CN100360550C - 肝脏x受体激动剂 - Google Patents
肝脏x受体激动剂 Download PDFInfo
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- CN100360550C CN100360550C CNB028134265A CN02813426A CN100360550C CN 100360550 C CN100360550 C CN 100360550C CN B028134265 A CNB028134265 A CN B028134265A CN 02813426 A CN02813426 A CN 02813426A CN 100360550 C CN100360550 C CN 100360550C
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- cholesterol
- acid
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Abstract
一种式(I)之化合物，其中每一R1、R2、R3、R4、R4’、R5、R6、R7、R11、R12、R15、R16、及R17，分别独立为氢、卤素、烷基、卤烷基、羟基、氨基、羧基、氧、磺酸基，或任选地插入了-NH-、-N(烷基)-、-O-、-S-、-SO-、-SO2-、-O-SO2、-SO2-O-、-SO3-O-、-CO-、-CO-O-、-O-CO-、-CO-NR’、或-NR’-CO-的烷基；或R3与R4一起、R4与R5一起、R5与R6一起、或R6与R7一起进行消去从而在其所连接之碳原子之间形成一个C＝C键；每一R8、R9、R10、R13、及R14，分别独立为氢、卤素、烷基、卤烷基、羟烷基、烷氧基、羟基或氨基；n为0、1或2；A为亚烷基、亚烯基或亚炔基；以及每一X、Y及Z分别独立为烷基、卤烷基、-OR’、-SR’、-NR’R”、-N(OR’)R”、或-N(SR’)R”；或X及Y一起为＝O、＝S或＝NR’；其中每一R’及R”分别独立为氢、烷基或卤烷基。
Description
本发明工作得到国立卫生研究院的基金资助(CA-58073和DK-41670)，因此美国政府在此项发明中享有一定的权益。
发明背景
肝脏X受体(Liver X Receptor，以下简称LXR)属于“核受体超家族”(nuclear receptor super-family)之一员，其包括了LXRα和遍在受体(Ubiquitous Receptor，UR，亦称LXRβ)。该受体对基因表达具有反式激活(transactivate)作用。若干与胆固醇平衡相关的基因已被确认为是LXR的直接靶向，例如，编码胆固醇外向转运蛋白ATP结合盒1(efflux transporter ATP-binding Cassette 1)ABCA1和ABCG1、胆固醇7α-羟化酶(由胆固醇合成胆汁酸作用中的限速酶)、胆固醇酯移转蛋白(CETP)、脂蛋白载脂蛋白E(ApoE)以及甾醇调节因子结合蛋白(sterol regulatory element-binding protein 1c(SREBP-1 c))等的基因皆为LXR之靶向。相关研究请参考Schwartz等，Biochem.Biophys.Res.Commun.，2000，274：794-802；Laffitte等，Proc.Natl.Acad.Sci.USA，2001，98(2)：508-512；及Repa等，Genes Dev.，2000，14：2819-30。
受到LXR调控的上述基因会改变胆固醇之逆向运送及消耗，而这些改变将直接影响脂肪和纤维成分之形成、ApoE基因之表达，以及核因子κ-B和AP-1的激活。脂肪及纤维元在动脉中累积会导致动脉硬化，而动脉硬化是心脏病、中风等疾病之潜在原因。目前已发现ApoE基因表达缺乏与阿尔茨海默病等疾病相关。而激活核因子κ-B和AP-1则会调节人体免疫系统并增进抗炎能力。
发明概述
本发明基于一新发现的类固醇化合物，其功能为LXR之激动剂。
本发明的一方面涉及一种具有式(I)结构之化合物：
每一R1、R2、R3、R4、R4’、R5、R6、R7、R11、R12、R15、R16、及R17，分别独立为氢、卤素、烷基、卤烷基、羟基、氨基、羧基、氧、磺酸基、或任选地插入了-NH-、-N(烷基)-、-O-、-S-、-SO-、-SO2-、-O-SO2、-SO2-O-、-SO3-O-、-CO-、-CO-O-、-O-CO-、-CO-NR’、或-NR’-CO-的烷基；或R3与R4一起、R4与R5一起、R5与R6一起、或R6与R7一起进行消去从而在其所连接之碳原子之间形成一个C＝C键；每一R8、R9、R10、R13及R14分别独立为氢、卤素、烷基、卤烷基、羟烷基、烷氧基、羟基或氨基；n为0、1或2；A为亚烷基、亚烯基或亚炔基；以及每一X、Y及Z分别独立为烷基、卤烷基、-OR’、-SR’、-NR’R”、-N(OR’)R”或-N(SR’)R”；或X及Y一起为＝O、＝S或＝NR’；每一R’及R”分别独立为氢、烷基或卤烷基。
文中术语“烷基”、其作为前缀的“烷”(例如烷氧基)及作为后缀的“烷基”(例如羟烷基)，皆指直链或支链的C1-18。
在如式(I)之化合物中有一个亚族(subset)，其特征为每一R5及R6分别独立为氢、烷基、卤烷基、羟基或氨基；另一亚族之特征为R5及R6一起进行消去从而在该二取代基所连接之碳原子之间形成一个C＝C键。另外两个本化合物之亚族特征分别为X及Y一起为＝O或＝S，且Z为-OR’、-SR’、-NR’R”、-N(OR’)R”或-N(SR’)R”；以及每一X、Y及Z分别独立为烷基、卤烷基、-OR’、-SR’、-NR’R”、-N(OR’)R”或-N(SR’)R”。
上述化合物亦包括其适用之盐类及前体药物。举例而言，该盐类可由本发明之化合物的其中一个带正电的取代基(例如氨基)与一阴离子作用而形成。合适的阴离子包括(但不限于)氯离子、溴离子、碘离子、硫酸盐、硝酸盐、磷酸盐、柠檬酸盐、甲磺酸盐、三氟醋酸盐、及醋酸盐。同样地，该盐类亦可由本发明化合物之带负电取代基(例如羧基)与一阳离子作用而得。适合之阳离子包括(但不限于)钠离子、钾离子、镁离子、钙离子及如四甲基铵离子之类的铵离子。前体药物可举例如酯类，以及其它药物学可接受之衍生物，而该衍生物被施用于一对象后能够提供上述类固醇化合物。
本发明之另一方面涉及一药物组合物，其包含一有效量的本发明的化合物，以及一种药物学可接受的载体。确实，本发明之化合物可用以治疗LXR介导的疾病，如心脏病、中风、阿尔茨海默病及炎症性疾病，因此本发明之范畴亦包括以本发明之化合物治疗上述疾病之一的方法，以及利用本发明之化合物生产可用以治疗上述疾病之一的药物的方法。
以下将对本发明之数种化合物进行详细的说明，本发明之其余特点、目的和优点可由本说明书与权利要求书得知。
具体实施方式
本发明之化合物可由本领域已知方法以适当之类固醇为起始物质而合成。更确切地说，该起始类固醇在C-17的位置(参见上述式(I)，即R17所连接之碳原子)具有一可经修饰而含有由X、Y及Z所定义的部分(亦请参见式(I))之取代基。该取代基之范例包括胆酸(cholic acid)、脱氢胆酸(dehydrocholic acid)、脱氧胆酸(deoxycholic acid)、石胆酸(lithocholic acid)、熊脱氧胆酸(ursodeoxycholic acid)、猪胆酸(hyocholicacid)、猪脱氧胆酸(hyodeoxycholic acid)、及胆烷酸(cholanoicacid)，而这些取代基可购得或由文献记载之方式合成，例如见Roda等所述(F.Lipid Res.，1994，35：2268-2279；及Roda等，Dig.Dis.Sci.，1987，34：24S-35S)。
本发明的一种在C-17位置具有含酰胺取代基(亦即，X和Y一起为＝O，而Z为氨基)之化合物，可通过将一在C-17位置具有羧基取代基之类固醇与一含氨基化合物(例如二甲基胺、苯胺、氨基醋酸及苯丙氨酸)反应而制备。相似地，本发明的一种在C-17位置具有含酯取代基(亦即，X和Y一起为＝O，而Z为一烷氧基)之化合物，可通过将一在C-17位置具有羧基取代基之类固醇与一含羟基之化合物(例如乙醇和异丙醇)反应而制备。上述之酰胺化或酯化反应可在任何适当之溶液中进行。若上述反应在水溶液中进行，则可不必为体内或体外筛选分析而对该类固醇产物进行分离。
本发明之一种于C-17位置具有一羰基取代基(亦即，X和Y一起为＝O)之化合物，例如可与硫化氢反应而形成一含硫羰基之化合物(亦即，X和Y一起为＝S)，或与肼反应而形成一含亚胺基之化合物(亦即X和Y一起为＝NR)。以上反应请分别参见Janssen等(Ed.)，OrganosulfurChemistry；Wiley：New York，1967，219-240；以及Patai等(Ed.)，TheChemistry of the Carbon-Nitrogen Double Bond；Wiley：New York，1970，64-83和465-504。
在必要的情况下，可通过本领域已知的方法对C-17之外的环原子(ring atom)的取代基进行进一步修改。举例而言，在C-3位置之羟基取代基可与醋酸之类的酸进行酯化反应而成为酯取代基。
本反应可轻易自动化，因其反应机制简单。生成物之分离及定量可通过薄层层析法、高压液相层析法、气相层析法、毛细管电泳或其它分析及制备程序而达成。
而于C-17位置取代基不含羰基、硫羰基或亚胺基之化合物，亦可由本领域已知的方法制备。举例而言，3α，6α，24-三羟基-24，24-二(三氟甲基)-5β-胆烷可经由下列步骤制备：
如上所示之步骤，胆酸先在酸性环境中与甲醇作用以形成甲基酯，该甲酯基化合物接着与叔丁基二甲基硅氯化物(tert-butyldimethylsilylchloride，TBDMSCl)作用以保护3β-羟基。该被保护的甲基酯与二(异丁基)铝氢化物(di(iso-butryl)alumina hydride)反应而形成一醛类，接着再与三甲基(三氟甲基)硅烷进行反应，形成α位置被三氟甲基取代的一种醇类。该醇类接着进行Dess-Martin反应以形成一种酮类。请参考Dess等，J.Org.Chem.，1983，38：4155。该酮类接着再次与三甲基(三氟甲基)硅烷反应形成α位置具有两个三氟甲基取代基的一种醇类。该具有两个取代基的醇类最后再与四正丁基氯化铵(TBAF)反应，除去保护而得到3α，6α，24-三羟基-24，24-二(三氟甲基)-5β-胆烷。
取一有效量之上述制备之化合物，与药物学可接受之载体以配制成可用来治疗与动脉粥样硬化或ApoE缺乏相关之疾病，或是炎症性疾病。在前文中“有效量”指的是用以对受测对象提供治疗效果所使用该化合物之量。在动物及人类之间所使用剂量之相互关系(根据“毫克/身体表面积每平方米”而计算)，可见于Freireich等，Cancer Chemother.Rep.1966，50，219。身体表面积可由病人之身高及体重而得到一近似值，该近似值计算可参见Scientific Tables，Geigy Pharmaceuticals，Ardley，New ork，1970，537。而本领域人员亦应知悉有效剂量会随着用药途径、使用的赋形剂、或搭配其它治疗程序而变化，而非一定值。举例而言，药物学可接受之载体包括胶态二氧化硅、硬脂酸镁、纤维素、硫酸月桂酸钠以及D&C Yellow#10。
该化合物用于药物时，可能以非肠胃方式使用，例如皮肤局部注射、腹腔注射或静脉注射。非肠胃用药之例子包括将有效化合物溶解在磷酸盐缓冲溶液中，或将该化合物与其它用药上可接受之载体混合。如环状糊精或其它习知之助溶剂亦可包括在该药物成分中。
由于本发明之化合物可有效刺激LXR，因此通过体外分析可初步筛选出该化合物，也因此可以治疗与LXR相关之疾病。举例而言，将肾脏细胞以一萤光酶报告基因(包括一人类c-fos最小启动子)以及一LXR进行转染(transfect)。将该经过转染之细胞与待测化合物共同培养之后，量测该萤光酶之活性以决定该报告基因被反式激活(transactivation)之程度。
在初步筛选中表达出刺激LXR效果之化合物，可更进一步根据本领域已知的方法在动物试验中进行评估。举例而言，可将一化合物搭配含胆固醇之食物以喂食实验老鼠。通过比较实验组(有喂食该化合物)与对照组(未喂食该化合物)之老鼠在不同组织中的胆固醇含量，即可测定该化合物之效用。
在不需进一步说明情况下，本领域人员应可根据本说明书之内容，将本发明应用至最广泛之程度。本说明书所列举之已发表文章系引证其文章整体。本说明书接着会说明几个特定实施例，以描述数个属于本发明之不同化合物之合成以及生物测试程序。需注意的是，下述实施例仅仅是用于说明书本发明，而非是将本发明的其他方面限制于实施例。
实施例1：本发明之化合物之合成
3α，6α，24-三羟基-24，24-二(三氟甲基)-5β-胆烷(化合物(1))之合成方法如前所述。
3α，6α-二羟基-5β-胆烷酸-N-甲基-N-甲氧基-24-酰胺(化合物2)，2，2，2，-三氟乙基-3α，6α-二羟基-5β-胆烷酸-24-酰胺(化合物3)，24-胆甾烯-酰胺(化合物4)，N，N-二甲基-24-胆甾烯-酰胺(化合物5)，以及N-甲氧基-24-胆甾烯-酰胺(化合物6)接依照下列方式合成：
在二甲基甲酰胺中溶入一类固醇24-羧酸(Sigma，St.Louis，Missouri)、一胺类、二乙基氰基磷酸盐(Aldrich，Milwaukee，Wisconsin)，以及三乙基胺。在20-70℃之间搅拌该溶液12-16小时，以冰块冷却之后再以乙酸乙酯萃取。接着分别以1.0N盐酸溶液、1.0N氢氧化钠溶液清洗该萃取液，接着再以无水硫酸钠吸去多余水分。将乙酸乙酯移去，并在必要时以硅石层析法纯化而得一粗产物。
实施例2：报告基因反式激活检验
将人类胚胎肾脏293细胞以每孔105个细胞的密度种入48孔培养皿中培养，培养基使用Dulbecco’s modified Eagle’s medium(DMEM)，并以10％胎牛血清补充。培养24小时之后，以磷酸盐共沉淀法将250ng之pGL3/UREluc报告基因、40ng之pSG5/hRxRα、40ng之pSG5/rUR或CMX/hLXRα、10ng之pSG5/hGripl、0.4ng之CMV/R-luc(转染正常化报告基因，Promega)、以及250ng之载体DNA转染至每一孔细胞中，其中该pGL3/UREluc报告基因系由三拷贝AGGTCAagccAGGTCA组成，其融合于位于质粒基础基因pGL3(Promega，Madison，WI)之萤火虫萤光酶基因之前的人类c-fos启动子的-56至+109位核苷酸。再培养12-24小时之后，以磷酸缓冲溶液清洗该培养皿，接着再以DMEM及4％脱脂胎牛血清提供养分。将一包含待测化合物(例如化合物2或3)之乙醇溶液加入双份的该DMEM细胞培养基中，最终该待测化合物之浓度为1-10μM、而乙醇浓度为0.2％。之后再培养24-48小时，收集该细胞，并在单光萤光仪(Becton Dickenson、Mountain View、CA)下以商业试剂盒(Premega Dual luciferase II)检验其萤光酶活性。
该检测结果显示，化合物2和化合物3皆为LXRα和UR之有效激动剂。
实施例3：对饮食诱发的高胆固醇血症小鼠的作用
以二组三个月大的non-Swiss白化小鼠(Harlan，Indianapolic，Indiana)分别作为实验组及对照组，并皆喂食含有1％之饲料7天(Harlan Teklad 7001，Harlan，Indianapolis，Indiana)。接着在对照组的饮水中加入0.25％羟丙基-β-环糊精(hydroxypropyl-β-cyclodextrin)(HPCD，Acros Organic，Somerville，NewJersey)而实验组则在其饮用水中加入0.25％HPCD以及化合物2(0.125、0.25及0.5g/L)。小鼠对于饲料及饮水皆可自由取用而非强迫。对照组与实验组之饮水量相差不到10％。
让小鼠禁食4小时之后收集其血液，并以商业试剂盒(Sigma，St.Louis，MO)利用酶学方法量测其血液中胆固醇及三酸甘油酯之含量。利用Warnick等，Clin.Chem.1982，281379-88所述之方法可分离出高浓度之脂蛋白胆固醇，并以酶学定量。而利用Bligh等，Canadian J.Biochem.Physiol.1959，37911918所述之方法则可分离并定量肝脏中之胆固醇及三酸甘油酯。利用Turiey等，J.Cardiovasc.Pharmacol.1996，27：71-79所述之方法，以硼氢化钠将残余之胆汁酸还原，接着萃取并以商业试剂盒(Sigma，St.Louis，MO)定量之。
实验结果显示出，小鼠饮食中之胆固醇虽未增加其血液中之胆固醇含量，但却增加其肝脏中之胆固醇含量。摄取化合物2可防止肝脏中的胆固醇含量增加，并可增加残余胆汁酸的分泌以加速除去胆固醇。在血清及肝脏中的三酸甘油酯含量则不因化合物2之摄取与否而改变。
易于发生动脉硬化之雄性小鼠C57BL/6J(Jackson Laboratory，BarHarbor，ME)亦接受相同之研究。在化合物2剂量改变的方法中，该雄性鼠血清中之胆固醇含量降低，而血清中之三酸甘油酯含量在整个实验过程中则并未剧烈增加。
实施例4：对饮食诱发的高胆固醇血症仓鼠的作用
仓鼠(非小鼠或大鼠)的胆汁酸及血液中的胆固醇量变曲线(profile)与人类相仿。人类与仓鼠血清中的主要胆固醇载体属于低密度脂蛋白(LDL)，而小鼠与大鼠的则是高密度脂蛋白(HDL)。因此本实施例利用仓鼠来评估化合物2对于胆固醇及三酸甘油酯之量变曲线的影响。
仓鼠系以口服方式摄取化合物2，为期二周，其剂量最高为200mg/Kg/日，喂养该仓鼠之饲料则为正常饲料(chow diet)。该仓鼠之血清胆固醇或三酸甘油酯含量并未变化。另一方面，当化合物2被仓鼠摄取而正常饲料中添加1％胆固醇时，可防止血清胆固醇或肝脏中胆固醇酯的增加。有摄取化合物2之仓鼠，其血清三酸甘油酯含量远高于空白组。然而喂养正常饲料之对照组动物亦有相同之三酸甘油酯含量，且该含量在Trautwein等、Comp.Biochem.Physiol.A Mol.Integ.Physiol.1999，124：93-103所做的报告中系属于正常范围。空白组仓鼠降低之三酸甘油酯含量或许是由于其肝脏中大量累积之胆固醇酯。
实施例5：对饮食诱发的高胆固醇血症大鼠的作用
本实施例之动物实验与实施例4所用的相同，除了实施例中的仓鼠与化合物2，分别换成雄性三个月大的Harlan Sprague-Dawley大鼠(Harlan Indianapolis，Indiana)与化合物3。该实验结果显示，化合物3与化合物2相似，皆具有降低胆固醇的效果。
实施例6：本发明化合物影响ApoE基因表达之体外研究
(1)在大鼠星形胶质细胞中
星形胶质细胞培养物系以LaDu等，J.Biol.Chem.，2000，275(43)：33974-80中所描述的方法，自刚出生-2天之Harlan Sprague-Dawley幼鼠(Harlan，Indianapolis，Indiana)的大脑皮质制备而得。在实验开始之前，该星形胶质细胞需成长至约填满培养皿90％面积。该细胞培养基换成含有N2养分的限制必要培养基(MEM)(LifeTechnologies，Inc.，Gaithersburg，Maryland)，并且以三倍量加入化合物2(0.1-1mM/L)。培养48-72小时之后，收集特定条件化之培养基并与SDS填充缓冲溶液混合。通过添加SDS上样缓冲溶液至培养盘中，可原位得到细胞裂解物。
依照LaDu等(见上)所述之方法进行蛋白印迹分析。将细胞裂解物和特定条件之培养基注入梯度为4-20％之SDS-聚丙烯酰胺电泳胶之中，并在电泳结束之后转移到硝化纤维素膜上。以氨基黑对该硝化纤维素膜进行染色，再以蒸馏水除去染色。对蛋白质之染色结果进行扫瞄之后，以含有0.2％Tween 20及1％脱脂奶粉之磷酸缓冲液封阻该硝化纤维素膜。以抗鼠ApoE多克隆抗体、辣根过氧化酶结合之山羊抗兔IgG、chmiluminescent底物(Pierce，Rockford，IL)及X光胶片来测定ApoE的表达量。
与空白组相比较之下，摄取化合物2之实验组在细胞培养基及细胞裂解物中之ApoE含量均较高。
(2)在人类THP-1细胞中
以人类单核细胞系中之THP-1细胞(ATCC，Manassas，VA)，进行实施例6之体外试验。更精确地说，该细胞在实验前系保存在以10％胎牛血清补充之RPMI1640培养基之中，并以PMA活化24小时。之后以CellgroTM完整培养基(Mediatech，Fisher Scientific，Pittsburgh，PA)替换原有之培养基，接着加入一含有化合物2(浓度为0.1-1 M/L)之乙醇溶液。静置48-72小时之后收获该细胞。测定细胞中ApoE含量之方法如前所述。
该实验结果显示，摄取化合物2会增加分泌的及与细胞相关之ApoE含量。
实施例7：ApoE基因表达之动物研究
以含有1.25％胆固醇、0.5％胆酸及15％玉米油之饲料，连续喂食20只四个月大的雄性C57BL/6J小鼠8周。将20只小鼠分成4组，每组5只。其中三组之饮用水含有0.25％HPCD及不同浓度的化合物2，以使该三组之小鼠每天分别摄取25、50及100mg/Kg体重。第四组则未摄取化合物2。8周之后，牺牲该20只小鼠并收集其大脑。每组所收集之大脑利用含酚之试剂(TrizolTM reagent，Life Technologies，Gaithersburg，Maryland)分离出ApoE基因之mRNA。以Northern印迹法分析该mRNA以决定ApoE基因之表达量。
该实验结果显示，实验组之ApoE mRNA含量较空白组为高，表示摄取化合物2会减低循环系统中的胆固醇含量，抑制肝脏中的胆固醇堆积。
实施例8：ApoE基因表达之动物研究
以致粥瘤性(atherogenic)饲料(15％油脂，0.2％胆固醇)喂食20只缺乏LDL受体基因之小鼠，并以每组5只分为4组，每天摄取含有化合物2分别为0(对照组)、25、50及100mg/体重Kg之饮用水，为期二周，水中并含有0.25％之HPCD。两周之后，牺牲该小鼠并收集其各部位组织(例如肝脏、大脑和肠)，并以实施例7所述之方法分析各部位组织。
该实验结果显示，实验组之总血清胆固醇含量为700mg/dL，而对照组则为1400mg/dL。实验组脑中之ApoE mRNA含量则为对照组的4-5倍。以抗ApoE探针进行原位杂交的结果显示，实验组大脑中的mRNA较对照组为高，尤其是位于海马回和大脑皮质层二部位。
实施例9：抗炎症作用之动物研究
本实验系依照Tonilli等，Endocrinology 1965，77：625-634所述之方法执行。以1％巴豆油、25％吡啶、60％乙醚、5％水以及待测化合物4或化合物6，制成一巴豆油混合液，使用在non-Swiss雄性白化鼠Harlan(Indianapolis，Indiana)。
每只小鼠的右耳之正反两面皆涂上100mL之巴豆油混合液，6小时之后剪下其右耳并量其重量。结果显示，以含有化合物4或化合物6之混合液涂布的耳朵所增加的重量，远低于仅涂布巴豆油的耳朵所增加的重量。因此，该化合物为有效之抗炎症制剂。
需注意的是，上述仅为本发明的一些具体实施例。但是，在不脱离本发明基本架构的情况下，可对本发明进行各种改动，其皆应为本专利以下所主张之权利要求书的范围内。
Claims (16)
1.一种式(I)之化合物：
其中，
每一R1、R2、R4、R4’、R5、R7、R8、R9、R11、R12、R15、及R16为氢；
每一R3及R6为羟基；
每一R10、R13、及R17分别独立为烷基；
n为0、1或2；
A为亚烷基；
每一X和Y，分别独立为卤烷基；以及
Z是-OR’；
其中R’为氢、烷基或卤烷基。
2.权利要求1的化合物，其中该化合物为
3.一种药物组合物，包括：
一有效量的具有下式化学结构的化合物：
其中，
每一R1、R2、R4、R4’、R5、R7、R8、R9、R11、R12、R15、及R16为氢；
每一R3及R6为羟基；
每一R10、R13、及R17分别独立为烷基；
n为0、1或2；
A为亚烷基；
每一X和Y分别独立为卤烷基；以及
Z为-OR’；
其中R’为氢、烷基或卤烷基；以及
一药物学上可接受之载体。
4.权利要求3的药物组合物，其中该化合物为
5.权利要求1的化合物，其中R10、R13、及R17分别独立为甲基。
6.权利要求5的化合物，其中A为CH2CH2。
7.权利要求6的化合物，其中Z为OH。
8.权利要求1的化合物，其中Z为OH。
9.权利要求1的化合物，其中A为CH2CH2。
10.权利要求9的化合物，其中Z为OH。
11.权利要求3的化合物，其中R10、R13、及R17分别独立为甲基。
12.权利要求11的化合物，其中A为CH2CH2。
13.权利要求12的化合物，其中Z为OH。
14.权利要求3的化合物，其中Z为OH。
15.权利要求3的化合物，其中A为CH2CH2。
16.权利要求15的化合物，其中Z为OH。
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- 2002-05-02 DK DK02731581T patent/DK1392713T3/da active
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2002090375A2 (en) | 2002-11-14 |
| CA2446314C (en) | 2011-02-22 |
| US7012069B2 (en) | 2006-03-14 |
| CN1585777A (zh) | 2005-02-23 |
| DE60223020D1 (de) | 2007-11-29 |
| ATE375994T1 (de) | 2007-11-15 |
| JP4309661B2 (ja) | 2009-08-05 |
| JP2005507855A (ja) | 2005-03-24 |
| WO2002090375A8 (en) | 2004-05-27 |
| DK1392713T3 (da) | 2008-02-18 |
| US20020193357A1 (en) | 2002-12-19 |
| EP1392713B1 (en) | 2007-10-17 |
| DE60223020T2 (de) | 2008-07-24 |
| CA2446314A1 (en) | 2002-11-14 |
| PT1392713E (pt) | 2008-01-25 |
| EP1392713A4 (en) | 2004-11-17 |
| EP1392713A2 (en) | 2004-03-03 |
| ES2296928T3 (es) | 2008-05-01 |
| WO2002090375A3 (en) | 2003-12-18 |
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