CN103702719B - 新型fxr(nr1h4)结合及活性调节化合物 - Google Patents
新型fxr(nr1h4)结合及活性调节化合物 Download PDFInfo
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- CN103702719B CN103702719B CN201280033148.4A CN201280033148A CN103702719B CN 103702719 B CN103702719 B CN 103702719B CN 201280033148 A CN201280033148 A CN 201280033148A CN 103702719 B CN103702719 B CN 103702719B
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Classifications
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- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
本发明涉及结合至NR1H4受体(FXR)并作为FXR的激动剂的化合物。本发明进一步涉及所述化合物在制备用于通过用所述化合物结合所述核受体来治疗疾病和/或病症的药物的用途和合成所述化合物的方法。Z选自(a)、(b)、(c)或(d)。
Description
技术领域
本发明涉及结合至NR1H4受体(FXR)并作为FXR的激动剂或调节剂的化合物。本发明进一步涉及所述化合物通过用该化合物结合所述核受体用于治疗及/或预防疾病和/或病症的用途。
背景技术
多细胞有机体依赖于在细胞与体液房室之间的高级信息传输机制。所传导的信息可以是高度复杂的并且可以造成涉及细胞分化、增生或复制的基因程序的改变。所述信号,或激素,通常为低分子量分子,诸如肽、脂肪酸或胆固醇衍生物。
许多这些信号通过最终改变特定基因的转录而产生其效应。一组已经深入研究过的调节细胞对各种信号应答的蛋白质为已知为核受体的转录因子家族,以下经常称为“NR”。该组成员包括:甾类激素、维生素D、蜕皮激素、顺式和反式维生素A酸、甲状腺激素、胆汁酸、胆固醇-衍生物、脂肪酸(及其他过氧化物酶体增值物)的受体;以及所谓的孤儿受体(orphan receptors),也即结构类似于该组其他成员的蛋白质,但是对其没有已知的配体。孤儿受体可能指示细胞中未知的信号通道或者可能是不需要配体激活就可以起作用的核受体。用这些孤儿受体中的一些进行的转录激活可能在缺乏外源配体的情况下和/或通过起源自细胞表面的信号转导途径发生(D.Mangelsdorf等人,Cell1995,83,835;R.M.Evans,Mol.Endocrinol.2005,19(6),1429)。
通常,在NR中已经限定了三个功能区域。氨基末端区域被认为是具有一些调节功能。其后是DNA结合域,以下简称为“DBD”,通常包括两个锌指单元并且识别在应答基因的启动子中的特定激素应答元件(以下简称为“HRE”)。在“DBD”中的特定氨基酸残基已经被证实赋予DNA序列结合特异性(M.Schena和K.R.Yamamoto,Science1988,241,965)。配体结合域,以下简称为“LBD”,位于已知NR的羧基末端区域。
在没有激素的情况下,LBD显示出会干扰DBD与其HRE的相互作用。激素结合似乎导致在NR中的构象变化并由此开启了这种干扰(A.Brzozowski等人,Nature1997,389,753)。没有LBD的NR组成型激活转录,但是水平较低。
有人已提出辅激活因子或者转录激活因子除了影响靶细胞的染色质结构以外,还在序列特异转录因子(基础转录机制)之间建立联系。几种像SRC-1、ACTR和Grip1的蛋白质以配体增强的方式与NR发生相互作用(D.Heery等人,Nature,1997,387,733;T.Heinzel等人,Nature1997,387,43;K.Nettles和G.Greene,Annu.Rev.Physiol.2005,67,309)。
像类固醇激素的核受体调节剂通过结合到细胞内受体上并形成核受体-配体复合物来影响特定细胞的生长与功能。然后核受体-激素复合物与特定基因的控制区域内的激素应答元件(HRE)发生相互作用并且改变特定的基因表达(A.Aranda和A.Pascual,Physiol.Rev.2001,81,1269)。
类法尼醇X受体α(当指的是人类受体时下文也常称为NR1H4)是一种原型2型核受体,其在以杂二聚体方式和类法尼醇X受体一起结合到靶基因的启动子区域时激活基因(B.Forman等人,Cell1995,81,687)。NR1H4的相关生理性配体为胆汁酸(D.Parks等人,Science1999,284,1365;M.Makishima等人,Science,1999,284,1362)。最有潜力的一个是鹅脱氧胆汁酸(CDCA),其调节参与胆汁酸体内平衡的几种基因的表达。法尼醇及其衍生物,一起被称为类法尼醇,最初描述为在高浓度时激活大鼠直向同源物,但是他们不激活人类或者小鼠受体。FXR在肝、包括食道、胃、十二指肠、小肠、结肠在内的整个胃肠道、卵巢、肾上腺和肾中表达。除了控制细胞内的基因表达外,FXR似乎还通过上调成纤维细胞生长因子15(啮齿动物)或19(猴、人)参与旁分泌和内分泌信号传导(J.Holt等,Genes Dev.2003,17,1581;T.Inagaki等人,Cell Metab.2005,2,217)。
充当FXR调节剂的小分子化合物已经在下列出版物中公开:WO2000/037077、WO2003/015771、WO2004/048349、WO2007/076260、WO2007/092751、WO2007/140174、WO2007/140183、WO2008/051942、WO2008/157270、WO2009/005998、WO2009/012125、WO2008/025539和WO2008/025540。最近已经综述了更多的小分子FXR调节剂(M.L.Crawley,Expert OpinTher.Pat.2010,20,1047;D.Merk等人,Future Med.Chem.2012,4,1015)。
在WO2011/020615中,我们公开了下面通式的手性环亚丙基化合物:
其中所述变量的定义与本申请类似。
发明内容
本发明所要解决的问题是产生这样的FXR激动剂,特别是与在WO2011/020615中要求保护的化合物相比,其具有总体上改进的物化性质,以及降低的疏水性、改进的水溶性和更好的膜渗透性。
该问题已经通过根据下面通式(1)的化合物、其对映异构体、非对映异构体、互变异构体、溶剂化物、前药和药物学上可接受的盐而解决:
其中,
R选自COOR6、CONR7R8、四唑基、SO2NR7R8、C1-6烷基、SO2-C1-6烷基和H,R6独立地选自:H或C1-6烷基,以及R7和R8独立地选自:H、C1-6烷基、卤代C1-6烷基、C1-6亚烷基-R9、SO2-C1-6烷基,其中R9选自:COOH、OH和SO3H;
A选自苯基、吡啶基、嘧啶基、吡唑基、吲哚基、噻吩基、苯并噻吩基、吲唑基、苯并异噁唑基、苯并呋喃基、苯并三唑基、呋喃基、苯并噻唑基、噻唑基、噁二唑基,它们各自任选地被独立地选自OH、O-C1-6烷基、O-卤代C1-6烷基、C1-6烷基、卤代C1-6烷基、C3-6环烷基和卤素中的一个或两个基团所取代;
Q选自苯基、吡啶基、噻唑基、苯硫基、嘧啶基,它们各自任选地被独立地选自C1-6烷基、卤代C1-6烷基、卤素和CF3中的一个或两个基团所取代;
Y选自N或CH;
Z选自
其中,
X=CH、N、NO;
R1选自氢、C1-3烷基、C3-6环烷基、C4-5烷基环烷基,其中C1-3烷基任选地被独立地选自卤素、羟基或C1-6烷氧基中的1-3个基团所取代;
R2和R3独立地选自氢、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和卤素。
在与任一上述或下述实施方式相结合的另一个实施方式中,在根据通式(1)的化合物中的R-A选自:
在与任一上述或下述实施方式相结合的另一个实施方式中,在根据通式(1)的化合物中的Q为:
在与任一上述或下述实施方式相结合的另一个实施方式中,在根据通式(1)的化合物中的Z为:
在与任一上述或下述实施方式相结合的另一个实施方式中,根据通式(1)的化合物选自:
在与任一上述或下述实施方式相结合的另一个实施方式中,根据通式(1)的化合物为:
其中,R选自CO2H、CONHSO2Me和四唑基。
在另一实施方式中,本发明涉及用作药物的根据通式(1)的化合物。
在另一实施方式中,本发明涉及用于预防和/或治疗由FXR介导的疾病的根据通式(1)的化合物。
在另一实施方式中,本发明涉及根据通式(1)的化合物用于制备预防和/或治疗由FXR介导的疾病的药物的用途。
在与任一上述或下述实施方式相结合的另一个实施方式中,所述疾病选自:慢性肝内或某些形式的肝外胆汁郁积性病症;肝纤维化;肝的梗阻性或慢性炎性紊乱;肝硬化;脂肪肝及并发症;与酒精引发的肝硬化或与病毒传染性形式的肝炎相关的胆汁郁积性和纤维变性效果;在部分肝切除术后的肝衰竭或肝缺血;化疗相关的脂肪性肝炎(CASH);急性肝衰竭;和/或炎性肠道疾病。
在与任一上述或下列实施方式相结合的另一个实施方式中,所述疾病选自:脂质和脂蛋白紊乱;II型糖尿病以及I型和II型糖尿病的临床并发症,包括糖尿病性肾病、糖尿病性神经病变、糖尿病性视网膜病、及临床显性长期糖尿病的其它观察到的效果;由于强迫脂质,特别是甘油三酯蓄积,然后促纤维化途径激活导致的慢性脂肪性和纤维性变性引起的病症和疾病,例如非酒精性脂肪肝病(NAFLD)或非酒精性脂肪性肝炎(NASH);肥胖或代谢综合征(血脂障碍、糖尿病和体重指数异常高的合并病症);和/或急性心肌梗塞、急性中风或作为慢性梗阻性动脉粥样硬化终点发生的血栓形成。
在与任一上述或下列实施方式相结合的另一个实施方式中,所述疾病选自非恶性过度增殖性紊乱和恶性过度增殖性紊乱,特别是肝细胞癌、结肠腺瘤和息肉病、结肠腺癌、乳腺癌、胰腺癌、巴特氏食管癌和胃肠道和肝脏的其它形式的肿瘤性疾病。
已经通过在代替前者的1,2-环亚丙基的1,3-环亚丁基或1,3-亚氮杂环丁烷基上引入极性羟基实现了改进的物化性能。
令人惊奇地,所得化合物保持了在FXR受体上的活性,而且显现出改进的物化性能,例如较高的水溶性和/或膜渗透性。
本发明的化合物共享权利要求1中根据通式(1)的共同化学结构。
在与任一上述或下列实施方式相结合的优选实施方式中,本发明涉及根据通式(1)的对映异构体、非对映异构体、或药物学上可接受的盐。
在与任一上述或下列实施方式相结合的优选实施方式中,通式(1)中的R选自COOR6、CONR7R8、SO2NR7R8和SO2-C1-6烷基。
在与任一上述或下述实施方式相结合的优选实施方式中,通式(1)中的R6为H。
在与任一上述或下述实施方式相结合的优选实施方式中,通式(1)中的R7和R8彼此独立地选自H和SO2-C1-6烷基。
在与任一上述或下述实施方式相结合的优选实施方式中,通式(1)中的R7为H。
在与任一上述或下述实施方式相结合的优选实施方式中,通式(1)中的R8为SO2-C1-6烷基。
在与任一上述或下述实施方式相结合的优选实施方式中,A选自苯基、吡啶基、嘧啶基、吡唑基、吲唑基和噁二唑基。
在与任一上述或下述实施方式相结合的优选实施方式中,A由选自C1-6烷基,更优选C1-3烷基中的一或两个基团取代。在与任一上述或下述实施方式相结合的优选实施方式中,A为未取代的。
在与任一上述或下述实施方式相结合的优选实施方式中,Q为苯基。
在与任一上述或下述实施方式相结合的优选实施方式中,Q由选自卤素中的一或两个基团取代,更优选由选自卤素中的一个基团,特别是Cl取代。
在与任一上述或下述实施方式相结合的优选实施方式中,Z为
在与任一上述或下述实施方式相结合的优选实施方式中,X=CH。
在与任一上述或下述实施方式相结合的优选实施方式中,R1为C3-6环烷基,特别是环丙基。
在与任一上述或下述实施方式相结合的优选实施方式中,R2和R3独立地选自卤素,特别是Cl。
本发明的化合物可以为前药化合物的形式。“前药化合物”指的是一种衍生物,其在活体内在生理条件下通过与酶、胃酸等的反应,例如通过氧化、还原、水解等(每一个反应都是在酶促下进行的)而转变为本发明的化合物。所述前药的实例为这样的化合物,其中本发明化合物中的氨基被酰化、烷基化或者磷酸化而形成,例如,二十酰氨基、丙氨酰氨基、新戊酰氧甲氨基,或者其中羟基被酰化、烷基化、磷酸化或者被转化为硼酸酯,例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙氨酰氧基,或者其中的羧基被酯化或者酰胺化。这些化合物可以根据公知的方法由本发明的化合物制备。所述前药的其它实例为这样的化合物,其中本发明化合物中的羧酸部分被转化为,例如,烷基-、芳基-、胆碱-、氨基、酰氧甲基酯、亚麻酰基酯。
本发明化合物的代谢物也在本发明的范围之内。
当本发明的化合物或者他们的前药可能发生互变异构,例如酮-烯醇互变异构时,则各种形式,例如酮式和烯醇式,以及它们任何比例的混合物都在本发明的范围之内。相同的情形也适用于立体异构体,例如对映异构体、顺式/反式异构体、构象异构体等。
如果需要,可以用在本领域中公知的方法,例如用液相色谱法,将异构体分离。相同的情形适用于用例如手性固定相法分离对映异构体。另外,可以通过将对映异构体转化为非对映异构体来将它们分离,也即,将它们和对映体纯的辅助化合物结合,随后分离所得到的非对映异构体并裂解所述辅助残基。或者,可以由利用光学纯原材料的立体选择性合成来获得本发明化合物的任何对映异构体。从外消旋混合物获得纯的对映异构体的另一种方式可采用手性抗衡离子的对映体选择性结晶。
本发明的化合物可以是药物学上可接受的盐或者溶剂化物的形式。术语“药物学上可接受的盐”指的是由药物学上可接受的无毒性碱或者酸,包括无机碱或者酸和有机碱或者酸,制备的盐。当本发明的化合物包含一种或多种酸性或者碱性基团时,本发明也包括它们相应的药物学上或者毒理学上可接受的盐,特别是它们药物学上可利用的盐。因此,含有酸性基团的本发明的化合物可以用这些组表示并且可以根据本发明以例如碱金属盐、碱土金属盐或者铵盐而使用。这些盐的更具体实例包括钠盐、钾盐、钙盐、镁盐、或者与氨或者有机胺,比如乙胺、乙醇胺、三乙醇胺或者氨基酸形成的盐。含有一种或多种碱性基团(也即可以被质子化的基团)的本发明化合物可以以它们与无机或者有机酸的加成盐的形式存在并根据本发明而使用。适合的酸的实例包括氯化氢、溴化氢、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸以及本领域中技术人员公知的其它酸。当本发明化合物在分子中同时含有酸性和碱性基团时,除了所提及的盐形式之外,本发明还包括内盐或者内铵盐(两性离子)。各个盐可以用本领域中技术人员公知的常规方法来制备,例如,通过在溶剂或者分散剂中将这些化合物与有机或无机酸或者碱相接触,或者通过与其它盐的阴离子交换或者阳离子交换。本发明还包括本发明化合物的所有盐,其由于较低的生理相容性不适合直接用在药品中,但是其可用作,例如,化学反应或者制备药物学上可接受的盐的中间体。
本发明的化合物还可以以溶剂合物的形式存在,例如包含溶剂化水,或者药学上可接受的溶剂化物质,例如醇,尤其是乙醇的那些。
而且,本发明提供了药物组合物,其包含作为活性成分的至少一种本发明的化合物、或者其前药化合物、或者其药物学上可接受的盐或者溶剂化物,以及还包含药物学上可接受的载体。
“药物组合物”指的是一种或多种活性成分和一种或多种构成载体的惰性成分以及任何产物,所述产物直接或者间接地源自任何两种或者多种所述成分的组合、络合或者集合,或者一种或多种所述成分的分解,或者一种或者多种所述成分的其它类型的反应或者相互作用。因此,本发明的药物组合物涵盖了通过混合本发明的至少一种化合物和药物学上可接受的载体而制备的任何组合物。
本发明的药物组合物可以另外包含作为活性成分的一种或多种其它的化合物,例如前药化合物或者其它的核受体调节剂。
虽然在任一给定的情况下最合适的给药方法依赖于所治疗病症的性质和严重程度以及所述活性成分的性质,但是所述组合物适于经口、经直肠、经局部、经胃肠外(包括皮下、肌注和静脉内)、经眼睛(眼的)、经肺(鼻或者口腔吸入)或者经鼻给药。它们可以方便地以单位剂型存在并用药物领域中公知的任何方法制备。
本发明的化合物可以通过在反应式I至III中描述的方法的组合进行制备。如反应式I中所绘,在3-位置中用取代基A取代的4元环酮可在非质子溶剂中及优选在低温下与金属化的芳环或杂芳环M-Q-O-CH2Z(M=金属,例如Li)反应,获得用羟基取代且带有取代基A及Q的4元环。在Y为CH的情况中,可形成二种异构体(A及Q呈顺或反式彼此跨环)。在优化条件下,可实现主要形成二种异构体中的一种。这二种异构体可通过本领域中已知的适当方法分离,如例如硅胶色谱法或制备型RP-HPLC。
反应式I
在反应式II中总结了用来制备合成本发明的化合物所需的4元环酮的方法。在选项a)中,带有乙烯基的中间体(例如,通过乙烯化含卤素的相应起始材料R-A-X(X=卤素)而制备)可以与原位形成的α,α-二氯烯酮反应,形成2,2-二氯环丁酮。在脱卤反应(例如,与Zn在醋酸中回流)后,得到想要的3-取代环丁酮类化合物。或者,所述乙烯基中间体可以与原位产生的未取代烯酮反应,一步获得想要的环丁酮中间体。在选项b)中使用3-亚曱基环丁烷腈作为起始材料。通过本领域技术人员已知的方法在几个步骤内从氰基建立取代的杂环化合物。可使用本领域技术人员已知的条件及试剂通过氧化断裂该环外双键(例如,使用OsO4、臭氧或RhCl3/NaIO4作为氧化剂)来获得想要的环丁酮类化合物。选项c)显示用于制备所述取代氮杂环丁酮类化合物的方法。Cu-或Pd-催化的3-羟基-氮杂环丁烷和卤代芳香环或卤代-杂芳环之间的C-N交叉偶联反应得到相应的N-取代3-羟基氮杂环丁烷化合物,其可以通过氧化转换成所期望的氮杂环丁酮类化合物。
反应式II
反应式III举例说明了在形成所述带羟基的4元环后修饰A基团处的取代基的一些可能性。例如,离去基团X(例如,溴)可通过过渡金属催化的交叉偶联反应由氰基、羧酸酯、曱磺酰基或硫醚取代。所获得的衍生物可通过本领域技术人员已知的方法进一步转换成其它衍生物。例如,氰基及酯基可在碱性条件下水解以获得羧酸,其随后可转换成酰基-磺酰胺类化合物。苄基硫醚可被氯化来得到氯磺酰基中间体,其与氨反应生成相应的磺酰胺类化合物
反应式III
因此,本发明涉及根据通式(1)的化合物,其结合至FXR并作为FXR的激动剂或调节剂起作用。
本发明进一步涉及所述化合物通过用该化合物结合所述核受体用于治疗和/或预防疾病和/或病症的用途。本发明进一步涉及所述化合物在制备用于通过用所述化合物结合所述核受体来治疗和/或预防疾病和/或病症的药物中的用途。具体说,本发明涉及根据通式(1)的化合物在制备用于预防和/或治疗以下疾病的药物中的用途,所述疾病包括:慢性肝内或一些形式的肝外胆汁郁积病症,慢性胆汁郁积病症导致的肝纤维化,急性肝内胆汁郁积病症,不恰当的胆汁组成导致的梗阻性或慢性炎症,伴随饮食脂肪和脂溶性饮食维生素摄取减少的胃肠道病症,炎性肠疾病,脂质和脂蛋白紊乱,II型糖尿病以及I型和II型糖尿病的临床并发症,由于强迫脂质和特异性甘油三酯蓄积然后促纤维化途径激活导致的慢性脂肪和纤维变性引起的疾病和病症,肥胖和代谢综合征(血脂障碍、糖尿病和异常高的体重指数的合并病症),急性心肌梗死,急性中风,慢性梗阻性动脉粥样硬化的终末点发生的血栓形成,胞内细菌或寄生原生动物的持久性感染,非恶性过度增殖性疾病,恶性过度增殖性疾病,结肠腺癌、特别是肝细胞癌,肝脏皮脂腺病及相关的综合征,慢性肝脏疾病或外科手术肝脏切除导致的肝衰竭或肝脏功能障碍,乙型肝炎病毒感染,丙型肝炎病毒感染和/或与酒精诱导的肝硬化或者与肝炎的带病毒形式有关的胆汁郁积和纤维变性效果。
本文所述的药物可以通过常规方法制备,包括将根据本发明的化合物与药学上可接受的载体组合。
FXR被认为是核胆汁酸敏感元件。因此,它同时调节在肝脏中胆汁酸合成产出和它们在肠内的再循环(通过调节胆汁酸结合蛋白)。但是除了胆汁酸生理机能以外,FXR似乎涉及调节许多在病原学上相关的各种各样的生理过程,并用于治疗各种各样的疾病,例如胆固醇胆结石;例如II型糖尿病、血脂异常或者肥胖的代谢紊乱;例如炎性肠病或者慢性肝内形式的胆汁淤积的慢性炎性疾病和许多其它疾病(T.Claudel等人,Arterioscler.Thromb.Vasc.Biol.2005,25,2020;Y.D.Wang等人,Cell Res.2008,18,1087)。
FXR调节肝脏和胃肠道中应答基因的复杂模式。基因产物对多种生理过程都有影响。在FXR的功能分析的过程中,进行分析的第一个调节网络是调节胆汁酸的合成。当经由调节核受体LRH-1的诱导,LXR诱导将胆固醇转化为胆汁酸的关键酶Cyp7A1时,FXR通过上调编码SHP的mRNA抑制Cyp7A1的诱导,SHP是显性抑制LRH-1的另外的核受体。因为FXR与该途径的最终产物,初级胆汁酸,例如胆酸(CA)或者鹅脱氧胆酸(CDCA)结合,这可以被认为是在基因表达水平上反馈抑制的一个实例(B.Goodwin等人,Mol.Cell2000,6,517;T.T.Lu等人,Mol.Cell2000,6,507)。除了经由SHP抑制胆汁酸合成以外,FXR还诱导一系列所谓的ABC(ATP结合盒)转运蛋白,所述转运蛋白负责将有毒的胆汁酸从肝细胞细胞溶胶中输出到小管(产生胆汁的小胆管分枝)中。通过对FXR基因敲除小鼠的分析,FXR的肝保护功能第一次变得明显(C.J.Sinal等人,Cell2000,102,731),其中显示了几种ABC-转运蛋白在肝脏中的表达不足或者超量表达。进一步的详细分析揭示了主要的胆汁盐排泄泵BSEP或者ABCB11(M.Ananthanarayanan等人,J.Biol.Chem.2001,276,28857;J.R.Plass等人,Hepatology2002,35,589)以及介导从脂蛋白到磷脂的脂质转化的关键酶PLTP(N.L.Urizar等人,J.Biol.Chem.2000,275,39313),和用于磷脂的两个关键小管膜转运蛋白,MRP-2(ABCC4)(H.R.Kast等人,J.Biol.Chem.2002,277,2908)和MDR-3(ABCB4);L.Huang等人,J.Biol.Chem.2003,278,51085)是通过FXR的配体导向转录激活的直接靶标(概括在下列文献中:M.Miyata,J.Pharmacol.Exp.Ther.2005,312,759;G.Rizzo等人,Curr.Drug TargetsImmune Endocr.Metabol.Disord.2005,5,289)。
FXR似乎是胆汁酸的合成、输出和再循环的主要代谢敏感元件和调节子的事实使人想到使用FXR配体来诱导胆汁流并使胆汁酸组合物朝着更亲水组合物的方向变化。随着作为工具化合物的第一个合成的FXR配体GW4064(P.R.Maloney等人.,J.Med.Chem.2000,43,2971;T.M.Willson等人,Med.Res.Rev.2001,21,513)和半合成人工胆汁酸配体6-α-乙基-CDCA的开发,可以分析由强力激动剂产生的FXR的超刺激效果。结果表明在胆管结扎的动物中两种配体都诱导了胆汁流。此外,除了利胆效果以外,也显示了肝保护效果(R.Pellicciari等人,J.Med.Chem.2002,45,3569;Y.Liu等人,J.Clin.Invest.2003,112,1678)。这个肝保护效果被进一步缩小到抗纤维化效果,该抗纤维化效果来自于由FXR激动剂产生的基质-金属蛋白酶组织抑制剂TIMP-1和2的抑制、在肝星状细胞中胶原沉淀解析基质-金属蛋白酶2(MMP-2)的诱导以及随后的两者均为促纤维化因子的α-胶原mRNA和转化生长因子β(TGF-β)mRNA的减少(S.Fiorucci等人,Gastroenterology2004,127,1497;S.Fiorucci等人,J.Pharmacol.Exp.Ther.2005,314,584)。而且,在胆管结扎动物模型以及在雌激素诱导的胆汁淤积的动物模型中显示了抗胆汁淤积活性(S.Fiorucci等人,J.Pharmacol.Exp.Ther.2005,313,604)。
遗传研究表明,在胆汁淤积的遗传类型(进行性家族性肝内胆汁淤积=PFIC,类型I~IV)中,或者由于在FIC1基因中的突变减少了FXR自身的核定位(在PFIC类型I中,也称为拜勒病)(F.Chen等人,Gastroenterology2004,126,756;L.Alvarez等人,Hum.Mol.Genet.2004,13,2451)或者减少了编码MDR-3磷脂输出泵的FXR靶基因水平(在PFIC类型III中)。总之,不断增加的证据表明FXR结合化合物将在慢性胆汁淤积病症,例如原发性胆汁性肝硬化(PBC)或者原发性硬化性胆管炎(PSC)的治疗方法中显示实际的临床应用(综述参见:G.Rizzo等人,Curr.Drug Targets ImmuneEndocr.Metabol.Disord.2005,5,289;G.Zollner等人,Mol.Pharm.2006,3,231;S.Y.Cai等人,Expert Opin.Ther.Targets2006,10,409)。
FXR激活对胆汁酸代谢和排泄的纵深影响不仅与胆汁淤积综合症相关并且甚至更直接地与胆结石形成的治疗相关。由于胆固醇(其主动从肝细胞泵入到小管的内腔中)的低溶解度而形成了胆固醇胆结石。三个主要组分,胆汁酸、磷脂和游离胆固醇的含量的相对百分数决定了混合胶束的形成并由此决定了游离胆固醇在胆汁中的表观溶解度。FXR多态性经数量性状遗传位点分析而定位为导致胆结石疾病的一个因素(H.Wittenburg,Gastroenterology2003,125,868)。使用合成性FXR工具化合物GW4064,可以表明,FXR的激活导致胆固醇饱和指数(CSI)的改善并直接导致C57L易成石小鼠中胆结石形成的停止,而在FXR基因敲除小鼠中的药物治疗显示对胆结石形成没有效果(A.Moschetta等人,NatureMedicine2004,10,1352)。
这些结果证明FXR为一种良好的靶标,其可用于开发可用于防止胆固醇胆结石形成或者防止在手术切除或者震波碎石后胆结石重新形成的小分子激动剂(论述参见:S.A.Doggrell,Curr.Opin.Investig.Drugs2006,7,344)。
因此,在本发明的一个实施方式中,式(I)的化合物和包含该化合物的组合物用于预防和/或治疗不恰当的胆汁组成导致的梗阻性或慢性炎症如胆石病,也称为胆固醇胆结石。
除了在肝脏中小分子刺激活化后显示的强效肝脏保护和利胆以及抗纤维化作用之外,FXR似乎还具有保护小肠免于致瘤性转化以及在肠道中形成息肉形成及其转化为腺癌的作用(S.Modica等人,Cancer Res.2008,68,9589和R.R.Maran等人,J.Pharmacol.Exp.Ther.2009,328,469)。类似于小肠的情况,缺乏FXR导致最普遍的肝癌形式-肝细胞癌(HCC)的形成大幅提高(I.Kim等人,Carcinogenesis2007,28,940和F.Yang等人,Cancer Res.2007,67,863)。而功能性FXR防止结肠腺癌和肝细胞癌形成,FXR活化诱导肝切除后的肝脏再生(W.Huang等人,Science2006,312,233)。
与FXR活化相关的肝脏保护、抗癌和肝脏再生作用的组合可以治疗性利用,采用FXR激动剂治疗严重的肝脏疾病。在一个实施方式中,本发明的化合物和包含该化合物的组合物可用于治疗肝脏疾病,例如肝细胞癌(HCC),刺激肝脏再生,缓解与主要肝切除、各种病因的肝硬化相关的副作用,以及在肝脏移植或主要肝脏手术的过程中预防或治疗肝脏缺血。
自从发现第一个合成FXR激动剂并将其给药啮齿动物后,事实证明FXR是血清甘油三酸脂的关键调节物(P.Maloney等人,J.Med.Chem.2000,43,2971;T.Willson等人,Med.Res.Rev.2001,21,513)。在过去的六年里,已经发表的累计证据表明通过合成激动剂产生的FXR激活不但导致血清甘油三酸脂的明显减少,主要以减少的VLDL的形式,并且导致总血清胆固醇的减少(H.R.Kast等人,Mol.Endocrinol.2001,15,1720;N.L.Urizar等人,Science2002,296,1703;G.Lambert等人,J.Biol.Chem.2003,278,2563;M.Watanabe等人,J.Clin.Invest.2004,113,1408;A.Figge等人,J.Biol.Chem.2004,279,2790;S.Bilz等人,Am.J.Physiol.Endocrinol.Metab.2006,290,E716)。
但是血清甘油三酸脂的降低不是一个孤立的效果。用合成FXR激动剂GW4064治疗db/db或者ob/ob小鼠导致血清甘油三酸脂、总胆固醇、游离脂肪酸、比如3-羟基丁酸盐的酮体的显著和联合减少。此外,FXR激活涉及在肝细胞中的细胞内胰岛素信号通道,导致来自肝脏糖原异生的葡萄糖输出的减少但是伴随着肝脏糖原的增加。胰岛素敏感度以及葡糖耐量受到FXR治疗的正面影响(K.R.Stayrook等人,Endocrinology2005,146,984;Y.Zhang等人,PNAS2006,103,1006;B.Cariou等人,J.Biol.Chem.2006,281,11039;K.Ma等人,J.Clin.Invest.2006,116,1102;D.Duran-Sandoval等人,Biochimie2005,87,93)。最近在用高脂饮食过度饲喂的小鼠中也观察到体重减轻的效果(C.Lihong等人,美国糖尿病协会(ADA)第66界科学年会,2006年6月,摘要编号856-P)。这种体重减轻效果可能得自于FGF-19(一种已知导致体重减轻和运动表现型的成纤维细胞生长因子)的FXR诱导(J.Holt等人,Genes Dev.2003,17,1581;E.Tomlinson等人,Endocrinology2002,143,1741)。在新近的专利申请中,显示了FXR激动剂在体重减轻上的效果(WO2004/087076;WO2003/080803)。
总之,FXR激动剂的这些药理学效果可以在不同的治疗方法中使用:由于FXR结合化合物的胰岛素敏化、葡萄糖异生作用和降脂效果,它们被认为是治疗II型糖尿病的良好候选。
在一个实施方式中,本发明的化合物和包含所述化合物的药物组合物用在II型糖尿病的预防和/或治疗中,该疾病可以通过FXR-介导的在肝脏内系统胰岛素敏感度和细胞内的胰岛素信号的上调、增加周边的葡萄糖吸收和代谢、增加肝脏中的糖原存储、减少从肝脏负荷的糖原异生产生的葡萄糖向血清中的输出而得到治疗。
在又一个实施方式中,所述化合物和药物组合物用于治疗慢性肝内胆汁淤积病症,例如PBC、PSC、进行性家族性胆汁淤积(PFIC)、乙醇诱导的肝硬化和相关的胆汁淤积,以及有些形式的肝外胆汁淤积病症或者肝脏纤维化。
本发明也涉及用于预防和/或治疗减少对饮食中脂肪和脂溶性饮食维生素的吸收的胃肠道病症的通式(I)的化合物或者含有所述化合物的药物组合物,所述病症可通过增加肠内胆汁酸和磷脂的水平而得到治疗。
在又一个实施方式中,所述化合物或者药物组合物用于防止和/或治疗选自下组中的疾病:脂质和脂蛋白紊乱,例如作为临床表现症状的高胆固醇血症、高甘油三酯血症和动脉粥样硬化,其可以通过FXR对降低血浆总胆固醇、降低血清甘油三酸脂、增加肝脏胆固醇向胆汁酸的转化和增加在肝脏中的VLDL和其它脂蛋白的清除和代谢性转化的有益效果而得到缓解。
在又一个实施方式中,所述化合物和药物组合物用于预防和/或治疗这样的疾病,其中FXR-靶向药剂的降脂、抗胆汁淤积和抗纤维化联合效果可以用于治疗肝脏脂肪变性和相关症状,例如非酒精性脂肪性肝炎(“NASH”)或者用于治疗与乙醇诱导的肝硬化或者病毒负荷形式的肝炎相关的胆汁淤积和纤维化效果。
结合降血脂效果,也表明功能性FXR的丧失导致在ApoE基因敲除小鼠中动脉粥样硬化的增加(E.A.Hanniman等人,J.Lipid Res.2005,46,2595)。因此,FXR激动剂可能具有作为抗动脉粥样硬化和保护心脏药物的临床用途。在血管平滑肌细胞中内皮肽-1的下调也可能导致这样的有益治疗效果(F.He等人,Circ.Res.2006,98,192)。
本发明也涉及通式(I)的化合物或者含有所述化合物的药物组合物,其用于预防性和创伤后治疗心血管紊乱,比如急性心肌梗塞、急性中风或者血栓形成,它们作为慢性梗阻性的动脉粥样硬化的最终结果而发作。
除了控制小肠和结肠息肉形成,FXR似乎还在乳腺癌组织和细胞系中表达并且与ER阳性乳腺癌细胞中的雌激素受体相互作用,但健康乳腺组织不表达(K.E.Swales等人,Cancer Res.2006,66,10120和F.Journe等人,Breast Cancer Res.Treat.2009,115,523)。
这使得人们考虑FXR也可以作为治疗增殖性疾病,尤其是表达FXR的小分子响应形式的转移癌形式的潜在靶标。
在又一个实施方式中,所述化合物和药物组合物用于预防和/或治疗恶性过度增殖性疾病,例如各种形式的癌症,尤其是某些乳腺癌、肝癌或结肠癌形式),其中用FXR配体干扰具有有益的影响。
最后,FXR似乎也涉及调控在肠中的抗菌防御(T.Inagaki等人,PNAS.2006,103,3920),虽然没有提供确切的作用机制。但是从这些发表的数据中,人们可以得出结论,采用FXR激动剂的治疗可能在炎性肠病(IBD),特别是影响肠道的上段(回肠)部分的那些形式(例如,回肠克罗恩病)的治疗中具有有益的影响,因为这似乎是FXR调控细菌滋长的作用位置。在IBD中,适应性免疫反应的脱敏作用在肠内免疫系统中不知何故被削弱了。由此细菌的过度生长可能造成触发慢性炎性响应的建立。由此细菌的过度生长可能造成触发慢性炎性响应的建立。因此,由FXR-负荷机制抑制细菌滋长可能是防止急性炎性病症的关键机制。
因此,本发明也涉及通式(I)的化合物或者包含所述化合物的药物组合物,其用于防止和/或治疗与炎性肠病,例如克罗恩病或者溃疡性结肠炎相关的疾病。FXR-介导的肠内障碍功能的恢复和非共生细菌负荷量的减少被认为是有助于减少细菌性抗原暴露于肠内免疫系统并且因此可以减少炎性响应。
本发明进一步涉及一种化合物或者药物组合物,其用于预防和/或治疗肥胖症和相关的紊乱,比如代谢性综合征(血脂异常、糖尿病和不正常的高体重指标的组合病症),所述病症可以通过FXR-介导的血清甘油三酸脂、血糖降低和胰岛素敏感度的增加以及FXR-介导的体重减轻而得到治疗。
在又一个实施方式中,本发明的化合物或者药物组合物用于防止和/或治疗I型和II型糖尿病的临床并发症。这些并发症的实例包括糖尿病性肾病、糖尿病性视网膜病、糖尿病性神经病变、周围组织动脉梗阻性疾病(PAOD)。本发明还包括糖尿病的其它临床并发症。
此外,那些由于增强的脂质和特别是甘油三酸脂的累积和随后促纤维化通道的激活导致的器官的慢性肥胖和纤维化病变而产生的病症和疾病也可以通过施用本发明的化合物或者药物组合物而得到预防和/或治疗。这样的病症和疾病包括在肝脏中的非酒精性脂肪性肝炎(NASH)和慢性胆汁淤积病症、在肾脏中的肾小球硬化症和糖尿病性肾病、在眼中的黄斑变性和糖尿病性视网膜病以及神经变性疾病,比如在脑中的阿尔茨海默病或者在周围神经系统中的糖尿病性神经病变。
在实际用途中,本发明的化合物可以作为活性成分根据常规药物配制技术与药物载体一起均匀结合在混合物中。根据给药所要求的制剂形式,例如口服或者胃肠外的(包括静脉内的),载体可以为各式各样的形式。当制备用于口服剂型的组合物时,可以使用任何常规的药物介质,例如,在制备口服液体药剂例如悬浮液、酏剂和溶液时使用水、乙二醇、油、醇、芳香剂、防腐剂、着色剂等等;或者在制备口服固体制剂例如粉末、硬胶囊和软胶囊和片剂时使用例如淀粉、糖、微晶纤维素、稀释剂、成粒剂、滑润剂、粘合剂、崩解剂等等,其中固体口服制剂是比液体药剂更优选的。
因为片剂和胶囊剂容易服用,所以它们代表了最有利的口服剂量单位形式,在这种情况下明显使用固体药物载体。如果需要的话,可以用标准水溶液或者非水溶液技术将片剂包衣。这样的组合物和制剂应当含有至少百分之0.1的活性化合物。当然,可以改变在这些组合物中的活性化合物的百分比,并且该百分比可以方便地在单位重量的约2%到约60%之间。在此类治疗上有用的组合物中的活性化合物的含量应能得到有效剂量。也可以采用例如液滴或者喷雾剂的形式鼻内给药该活性化合物。
所述片剂、药丸、胶囊剂等也可以包含:粘合剂比如黄蓍树胶、阿拉伯胶、玉米淀粉或者明胶;赋形剂比如磷酸二钙;崩解剂比如玉米淀粉、马铃薯淀粉、藻酸;滑润剂比如硬脂酸镁;和甜味剂比如蔗糖、乳糖或者糖精。当剂量单位形式是胶囊时,除了上述类型的材料以外,它可以包含液体载体比如脂肪油。
可以存在各种各样的其它材料作为包衣或者来改变所述剂量单位的外形。例如,片剂可以用虫胶、糖或者两者进行包衣。除了所述活性成分以外,糖浆剂或者酏剂可以包含作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯或丙酯、染料和例如樱桃味或者橙味的调味剂。
由于本发明的化合物大多代表羧酸或其类似的阴离子等构物,并且由于众所周知离子化药物化合物的盐形式可显著改变药物化合物的生物利用度,也可以用各种抗衡阳离子使本发明的化合物形成盐以产生可口服利用的制剂。这些药学上可接受的阳离子可以是单价或二价离子,例如铵离子,碱金属钠或钾,或碱土金属镁或钙,某些药学上可接受的胺如三(羟甲基)氨基甲烷、乙二胺、二乙胺、哌嗪或其它,或某些阳离子氨基酸如赖氨酸或精氨酸。
本发明的化合物也可以经胃肠外给药。可以在水中与表面活性剂比如羟丙基纤维素适当地混合来制备这些活性物质的溶液或者悬浮液。在甘油、液体聚乙二醇及其混合物中和在油中也可以制备分散剂。在常见的储存和使用条件下,这些制剂含有防腐剂以防止微生物生长。
适于注射用途的药品形式包括无菌水溶液或者分散剂和用于即时制备无菌可注射溶液或者分散剂的无菌粉末。在所有的情况下,所述药品形式都必须是无菌的并且必须是以容易注射的形式存在的流体。它在制造和贮存的条件下必须是稳定的并且必须在抗微生物比如细菌和真菌的污染作用的条件下保存。载体可以是溶剂或者分散介质,其含有,例如,水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)、它们适合的混合物和植物油。
可以使用任何适合的给药途径向哺乳动物,尤其是人提供有效剂量的本发明化合物。例如,可以使用经口、经直肠、经局部、经胃肠外、经眼、经肺、经鼻等给药方法。剂型包括片剂、锭剂、分散剂、悬浮剂、溶液剂、胶囊剂、乳剂、软膏剂、气溶胶等。优选本发明的化合物经口服给药。
根据所使用的具体化合物、给药方式、所治疗的病症和被治疗的病症的严重程度可以改变所使用的活性成分的有效剂量。这样的剂量可由所属技术领域的专业人员容易地确定。
当治疗或者预防本发明化合物所指示的FXR介导的病症时,通常以约0.1毫克至约100毫克/千克动物体重的每日剂量,优选以单次日剂量、或者以两到6次每天的分剂量、或者以缓释形式施用给药本发明的化合物时获得了满意的效果。对于大多数大型哺乳动物,每日总剂量为约1.0毫克至约1000毫克,优选约1毫克至约50毫克。对于70公斤的成年人,每日总剂量一般为7毫克至约350毫克。可以调整这个剂量方法以提供最佳治疗效果。
本发明化合物可以根据下面的反应式和实施例的步骤使用适当地材料制备并且进一步通过下面的具体实施例来进行举例说明。此外,通过使用在这里描述的步骤,结合在本领域中的常规技术,可以容易地制备在本申请中主张的其它本发明化合物。但是,在所述实施例中阐明的化合物不能被理解为是构成被认为是本发明的唯一化合物。所述实施例进一步阐明了用于制备本发明化合物的细节。本领域技术人员容易理解,可用以下制备步骤的条件和过程的已知变化来制备这些化合物。本发明化合物一般以它们的药物学上可接受的盐(比如上面描述的那些)的形式进行分离。
相应于所分离的盐的游离胺碱可以通过与适当碱,例如碳酸氢钠、碳酸钠、氢氧化钠和氢氧化钾水溶液的中和,以及将释放出的游离胺碱萃取到有机溶剂中,随后蒸发来制备。可以将用这种方式分离的游离胺碱通过溶解在有机溶剂中,随后加入适当的酸和后续的蒸发、沉淀或者结晶进一步转变为另一种药物学上可接受的盐。与所分离的盐相对应的游离羧酸可以通过与适当的酸,比如盐酸、硫酸氢钠、磷酸二氢钠水溶液中和,以及将释放出的游离羧酸萃取到有机溶剂中,随后蒸发来制备。可以将用这种方式分离的羧酸通过溶解在有机溶剂中,随后加入适当的碱和后续的蒸发、沉淀或者结晶进一步转变为另一种药物学上可接受的盐。
具体实施方式
下文中举例说明了本发明化合物的制备。除非另外在方法中指明,所述变量具有如上所述的相同意义。下面给出的实施例意图解释本发明的具体实施方式。在如下所述的合成中使用的适当起始原料、基本成分和试剂为市售的,可从下列公司购买到:例如,西格玛奥德里奇(Sigma-Aldrich)或者Acros Organics,或者用在下列文献中描述的步骤常规制备:例如《马氏高等有机化学:反应、机理和结构》(March′s Advanced OrganicChemistry:Reactions,Mechanisms,and Structure)第5版,John Wiley&Sons;或者T.Eicher,S.Hauptmann的《杂环化学;结构、反应、合成和应用》(The Chemistry ofHeterocycles;Structures,Reactions,Synthesis and Application),第2版,Wiley-VCH2003;Fieser等人的《菲氏有机合成试剂》Fiesers′Reagents for organicSynthesis》,John Wiley&Sons,2000。
实施例
实施例1:3-((1s,3s)-3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基) 甲氧基)苯基)-3-羟基环丁基)苯甲酸甲酯(1)
步骤1:4-((4-溴-3-氯苯氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)-异噁唑(1a)
向(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇(13g,45.8mmol)在CH2Cl2(DCM)(200mL)中的溶液中滴加SOCl2(40mL,336mmol)。所得混合物在室温下搅拌24小时,并减压去除溶剂。将残余物溶解在N,N-二甲基甲酰胺(DMF)(200mL)中,并向该溶液中加入4-溴-3-氯苯酚(9.7g,47mmol)、K2CO3(40g,290mmol)和NaI(12g,80mmol)。将混合物在60℃搅拌过夜,然后冷却至室温,用水(1000mL)稀释并用乙酸乙酯(EA)(500mL×3)萃取。有机相合并,用盐水(500mL×3)洗涤,用Na2SO4干燥,并真空浓缩。残余物用在硅胶上的快速色谱法(CC)纯化得到题述化合物1a(19g,88%),为白色固体。
步骤1:3-(2,2-二氯-3-氧代环丁基)苯甲酸甲酯(1b)
在氮气气氛下,在配备有冷凝器、顶置式搅拌器和压力平衡滴液漏斗的3口圆底烧瓶中,将3-乙烯基苯甲酸甲酯(5g,31mmol)溶解在干燥Et2O(150mL)中。该烧瓶中加入锌粉(6g,3当量),并超声处理该反应30分钟。在此时间后,逐滴加入三氯乙酰氯(8.7mL,2.5当量)在干燥Et2O(50mL)中的溶液,同时在下一个30分钟内进行进行超声处理。在该步骤过程中,反应混合物被加热至35℃。在回流下继续进行超声处理2.5小时,并且通过1H NMR分析显示反应完成。使反应冷却至室温并用水(~50mL)淬灭。因为放热反应延迟发生,所以该步骤以逐滴加入的方式几分钟穿插几次完成。在水中搅拌20分钟后,反应混合物通过硅藻土垫过滤并用Et2O淋洗。有机层用几部分的水(2x250mL)、饱和碳酸氢钠(2x250mL)和盐水(1x250mL)洗涤,用硫酸钠干燥,过滤并减压浓缩得到粗产物1b,为暗黄色稠油(粗产物8.7g)。
步骤2:3-(3-氧代环丁基)苯甲酸甲酯(1c)
在氮气气氛中在圆底烧瓶中,将粗产物化合物1b(8.7g)溶解在冰醋酸(55mL)中。向该烧瓶中加入锌粉(4.6g,2.2当量),并搅拌该反应并加热至120℃进行3小时。在冷却至室温后,将混合物进过硅藻土垫过滤,将此用几部分EA洗涤。在溶解在EA(500mL)之前,溶液合并并减压浓缩,用盐水(150mL x2)洗涤,然后用硫酸钠干燥,过滤并再次浓缩。将粗产物混合物在氯仿(250mL)中搅拌5分钟,并且经过烧结漏斗过滤。将滤液浓缩得到粗产物,为淡黄色油状物。通过CC在(PE/EA=9:1,PE=石油醚)中纯化该粗产物得到所需产物1c(2.5g,两步总产率38%),为淡黄色油状物。
步骤3:3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯
基)-3-羟基环丁基)苯甲酸甲酯(1)
在氮气气氛下在-78℃向化合物1a(1.67g,3.5mmol)在干燥THF(30mL)中的溶液中在10分钟内滴加n-BuLi(2.5M在己烷中,1.2当量,1.69mL)。将其在该温度下搅拌1小时,然后滴加化合物1c(0.72g,1当量)在干燥THF(10mL)中的溶液,并在此温度下搅拌1小时。将混合物缓慢升温至室温并搅拌过夜。反应用饱和氯化铵溶液(50mL)和EA(250mL)的溶液淬灭。分离有机层,并用EA(2x100mL)洗涤水溶液层。有机萃取液合并,用硫酸钠干燥,过滤并浓缩得到粗产物,为棕色油状物。在用PE/EA(19:1至3:1)CC后分离产物。以相同规模重复该反应和纯化两次,并在相同条件下再纯化合并后的产物(3.13g)得到最终产物1(1.7g,19%)。1HNMR(CDCl3):7.93(m,1H),7.90-7.85(m,1H),7.50-7.30(m,5H),6.88(s,1H),6.75-6.72(m,1H),4.80(s,2H),3.88(s,3H),3.20-3.10(m,1H),3.00-2.91(m,2H),2.60-2.49(m,2H),2.15-2.08(m,1H),1.30-1.25(m,2H),1.15-1.10(m,2H)。
实施例2:3-((1s,3s)-3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)
甲氧基)苯基)-3-羟基环丁基)苯甲酸(2)
在室温下将化合物1(1.7g,2.84mmol)溶解在THF(100mL)中。加入LiOH(285mg,4.2当量)在水(20mL)中的溶液并搅拌该溶液并升温至35℃保持三天。在此时间后,减压除去THF。剩下的水溶液用水(25mL)稀释并用Et2O(2x50mL)洗涤。然后将水溶液层转移至圆底烧瓶中,并使用1NHCl酸化至pH6。过滤出所形成的白色沉淀,并在50℃减压干燥得到题述化合物2(1.3g,78%,通过1H-NMR和LC-MS确定为单一异构体),为白色固体。1H NMR(400MHz,CD3OD)δ:7.98(s,1H),7.86(d,J=7.6Hz,1H),7.58-7.46(m,5H),7.41(t,J=7.6Hz,1H),6.91(d,J=2.4Hz,1H),6.80(dd,J=8.8,2.4Hz,1H),4.95(s,2H),3.29-3.25(m,2H),2.96(m,1H),2.55-2.49(m,2H),2.37(m,1H),1.24-1.22(m,4H)。MS(ESI-)m/z:584(582)[M-1]-。
相关强度NOEs(从ROESY光谱获得;下面的箭头)指示出,二个芳香族部分在实施例2中为1,3-反式定向。
实施例2的替代路线
步骤1:3-(3-溴苯基)环丁酮(2a)
将N,N-二甲基乙酰胺(9.0g,103mmol)溶解在1,2-二氯乙烷(200mL)中。将溶液冷却至0℃,然后加入三氟甲磺酸酐(63g,223mmol)。反应在0℃再搅拌60分钟。然后加入1-溴-3-乙烯基苯(15g,81.9mmol)和2,4,6-三甲基吡啶(10.5g,86.6mmol)。将该反应加热至回流过夜,通过加入水(300毫升)淬灭并在室温下搅拌2小时。混合物用DCM(300mL×3)萃取。有机层合并,用Na2SO4干燥,并真空浓缩。用CC(EA/PE=1:20)纯化得到题述化合物2a(5.0g,27%),为淡黄色固体。
步骤2:3-(3-溴苯基)-1-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)
甲氧基)苯基)环丁醇(2b)
向在-78℃的化合物1a(14g,29.6mmol)在干燥THF(500mL)中的溶液中滴加n-BuLi(18.5mL,1.6M在己烷中,29.6mmol)。将该混合物在-78℃再搅拌1小时,然后滴加化合物2a(6.5g,28.9mmol)在干燥THF(50mL)中的溶液。将所得混合物在-78℃搅拌1小时,然后升温至室温,并用饱和NH4Cl水溶液(500mL)淬灭。混合物用EA(500mL×2)萃取,有机层合并,用盐水洗涤,用Na2SO4干燥,并真空浓缩。残余物用CC(EA/PE=1:5)纯化得到题述化合物2b(6.5g,37%),为白色固体。
步骤3:3-(3-氰基苯基)-1-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-
基)甲氧基)苯基)环丁醇(2c)
在氩气气氛下向化合物2b(3.1g,5mmol)在DMF(50mL)的溶液中加入Zn(CN)2(500mg,4.3mmol)、Pd2(dba)3(300mg,0.33mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)(150mg,0.31mmol)。在微波辐照下将该混合物在115℃搅拌10小时。在冷却至室温后,用水(250mL)稀释反应混合物并用EA(250mL×2)萃取。有机相合并,用盐水(100mL×3)洗涤并用Na2SO4干燥。残余物用CC(EA/PE)纯化得到题述化合物2c(1.2g,42%),为淡黄色固体。
步骤4:3-((1s,3s)-3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲
氧基)苯基)-3-羟基环丁基)苯甲酸(2)
向化合物2c(15g,24.2mmol)在EtOH(750mL)的溶液中加入NaOH水溶液(在100mL水中40g)。将所得混合物加热至回流过夜,然后冷却至室温。真空浓缩反应除去挥发性溶剂,用水(1000mL)稀释,并用稀盐酸(1N)调节pH至2。过滤收集形成的沉淀得到粗产物,为黄色固体(13.8g)。用制备反相HPLC(RP-HPLC)纯化得到题述化合物2(8.0g,56%,用1H-NMR验证为单一异构体),为白色固体。
制备实施例3
步骤1:3-(3-羟基氮杂环丁烷-1-基)苯甲酸甲酯(3a)
向3-碘苯甲酸甲酯(4.5g,17.2mmol)在DMSO(30mL)的溶液中加入3-氮杂环丁烷-3-醇盐酸盐(1.3g,11.8mmol)、Cs2CO3(9.5g,29.2mmol)、CuI(446mg,2.3mmol)和L-脯氨酸(540mg,4.7mmol),然后将该混合物在氩气气氛下在90℃加热18小时。溶液用EA和水稀释,然后将有机层用盐水洗涤三次,减压浓缩,并用CC(PE/EA=2:1)纯化得到化合物3a(1.6g,66%),为黄色固体。
步骤2:3-(3-氧代氮杂环丁烷-1-基)苯甲酸甲酯(3)
在0℃向化合物3a(1.60g,7.7mmol)在干燥DCM(30mL)的溶液中加入戴斯-马丁氧化剂(Dess-Martin periodinane)(6.5g,15.4mmol),并在N2气氛下将该混合物在室温搅拌2小时。用饱和碳酸氢钠溶液淬灭该混合物并用EA稀释。有机部分用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩,然后用CC(PE/EA=4:1)纯化得到化合物3(1.2g,75%),为白色固体。
实施例4:3-((1s,3s)-3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)
甲氧基)苯基)-3-羟基环丁基)-N-(甲基磺酰基)苯甲酰胺(4)
向化合物2(100mg,0.17mmol)在DCM(5mL)的溶液中加入EDCI·HCl(100mg,0.52mmol)、DMAP(100mg,0.81mmol)和MeSO2NH2(40mg,0.42mmol)。将该混合物在30℃搅拌过夜,然后用EA稀释,用H2O、盐水洗涤,并用Na2SO4干燥。真空浓缩并用制备薄层层析(prep-TLC)纯化得到粗目标化合物,为淡黄色固体。RP-HPLC纯化得到题述化合物4(38mg,33%),为白色固体。1H NMR(400MHz,CD3OD)δ:7.87(s,1H),7.74(d,J=7.6Hz,1H),7.61-7.53(m,5H),7.50(t,J=7.6Hz,1H),6.91(d,J=2.4Hz,1H),6.80(dd,J=8.8,2.4Hz,1H),4.95(s,2H),3.30-3.26(m,2H),3.01(m,1H),2.57-2.51(m,2H),2.37(m,1H),1.25-1.23(m,4H)。MS(ESI-)m/z:659[M-1]-。
实施例5:3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯
基)-3-羟基环丁基)苯磺酰胺(5)
步骤1:3-(3-(苄硫基)苯基)-1-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-
4-基)甲氧基)苯基)环丁醇(5a)
在氩气气氛下向化合物2b(619mg,1mmol)在甲苯(20mL)中的溶液中加入K2CO3(276mg,2mmol)、苯甲硫醇(125mg,1mmol)、Pd2(dba)3(200mg,0.22mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(75mg,0.16mmol)。然后将混合物在115℃搅拌4小时。在冷却至室温后,用水(100mL)稀释反应物并用EA(100mL×2)萃取。有机相合并,用盐水(100mL×2)洗涤,用Na2SO4干燥,并浓缩至干燥状态。用CC纯化得到化合物5a(200mg,30%),为淡黄色固体。1HNMR(400MHz,CDCl3)δ:7.36-7.32(m,3H),7.28-7.07(m,9H),7.01(d,J=7.2Hz,1H),6.82(d,J=2.0Hz,1H),6.66(dd,J=8.8,2.0Hz,1H),4.75(s,2H),4.04(s,2H),3.06-3.00(m,2H),2.84-2.78(m,2H),2.44-2.38(m,3H),2.09(m,1H),1.24-1.18(m,2H),1.11-1.08(m,2H)。MS(ESI+)m/z:662[M+1]+。
步骤2:3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯
基)-3-羟基环丁基)苯-1-磺酰氯(5b)
向化合物5a(34mg,0.05mmol)在CH3CN/HOAc/H2O(1mL/37μL/25μL)中的溶液中加入2,4-二氯-5,5-二甲基乙内酰脲(20mg,0.1mmol)。将该混合物在0-5℃搅拌2小时。将反应物用水稀释并用CH2Cl2萃取。有机层合并,用5%NaHCO3溶液、盐水洗涤,并用Na2SO4干燥。浓缩至干燥状态得到粗产物5b(30mg),为无色油状物,其直接用作下一步中。
步骤3:3-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯
基)-3-羟基环丁基)苯磺酰胺(5)
向化合物5b(30mg)在CH3CN(2mL)中的溶液中加入NH4OH(0.3mL)。将该混合物在室温搅拌1小时。浓缩至干燥状态并用制备RP-HPLC纯化得到题述化合物5(3.5mg,两步总产率10%),为白色固体。1H NMR(400MHz,CDCl3)δ:7.85(s,1H),7.77(d,J=7.6Hz,1H),7.54-7.41(m,5H),7.35(d,J=8.4Hz,1H),6.90(s,1H),6.75(d,J=8.4Hz,1H),4.83(s,2H),4.77(s,宽,2H),3.20(t,J=10.4Hz,2H),3.04(m,1H),2.58(t,J=10.6Hz,2H),2.17(m,1H),1.31-1.30(m,2H),1.20-1.16(m,2H)。MS(ESI-)m/z:617[M-1]-
实施例6:1-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯
基)-3-(3-(甲基磺酰基)苯基)环丁醇(6)
向化合物2b(200mg,0.32mmol)在DMSO中的溶液中,加入甲烷亚磺酸钠(50mg,0.46mmol)、CuI(20mg,0.1mmol)、L-脯氨酸(37mg,0.32mmol)和二异丙基乙胺(DIEA)(41mg,0.32mmol)。将该混合物在95℃搅拌过夜,然后用水稀释并用EA萃取。有机层合并,用水洗涤并用Na2SO4干燥。减压浓缩至干并用制备RP-HPLC纯化得到题述化合物6,为白色固体(35mg,21%,用1H NMR和LC-MS验证为单一异构体)。1H NMR(400MHz,CDCl3)δ:7.84(s,1H),7.79(d,J=7.6Hz,1H),7.60(d,J=7.6Hz,1H),7.53(t,J=7.6Hz,1H),7.44-7.41(m,3H),7.34(t,J=7.2Hz,1H),6.90(d,J=2.8Hz,1H),6.75(dd,J=8.4,2.0Hz,1H),4.83(s,2H),3.24-3.19(m,2H),3.08-3.04(m,4H),2.62-2.56(m,2H),2.17(m,1H),1.31-1.29(m,2H),1.20-1.16(m,2H)。MS(ESI+)m/z:618(620)[M+1]+,600(602)[M-H2O+1]+。
实施例7:5-((1s,3s)-3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)
甲氧基)苯基)-3-羟基环丁基)-1-异丁基-1H-吡唑-3-甲酸甲酯(7)
步骤1:1-异丁基-5-乙烯基-1H-吡唑-3-甲酸甲酯(7a)
将甲基三苯基溴化鏻(2.69g,7.52mmol)在干燥THF(40mL)中的悬浮液冷却至-78℃,并滴加正丁基锂(在己烷中的1.6M溶液,3.7mL,5.91mmol)。将该橙黄色悬浮液在-78℃搅拌50分钟,然后滴加5-甲酰基-1-异丙基-1H-吡唑-3-甲酸甲酯(按照WO2011/020615中的描述制备,1.05g,5.37mmol)在干燥THF(10mL)的溶液。将该混合物在-78℃搅拌1.75小时,移除冷却浴,并将该混合物(灰白色悬浮液)在室温搅拌1小时。将水溶液层用EA(每次50mL)萃取两次,并将有机层合并,用水(每次50mL)洗涤两次,并在没有干燥的情况下浓缩得到2.74g黄色油状物,其缓慢结晶。用CC(用CH2Cl2预吸附,己烷/EA4:1)纯化该粗产物得到烯烃7a(590mg,57%),为无色油状物。1H NMR(DMSO-d6)δ:7.02(s,1H),6.87(dd,J=17.3,11.2Hz,1H),5.94(dd,J=17.3,1.3Hz,1H),5.45(dd,J=11.2,1.3Hz,1H),4.80(sept,J=6.6Hz,1H),3.79(s,3H),1.38(d,J=6.6Hz,6H)。C10H14N2O2(194.23)。LC-MS(ESI):195[M+H]+。
步骤2:1-异丁基-5-(3-氧代环丁基)-1H-吡唑-3-甲酸甲酯(7b)
反应在两个干燥的密封试管中进行(等量的两个批次)。将所述批次合并以进行检测和纯化。单批次程序:在氮气气氛下在-15至-20℃向N,N-二甲基乙酰胺(0.22mL,2.34mmol)在1,2-二氯乙烷(12mL)中的溶液中滴加三氟甲磺酸酐(0.43mL,2.57mmol),形成浑浊悬浮液。将该混合物在-15℃搅拌10分钟,然后滴加烯烃7a(151mg,0.78mmol)和对称三甲基吡啶(0.42mL,3.12mmol)在1,2-二氯乙烷(3mL)中的溶液(形成黄色溶液)。滴加完成后,移除冷却浴,将混合物升温至室温(橙色浑浊液),并将试管密封。然后将该混合物在90℃搅拌15小时(棕色混合物)。在室温加入水(5mL),并将混合物在100℃搅拌2小时(浑浊的两相溶液)。在冷却至室温后,合并混合物并在稀NaHCO3水溶液和CH2Cl2之间分配,并将水溶液层用CH2Cl2(每次30mL)萃取三次。将有机层合并,干燥(Na2SO4)、过滤并浓缩得到棕色油状物(2.2g)。用CC(6×13cm,用CH2Cl2预吸附,甲苯/EA3:1)纯化得到环丁酮7b(115.5mg,31%),为黄色油状物。1H NMR(DMSO-d6)δ:6.81(s,1H),4.58(sept,J=6.5Hz,1H),3.78(s,3H),3.85-3.73(m,1H),3.59-3.45(m,2H),3.37-3.24(m,2H,被水信号部分重叠),1.39(d,J=6.6Hz,6H)。C12H16N2O3(236.27)。LC-MS(ESI):237[M+H]+。
步骤3:5-((1s,3s)-3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲
氧基)苯基)-3-羟基环丁基)-1-异丁基-1H-吡唑-3-甲酸甲酯(7)
将溴化物1a(368mg,0.78mmol)在干燥THF(6mL)中的溶液冷却至-78℃,并滴加在己烷中的1.6M正丁基锂溶液(0.48mL,0.76mmol)。将该混合物在-78℃搅拌20分钟,然后滴加环丁酮7b(164mg,0.69mmol)在干燥THF(4mL)中的溶液。将该混合物在-78℃搅拌2.5小时,并在该温度下滴加饱和NH4Cl水溶液(1mL)。移除冷却浴,并将该混合物升温至室温并在室温下搅拌0.5小时。然后将该混合物加入到稀NH4Cl水溶液中并用EA萃取三次。将有机层合并,干燥(Na2SO4)、过滤并浓缩得到516mg几乎无色的油状物。用CC(4.5×23cm,用CH2Cl2预吸附,洗脱液己烷/丙酮2:1)纯化得到回收的环丁酮7b(31.3mg,19%,稍黄色油状物)和不纯的产物(333mg)。用CC(4×22cm,己烷/EA=1:1)或prep-TLC再纯化得到纯产物7(210mg,48%),为白色泡沫。1H NMR(DMSO-d6)δ:7.65(d,J=2.1Hz,1H),7.62(s,1H),7.59-7.48(m,2H),6.92(d,J=2.4Hz,1H),6.76(dd,J=8.6,2.6Hz,1H),6.66(s,1H),5.49(s,1H),4.92(s,2H),4.42(类似六重峰的m,J=6.5Hz,1H),3.78(s,3H),3.24-3.11(m,2H,被水信号部分重叠),3.04-2.90(m,1H),2.54-2.33(m,3H,被DMSO信号部分重叠),1.32(d,J=6.5Hz,6H),1.26-1.08(m,4H)。C31H30Cl3N3O5(630.95)。LC-MS(ESI):630,632[M+H]+。
实施例8:5-((1s,3s)-3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)
甲氧基)苯基)-3-羟基环丁基)-1-异丁基-1H-吡唑-3-甲酸(8)
将酯7(98.3mg,0.156mmol)溶解在THF(7.5mL)、MeOH(2.5mL)和水(2.5mL)的混合物中,并在室温下加入LiOH·H2O(65mg,1.56mmol)。将该混合物在室温搅拌18小时。将该混合物在稀NH4Cl水溶液和EA之间分配,然后将有机层用水洗涤一次。将水溶液层合并并用EA萃取两次。将有机层合并,干燥(Na2SO4)、过滤并浓缩得到103mg几乎白色的固体。将该产物用CC(3×3.5cm,EA/EtOH=10:1至1:4)纯化得到8(94.8mg,99%),为白色固体。1H NMR(DMSO-d6)δ:7.66-7.60(m,1H),7.62(s,1H),7.59-7.49(m,2H),6.91(d,J=2.5Hz,1H),6.76(dd,J=8.6,2.4Hz,1H),6.38(s,1H),5.51(s,1H,与D2O可交换),4.92(s,2H),4.31(类似六重峰的m,J=6.5Hz,1H),3.25-3.08(m,2H,被水信号部分重叠),2.93-2.77(m,1H),2.57-2.43(m,1H,被DMSO信号遮蔽),2.43-2.29(m,2H,被DMSO信号部分重叠),1.29(d,J=6.5Hz,6H),1.26-1.08(m,4H)。在光谱中没有显现CO2H信号。C30H28Cl3N3O5(616.92)。LC-MS(ESI):616,618[M+H]+。
实施例8的替代路线
步骤1:1-(3-亚甲基环丁基)乙酮(8a)
将亚甲基环丁烷甲腈(5.0g,53.7mmol)溶解在干燥乙醚(25mL)中,在冰浴中冷却,并滴加MeMgBr(26.8mL,80.5mmol,3M在乙醚中)。将该混合物在室温搅拌过夜,冷却至0℃,用15%NaHSO4水溶液(100mL)小心淬灭。将该混合物在室温搅拌30分钟,然后分层。将水溶液相用戊烷(50mL)和乙醚(50mL)萃取。有机层合并,用盐水洗涤并用Na2SO4干燥。在室温下真空除去溶剂,得到粗产物,为淡黄色液体。
步骤2:4-(3-亚甲基环丁基)-2,4-二氧代丁酸乙酯(8b)
将钠(1.15g,49.9mmol)溶解在干燥EtOH(30mL,用5%乙醚变性)中。将化合物8a(5.5g,49.9mmol,粗产物)溶解在干燥EtOH(45mL)中,并加入上述制备的乙醇钠溶液。将该混合物在室温搅拌15分钟,然后滴加草酸二乙酯(6.8mL,49.9mmol)。将反应混合物置于预热(至67℃)的油浴中,并在此温度下搅拌4.5小时。将该混合物在室温下静置过夜。除去溶剂,加入EA(100mL)和1MHCl(70mL),并分离有机相。将水溶液相用EA(50mL)再次萃取。有机层合并,用水、盐水洗涤,并用无水Na2SO4干燥。减压除去溶剂,并将残余物用己烷/MTBE9:1作为洗脱液在硅胶上纯化得到纯化合物8b。产量:6.29g,两步骤总产率56%。1H-NMR(CDCl3),δ(ppm):6.36(s,1H),4.85-4.80(m,2H),4.34(q,J=8.0Hz,2H),3.35-3.25(m,1H),3.05-2.85(m,4H),1.36(t,J=8.0Hz,3H)。
步骤3:1-异丁基-5-(3-亚甲基环丁基)-1H-吡唑-3-甲酸乙酯(8c)
将化合物8b(6.29g,29.9mmol)溶解在干燥EtOH(65mL,用5%的MeOH变性)中,并加入异丙基肼盐酸盐(3.97g,35.9mmol)。将反应混合物在室温搅拌3小时。除去溶剂,并向油状残余物中顺序加入EA(100mL)、水(50mL)和饱和NaHCO3(50mL)。分离有机层,并用EA(50mL)再萃取水溶液层。有机相合并,用盐水(70mL)洗涤,并用无水Na2SO4干燥。真空除去溶剂,并减压干燥残余物。产量:7.23g(通过NMR验证包含3.4%的EtOAc,重新计算的净产量:6.98g,94%)。通过HPLC和NMR验证,粗产物8c为98%纯度。1H-NMR(CDCl3),δ(ppm):6.62(s,1H),4.88-4.82(m,2H),4.42-4.32(m,3H),3.56-3.45(m,1H),3.17-3.07(m,2H),2.88-2.79(m,2H),1.49(d,J=8.0Hz,6H),1.37(t,J=8.0Hz,3H)。
步骤4:1-异丁基-5-(3-氧代环丁基)-1H-吡唑-3-甲酸乙酯(8d)
将化合物8c(6.45g,26.0mmol)溶解在MeCN(77mL)和水(13mL)的混合物中,并在冰浴中冷却。向该溶液中加入RuCl3×H2O(0.19g,0.86mmol),随后分批加入NaIO4(19.35g,90.9mmol)。在该加料过程中观察到放热。将所得稠浆在室温下搅拌45分钟。将反应混合物用Na2S2O3水溶液(10%,260mL)、水(50mL)和DCM(100mL)稀释。发生相分离,并用DCM(2×70mL)萃取水溶液相。有机相合并,用Na2S2O3水溶液(10%,50mL)、水(100mL)、盐水(100mL)洗涤,并用无水Na2SO4干燥。粗产物(6.5g)使用己烷/MTBE洗脱在硅胶上纯化得到纯化合物,为油状物,在-20℃储存时凝固。产量:5.8g(两步骤总产率78%)。1H-NMR(DMSO-d6),δ(ppm):6.78(s,1H),4.57(h,J=8.0Hz,1H),4.26(q,J=8.0Hz,2H),3.85-3.75(m,1H),3.58-3.45(m,2H),3.35-3.25(m,2H),1.39(d,J=8.0Hz,6H),1.28(t,J=8.0Hz,3H)。
步骤5:4-((4-溴-3-氯苯氧基)甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(8e)
将3-氯-4-溴苯酚(3.8g,18.3mmol)与(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲醇(3.47g,12.2mmol)和三苯基膦(6.41g,24.4mmol)在甲苯(150mL)中混合。将该混合物在冰浴中冷却,并滴加溶液形式的DIAD(4.8mL,24.4mmol)(甲苯(10mL)中)。将反应物在室温搅拌21小时,然后在旋转蒸发仪上除去溶液,留下黄色油状残余物。将该残余物溶解在DCM(200mL)中,加入硅胶(~20g),并将该混合物蒸发至干燥状态。将该材料负载在硅胶柱顶部并使用己烷/MTBE9:1洗脱进行纯化。合并包含产物的馏分并减压除去溶剂,留下纯产物8e,为无色油状物,其在真空下干燥过夜时结晶。产量:5.07g(88%)。1H-NMR(CDCl3),δ(ppm):7.45-7.30(m,4H),6.90(s,1H),6.60-6.55(m,1H),2.15-2.07(m,1H),1.32-1.25(m,2H),1.20-1.11(m,2H)。
步骤6:5-((1s,3s)-3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲
氧基)苯基)-3-羟基环丁基)-1-异丁基-1H-吡唑-3-甲酸乙酯(8f)
在室温下将LiCl(0.684g,16.15mmol)溶解在THF(20mL)中,并加入iPrMgCl(2.0M在THF中,8.1mL,16.15mmol)。将该混合物在室温搅拌10分钟,在冰浴中冷却,并在5分钟内加入化合物8e(2.55g,5.38mmol)在THF(20mL)中的溶液。移除冷却浴,并将该混合物在室温下搅拌4小时。将该混合物冷却至-10℃,并快速加入化合物8d(1.48g,5.92mmol)在THF(16mL)中的溶液。将该混合物在室温搅拌90分钟,然后加入0.5M NaHSO4水溶液(35mL)和EA(50mL)。将所得混合物搅拌10分钟,分层并将水溶液层用EA(30mL)萃取。有机相合并,用NaHCO3水溶液(50mL)、盐水(50mL)洗涤,并用无水Na2SO4干燥。除去溶剂得到粗产物(3.79g),为白色泡沫。用己烷/EA3:2洗脱在硅胶柱上纯化3.6g的该粗产物得到纯化合物8f,为固体泡沫。产量:1.62g(49%)。1H-NMR(DMSO-d6),δ(ppm):7.65-7.47(m,4H),6.93-6.91(m,1H),6.79-6.72(m,1H),6.65(s,1H),5.48(s,1H),4.92(s,2H),4.42(h,J=8.0Hz,1H),4.26(q,J=8.0Hz,2H),3.32(s,2H),3.22-3.14(m,2H),3.05-2.90(m,1H),2.45-2.35(m,2H),1.35-1.10(m,14H)。
步骤7:5-((1s,3s)-3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲
氧基)苯基)-3-羟基环丁基)-1-异丁基-1H-吡唑-3-甲酸(8)
将化合物8f(1.60g,2.48mmol)溶解在THF(100mL)中,然后顺序加入MeOH(50mL)、水(50mL)和LiOH×H2O(1.04g,24.8mmol)。将该混合物在室温搅拌4.5小时,然后减压浓缩除去MeOH和THF。通过加入1M HCl水溶液(24mL)酸化剩余的水溶液至pH4.05(pH电极参比)。在大约pH7时,开始形成沉淀。过滤出所形成的固体,在过滤器上用水洗涤,并在室温下真空干燥得到产物8,为白色粉末。产量:1.40g(92%)。1H-NMR(CDCl3),δ(ppm):7.44-7.32(m,4H),6.91(d,J=4.0Hz,1H),6.78(s,1H),6.75(dd,J=4.0Hz,J=8.0Hz,1H),4.83(s,2H),4.35-4.20(m,1H),3.25-3.14(m,2H),3.04-2.90(m,1H),2.62-2.54(m,2H),2.21-2.11(m,1H),1.46(d,J=8.0Hz,6H),1.34-1.28(m,2H),1.20-1.14(m,2H)。13C-NMR(CDCl3),δ(ppm):172.7,164.8,159.2,158.4,147.2,141.3,135.8,134.1,132.8,131.3,128.1,127.6,127.3,117.7,113.3,110.0,106.3,73.1,59.8,51.1,41.7,22.6,22.0,8.5,7.8.MS(ESI+)m/z:616.4[M+1]+。
实施例8A:5-((1r,3r)-3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)
甲氧基)苯基)-3-羟基环丁基)-1-异丁基-1H-吡唑-3-甲酸盐(8A)
实施例8A可以如下制备:通过将粗产物8f进行如对于8所述的酯水解反应,并通过制备RP-HPLC以次异构体的形式从粗产物8中分离。1H-NMR(CDCl3),δ(ppm):7.42-7.30(m,2H),7.11(d,J=8.0Hz,1H),6.75-6.65(m,1H),6.57(s,1H),4.79(s,2H),4.50-4.41(m,1H),3.96-3.85(m,1H),2.98-2.90(m,2H),2.67-2.57(m,2H),2.20-2.09(m,1H),1.51(d,J=8.0Hz,6H),1.32-1.14(m,4H)。13C-NMR(CDCl3),δ(ppm):172.6,166.2,159.2,158.4,147.4,141.2,135.7,134.6,132.8,131.3,128.1,127.7,127.5,116.8,113.5,110.0,105.8,75.1,59.8,51.2,41.8,25.4,22.6,8.5,7.8.MS(ESI+)m/z:616.3[M+1]+。
主异构体(化合物8)和次异构体(化合物8A)的跨环构型通过NOE实验证实。所检测到的质子间的指示性NOEs在下式中用双箭头标示。
对于带有芳香族部分的1,3-反式跨环构型的实施例8所检测的NOEs
对于带有芳香族部分的1,3-顺式跨环构型的实施例8A所检测的NOEs
实施例9:6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯
基)-3-羟基环丁基)-1-甲基-1H-吲唑-3-甲酸甲酯(9)
步骤1:1-甲基-6-乙烯基-1H-吲唑-3-甲酸甲酯(9a)
向6-溴-1-甲基-1H-吲唑-3-甲酸甲酯(60mg,0.22mmol)在DMF(10mL)中的溶液中,加入三丁基(乙烯基)锡(99μL,0.34mmol)、Pd(Ph3)4(11mg,9μmol)。加料完成后,在氩气气氛下将该混合物在90℃搅拌4小时。然后检测除去溶剂。用CC纯化得到化合物9a(52mg,88%)。
步骤2:1-甲基-6-(3-氧代环丁基)-1H-吲唑-3-甲酸甲酯(9b)
按照在实施例7/步骤2描述的程序,从9a得到化合物9b,产率57%。1H NMR(400MHz,CDCl3)δ:8.14(d,J=8.4Hz,1H),7.31(s,1H),7.23(d,J=8.8Hz,1H),4.13(s,3H),3.99(s,3H),3.87-3.79(m,1H),3.58-3.51(m,2H),3.33-3.26(m,2H)。m/z:259[M+1]+。
步骤3:6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)苯
基)-3-羟基环丁基)-1-甲基-1H-吲唑-3-甲酸甲酯(9)
按照在实施例7/步骤3描述的程序,从9b得到化合物9,产率40%。
实施例10:6-(3-(2-氯-4-((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基)
苯基)-3-羟基环丁基)-1-甲基-1H-吲唑-3-甲酸(10)
按照在实施例8描述的程序,从化合物9得到化合物10,产率45%,为白色固体。1HNMR(400MHz,CDCl3)δ:8.14(d,J=8.0Hz,1H),7.48(d,J=8.8Hz,1H),7.43-7.32(m,4H),7.29(m,1H),6.92(d,J=2.4Hz,1H),6.76(dd,J=7.2Hz,2.4Hz,1H),4.84(s,2H),4.18(s,3H),3.45-3.40(m,1H),3.28-3.23(m,2H),3.19-3.10(m,1H),2.68-2.63(m,2H),2.21-2.14(m,1H),1.33-1.29(m,2H),1.20-1.15(m,2H)。m/z:638[M+1]+。
制备实施例11
步骤1:5-(3-羟基氮杂环丁烷-1-基)烟酸甲酯(11a)
将5-溴烟酸甲酯(2.00g,9.26mmol)、氮杂环丁烷-3-醇(1.01g,9.26mmol)、Cs2CO3(9.06g,27.8mmol)、BINAP(1.15g,1.85mmol)和Pd(OAc)2(0.44g,1.85mmol)在干燥二噁烷(115mL)中的混合物在N2气氛下在85℃加热过夜。过滤所得混合物,减压浓缩并用制备HPLC纯化得到化合物11a(250mg,13%),为黄色固体。
步骤2:5-(3-氧代氮杂环丁烷-1-基)烟酸甲酯(11)
在N2气氛下在0℃向化合物11a(250mg,1.20mmol)在干燥DCM(15mL)中的溶液中加入戴斯-马丁氧化剂(1.014g,2.40mmol),并将该溶液在室温搅拌2小时。用饱和碳酸氢钠溶液淬灭所得溶液并用EA稀释。有机部分用盐水洗涤,用Na2SO4干燥,过滤,减压浓缩,然后用CC(DCM/MeOH=150:1)纯化得到化合物11(140mg,57%),为黄色固体。
制备实施例12
使用与制备实施例11中描述的方法类似的程序,制备下列化合物:
实施例13/1至13/9
下表列出了根据上述制备实施例和实施例制备的更多实例。所有列出的化合物都制备为单一异构体。
实施例14/1和14/2
使用在上述实施例1至13和反应式中描述的程序相似的程序,通过使用适当的反应原料得到下列化合物。
下列化合物可以以相同的方式使用与上述类似地程序制备:
评价
FRET活性评价
如下进行配体介导的辅因子肽相互作用的测量以量化结合到核受体FXR上的配体:人FXRα配体结合区域的准备:人FXRαLBD在大肠杆菌(E.coli)菌株BL21(DE3)中表达为N-末端GST标记的融合蛋白。将编码FXR配体结合区域的DNA克隆到载体pDEST15(Invitrogen)中。表达由IPTG可诱导的T7启动子控制。配体结合区域的氨基酸边界是数据库登记项(Databaseentry)NM_005123(RefSeq)的氨基酸187~472。FXR-LBD的表达和提纯:将整夜预培养的转化大肠杆菌菌株在LB-氨苄青霉素培养基中稀释1:20并在30℃生长到OD600=0.4~0.6的光密度。然后通过加入0.5mM的IPTG诱导基因表达。细胞在30℃、180rpm另外培养6h。通过离心(7000×g、7分钟、室温)收集细胞。将每升原始细胞培养液的细胞重新悬浮在10ml溶菌缓冲液(50mM葡萄糖,pH7.9的50mM三羟甲基氨基甲烷,1mM EDTA和4mg/ml溶菌酶)中并放置在冰上30分钟。然后将细胞进行超声处理并用离心(22000×g,30分钟,4℃)除去细胞残骸。每10ml上清液加入0.5ml预洗过的谷胱苷肽4B琼脂糖浆(Qiagen)并将该悬浮液在4℃保持缓慢旋转1小时。用离心(2000g,15秒,4℃)使谷胱苷肽4B琼脂糖小珠成球并在洗涤缓冲液(25mM三羟甲基氨基甲烷,50mM KCl,4mM MgCl2和1M NaCl)中洗涤两次。基于每升原始培养液,将该球重新悬浮在3ml洗脱缓冲液(洗脱缓冲液:20mM三羟甲基氨基甲烷,60mM KCl,5mM MgCl2和80mM谷胱苷肽,在使用前以粉末形式直接加入)。将该悬浮液在4℃保持旋转15分钟,使小珠成球并用与第一次相比一半体积的洗脱缓冲液再次洗脱。将洗脱物集中并在含有60mM KCl、5mM MgCl2以及1mM二硫苏糖醇和10%(v/v)甘油的20mM羟乙基哌嗪乙磺酸缓冲液(pH7.5)透析整夜。蛋白用SDS-Page进行分析。
本方法测量假定配体对纯化的细菌表达的FXR配体结合区域(LBD)和基于SRC-1(LCD2,676~700)的残基676~700的合成生物素化的肽之间的相互作用的调节能力。所使用的肽序列是其中N-末端被生物素化的B-CPSSHSSLTERHKILHRLLQEGSPS-COOH。所述FXR的配体结合区域(LBD)在BL-21细胞中使用载体pDEST15表达为带有GST的融合蛋白。将细胞超声裂解并将融合蛋白用谷胱苷肽琼脂糖(Pharmacia)根据制造商的使用说明进行纯化。为了根据他们对FXR-肽相互作用的影响筛选化合物,使用了Perkin Elmer LANCE技术。这种方法依赖于从给体到连接到目标结合分子上的受体荧光体的结合依赖性能量转移(binding dependent energy transfer)。为了便于处理和减少来自化合物荧光的背景,LANCE技术使用一般荧光标记,并且在384孔板中,在基于三羟甲基氨基甲烷的缓冲液(pH7.5的20mM三羟甲基氨基甲烷-HCl、60mM KCl、5mM MgCl2、35ng/μl BSA)中以25μl的最终体积进行时间分辨检测分析,所述基于三羟甲基氨基甲烷的缓冲液含有20~60ng/孔融合到GST上的重组表达FXR-LBD、200~600nM表示SRC1氨基酸676~700的N-末端生物素化的肽、200ng/孔链霉抗生物素-xlAPC结合物(Prozyme)和6~10ng/孔Eu W1024–antiGST(Perkin Elmer)。将样品的DMSO含量保持在1%。在产生分析混合物并稀释假定FXR调节配体后,将被分析物在暗处在室温下在黑色384孔FIA-板(Greiner)中平衡1小时。用PerkinElmer VICTOR2VTM Multilabel Counter检测LANCE信号。通过将在665nm和615nm的发射光之间的比例作图使结果可视化。在没有加入配体的情况下观察到FXR-肽形成的基线水平。促进复合物形成的配体在时间分辨荧光信号中诱导一个浓度依赖性的增加。预期与单体FXR和FXR-肽复合物两者的结合都同样好的化合物为在信号上没有变化,而对单体受体优先结合的配体被预期为将在观察到的信号中诱导一个浓度依赖性的降低。
为评价所述化合物的抑制潜力,对于下表1中列出的实施例化合物测定了EC50-值(A=EC50<25nM;B=25≤EC50<100nM;C=EC50≥100nM)。
表1
组别 | 实施例# |
A | 4,8,10,13/8,13/9,14/1,14/2 |
B | 1,2,5,6,8A,13/1,13/3,13/4,13/5,13/7 |
C | 13/2,13/6 |
哺乳动物单一杂交(M1H)评价
如下所述测定配体介导的Gal4启动子驱动的反式活化以量化配体结合介导的FXR活化:将编码FXR配体结合域的cDNA部分克隆到载体pCMV-BD(斯特拉塔基因公司(Stratagene))中,在CMV启动子的控制下融合至酵母GAL4DNA结合域。配体结合区域的氨基酸边界是数据库登记项(Databaseentry)NM_005123(RefSeq)的氨基酸187~472。质粒pFR-Luc(斯特拉塔基因公司)用作报告质粒,含有合成启动子和酵母GAL4结合位点的5个串联重复,驱动螟娥萤火虫(Photinuspyralis)(美国萤火虫)萤光素酶基因作为报告基因的表达。为提高试验准确性,共转染质粒pRL-CMV(普罗迈格公司(Promega))。pRL-CMV包含组成型CMV启动子,控制海肾(Renillareniformis)萤光素酶的表达。所有Gal4报告基因试验在HEK293细胞中进行(获自德国布伦施威克(Braunschweig)的DSMZ),所述细胞在37℃、5%CO2,补充有10%胎牛血清、0.1mM非必需氨基酸、1mM丙酮酸钠和100单位青霉素/链霉素/毫升的含L-谷氨酰胺和厄尔(Earle)BSS的MEM中生长。培养基和补充添加剂都从Invitrogen得到。为了所述评价,将5×105个细胞/孔接种于96孔板中,每孔含100微升MEM,其不含酚磺酞和L-谷氨酰胺,但含补充有10%木炭/葡聚糖处理的FBS(HyClone,SouthLogan,Utah))、0.1mM非必需氨基酸、2mM谷氨酰胺、1mM丙酮酸钠和100单位青霉素/链霉素/毫升的厄尔(Earle)BSS,37℃、5%CO2下培养。第二天,细胞汇合>90%。除去培养基,用20微升/孔包含三种上述质粒的OptiMEM-聚乙烯-亚胺-基转染试剂(OptiMEM,Invitrogen;聚乙烯亚胺,Aldrich目录号40,827-7)瞬时转染细胞。加入转染混合物之后2-4小时加入与接种细胞具有相同组成的MEM。然后,加入预先用MEM稀释的化合物储备液(最终的载体浓度不超过0.1%)。细胞再培养16小时,然后采用双重光-萤光素酶-测试系统在相同的细胞萃取物中相继测定萤火虫和海肾萤光素酶活性(Dyer等人,Anal.Biochem.2000,282,158-161)。所有实验均平行三次。
为评价实施例化合物的FXR激动剂效能,在M1H评价中测定了效能范围,如下在表2中列出(A=EC50<25nM;B=25≤EC50<100nM;C=EC50≥100nM)。
表2
组别 | 实施例# |
A | 13/4,13/5,13/6 |
B | 2,8,8A,10,13/1,13/3,13/7 |
C | 1,4,5,6,13/2,13/8,13/9,14/1 |
水溶性评价
如下测定在PBS中pH7.4的水溶性。将在DMSO中的10mM化合物储备溶液加入到PBS(pH7.4)以达到200μM的理论最终浓度。将所得溶液/悬浮液在1250rpm震荡1小时,然后在室温下储存在黑暗中23小时。此时,通过以3900rpm离心30分钟从该溶液中分离任何沉淀。通过比较在有机溶剂(甲醇/水60:40,v/v)在校准用基准(200μM)中主峰的峰面积和在缓冲液样品中相应峰的峰面积来测定水溶性。使用在230nm的HPLC-UV/VIS作为检测方法。
平行人工膜渗透分析(PAMPA)
对于PAMPA,在DMSO中制备检测物的5mM的储备溶液。在EtOH(卡巴咪嗪,胍那苄)或者在EtOH:H2O1:1(v/v)(头孢曲松)中分别制备对照物的5mM储备溶液。将化合物在PBS(pH7.4)中稀释分别得到包含5%的各个有机溶剂和250μM对照化合物或10μM检测物的起始溶液。对于该评价,使用如Kansy等人(J.Med.Chem.1998,41,1007)描述的PAMPA的改进程序。包括用于低(头孢曲松)、中(胍那苄)和高(卡巴咪嗪)渗透性的参考化合物作为内部对照。
在用96孔Multiscreen Immobilon(受体)覆盖的Multiscreen96孔盘(给体)中进行渗透实验。该Immobilon板的疏水性过滤材料用70%乙醇预先润湿,并用脂质溶液(溶解在十二烷中的卵磷脂)处理。用检测化合物和对照化合物填充给体板,并将两个板彼此插入并置于100rpm的定轨振荡器上15分钟。通过将150μL包含检测和对照化合物的PBS缓冲液施加至给体板上开始传输研究。在室温下扩散15-16小时后,收集受体和给体板的内容物,并使用LC/MS-检测(检测物)或者用UV光谱使用Spectramax Plus384(分子器件)(对照物)定量。对照物头孢曲松、胍那苄和卡巴咪嗪的最大吸收分别为240nm、270nm和286nm。和对渗透分析样品所描述的一样制备回收样品,并在相同条件下,在渗透期间在代表性小玻璃瓶中培养。
对检测物的LC/MS分析,将100μL培养物从受体和给体室中取出,并如下所述对乙腈(ACN)沉淀进行处理。另外,通过用150μL EA冲洗各个孔两次来提取来自脂质层的检测物样品。将该溶液收集在1.5mL的反应试管中,并蒸发溶剂。经干燥的残余物冲洗悬浮在反映受体和给体样品组成的PBS/DMSO/ACN混合物(即,100μL缓冲液补充有5%DMSO、200μL ACN+ISTD)中。各个样品的最终溶剂含量为66%ACN。
通过分别加入200μL ACN/ISTD或400μL ACN/ISTD将从给体和受体室和校准用基准得到的样品沉淀。在剧烈震荡(10秒)和离心(以4800×g,5分钟,室温)后,将无颗粒物的上清液进行LC-MS/MS。如上所述萃取薄膜室。在重建后,将样品剧烈震荡(10秒)并减慢旋转(以4800×g,5分钟,室温)。将无颗粒物的上清液进行LC-MS/MS。
为了分析本发明的化合物,所述HPLC系统由Accela U-HPLC泵和Accela自动取样器(Thermo Fisher Scientific,USA)组成。在装备有连接至运转标准软件Xcalibur2.1的PC的加热的电喷雾(H-ESI2)接口(Thermo Fisher Scientific,USA)的Exactive质谱仪(具有准确质量的轨道阱(orbitrap)技术)上进行质谱光谱。
使用ACN/0.1%蚁酸作为有机相(A)和10mM甲酸铵/0.1%蚁酸作为水相(B)在梯度模式(表3)下进行LC,并且将泵流速设定至500微升/分钟。在Gemini C6-Phenyl,3μm,50×2.0mm(Phenomenex,德国)分析柱和前置柱(Gemini C6-Phenyl,3μm,4×2.0mm)上进行分离。
表3:HPLC梯度
流动相 | 0分钟 | 0.1分钟 | 1.2分钟 | 2.6分钟 | 2.7分钟 | 3.5分钟 |
A(%) | 5 | 5 | 97 | 97 | 5 | 5 |
B(%) | 95 | 95 | 3 | 3 | 95 | 95 |
对应用正或负离子模式的所有分析物都使用通用调谐文件(tune file)作为MS调谐文件。作为用于内部质量校正的锁定质量(lock mass),使用普遍存在于溶剂系统中的邻苯二甲酸二异辛酯的[M+H]+离子(m/z391.28429)。
通过在单一同位素[M+H]+或[M-H]-离子的预期质量周围扫描±1Thomson获得分析物。轨道肼的质量分辨率设定为50,000。每种分析物的准确质量用于峰积分。其他仪器设置如下:HCD-气体关闭,AGC高动态范围,最大肼注射时间(max.trap injection time)100ms,鞘气(sheath gas)30,辅助气(aux gas)8,吹扫气(sweep gas)2,喷雾电压4kV,毛细管温度250℃,ESI2加热器温度250℃。
本发明的目的是产生与WO2011/020615要求保护的化合物相比具有改进的物化性能的FXR激动剂。通过在代替前者的1,2-环亚丙基的1,3-环亚丁基或1,3-亚氮杂环丁烷基上引入极性羟基实现了这个目的。
令人惊奇地,所得化合物保持了在FXR受体上的活性,而且显现出改进的物化性能,例如较高的水溶性和/或膜渗透性。表4中给出了这两个系列的相应化合物的直接比较。
*Flux(%)=(c受体孔)/sum(c给体孔+c受体孔)×100×2
**n.d.=未测定
在每种情况下,通过引入羟基-环丁基或羟基-氮杂环丁烷基显著改善了水溶解性或PAMPA薄膜渗透性或二者同时得到了改善。和大多数核受体活性分子一样,FXR激动剂通常为非常亲油性的(M.L.Crawley,Expert Opin.Ther.Patents2010,20,1047)。因此,有人提出更好的水溶解度和薄膜渗透性导致更高的口服生物利用度,以及通常而言,对作为药物的那些化合物的临床开发有更好的适应性(L.Huang,J.Dong,S.Karki在Evaluation ofdrug candidates for preclinical development(Eds.C.Han,C.B.Davis,B.Wang),Wiley&Sons,Hoboken2010,187-217)。
Claims (27)
1.根据下面通式(1)的化合物、其对映异构体、非对映异构体、互变异构体和药物学上可接受的盐:
其中,
R选自COOR6、CONR7R8、四唑基、SO2NR7R8、C1-6烷基、SO2-C1-6烷基和H,R6独立地选自:H或C1-6烷基,以及R7和R8独立地选自:H、C1-6烷基、卤代C1-6烷基、C1-6亚烷基-R9、SO2-C1-6烷基,其中R9选自:COOH、OH和SO3H;
A选自苯基、吡啶基、嘧啶基、吡唑基、吲哚基、噻吩基、苯并噻吩基、吲唑基、苯并异噁唑基、苯并呋喃基、苯并三唑基、呋喃基、苯并噻唑基、噻唑基、噁二唑基,它们各自任选地被独立地选自OH、O-C1-6烷基、O-卤代C1-6烷基、C1-6烷基、卤代C1-6烷基、C3-6环烷基和卤素中的一个或两个基团所取代;
Q选自苯基、吡啶基、噻唑基、苯硫基、嘧啶基,它们各自任选地被独立地选自C1-6烷基、卤代C1-6烷基、和卤素中的一个或两个基团所取代;
Y选自N或CH;
Z选自
其中,
X=CH、N、NO;
R1选自氢、C1-3烷基、C3-6环烷基、C4-5烷基环烷基,其中C1-3烷基任选地被独立地选自卤素、羟基或C1-6烷氧基中的1-3个基团所取代;
R2和R3独立地选自氢、C1-3烷基、C1-3卤代烷基、C1-3烷氧基、C1-3卤代烷氧基和卤素。
2.根据权利要求1所述的化合物,其中,R-A选自:
3.根据权利要求1或2所述的化合物,其中,Q为
4.根据权利要求1或2所述的化合物,其中,Z为
5.根据权利要求1或2所述的化合物,其中,所述化合物选自:
6.根据权利要求1或2所述的化合物,所述化合物具有如下结构:
7.根据权利要求1或2所述的化合物,所述化合物具有如下结构:
8.一种药物组合物,其包含根据权利要求1至7中任一项所述的化合物或其药物学上可接受的盐,以及至少一种药物学上可接受的载体。
9.用作药物的根据权利要求1至7中任一项所述的化合物。
10.用于预防和/或治疗由FXR介导的疾病中使用的根据权利要求1至7中任一项所述的化合物。
11.根据权利要求10的用于使用的化合物,其中,所述疾病选自:慢性肝内胆汁郁积性病症;肝纤维化;肝的梗阻性或慢性炎性紊乱;肝硬化;脂肪肝及并发症;与酒精引发的肝硬化或与病毒传染性形式的肝炎相关的胆汁郁积性和纤维变性效果;在部分肝切除术后的肝衰竭或肝缺血;化疗相关的脂肪性肝炎;急性肝衰竭;和/或炎性肠道疾病。
12.根据权利要求10的用于使用的化合物,其中,所述疾病选自:脂质和脂蛋白紊乱;II型糖尿病以及I型和II型糖尿病的临床并发症;由于强迫脂质蓄积,然后促纤维化途径激活导致的慢性脂肪性和纤维性变性引起的病症和疾病;肥胖或代谢综合征;和/或急性心肌梗塞、急性中风或作为慢性梗阻性动脉粥样硬化终点发生的血栓形成。
13.根据权利要求12的用于使用的化合物,其中,
所述I型和II型糖尿病的临床并发症包括糖尿病性肾病、糖尿病性神经病变及糖尿病性视网膜病;
所述由于强迫脂质蓄积然后促纤维化途径激活导致的慢性脂肪性和纤维性变性引起的病症和疾病包括非酒精性脂肪肝病;
所述肥胖或代谢综合征包括血脂障碍、糖尿病和体重指数异常高的合并病症。
14.根据权利要求13的用于使用的化合物,其中,所述非酒精性脂肪肝病包括非酒精性脂肪性肝炎。
15.根据权利要求12或13的用于使用的化合物,其中,所述强迫脂质蓄积为甘油三酯蓄积。
16.根据权利要求10的用于使用的化合物,其中,所述疾病选自:非恶性过度增殖性紊乱和恶性过度增殖性紊乱。
17.根据权利要求10的用于使用的化合物,其中,所述疾病选自:肝细胞癌、结肠腺癌、乳腺癌、胰腺癌、巴特氏食管癌。
18.根据权利要求17的用于使用的化合物,其中,所述结肠腺癌包括结肠腺瘤和息肉病。
19.根据权利要求1至7中任一项所述的化合物用于制备用于预防和/或治疗由FXR介导的疾病的药物的用途。
20.根据权利要求19的用途,其中,所述疾病选自:慢性肝内胆汁郁积性病症;肝纤维化;肝的梗阻性或慢性炎性紊乱;肝硬化;脂肪肝及并发症;与酒精引发的肝硬化或与病毒传染性形式的肝炎相关的胆汁郁积性和纤维变性效果;在部分肝切除术后的肝衰竭或肝缺血;化疗相关的脂肪性肝炎;急性肝衰竭;和/或炎性肠道疾病。
21.根据权利要求19的用途,其中,所述疾病选自:脂质和脂蛋白紊乱;II型糖尿病以及I型和II型糖尿病的临床并发症;由于强迫脂质蓄积,然后促纤维化途径激活导致的慢性脂肪性和纤维性变性引起的病症和疾病;肥胖或代谢综合征;和/或急性心肌梗塞、急性中风或作为慢性梗阻性动脉粥样硬化终点发生的血栓形成。
22.根据权利要求21的用途,其中,
所述I型和II型糖尿病的临床并发症包括糖尿病性肾病、糖尿病性神经病变及糖尿病性视网膜病;
所述由于强迫脂质蓄积然后促纤维化途径激活导致的慢性脂肪性和纤维性变性引起的病症和疾病包括非酒精性脂肪肝病;
所述肥胖或代谢综合征包括血脂障碍、糖尿病和体重指数异常高的合并病症。
23.根据权利要求22的用途,其中,所述非酒精性脂肪肝病包括非酒精性脂肪性肝炎。
24.根据权利要求21或22的用途,其中,所述强迫脂质蓄积为甘油三酯蓄积。
25.根据权利要求19的用途,其中,所述疾病选自:非恶性过度增殖性紊乱和恶性过度增殖性紊乱。
26.根据权利要求19的用途,其中,所述疾病选自:肝细胞癌、结肠腺癌、乳腺癌、胰腺癌、巴特氏食管癌。
27.根据权利要求26的用途,其中,所述结肠腺癌包括结肠腺瘤和息肉病。
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