和Y分别为氧；R1是碳数2～3的次烯烃基；R2是碳数1～3的次烷基；而A1和A2分别是芳基，并且可以卤素，-CN，-OH，-SH，-OR3，-SR3，-R3，-R3-OR4，或-NR4R5任意地取代。
21.如权利要求20所述的制品，其中R1是-CH＝CH-；R2是-CH2-CH2-；
A1是3，4-二羟基苯基，以及A2是苯基。
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| CN103260614A (zh) * | 2010-10-18 | 2013-08-21 | 开米根公司 | 联合疗法 |
| CN103384522A (zh) * | 2010-11-15 | 2013-11-06 | 开米根公司 | 咖啡酸衍生物和它们在改善神经细胞生存力中的用途 |
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| US20070208087A1 (en) | 2001-11-02 | 2007-09-06 | Sanders Virginia J | Compounds, compositions and methods for the treatment of inflammatory diseases |
| SI2527315T1 (sl) | 2002-05-31 | 2014-06-30 | Proteotech Inc., | Spojine, sestavki in metode za zdravljenje amiloidnih bolezni in sinukleinopatij, kot so Alzheimerjeva bolezen, diabetes tipa 2 in Parkinsonova bolezen |
| US20040167217A1 (en) * | 2003-02-26 | 2004-08-26 | Giovanni Scapagnini | Neuroprotective effects of polyphenolic compounds |
| EP1988887A2 (en) * | 2006-01-13 | 2008-11-12 | University of South Carolina | Method and composition for the treatment of parkinson's disease |
| US8058309B2 (en) * | 2006-12-04 | 2011-11-15 | Novotyr Therapeutics Ltd. | Protein kinase modulators and therapeutic uses thereof |
| US8637575B2 (en) | 2008-06-05 | 2014-01-28 | Novotyr Therapeutics Ltd. | Modulators of protein kinase signaling |
| EP3021944B1 (en) | 2013-07-14 | 2018-12-19 | Yissum Research Development Company of the Hebrew University of Jerusalem, Ltd. | Igf-1r signaling pathway inhibitors useful in the treatment of neurodegenerative diseases |
| WO2016125169A1 (en) | 2015-02-05 | 2016-08-11 | Tyrnovo Ltd. | Combinations of irs/stat3 dual modulators and anti-cancer agents for treating cancer |
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| US4959503A (en) * | 1986-04-11 | 1990-09-25 | Warner-Lambert Company | Diarylalkanoids having activity as lipoxygenase inhibitors |
| JPH0678286B2 (ja) * | 1988-03-18 | 1994-10-05 | 三井東圧化学株式会社 | ジヒドロカフェイン酸誘導体およびそれを有効成分として含有する治療剤 |
| DE3920616A1 (de) * | 1989-06-23 | 1991-01-03 | Boehringer Mannheim Gmbh | Arzneimittel, enthaltend di-tert.-butylhydroxyphenyl-derivate sowie neue derivate |
| DE4126662A1 (de) * | 1991-08-13 | 1993-02-18 | Boehringer Mannheim Gmbh | Neue 3,5-di-tert.butyl-4-hydroxyphenyl-derivate, verfahren zu ihrer herstellung und arzneimittel |
| WO1997023202A1 (en) * | 1995-12-22 | 1997-07-03 | STATE OF OREGON, acting by and through THE OREGON STATE BOARD OF HIGHER EDUCATION, acting for and on behalf of THE OREGON HEALTH SCIENCES UNIVERSITYA ND THE UNIVERSITY OF OREGON, EUGENE OREGON | Subtype-selective nmda receptor ligands and the use thereof |
| CN100413961C (zh) * | 1996-09-05 | 2008-08-27 | 研究发展基金会 | 用咖啡酸苯乙酯衍生物、辣椒素和树脂毒素抑制NF-κB |
| TW466115B (en) * | 1996-12-10 | 2001-12-01 | American Home Prod | Pharmaceutical composition of antioxidant from equilenin |
| AU741802B2 (en) * | 1997-02-15 | 2001-12-13 | Millennium Pharmaceuticals, Inc. | Treatment of infarcts through inhibition of NF-kappaB |
| GB9801398D0 (en) * | 1998-01-22 | 1998-03-18 | Anggard Erik E | Chemical compounds |
| CA2350992C (en) * | 1999-09-17 | 2009-06-23 | Suntory Limited | Preventive or therapeutic agents for myocarditis, dilated cardiomyopathy and heart failure comprising nf-kb inhibitors as active ingredients |
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| CN101941907A (zh) * | 2010-05-28 | 2011-01-12 | 帕迪有限公司 | 4-叔丁基苄基-3,4-二羟基肉桂酸酯及其用途和制备方法 |
| CN101941907B (zh) * | 2010-05-28 | 2015-04-01 | 毛腾淑 | 4-叔丁基苄基-3,4-二羟基肉桂酸酯及其用途和制备方法 |
| CN103260614A (zh) * | 2010-10-18 | 2013-08-21 | 开米根公司 | 联合疗法 |
| CN103260614B (zh) * | 2010-10-18 | 2016-09-14 | 北京脉迪法莫医药科技有限公司 | 联合疗法 |
| CN103384522A (zh) * | 2010-11-15 | 2013-11-06 | 开米根公司 | 咖啡酸衍生物和它们在改善神经细胞生存力中的用途 |
| CN103384522B (zh) * | 2010-11-15 | 2016-09-07 | 帕迪有限公司 | 咖啡酸衍生物和它们在改善神经细胞生存力中的用途 |
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