CN101506139A - 取代的1,3-二苯基丙烷衍生物、它们的制备及用途 - Google Patents
取代的1,3-二苯基丙烷衍生物、它们的制备及用途 Download PDFInfo
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- CN101506139A CN101506139A CNA2007800310203A CN200780031020A CN101506139A CN 101506139 A CN101506139 A CN 101506139A CN A2007800310203 A CNA2007800310203 A CN A2007800310203A CN 200780031020 A CN200780031020 A CN 200780031020A CN 101506139 A CN101506139 A CN 101506139A
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- phenyl
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- dimethyl
- methylpropionic acid
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Abstract
本发明涉及取代的1,3-二苯基丙烷衍生物、包含它们的药物组合物和它们的治疗用途,特别是在人类和动物健康领域。
Description
本发明涉及取代的1,3-二苯基丙烷衍生物、包含它们的药物组合物和它们的治疗用途,特别是在人类和动物健康领域。
令人惊奇地,本发明人已证明本发明的化合物具有内在的PPAR激动剂性质。
因此,本发明中所述的分子在治疗代谢综合征并发症、胰岛素抵抗、糖尿病、血脂异常、动脉粥样硬化、心血管疾病、肥胖症、高血压、炎性疾病(哮喘等)、神经变性疾病(阿尔茨海默氏病等)、癌症等以及降低总体风险方面特别令人感兴趣。本发明的化合物优选用于治疗血脂异常。
糖尿病、肥胖症和血脂异常(高血浆LDL-胆固醇和甘油三酯水平,低HDL-胆固醇水平等)是一些被清楚地鉴定的心血管风险因素,它们使人易于患心血管疾病(Mensah M,2004)。还要考虑生活方式风险因素,例如使用烟草、久坐的生活方式和不均衡的饮食。这些因素具有协同作用:几种这些因素同时存在显著增加心血管病的风险。因此,心血管疾病的总体风险值得探讨。2004年,工业化国家中血脂异常流行率达到人口的43.6%。糖尿病患者的迅速增加目前正使糖尿病成为心血管流行病学的更重要的因素:据估计,到2010年,7.6%的人口将成为糖尿病患者(Fox-Tucker J,2005)。
根据国际动脉粥样硬化学会(International Atherosclerosis Society,2003),心血管疾病是工业化国家主要的死亡原因并且正在发展中国家变得更加普遍。主要的心血管疾病是心脏病、脑缺血和外周动脉疾病。
因此,这些数据证明应采取有力的措施以显著地减少心血管发病和发病率,并且揭示寻找有效的治疗方法并结合改变生活方式的必要性。考虑患心血管疾病的风险因素和它们的后果,这是全世界范围的紧急需要。
因为本发明的化合物的PPAR激动剂性质,所以它们在与脂质和/或糖代谢异常相关的疾病(pathologies)如糖尿病、肥胖症、血脂异常或者炎症的治疗以及降低心血管总体风险方面令人感兴趣。
已知PPARs(α、γ和δ)涉及这类疾病(Kota BP等人,2005):因此,配体和受体被上市以治疗这些疾病(Lefebvre P等人,2006),而且各种选择性的或者非选择性的PPAR调节剂、激动剂或者拮抗剂目前正处于高度开发中。对胰岛素抵抗、肥胖症、血脂异常、高血压和/或炎症具有有益效果的PPAR调节剂可被用于代谢综合征(或X综合征)的治疗(Liu Y和Miller A,2005)。
PPAR家族包括三种亚型,称为α、γ和δ(也称为β),各自由不同的基因编码。这些受体属于细胞核受体和转录因子超家族,它们在与某些脂肪酸和/或它们的脂质代谢产物接触时被激活。激活的PPAR与9-顺式维甲酸受体(RXR或者类视黄质X受体)形成异二聚体并与靶基因启动子的特定应答元件(PPRE或者过氧化物酶体增殖物应答元件)结合,由此提供转录控制。
PPARα控制(肝脏和肌肉的)脂质代谢和葡萄糖的体内稳态,通过直接控制编码涉及脂质体内稳态的蛋白质的基因的转录来影响细胞内脂质和糖类的代谢,具有抗炎和抗增殖效力,并且通过刺激胆固醇流出来防止胆固醇在巨噬细胞中蓄积的致动脉粥样硬化效应(Lefebvre P,Chinetti G,Fruchart JC和Staels B,2006)。贝特类(非诺贝特、苯扎贝特、环丙贝特、吉非贝齐)通过PPARα用于临床医学,通过降低甘油三酯和提高HDL(高密度脂蛋白)水平来治疗某些血脂异常。
PPARγ是脂肪形成的关键调节剂。而且,它参与成熟脂肪细胞的脂质代谢、葡萄糖体内稳态、特别是胰岛素抵抗、炎症、巨噬细胞胆固醇蓄积和细胞增殖(Lehrke M和Lazar MA,2005)。因此,PPARγ在肥胖症、胰岛素抵抗和糖尿病的发病机理中起作用。噻唑烷二酮类(罗格列酮、曲格列酮等)是用于治疗II型糖尿病的PPARγ配体。
现已有PPARδ配体(L-165041,GW501516目前正处在临床开发中),但是目前没有PPARδ配体被用作药物。然而,这种受体是开发用于治疗血脂异常、动脉粥样硬化、肥胖症和胰岛素抵抗的可用药物的具有吸引力的目标:PPARδ实际上参与脂质和碳水化合物代谢的控制、能量平衡、神经变性、肥胖症、巨噬泡沫细胞的形成和炎症(Gross B等人,2005)。
除了PPAR配体直接作用于脂质和糖类代谢的调节,这些分子因为PPAR的靶基因的极其多样性而具有多效性的作用谱。这些多重性质使PPAR成为对治疗以下疾病和降低总体风险的令人感兴趣的治疗靶点:动脉粥样硬化、脑缺血、高血压、与新血管形成有关的疾病(视网膜病变、糖尿病等)、炎症和自身免疫疾病(克罗恩病、银屑病、多发性硬化、哮喘等)、肿瘤病(癌发生等)、神经变性疾病、与代谢综合征相关的并发症、胰岛素抵抗、糖尿病、血脂异常、心血管疾病、肥胖症等。
因为本发明的化合物的PPAR激动剂性质,它们是用于改善与脂质和/或糖类代谢异常相关的疾病特别是血脂异常的治疗以及降低心血管总体风险的有利的治疗工具。
更一般地,通过同时作用于几种调节过程,本发明的化合物是用于治疗以下疾病以及降低总体风险的有利治疗手段:与代谢综合征有关的并发症(其特征是肥胖、特别是腹部肥胖、异常的血脂浓度(高甘油三酯水平和/或低HDL-胆固醇水平(血脂异常))、高血糖症和/或胰岛素抵抗和高血压)、动脉粥样硬化、心血管疾病、胰岛素抵抗、肥胖症、高血压、糖尿病、血脂异常、心血管疾病、炎性疾病(哮喘等)、神经变性疾病(阿尔茨海默氏病等)、癌症等。
本发明涉及衍生自1,3-二苯基丙烷的化合物,其具有以下通式:
其中:
X1代表卤素原子、R1或者G1-R1基团;
X2代表卤素原子、R2或者G2-R2基团;
X3代表R3或者G3-R3基团;
X4代表卤素原子、R4或者G4-R4基团;
X5代表R5或者G5-R5基团;
R1代表卤代烷基;
R2代表氢原子或者非卤代烷基;
R3、R4和R5相同或者不同,代表氢原子或者由一个或者多个组1或组2取代基取代的烷基或者非取代烷基;
G1、G2、G3、G4和G5相同或者不同,代表氧原子或者硫原子;
X3、X4或者X5中至少一个基团与R3、G3R3、R4、G4R4、R5或者G5R5式对应,其中:
G3、G4和G5如上所述,并且
R3、R4和R5相同或者不同,代表由一个或者多个组1或组2取代基取代的烷基;
A代表:
(i)-CR6R7基团,其中:
R6代表氢原子、烷基或者-OR8基团,
并且R7代表烷基、羟基或者-OR8基团,R8定义如下,
(ii)羰基(CO),
(iii)肟基(C=N-O-H)或者肟醚(C=N-O-R8),
R8相同或者不同,代表由芳基或者环烷基取代的烷基或者非取代烷基;
D代表:
(i)与两个氢原子连接的碳原子(CH2),
(ii)与氢原子和G2连接以形成氧化或者硫化杂环的碳原子;
组1取代基选自-COOR9和-CONR9R10;
组2取代基选自-SO3H和-SO2NR9R10;
R9和R10相同或者不同,代表氢原子或者由至少一个组1或组2取代基取代的烷基或者非取代烷基;
其纯立体异构体(非对映异构体、对映异构体)或者混合立体异构体、外消旋混合物、几何异构体、互变异构体、盐、水合物、溶剂合物、固体形式以及它们的混合物。
在本发明的范围内,术语“烷基”指饱和的、直链、支链或者环状的、卤代或者非卤代的烃基,特别是具有1-24、优选1、2、3、4、5、6、7、8、9或者10个碳原子的烃基,例如甲基、三氟甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、戊基、新戊基、正己基或者环己基。
术语“环烷基”指如上所定义的烷基并且形成至少一个环(例如具有3-8个碳原子的环烷基:环丙基、环丁基、环戊基、环己基、环庚基和环辛基)。
术语“烷氧基”指通过氧原子(醚键)的方式连接到分子上的烷基链。所述烷基链对应于上述定义。可提供的例子是甲氧基、三氟甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基或者己氧基。
术语“芳基”指优选包含5-14、有利地包含6-14个碳原子的芳族基团,其可能插入一个或者多个选自N、O、S或者P的杂原子(更具体地称为“杂芳基”)。它们通常是单环或者双环,而且有利地包含6-14个碳原子,例如苯基、α-萘基、β-萘基、蒽基或者芴基。
术语“氧化或者硫化杂环”指插入一个或者多个选自O和S的杂原子的如上定义的环烷基。可以引用的例子有噻喃或者吡喃。
卤素原子被理解为溴原子、氯原子、氟原子或者碘原子。
卤代烷基是包含至少一个卤素原子或者全卤代的如上定义的烷基。
因此,至少存在一个与R3、G3R3、R4、G4R4、R5或者G5R5式对应的X3、X4或者X5基团的通式(I)化合物(其中:G3、G4和G5如上所述,并且R3、R4和R5相同或者不同,代表由一个或者多个组1或组2取代基取代的烷基)因此具有至少一个分别代表由一个或者多个组1或组2取代基取代的烷基的X3、X4或者X5的R3、R4和R5基团。
本发明的一个具体方面涉及通式(I)的化合物,其中A代表羰基(CO)。
本发明的另一个具体方面涉及通式(I)的化合物,其中,A代表肟基(C=N-O-H)或者肟醚(C=N-O-R8),并且R8代表被芳基或者环烷基取代的烷基或者非取代烷基。优选地,R8代表甲基。
本发明的另一个具体方面涉及通式(I)的化合物,其中,A代表-CR6R7基团,R6代表氢原子,并且R7代表羟基、烷基或者-OR8基团,R8代表被芳基或者环烷基取代的烷基或者非取代烷基。
优选地,本发明涉及通式(I)的化合物,其中,A代表-CR6R7基团,R6代表氢原子,并且R7代表羟基。
本发明的另一个优选方面涉及通式(I)的化合物,其中,A代表-CR6R7基团,R6代表氢原子,并且R7代表-OR8基团,R8如上定义。具体地,R8代表优选包含1、2、3或者4个碳原子的烷基。甚至更优选地,R8代表由芳基或者环芳基取代的烷基,所述芳基或者环烷基特别地包含6个碳原子。
本发明的另一个具体方面涉及通式(I)的化合物,其中,A代表-CR6R7基团,其中R6代表烷基或者-OR8基团,R7代表羟基、烷基或者-OR8基团,R8代表被芳基或者环烷基取代的烷基或者非取代烷基。
本发明的另一个具体主题涉及通式(I)的化合物,其中,X3和X5相同或者不同,分别代表R3和R5基团,具体地,R3和R5代表氢原子。
本发明的另一个具体主题涉及通式(I)的化合物,其中,X3和X5相同或者不同,分别代表R3和R5基团,R3和R5相同或者不同,代表如上定义的由一个或者多个组1或组2取代基取代的烷基或者非取代烷基。
优选地,X3和X5相同或者不同,分别代表R3和R5基团,R3和R5相同或者不同,代表优选包含1、2、3或者4个碳原子的非取代烷基。甚至更优选地,X3和X5相同或者不同,代表甲基。
本发明的另一个具体方面涉及通式(I)的化合物,其中,X3和X5相同或者不同,分别代表G3R3或者G5R5基团,G3和G5如上所述,并且R3和R5代表氢原子。
本发明的另一个具体方面涉及通式(I)的化合物,其中,X3和X5相同或者不同,分别代表G3R3或者G5R5基团,G3和G5如上所述,并且R3和R5相同或者不同,代表由一个或者多个如上定义的组1或组2取代基取代的烷基或者非取代烷基。
本发明的另一个具体方面涉及通式(I)的化合物,其中,X3和X5相同或者不同,分别代表G3R3或者G5R5基团,G3和G5如上所述,并且R3和R5相同或者不同,代表由一个或者多个如上定义的组1或组2取代基取代的烷基。
本发明的另一个具体方面涉及通式(I)的化合物,其中X4代表卤素原子(溴、氯、氟、碘)。
本发明的另一个具体方面涉及通式(I)的化合物,其中,X4代表R4或者G4-R4基团,G4如上定义,并且R4代表氢原子。
本发明的另一个具体方面涉及通式(I)的化合物,其中,X4代表R4或者G4-R4基团,G4如上定义,并且R4代表被一个或者多个如上定义的组1或组2取代基取代的烷基或者非取代烷基。
本发明的另一个具体方面涉及通式(I)的化合物,其中,X4代表R4或者G4-R4基团,G4如上定义,并且R4代表被一个或者多个组1或组2取代基取代的烷基。优选地,G4代表氧原子和/或R4代表被组1取代基、特别是COOH取代的烷基。甚至更优选地,X4代表-OC(CH3)2COOH、-OCH2COOH或者-SC(CH3)2COOH基团。
本发明的另一个具体主题涉及通式(I)的化合物,其中,所述X3、X4和X5中仅一个代表R3、R4、R5、G3R3、G4R4或者G5R5基团,G3、G4和G5如上所述,并且R3、R4和R5相同或者不同,代表被一个或者多个如上定义的组1或组2取代基取代的烷基。
本发明的另一个具体主题涉及通式(I)的化合物,其中,所述X3、X4和X5中仅X4代表R4或者G4R4,G4如上定义,并且R4代表被一个或者多个如上定义的组1或组2取代基取代的烷基。
本发明的另一个具体主题涉及通式(I)的化合物,其中,所述X3、X4和X5中的两个或者三个代表R3、R4、R5、G3R3、G4R4或者G5R5基团,G3、G4和G5如上所述,并且R3、R4和R5相同或者不同,代表被一个或者多个如上定义的组1或组2取代基取代的烷基。
本发明的另一个具体方面涉及通式(I)的化合物,其中,G3、G4和/或G5代表氧原子。
优选地,本发明涉及通式(I)的化合物,其中,所述X3、X4和X5中仅一个与G3R3、G4R4或者G5R5式对应,G3、G4和G5代表氧原子,并且R3、R4或者R5相同或者不同,代表被一个或者多个如上定义的组1或组2取代基取代的烷基。
甚至更优选地,本发明涉及通式(I)的化合物,其中,所述X3、X4和X5中仅X4基团与G4R4式对应,G4代表氢原子,并且R4代表被一个或者多个如上定义的组1或组2取代基取代的烷基。
本发明的另一个优选方面涉及通式(I)的化合物,其中,所述X3、X4和X5中两个或者三个与所述G3R3、G4R4或者G5R5式对应,G3、G4和G5代表氧原子,并且R3、R4和R5代表被一个或者多个如上定义的组1或组2取代基取代的烷基。
本发明的具体的方面涉及通式(I)的化合物,其中,所述取代基选自组1取代基。优选地,组1取代基是-COOR9类,R9如上定义并且优选代表氢原子或者包含1、2、3、4、5或者6个碳原子的烷基。
本发明的具体方面涉及通式(I)的化合物,其中,所述X3、X4和X5中仅一个与式-OC(CH3)2COOR9对应,R9如上定义并且优选代表氢原子或者包含1、2、3、4、5或者6个碳原子的烷基。
甚至更优地,X4代表-OC(CH3)2COOR9基团,R9如上定义并且优选代表氢原子或者包含1、2、3、4、5或者6个碳原子的烷基。
本发明的一个具体方面涉及通式(I)的化合物,其中,X1代表R1或者G1R1羰基,G1如上定义,并且R1代表卤代烷基。
优选地,R1代表包含1、2或者3个碳原子的卤代烷基。
甚至更优地,X1代表-CF3、-OCF3、-SCF3、-ORCF3基团,R代表如上定义的烷基。
本发明的具体方面涉及通式(I)的化合物,其中,X1代表卤素原子(溴、氯、氟、碘)。优选地,X1代表氯原子或者溴原子。
本发明的具体的方面涉及通式(I)的化合物,其中,X2代表氢原子。
本发明的具体方面涉及通式(I)的化合物,其中,X2代表卤素原子(溴、氯、氟、碘)。
本发明的具体主题涉及通式(I)的化合物,其中,X2代表R2或者G2R2基团,R2和G2如上所述。优选地,R2代表氢原子、-CF3基团或者包含1、2、3、4、5、6、7或者8个碳原子的烷基。甚至更优选地,X2代表-OR’基团,R’代表烷基、-CF3、-OCF3、-OH。
本发明的具体方面涉及通式(I)的化合物,其中,D代表CH2基团。
本发明的另一个具体主题涉及通式(I)的化合物,其中,G2和D形成氧化或者硫化杂环以形成具有以下式(II)的化合物:
优选地,G2在通式(II)中代表硫原子。
根据本发明的具体实施方案,优选的化合物如下所示:
化合物1:2-[2,6-二甲基-4-[3-[4-(三氟甲氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物2:2-[2,6-二甲基-4-[3-[4-(三氟甲硫基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物3:2-[2,6-二甲基-4-[3-[4-溴苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物4:2-[2,6-二甲基-4-[3-[4-(三氟甲基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物5:2-[4-[3-[4-氯-2-羟基苯基]-3-氧代丙基]苯硫基]-2-甲基丙酸
化合物6:2-[2-甲基-4-[3-[4-(3,3,3-三氟丙氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物7:2-[2,6-二甲基-4-[3-羟基-3-[4-(三氟甲硫基)苯基]丙基]苯氧基]-2-甲基丙酸
化合物8:2-[2,6-二甲基-4-[3-(吡啶-3-基甲氧基)-3-[4-(三氟甲氧基)苯基]丙基]苯氧基]-2-甲基丙酸
化合物9:2-[4-(3-(4-碘苄氧基)-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物10:2-[4-(3-甲氧基-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物11:2-[2,6-二甲基-4-[3-[4-(3,3,3-三氟丙氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物12:2-(2,6-二甲基-4-(3-氧代-3-(4-(2,2,2-三氟乙氧基)苯基)丙基)苯氧基)-2-甲基丙酸
化合物13:2-(2,6-二甲基-4-(3-氧代-3-(4-(2,2,2-三氟乙硫基)苯基)丙基)苯氧基)-2-甲基丙酸
化合物14:2-(4-(3-(4-氯-2-(甲硫基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物15:2-(4-(3-(2,4-双(三氟甲基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物16:2-(4-(3-(2-氟-4-(三氟甲基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物17:2-(4-(3-(2-氟-4-(2,2,2-三氟乙氧基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物18:2-(2,6-二甲基-4-(3-(2-甲基-4-(2,2,2-三氟乙氧基)苯基)-3-氧代丙基)苯氧基)-2-甲基丙酸
化合物19:2-(4-(3-(2-甲氧基-4-(2,2,2-三氟乙氧基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物20:2-(4-(3-(2-羟基-4-(三氟甲基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物21:2-(4-(3-(2-甲氧基-4-(三氟甲基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物22:2-(2,6-二甲基-4-(3-(2-异丙氧基-4-(三氟甲基)苯基)-3-氧代丙基)苯氧基)-2-甲基丙酸
化合物23:2-(2,6-二甲氧基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2-甲基丙酸
化合物24:2-(4-(3-(2-氟-4-(三氟甲基)苯基)-3-氧代丙基)-2,6-二甲氧基苯氧基]-2-甲基丙酸
化合物25:2-甲基-2-(2-甲基-4-(3-氧代-3-(4-(三氟甲硫基)苯基)丙基)苯氧基)丙酸
化合物26:2-甲基-2-(2-甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)丙酸
化合物27:2-(4-(3-(2-氟-4-(三氟甲基)苯基)-3-氧代丙基)苯硫基]-2-甲基丙酸
化合物28:2-甲基-2-(3-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)丙酸
化合物29:2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)丙酸
化合物30:2-[4-(3-羟基-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物31:2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2-甲基丙酰胺
化合物32:2-(4-(3-肟基-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物33:2-(4-(3-甲氧亚胺基-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基]-2-甲基丙酸
化合物34:4-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2,2-二甲基丁酸
化合物35:2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2-甲基丙酸叔丁酯
化合物36:2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2-甲基丙酸异丙酯
化合物37:2,2-二氟-2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)乙酸
化合物38:2-(2-甲氧基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯硫基)-2-甲基丙酸
本发明优选涉及以下化合物:
化合物1:2-[2,6-二甲基-4-[3-[4-(三氟甲氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物2:2-[2,6-二甲基-4-[3-[4-(三氟甲硫基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物3:2-[2,6-二甲基-4-[3-[4-溴苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物4:2-[2,6-二甲基-4-[3-[4-(三氟甲基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物6:2-[2-甲基-4-[3-[4-(3,3,3-三氟丙氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物11:2-[2,6-二甲基-4-[3-[4-(3,3,3-三氟丙氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸
化合物26:2-甲基-2-(2-甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)丙酸
化合物36:2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2-甲基丙酸异丙酯
本发明的化合物包括其纯立体异构体(非对映异构体、对映异构体)或者混合立体异构体、消旋式、其几何异构体、其互变异构体、其盐、其水合物、其溶剂合物、其固体形式以及它们的混合物。
本发明的化合物可以包含一个或者几个不对称中心。本发明包括纯的立体异构体(非对映异构体、对映异构体)或者混合立体异构体,以及消旋式和几何异构体。当需要对映体纯(或者富集)的混合物时,其可以通过纯化最终产物或者手性中间体,或者通过根据本领域普通技术人员已知的方法(比如使用试剂和手性催化剂)进行不对称合成来得到。本发明的一些化合物可以具有不同的稳定的互变异构形式,并且所有这些形式以及它们的混合物被包括在本发明中。
本发明还涉及本发明化合物的“药学上可接受”的盐。通常,该术语指得自有机或无机碱或酸的有轻微毒性或者无毒性的盐。这些盐可以在本发明的化合物的最后纯化步骤中获得或者通过将所述盐包含在已纯化的化合物中而获得。
本发明的一些化合物和它们的盐可能有几种稳定的固体形式。本发明包括本发明化合物的所有固体形式,包括无定形、多形、单晶和多晶形式。
本发明的化合物可以以非溶剂化或者溶剂化(例如用药学上可接受的溶剂如水(水合物)或者乙醇)的形式存在。
用一种或者多种同位素标记的本发明的化合物也包括在本发明中:这些化合物在结构上相同,而不同之处在于结构中的至少一个原子被同位素(放射性的或者非放射性的)代替。可以包括在本发明的化合物的结构中的同位素的例子可以选自氢、碳、氧和硫,例如分别为2H、3H、13C、14C、18O、17O、35S。特别优选放射性同位素,因为它们在所述物质的体内生物利用度的研究范围内容易制备和检测。特别优选重同位素(例如2H),因为它们在分析研究中用作内标。
本发明还涉及合成如上定义的通式(I)的化合物的方法。
本发明的方法包括:
-在碱性或者酸性介质中,至少一种式(A)化合物与至少一种式(B)化合物的混合的步骤(i),
其中,X1、X2、X3、X4和X5具有以上给出的定义,
-然后,所得化合物的还原步骤(ii),
-以及最后,使官能团连接的步骤(iii)。
在酸性或者碱性介质中的步骤(i)和步骤(ii)的实验条件对于本领域的技术人员来说容易实现并且可以有很大的变化。合成的步骤具体可以是本发明的“实施例”下描述的那些步骤。
两种化合物的混合优选按化学计量法进行。其优选在室温(约18℃-25℃)和正常大气压下进行。
在碱性介质中,优选反应在强碱例如碱金属氢氧化物(如氢氧化钠)或者碱金属醇盐(如乙醇钠)的存在下进行。
在酸性介质中,优选反应在强酸例如盐酸的存在下进行。
所得化合物可以通过本领域普通技术人员已知的经典方法来分离。然后,它们可以被用作例如药物或者化妆品。
本发明还涉及如上所述的作为药物的化合物。
本发明的另一个主题涉及药物组合物,所述组合物在药学上可接受的载体中包含至少一种如上所述的化合物,所述化合物可能与一种或者多种其它的治疗和/或化妆活性组份结合。
本发明优选涉及用于与代谢综合征相关的并发症、胰岛素抵抗、糖尿病、血脂异常、动脉粥样硬化、心血管疾病、肥胖症、高血压、炎性疾病(哮喘等)、神经变性疾病(阿尔茨海默氏病等)或者癌症的治疗的药物组合物。本发明的药物组合物优选用于治疗血脂异常。
它优选是通过降低总体风险来治疗与脂质和/或糖代谢异常(高血脂、II型糖尿病、肥胖症等)相关的心血管风险因素的药物组合物。
本发明的另一个主题涉及包含至少一种如上所述化合物的营养组合物。
本发明的另一个主题涉及至少一种如上所述的化合物用于制备用于治疗多种疾病,特别是与代谢异常相关的疾病(比如血脂异常)的药物组合物的用途。更一般地,本发明的主题涉及至少一种上述的化合物用于制备用于治疗与脂质和/或糖代谢病症相关的心血管风险因素以降低总体风险的药物组合物的用途。
例如(但非限制性地),理想地,本发明的化合物可有利地与目前市场上可获得的或者正在开发的其它治疗和/或化妆药剂联合给药,例如:
-抗糖尿病药:促分泌剂(磺酰脲类(格列本脲、格列美脲、格列齐特等)和格列奈类(glinides)(瑞格列奈、那格列奈等))、α-葡糖苷酶抑制剂、PPARγ激动剂(噻唑烷二酮类如罗格列酮、吡格列酮)、混合PPARα/γ激动剂(替赛格列他(tesaglitazar)、莫格列他(muraglitazar))、全PPAR(同时激活三种PPAR亚型的化合物)、双胍(二甲双胍)、二肽基肽酶IV抑制剂(MK-431、维格列汀(vildagliptin))、高血糖素样肽-1(GLP-1)激动剂(依泽那太)等。
-胰岛素
-降脂和/或降胆固醇分子:贝特类(非诺贝特、吉非贝齐)、HMG CoA还原酶或者羟基甲基戊二酰辅酶A还原酶抑制剂(他汀类,例如阿托伐他汀、辛伐他汀、氟伐他汀)、胆固醇吸收抑制剂(依折麦布、植物甾醇类)、CETP或者胆固醇酯转移蛋白抑制剂(托彻普(torcetrapib))、ACAT或者酰基辅酶A胆固醇酰基转移酶抑制剂(阿伐麦布、依鲁麦布(eflucimibe))、MTP(微粒体甘油三酯转移蛋白)抑制剂、胆汁酸多价螯合剂(考来烯胺)、维生素E、多不饱和脂肪酸、ω-3脂肪酸、烟酸类衍生物(烟酸)等。
-抗高血压剂和降压剂:ACE(血管紧张素转换酶)抑制剂(卡托普利、依那普利、雷米普利或者喹那普利)、血管紧张素II受体抑制剂(氯沙坦、缬沙坦、替米沙坦、埃坡沙坦(eposartan)、厄贝沙坦等)、β阻断剂(阿替洛尔、美托洛尔、拉贝洛尔、普萘洛尔)、噻嗪类和非噻嗪类利尿剂(呋塞米、吲达帕胺、双氢氯噻嗪、抗醛固酮类)、血管扩张剂、钙通道阻滞剂(硝苯地平、非洛地平、氨氯地平、地尔硫卓或者维拉帕米)等。
-抗血小板剂:阿司匹林、噻氯匹定、双嘧达莫、氯吡格雷、氟比洛芬等。
-减肥药:西布曲明、脂肪酶抑制剂(奥利司他)、PPARδ、大麻素CB1受体拮抗剂(利莫那班)等。
-抗炎剂:例如,肾上腺皮质激素(泼尼松、倍他米松、地塞米松、泼尼松龙、甲泼尼龙、氢化可的松等)、NSAID或者得自吲哚的非甾体抗炎药(吲哚美辛、舒林酸)、芳基烷酸(arylcarboxylic)类NSAID(噻洛芬酸、双氯芬酸、依托度酸、氟比洛芬、布洛芬、酮洛芬、萘普生、萘丁美酮、阿明洛芬)、得自昔康的NSAID(美洛昔康、吡罗昔康、替诺昔康)、来自芬那酯类的NSAID、COX2选择性抑制剂(塞来昔布、罗非昔布)等。
-抗氧化剂:例如普罗布考等。
-用于治疗心功能不全的药剂:噻嗪类和非噻嗪类利尿剂(呋塞米、吲达帕胺、氢氯噻嗪、抗醛甾酮类)、ACE抑制剂(卡托普利、依那普利、雷米普利或者喹那普利)、洋地黄药物(地高辛、洋地黄毒苷)、β阻断剂(阿替洛尔、美托洛尔、拉贝洛尔、普萘洛尔)、磷酸二酯酶抑制剂(依诺昔酮、米力农)等。
-用于治疗冠状动脉功能不全的药剂:β阻断剂(阿替洛尔、美托洛尔、拉贝洛尔、普萘洛尔)、钙通道阻滞剂(硝苯地平、非洛地平或者氨氯地平、苄普地儿、地尔硫卓或者维拉帕米)、NO(一氧化氮)供体(三硝基甘油、硝酸异山梨酯、吗多明)、胺碘酮等。
-抗癌药:细胞毒素剂(与DNA(脱氧核糖核酸)相互作用的药物、烷化剂、顺铂及衍生物)、杀细胞药(GnRH(促性腺激素释放激素)类似物、生长抑素类似物、黄体酮、抗雌激素药、芳香酶抑制剂等)、免疫应答调节剂(干扰素类、IL2等))等。
-平喘药,例如支气管扩张剂(β2受体激动剂)、肾上腺皮质激素、色苷酸盐、白三烯受体拮抗剂(孟鲁司特)等。
-用于治疗皮肤病如银屑病和皮炎的肾上腺皮质激素
-血管扩张剂和/或抗局部缺血药(丁咯地儿、银杏叶提取物、萘呋胺、己酮可可碱、吡贝地尔)等。
本发明还涉及用于治疗与脂质和/或糖代谢相关的疾病的方法,所述方法包括向个体、特别是人给药有效量的如上定义的化合物或者药物组合物。在本发明的范围内,术语“有效量”指足以产生期望的生物学效果的化合物量。在本发明的范围内,术语“个体”指哺乳动物并且特别地指人。
术语“治疗”指治愈性的、对症的或者预防性的治疗。因此,本发明的化合物可以用于具有确诊疾病的个体(例如哺乳动物,特别是人类)。本发明的化合物也可以用于延迟或者减慢所述疾病的进展或者防止疾病的进一步进展,由此改善所述个体的病症。最后,本发明的化合物可以给药于通常可能罹患所述疾病或者具有罹患所述疾病的重大风险的健康个体。
本发明的药物组合物有利地包含一种或者多种制药范围内可接受的赋形剂或者载体(比如与药物用途相容的和本领域的普通技术人员熟知的盐水溶液、生理溶液、等渗溶液等)。该组合物可以包含一种或者多种选自分散剂、增溶剂、稳定剂、防腐剂等的试剂或者载体。用于这些制剂的试剂或者载体(液体和/或可注射的和/或固体)具体是甲基纤维素、羟甲基纤维素、羧甲基纤维素、聚山梨醇80、甘露醇、明胶、乳糖、植物油、阿拉伯胶、脂质体等。所述组合物可以最终通过确保延长释放和/或缓释的盖仑制剂(galenic forms)或者盖伦装置(galenic devices)的方式被配制成可注射混悬剂、凝胶、油、丸剂、栓剂、散剂、软胶囊、胶囊、气雾剂等形式。对于这类制剂,可以有利地使用例如纤维素、碳酸盐或者淀粉的试剂。
本发明的化合物或者组合物可以以不同的方式和不同的形式给药。因此,例如,它们可以通过全身性的方式、经口、肠胃外、通过吸入、或者通过注射例如由静脉内地、肌肉注射、皮下注射、经皮途径、动脉内注射等。对于注射,所述化合物通常以可以使用例如注射器或者灌注来注射的液体混悬剂的形式保存(conditioned)。
应该理解,关于所述注射的速度和/或剂量可以由本领域的普通技术人员根据患者、病理和给药方式等来调整。通常,所述化合物以每次给药1μg至2g、优选每次给药0.1mg至1g来给药。如果需要,可以每天给药,甚至一天几次。而且,本发明的组合物可包括其它药剂或者活性组份。
附图说明
这些附图中使用的缩写:
-Cpd=化合物
-Ctrl=对照
-mpk=mg/kg/天
-LDL-胆固醇=低密度脂蛋白胆固醇
-HDL-胆固醇=高密度脂蛋白胆固醇
-VLDL-胆固醇=极低密度脂蛋白胆固醇
图1-1至1-18:根据所述剂量的本发明化合物的PPAR激活性质的体
外评价
使用猴肾成纤维细胞系(COS-7),通过测定嵌合体的转录活性来体外评价PPAR的激活,所述嵌合体由酵母Gal4转录因子的DNA结合结构域和不同的PPAR配体的结合结构域组成。
所述化合物以10-7至100μM的剂量对Gal4-PPARα、γ和δ嵌合体进行测试。测量每种条件下的诱导因子,即所述化合物诱导的发光与对照诱导的发光之比。诱导因子越高,则所述化合物具有越多的PPAR激活性质。
-图1-1、1-2、1-3:化合物1的PPARα、γ、δ激活性质的体外评价;
-图1-4、1-5、1-6:化合物2的PPARα、γ、δ激活性质的体外评价;
-图1-7、1-8、1-9:化合物3的PPARα、γ、δ激活性质的体外评价;
-图1-10、1-11、1-12:化合物4的PPARα、γ、δ激活性质的体外评价;
-图1-13、1-14、1-15:化合物5的PPARα、γ、δ激活性质的体外评价;
-图1-16、1-17、1-18:化合物7的PPARα、γ、δ激活性质的体外评价;
图2-1至2-7:在ApoE2/E2小鼠上进行的本发明化合物的体重性质、
降血脂性质和刺激HDL-胆固醇合成的性质的体内评价
在体内评价本发明的化合物对通过E2亚型载脂蛋白E(E2/E2)人源化的小鼠的影响。
在用本发明的化合物口服治疗8天后,测量血脂异常的E2/E2小鼠的体重、总胆固醇比率、甘油三酯比率和血浆游离脂肪酸比率。将这些参数与得自对照动物(未用本发明的化合物治疗的动物)的参数作比较:测得的差异显示本发明的化合物对体重的影响和降血脂效力。
-图2-1:用化合物1以5、10和50mpk给药治疗8天后的体重增加;
-图2-2:用化合物1以5、10和50mpk给药治疗8天后的血浆胆固醇水平;
-图2-3:用化合物1以5、10和50mDk给药治疗8天后的血浆HDL胆固醇水平;
-图2-4:用化合物以5、10和50mDk给药1治疗8天后的血浆甘油三酯水平;
-图2-5:用化合物1以5、10和50mpk给药治疗8天后的血浆游离脂肪酸水平。
还通过测定肝组织中参与脂质和/或糖代谢以及能量耗散的基因的表达来评价本发明的化合物的效力。将基因表达的各个水平关于参照基因36B4的表达水平进行标准化。然后计算诱导因子,即(本发明的化合物诱导的)相对信号与得自对照组的相对值的平均值的比。诱导因子越高,则所述化合物就越高地促进肝脏基因的表达。最终结果表示为得自各个实验组的诱导值的平均值。
-图2-6:用化合物1以5、10和50mpk给药治疗8天后,E2/E2小鼠的肝组织中PDK4(丙酮酸脱氢酶激酶,亚型4)的表达;
-图2-7:用化合物1以5、10和50mpk给药治疗8天后,E2/E2小鼠的肝组织中ApoCIII(载脂蛋白C3)的表达。
图3-1至3-5:在C57BI6小鼠上讲行的本发明化合物的体重性质、降
血脂性质和刺激HDL-胆固醇合成的性质的体内评价
用本发明的化合物口服治疗14天后,通过测量体重发展、血浆HDL胆固醇和甘油三酯水平,来体内评价本发明的化合物对C57BI6小鼠的影响。这些参数与得自对照动物(未用本发明的化合物治疗的动物)的参数作比较。测得的差异显示本发明的化合物对体重的影响,并显示它们的降血脂效力。
-图3-1:用化合物1以3、10和50mDkg给药治疗14天后的体重增加;
-图3-2:用化合物1以3、10和50mpk给药治疗14天后的血浆HDL胆固醇水平;
-图3-3:用化合物1以3、10和50mDk给药治疗14天后的血浆甘油三酯水平。
还通过测量肝组织中参与脂质代谢的基因的表达来评价本发明的化合物的效力。将基因表达的各个水平关于参照基因36B4的表达水平进行标准化。然后计算诱导因子。诱导因子越高,则所述化合物就越高地促进肝脏基因的表达。最终结果表示为得自各个实验组的诱导值的平均值。
-图3-4:用化合物1以3、10和30mpk给药治疗14天后,C57BI6小鼠的肝组织中PDK4的表达;
-图3-5:用化合物1以3、10和30mpk给药治疗14天后,C57BI6小鼠的肝组织中ApoCIII的表达。
图4-1至4-9:在db/db小鼠上进行的本发明化合物的体重性质、抗糖
尿病性质、降血脂性质和刺激HDL-胆固醇合成的性质的体内评价
用本发明的化合物口服治疗28天后,通过测量体重发展、葡萄糖水平、胰岛素水平、血清总胆固醇和甘油三酯水平,以及通过分析胆固醇在不同血浆脂蛋白部分中的分布,来体内评价本发明的化合物对db/db小鼠的影响。这些参数与得自对照动物(未用本发明的化合物治疗的动物)的参数作比较。测得的差异显示本发明的化合物对体重、胰岛素抵抗的影响,并显示它们的降血脂效力。
-图4-1:用化合物1以50mpk给药治疗28天后的体重增加;
-图4-2:用化合物1以50mpk给药治疗28天后的血糖(glycemia);
-图4-3:用化合物1以50mpk给药治疗28天后的血胰岛素(insulemia);
-图4-4:用化合物1和化合物3以50mDk给药治疗14天后的血浆胆固醇水平;
-图4-5:用化合物1和化合物3以50mpk给药治疗28天后,胆固醇在不同血浆脂蛋白部分中的分布;
-图4-6:用化合物1和化合物3以50mpk给药治疗28天后的血浆甘油三酯水平;
-图4-7:用化合物1和化合物3以50mDk给药治疗28天后的血浆游离脂肪酸水平。
还通过测量肝脏和肌肉(骨骼)组织中参与脂质和/或糖代谢和能量耗散的基因的表达来评价本发明化合物的效力。将基因表达的各个水平关于参照基因36B4在肝组织内的表达水平或者关于参照基因18S在腓肠肌骨骼肌中的表达水平进行标准化。然后计算诱导因子,即(本发明的化合物诱导的)相对信号与得自对照组的相对值的平均值的比。诱导因子越高,则所述化合物就越高地促进基因的表达。最终结果表示为得自各个实验组的诱导值的平均值。
-图4-8:用化合物1和化合物3以50mpk给药治疗28天后,db/db小鼠肝组织中PDK4的表达;
-图4-9:用化合物1和化合物3以50mpk给药治疗28天后,db/db小鼠骨骼肌组织中UCP2(解偶联蛋白2)的表达
图5:通过测定用本发明的化合物治疗并用PMA刺激的单核细胞的
MCP1分泌,来体外评价本发明的化合物的抗炎性质
通过测定用本发明的化合物处理24小时并同时用PMA(佛波醇12-肉豆蔻酸酯13-乙酸酯(Phorbol 12-myristate 13-acetate),它促进细胞的炎症应答并促进它们分化为巨噬细胞)刺激的THP1单核细胞的MCP1(单核细胞趋化蛋白-1)分泌,来评价本发明的化合物抗炎效力。MCP-1分泌越少,则本发明的化合物就越抑制炎症反应。
统计学分析
统计学研究由t检验(o/oo/ooo)和/或单变量ANOVA方差分析以及随后的图基(Tukey)检验(*/**/***)组成。根据参数p的值,将结果与对照组比较:
o/*:p<0.05;oo/**:p<0.01;ooo/***:p<0.001。
实施例
标准试剂和催化剂是可商购获得的(Aldrich、AlfaAesar、Acros、Fluka或者Lancaster)。
质子核磁共振谱(NMR 1H)在Bruker AC300P波谱测定仪上测量。化学位移以ppm(百万分率)表示,NMR信号的分裂用通常的缩写词表述。
实施例1:合成本发明化合物的一般步骤
本发明的大多数化合物特别地使用美国专利2005176808中要求保护的和/或描述的化合物,通过还原和随后的以下所述步骤之一而获得。
根据本领域技术人员可得到的类似的、公知的制备方法可容易地获得其它化合物。
一般步骤A:用三乙基硅烷还原二苯基丙烯-2-酮
向二苯基丙烯-2-酮的二氯甲烷溶液中加入三乙基硅烷,然后滴加三氟乙酸(7.5当量)。在室温下搅拌反应混合物,通过薄层色谱法进行反应跟踪。用水洗涤反应混合物。用二氯甲烷萃取水层。合并的有机层用硫酸镁干燥并真空浓缩。剩余物进行柱层析(制备HPLC,多孔玻璃(Merck)RP1812μm 100,柱:25*250mm)。
一般步骤B:用四氯化硅还原二苯基丙烯-2-酮
向二苯基丙烯-2-酮的乙腈溶液中加入碘化钠,然后滴加四氯化硅。在室温下搅拌反应混合物,通过薄层色谱法进行反应跟踪。30分钟至2小时后,将混合物在氯仿和水之间分配。用氯仿萃取水层。合并的有机层用亚硫酸钠干燥,然后用硫酸镁干燥并真空浓缩。剩余物进行柱层析(制备HPLC,多孔玻璃(Merck) RP18 12μm 100,柱:25*250mm)。
一般步骤C:用炭载钯还原二苯基丙烯-2-酮
向二苯基丙烯-2-酮的乙醇溶液中加入催化量的炭载钯(10%)。在室温于标准压力的氢下搅拌反应混合物。过滤催化剂,滤液真空浓缩。剩余物进行柱层析。
一般步骤D:醇的合成
向二苯基丙-3-酮的乙醇溶液中加入硼氢化钠。将反应混合物在50℃(122℉)下搅拌16小时。冷却后,使反应混合物水解并真空浓缩。将剩余物在二氯甲烷和稀盐酸溶液之间分配。
一般步骤E:醚的合成
将二苯基丙-3-醇在水/醇(1/3:2/3)混合物中的溶液在催化量的三氟乙酸的存在下在60℃搅拌16小时。然后真空浓缩反应混合物。剩余物进行柱层析(制备HPLC,多孔玻璃(Merck)RP18 12μm 柱:25*250mm)。
一般步骤F:使用肟和肟醚的合成
向二苯基丙-3-酮的吡啶溶液中加入O-烷基盐酸羟胺(O-alkylhydroxylamine hydrochloride)。回流16小时后,真空浓缩反应混合物。剩余物进行柱层析。
实施例2:本发明化合物的合成
化合物1:2-[2,6-二甲基-4-[3-[4-(三氟甲氧基)苯基]-3-氧代丙基]苯氧
基]-2-甲基丙酸
根据所述一般步骤B,使用2-[2,6-二甲基-4-[3-[4-(三氟甲氧基)苯基]-3-氧代丙-2-烯基]苯氧基]-2-甲基丙酸、15当量碘化钠和15当量四氯化硅来制备该化合物;
外观:白色固体;F=64-66℃。
NMR1H(300MHz,CDCl3,δ ppm):1.52(s,6H),2.22(s,6H),2.96(t,2H,J=7.51Hz),3.26(t,2H,J=7.51Hz),6.87(s,2H),7.28(d,2H,J=8.61Hz),8.01(d,2H,J=8.61Hz)。
MS(ES-MS):423.3(M-1)。
化合物2:2-[2,6-二甲基-4-[3-[4-(三氟甲硫基)苯基]-3-氧代丙基]苯氧
基]-2-甲基丙酸
根据所述一般步骤A,使用2-[2,6-二甲基-4-[3-[4-(三氟甲硫基)苯基]-3-氧代丙-2-烯基]苯氧基]-2-甲基丙酸和1当量的三乙基硅烷来制备该化合物;
外观:白色固体;F=83-85℃。
NMR1H(300MHz,CDCl3,δ ppm):1.52(s,6H),2.23(s,6H),2.97(t,2H,J=7.59Hz),3.29(t,2H,J=7.59Hz),6.88(s,2H),7.74(d,2H,J=8.46Hz),7.99(d,2H,J=8.46Hz)。
MS(ES-MS):439.2(M-1)。
化合物3:2-[2,6-二甲基-4-[3-[4-溴苯基]-3-氧代丙基]苯氧基]-2-甲基丙
酸
根据所述一般步骤A,使用2-[2,6-二甲基-4-[3-[4-溴苯基]-3-氧代丙-2-烯基]苯氧基]-2-甲基丙酸和1当量的三乙基硅烷来制备该化合物;
外观:白色粘性油。
NMR1H(300MHz,CDCl3,δ ppm):1.52(s,6H),2.23(s,6H),2.96(t,2H,J=7.60Hz),3.24(t,2H,J=7.02Hz),6.89(s,2H),7.61(d,2H,J=8.46Hz),7.83(d,2H,J=8.46Hz)。
MS(ES-MS):417.2(M-1)79Br和419.2(M-1)81Br。
化合物4:2-[2,6-二甲基-4-[3-[4-(三氟甲基)苯基]-3-氧代丙基]苯氧基]-2-
甲基丙酸
根据所述一般步骤A,使用2-[2,6-二甲基-4-[3-[4-(三氟甲基)苯基]-3-氧代丙-2-烯基]苯氧基]-2-甲基丙酸和1当量的三乙基硅烷来制备该化合物;
外观:微黄色粘性油。
NMR1H(300MHz,CDCl3,δ ppm):1.52(s,6H),2.23(s,6H),2.98(t,2H,J=7.29Hz),3.30(t,2H,J=7.29Hz),6.88(s,2H),7.72(d,2H,J=8.17Hz),8.06(d,2H,J=8.17Hz)。
MS(ES-MS):407.4(M-1)。
化合物5:2-[4-[3-[4-氯-2-羟基苯基]-3-氧代丙基]苯硫基]-2-甲基丙酸
根据所述一般步骤B,使用2-[4-[3-[4-氯-2-羟基苯基]-3-氧代丙-2-烯基]苯硫基]-2-甲基丙酸、5当量碘化钠和5当量四氯化硅来制备该化合物;
外观:白色固体;F=136-137℃。
NMR1H(300MHz,CDCl3,δ ppm):1.52(s,6H),3.08(t,2H,J=7.59Hz),3.30(t,2H,J=7.59Hz),6.87(dd,1H,J=1.89Hz,J=8.79Hz),7.02(d,1H,J=1.89Hz),7.22(d,2H,J=7.89Hz),7.47(d,2H,J=8.19Hz),7.66(d,1H,J=8.46Hz),12.38(s,1H)。
MS(ES-MS):377.01(M-1)。
化合物6:2-[2-甲基-4-[3-[4-(3,3,3-三氟丙氧基)苯基]-3-氧代丙基]苯氧
基]-2-甲基丙酸
通过使用2-(4-(3-(4-羟基苯基)-3-氧代丙-1-烯)-2-甲基苯氧基)-2-甲基丙酸叔丁酯,根据所述一般步骤C进行还原,然后,根据US 2005/176808中所述的方法进行酚的O-烷基化和叔丁酯的酸解,从而制备该化合物;
外观:无色粘性油。
NMR1H(300MHz,CDCl3,δ ppm):1.60(s,6H);2.23(s,3H);2.61-2.70(m,2H);2.95-2.99(m,2H);3.19-3.24(m,2H);4.26(t,2H,J=6.5Hz);6.77(d,1H,J=8.5Hz);6.93(d,2H,J=8.9Hz);6.93-6.98(m,1H);7.06(d,1H,J=2.1Hz);7.95(d,2H,J=8.9Hz)。
MS(ES-MS):437.3(M-1)。
化合物10:2-[4-(3-甲氧基-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯
氧基]-2-甲基丙酸
根据所述一般步骤E,使用2-(4-(3-羟基-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基)-2-甲基丙酸在水/甲醇(1/3:2/3)混合物中的溶液来制备该化合物;
外观:无色粘性油。
NMR1H(300MHz,CDCl3,δ ppm):1.46(s,6H);1.91-2.21(m,2H);2.15(s,6H);2.49-2.69(m,2H),3.83(s,3H);4.69(dd,1H,J=7.7Hz,J=5.1Hz);6.78(s,2H);7.19(d,2H,J=8.5Hz);7.36(d,2H,J=8.5Hz)。
MS(ES-MS):458.3(M+NH4 +),463.2(M+Na+),479.2(M+K+)。
化合物12:2-(2,6-二甲基-4-(3-氧代-3-(4-(2,2,2-三氟乙氧基)苯基)丙基)
苯氧基)-2-甲基丙酸
通过使用2-(4-(3-(4-羟基苯基)-3-氧代丙-1-烯)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯,根据所述一般步骤C进行还原,然后,根据US 2005176808中所述的方法进行酚的O-烷基化和叔丁酯的酸解,从而以此制备该化合物;
外观:白色固体;F=98-99℃。
NMR1H(300MHz,CDCl3,δ ppm):1.45(s,6H);2.17(s,6H);2.89(m,2H);3.18(m,2H);4.40(q,2H,J=8.1Hz);6.82(s,2H);6.95(d,2H,J=9.1Hz);7.93(d,2H,J=9.1Hz)。
MS(ES-MS):437.4(M-1)。
化合物17:2-(4-(3-(2-氟-4-(2,2,2-三氟乙氧基)苯基)-3-氧代丙基)-2,6-二
甲基苯氧基]-2-甲基丙酸
通过使用2-(4-(3-(2-氟-4-羟基苯基)-3-氧代丙-1-烯)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯,根据所述一般步骤C进行还原,然后,根据专利US 2005176808进行酚的O-烷基化和叔丁酯的酸解,从而制备该化合物。
外观:无色粘性油。
NMR1H(300MHz,CDCl3,δ ppm):1.51(s,6H);2.21(s,6H);2.92(t,2H,J=7.6Hz);3.23(td,2H,J=7.6Hz J=3.1Hz);6.70(dd,J=8.7Hz J=2.3Hz);6.81(dd,J=12.6Hz J=2.3Hz);6.86(s);7.91(t,1H,J=8.7Hz)。
MS(MALDI-TOF):479(M+Na+)。
化合物30:2-[4-(3-羟基-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧
基]-2-甲基丙酸
根据所述一般步骤D,使用2-[2,6-二甲基-4-[3-[4-(三氟甲氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸和1当量的硼氢化钠来制备该化合物。
外观:无色粘性油。
NMR1H(300MHz,CDCl3,δ ppm):1.46(s,6H);1.94-2.10(m,2H);2.17(s,6H);2.46-2.66(m,2H);4.69(dd,1H,J=7.6Hz J=5.5Hz);6.78(s,2H);7.17(d,2H,J=8.3Hz);7.34(d,2H,J=8.3Hz)。
MS(ES-MS):425.3(M-1)。
化合物33:2-(4-(3-甲氧亚胺基)-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲
基苯氧基]-2-甲基丙酸
根据所述一般步骤F,使用2-[2,6-二甲基-4-[3-[4-(三氟甲氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸来制备该化合物。
外观:微黄色粘性油。
NMR1H(300MHz,CDCl3,δ in ppm):1.49(s,6H),2.21(s,6H),2.71-2.77(m,2H),2.95-3.01(m,2H),4.01(s,3H),6.82(s,2H),7.17(d,2H,J=8.7Hz),7.59(d,2H,J=8.7Hz)。
MS(ES-QTOF):476(M+Na+)。
化合物35:2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧
基)-2-甲基丙酸叔丁酯
通过使用3-(4-羟基-3,5-二甲基苯基)-1-(4-(三氟甲氧基)苯基)丙-1-酮,根据所述一般步骤C进行还原,然后,根据专利专利US 2005176808进行酚的O-烷基化和叔丁酯的酸解,从而制备该化合物。
外观:无色粘性油。
NMR1H(300MHz,CDCl3,δ ppm):1.42(s,6H);1.51(s,9H);2.21(s,6H);2.94(t,2H,J=7.9Hz);3.25(t,2H,J=7.9Hz);6.82(s,2H);7.28(d,2H,J=9.1Hz);8.01(d,2H,J=9.1Hz)。
根据与所述步骤A-F类似的步骤获得其它化合物,并且对本领域的技术人员来说很容易实现。
实施例3:本发明化合物的PPAR激活性质的体外评价
体外评价本发明化合物的PPAR激活性质。
原理
使用猴肾成纤维细胞系(COS-7),通过测定嵌合体的转录活性来体外评价PPAR的激活,所述嵌合体由酵母Gal4转录因子的DNA结合结构域和不同的PPAR配体的结合结构域组成。化合物以10-7-100μM的剂量在Gal4-PPARα、γ和δ嵌合体上进行测试。
实验方案
细胞培养
COS-7细胞来自ATCC(美国典型培养物保藏中心),培养在DMEM(达尔伯克改良伊格尔培养基)培养基中,该培养基中补充了10%(体积/体积)胎牛血清、100U/ml青霉素(Gibco,Paisley,UK)和2mM L-谷氨酰胺(Gibco,Paisley,UK)。细胞在37℃下于含5%CO2的湿润气氛中培养。
用于转染的质粒的描述
质粒 Gal4(RE)_TkpGL3、pGal4-hPPARα、pGal4-hPPARγ、pGal4-hPPARδ和pGal4-φ已在文献(Raspe E等人,1999)中有描述。通过在pGal4-φ载体中克隆通过PCR扩增的并与人PPARα、PPARγ和PPARδ细胞核受体的DEF结构域对应的DNA片段获得构建pGal4-hPPARα、pGal4-hPPARγ和pGal4-hPPARδ。
转染
在10%胎牛血清存在下,以1/10的pGal4-PPAR/Gal4(RE)_TkpGL3比,以每孔150ng的DNA转染悬浮液中的COS-7细胞。将这些细胞涂布在96孔板中(4×104细胞/孔),然后在37℃孵育24小时。于37℃、在不含血清的培养基中用供试化合物进行激活持续24小时。实验结束时,使细胞溶解,并且使用Steady-LiteTM HTSPerkin Elmer)或者Steady Glow Luciferase(Promega),根据供应商的建议,测定荧光素酶的活性。
结果
在三种PPAR亚型上测试了本发明化合物。得自化合物1、2、3、4、5和7的结果详细表述在图(1-1)至(1-18)中。
本发明人已证明,用质粒pGal4-hPPAR转染并用本发明化合物处理的细胞中荧光素酶活性的显著的且剂量依赖性的提高。
出乎意料地,所示的实验数据显示,本发明的化合物在体外与PPAR结合并诱导激活转录活性。
实施例4:在ApoE2/E2小鼠上进行的本发明化合物的体重性质、降血脂性质和刺激HDL-胆固醇合成的性质的体内评价
原理
用本发明的化合物治疗血脂异常的E2/E2小鼠后,通过测量体重和血浆脂质并分析PPAR基因靶的基因表达来体内评价本发明的化合物影响体重的性质和降血脂的性质。
所用的鼠模型是ApoE2/E2小鼠,其为具有人类载脂蛋白E亚型E2的转基因小鼠(Sullivan PM等人,1998)。在人类,这种载脂蛋白是低密度和极低密度脂蛋白(LDL-VLDL)的一种组份,它以E2、E3和E4三种亚型存在。E2亚型存在影响第158位氨基酸的突变,该突变相当大地减弱了该蛋白与LDL受体的亲和性。因此,几乎不存在VLDL清除。然后,发生低密度脂蛋白蓄积以及被称为III型的混合性高脂血症(高胆固醇与甘油三酯比率)。
PPARα调节参与脂质运输的基因(载脂蛋白,例如Apo AI、Apo AII和Apo CIII;膜运载蛋白,例如FAT)和脂质分解代谢的基因(ACO、CPT-I或者CPT-II、脂肪酸β-氧化酶)的表达。因此,在人类和啮齿动物,用PPARα激活剂治疗导致循环甘油三酯水平降低。在用本发明的化合物治疗后,测定血浆脂质比率能评价本发明化合物的PPAR激动剂性质和降血脂效力。
在人类和啮齿动物,用PPAR激活剂治疗有时还导致血浆HDL-胆固醇比率的提高。因此,测定血浆HDL-胆固醇比率能显示本发明的化合物对HDL-胆固醇的合成的刺激作用。
以上在体外测定的PPARα的激动剂性质会在肝脏中、直接在PPARα控制下导致靶基因的过度表达。在本实验中我们已研究的基因是Apo CIII(参与脂质代谢的载脂蛋白)和PDK-4(参与糖代谢的酶)。因此,在用本发明的化合物治疗后,测定PPARα靶基因的转录活性能评价本发明化合物的降血脂性质。
实验方案
动物的治疗
在20±3℃的恒定温度下,将ApoE2/E2转基因小鼠保持在12小时/12小时的明/暗循环中。在一周的适应期后,将小鼠称重并分组,每组选择6只动物,以使它们实验之前测定的体重和血浆脂质比率分布均匀。将供试化合物悬浮在羧甲基纤维素(Sigma C4888)中,以所选的剂量通过胃内管饲给药,每天一次,持续8天。动物可自由进食和饮水(标准饮食)。在整个实验过程中,记录食物的摄取和体重增加。在实验结束时,在4小时的禁食后,将动物麻醉,用(EDTA)抗凝血剂采集血样,然后将小鼠称重并使其安乐死。通过以3000转/分离心20分钟制备血浆。将样品保存在+4℃。
采集肝脏样品,在液氮中冷冻,然后保存在-80℃以用于后续分析。
血浆脂质的测定
通过酶剂量(bioMérieux-Lyon-France),根据供应商的建议,测定血浆脂质浓度(总胆固醇和甘油三酯)。
在用本发明化合物口服治疗8天后,测定血浆胆固醇比率和甘油三酯比率。将这些比率与得自对照动物(未用本发明的化合物治疗)的比率作比较。测得的差异显示本发明化合物的降血脂效力。
HDL-胆固醇的测定
通过磷钨酸盐将低密度脂蛋白(VLDL和LDL)沉淀。通过离心除去沉淀物。通过酶剂量(bioMérieux-Lyon-Franc),根据供应商的建议,测定存在于上清液中的HDL胆固醇。
通过定量RT-PCR分析基因表达
然后,通过在37℃于20μl含有1X缓冲液(Sigma)、1.5mM DTT、0.18mM dNTP(Promega)、200ng pdN6(Amersham)、30U RNA酶抑制剂(Sigma)和1μl MMLV-RT(Sigma)的总体积中反应1小时,将1μg总RNA(通过使用Ribogreen RNA定量试剂盒(Molecular Probes)定量)反转录为互补DNA。
根据生产商的建议,在55℃的杂交温度下、在96孔板中于5μl稀释的反转录溶液中,使用MyiQ Single-Color Real-Time PCR Detection System(Biorad,Marnes-la-Coquette,France)和iQ SYBR Green Supermix试剂盒进行PCR定量实验。使用了所研究的基因的以下特异性引物对:
·PDK4:同义引物:5’-TACTCCACTGCTCCAACACCTG-3’(SEQ IDNO:1)和反义引物5’-GTTCTTCGGTTCCCTGCTTG-3’(SEQ IDNO:2))
·ApoCIII:同义引物:5’-CTCTTGGCTCTCCTGGCATC-3’(SEQ IDNO:3)和反义引物5’-GCATCCTGGACCGTCTTGGA-3’(SEQ IDNO:4)。
发射荧光的量与反应开始时存在的并在PCR过程中扩增的cDNA的量成正比。对于所研究的各个靶,试验了由几微升不同的反转录溶液组成混合物的具有连续稀释度的一系列溶液。由此,通过使用得自与PCR溶液系列相关的点的效率曲线来确定各个靶的相对表达水平。
然后,将感兴趣的基因的表达水平关于一种参照基因36B4(其特异性引物为:同义引物:5’-CATGCTCAACATCTCCCCCTTCTCC-3’(SEQ ID NO:7)和反义引物:5’-GGGAAGGTGTAATCCGTCTCCACAG-3’(SEQ ID NO:8))进行标准化。
然后,计算各个样品的诱导因子,即(本发明的化合物诱导的)相对信号与得自对照组的相对值的平均值的比。诱导因子越高,则所述化合物就越高地促进肝脏基因的表达。最终结果表示为得自各个实验组的诱导值的平均值。
结果
体重
图2-1比较了用化合物1以5、10和50mpk给药治疗8天后动物的体重增加和对照动物的体重增加。出乎意料地,测量到用化合物1治疗的动物的体重减少。
血浆脂质的测定
图2-2和2-3比较了用化合物1以5、10和50mpk给药治疗8天后血浆总胆固醇比率和HIDL-胆固醇比率和得自对照动物的比率。出乎意料地,通过治疗,循环总胆固醇比率显著降低,而HDL-胆固醇比率显著增加。
图2-4和2-5比较了用化合物1以5、10和50mpk给药治疗8天后的血浆甘油三酯比率和游离脂肪酸比率和得自对照动物的比率。出乎意料地,由于治疗,循环甘油三酯比率和游离脂肪酸比率非常显著的减少。
通过定量RT-PCR分析基因表达
本发明人还证明,本发明的化合物是PPAR靶基因表达的体内调节剂。图2-6和2-7中所示的结果显示,化合物1以5、10和50mpk向E2/E2小鼠给药8天诱导编码PDK4的基因的肝脏表达的显著增加(图2-6),并诱导编码ApoCIII的基因的肝脏表达的减少(图2-7)。编码特别地参与脂质和糖代谢的酶的所有编码基因以及它们的表达受到本发明化合物调节的事实加强了这些化合物表现出用于治疗代谢疾病的巨大潜力的观点。
结论
出乎意料地,所示的实验数据显示,本发明的化合物在体内诱导体重减少并刺激HDL胆固醇合成而且具有降血脂效力(降低甘油三酯和游离脂肪酸的血浆水平)。而且,所示的实验数据显示,本发明的化合物调节受PPAR的激活的调节的基因的表达,这些基因编码特别地参与脂质和糖代谢的酶。
实施例5:在C57BI6小鼠上进行的本发明化合物的体重性质、降血脂性质和刺激HDL-胆固醇合成的性质的体内评价
原理
用本发明的化合物治疗血脂异常的C57BI6小鼠后,通过测量体重和血浆脂质并分析PPAR靶基因的基因表达来体内评价本发明的化合物对体重的影响和它们的降血脂性质。
实验方案
动物的治疗
在20±3℃的恒定温度下,将雄性C57BI6小鼠保持在12小时/12小时的明/暗循环中。在一周的适应期后,将小鼠称重并分组,每组选择6只动物,使实验之前测定的体重和血浆脂质比率的分布是均匀的。将供试化合物悬浮在羧甲基纤维素(Sigma C4888)中,以所选的剂量通过胃管饲法给药,每天一次,持续14天。动物可自由进食和饮水(标准饮食)。在整个实验过程中,记录食物的摄取和体重增加。在实验结束时,在4小时的禁食后,将动物麻醉,用抗凝血剂(EDTA)采集血样,然后将小鼠称重并使其安乐死。通过以3000转/分离心20分钟分离血浆。将样品保存在+4℃。
采集肝组织样品,在液氮中冷冻,然后保存在-80℃以用于后续分析。
HDL-胆固醇的测定
通过磷钨酸盐将低密度脂蛋白(VLDL和LDL)沉淀。通过离心除去沉淀物。通过酶法测定(bioMérieux-Lyon-Franc),根据供应商的建议,测定存在于上清液中的HDL胆固醇。
血浆甘油三酯的测定
通过酶法测定(bioMérieux-Lyon-Franc),根据供应商的建议,测定血浆甘油三酯浓度。
通过定量RT-PCR分析基因表达
通过使用 96 RNA试剂盒(Macherey Nagel,Hoerdt,France),根据生产商的使用说明,从肝脏碎块中提取总RNA。
然后,通过在37℃于20μl含有1X缓冲液(Sigma)、1.5mM DTT、0.18mM dNTP(Promega)、200ng pdN6(Amersham)、30U RNA酶抑制剂(Sigma)和1μl MMLV-RT(Sigma)的总体积中反应1小时,将1μg总RNA(通过分光光度法定量)反转录为cDNA。
根据供应商的建议,在55℃的杂交温度下、在96孔板中于5μl稀释的反转录溶液中,使用MyiQ Single-Color Real-Time PCR Detection System(Biorad,Marnes-la-Coquette,France)和iQ SYBR Green Supermix试剂盒进行PCR定量实验。使用了所研究的基因的以下特异性引物对:
·PDK4:同义引物:5’-TACTCCACTGCTCCAACACCTG-3’(SEQ IDNO:1)和反义引物5’-GTTCTTCGGTTCCCTGCTTG-3’(SEQ IDNO:2))
·ApoCIII:同义引物:5’-CTCTTGGCTCTCCTGGCATC-3’(SEQ IDNO:3)和反义引物5’-GCATCCTGGACCGTCTTGGA-3’(SEQ IDNO:4)。
发射荧光的量与反应开始时存在的并在PCR过程中扩增的cDNA的量成正比。对于所研究的各个靶,试验了由几微升不同的反转录溶液组成混合物的具有连续稀释度的一系列溶液。由此,通过使用得自与所述系列相关的点的效率曲线来确定各个靶的相对表达水平。
然后,将感兴趣的基因的表达水平关于参照基因36B4(其特异性引物为:同义引物:5’-CATGCTCAACATCTCCCCCTTCTCC-3’(SEQ ID NO:7)和反义引物:5’-GGGAAGGTGTAATCCGTCTCCACAG-3’(SEQ ID NO:8))的表达水平进行标准化。
然后,计算各个样品相关的诱导因子。诱导因子越高,则所述化合物就越高地促进基因表达。最终结果表示为得自各个实验组的诱导值的平均值。
结果
体重
图3-1比较了用化合物1以3、10和30mpk给药治疗14天后动物的体重增加和对照动物的体重增加。出乎意料地,测量到用化合物1治疗的动物的体重减少。
血浆脂质的测定
图3-2比较了用化合物1以3、10和30mpk给药治疗14天后血浆HDL-胆固醇比率和得自对照动物的比率。出乎意料地,由于治疗,循环HDL-胆固醇比率非常显著增加。
图3-3比较了用化合物1以3、10和30mpk给药治疗14天后的血浆甘油三酯比率和得自对照的比率。出乎意料地,由于治疗,循环甘油三酯比率非常显著的减少。
通过定量RT-PCR分析基因表达
本发明人还证明,本发明的化合物是PPAR靶基因表达的体内调节剂。图3-4和3-5中所示的结果显示,化合物1以3、10和30mpk向C57BI6小鼠给药14天诱导编码PDK4的基因的肝脏表达的显著增加(图3-4),并诱导编码ApoCIII的基因的肝脏表达的减少(图3-5)。编码特别地参与脂质和糖代谢的酶的所有基因以及它们的表达受到本发明化合物调节的事实加强了这些化合物具有用于治疗代谢疾病的巨大潜力的观点。
结论
出乎意料地,所示的实验数据显示,本发明的化合物在体内诱导体重减少,刺激HDL胆固醇合成而且具有降血脂效力(降低甘油三酯的血浆水平)。而且,所示的实验数据显示,本发明的化合物调节受PPAR的激活的调节的基因的表达,这些基因编码特别地参与脂质和糖代谢的酶。
实施例6:在db/db小鼠上进行的本发明化合物的体重性质、抗糖尿病
性质、降血脂性质和刺激HDL-胆固醇合成的性质的体内评价
原理
用本发明的化合物口服治疗db/db小鼠后,通过测量体重和血浆葡萄糖比率和胰岛素比率以及血浆脂质比率,并分析胆固醇在不同血浆脂蛋白部分中的分布和PPAR靶基因的基因表达的分布来体内评价本发明的化合物对体重、胰岛素抵抗的影响以及这些化合物的降血脂性质。
实验方案
动物的治疗
在20±3℃的恒定温度下,将雌性db/db小鼠保持在12小时/12小时的明/暗循环中。在一周的适应期后,将小鼠称重并分组,每组选择8只动物,以它们实验之前测定的体重和血浆脂质比率的分布均匀。将供试化合物悬浮在羧甲基纤维素(Sigma C4888)中,以所选的剂量通过胃内管饲给药,每天一次,持续28天。动物可自由进食和饮水(标准饮食)。在整个实验过程中,记录食物的摄取和体重增加。在实验结束时,在4小时的禁食后,将动物麻醉,用(EDTA)抗凝血剂采集血样,然后将小鼠称重并使其安乐死。通过以3000转/分离心20分钟分离血浆。将样品保存在+4℃。
采集肝组织和骨骼肌组织样品,并立即在液氮中冷冻,然后保存在-80℃以用于后续分析。
血浆血糖和血胰岛素的测定
根据酶比色法,使用Glucose RTU试剂盒(Biomérieux)测出小鼠血浆葡萄糖。将葡萄糖在葡萄糖氧化酶的作用下转化为葡糖酸;该反应释放过氧化氢。根据Thrinder反应测定过氧化氢,在过氧化物酶的作用下和酚以及氨基-4-安替比林的存在下,该反应产生水和有色产品醌亚胺。归因于醌亚胺的颜色强度与样品中存在的葡萄糖的量成正比。
使用ELISA法(使用来自供应商Crystal chem.的INSKR020试剂盒)测定小鼠胰岛素。在微量培养板上涂布小鼠抗胰岛素抗体。然后,将胰岛素待测血清置于该板上。使用豚鼠抗胰岛素抗以体识别由小鼠胰岛素和抗胰岛素单克隆抗体形成的复合物。最后,加入用过氧化物酶标记的抗豚鼠抗体,其与豚鼠抗胰岛素抗体结合。通过加入OPD(邻苯基二胺)酶底物进行比色反应。颜色强度与样品中存在的胰岛素的量成正比。
血浆脂质的测定
通过酶法测定(bioMérieux-Lyon-France),根据供应商的建议,测定血浆脂质浓度(总胆固醇和甘油三酯)。
分析胆固醇在血浆脂蛋白部分中的分布
使用凝胶过滤色谱法分离血浆中不同的脂质部分(VLDL、LDL、HDL)。然后,通过酶法测定(bioMérieux-Lyon-France),根据供应商的建议,测定各部分的胆固醇浓度。
通过定量RT-PCR分析基因表达
肝组织
骨骼肌组织
然后,通过在37℃下于20μl含有1X缓冲液(Sigma)、1.5mM DTT、0.18mM dNTP(Promega)、200ng pdN6(Amersham)、30U RNA酶抑制剂(Sigma)和1μl MMLV-RT(Sigma)的总体积中反应1小时,将1μg总RNA(以分光光度法定量)反转录为互补DNA。
根据供应商的建议,在55℃的杂交温度下,在96孔板中于5μl稀释的反转录溶液中,使用MyiQ Single-Color Real-Time PCR Detection System(Biorad,Marnes-la-Coquette,France)和iQ SYBR Green Supermix试剂盒进行PCR定量实验。使用了所研究的基因的以下特异性引物对:
·PDK4:同义引物:5’-TACTCCACTGCTCCAACACCTG-3’(SEQ IDNO:1)和反义引物5’-GTTCTTCGGTTCCCTGCTTG-3’(SEQ ID NO:2))
·UCP2:同义引物:5’-GTCGGAGATACCAGAGCACTGTCG-3’(SEQID NO:5)和反向引物5’-CACATCAACAGGGGAGGCGA-3’(SEQID NO:6)
发射荧光的量与反应开始时存在的并在PCR过程中扩增的互补DNA的量成正比。对于所研究的各个靶,由几微升不同的反转录溶液组成混合物的具有连续稀释度的一系列溶液。由此,通过使用得自与PCR溶液系列相关的点的效率曲线来确定各个靶的相对表达水平。
然后,将感兴趣的基因在肝组织中的表达水平关于参照基因36B4(其特异性引物为:同义引物:5’-CATGCTCAACATCTCCCCCTTCTCC-3’(SEQ IDNO:7)和反义引物:5’-GGGAAGGTGTAATCCGTCTCCACAG-3’(SEQ IDNO:8))的表达水平进行标准化,并将感兴趣的基因在骨骼肌组织中的表达水平关于参照基因18S(其特异性引物为:同义引物:5’-CGGACACGGACAGGATTGACAG-3′(SEQ ID NO:9)和反义引物:5’-AATCTCGGGTGGCTGAACGC-3′(SEQ ID NO:10))的表达水平进行标准化。然后,计算各个样品相关的诱导因子。诱导因子越高,则所述化合物就越高地促进基因表达。最终结果表示为各个实验组的诱导值的平均值。
结果
体重
图4-1比较了用化合物1以50mpk给药治疗28天后的动物的体重增加和对照动物的体重增加。出乎意料地观察到用化合物1治疗的动物的体重减少。
血糖和血胰岛素的测定
图4-2和4-3比较了用化合物1以50mpk给药治疗28天后的血浆葡萄糖和胰岛素水平。出乎意料地,通过治疗,血糖和血胰岛素明显减少。
血浆脂质的测定
图4-4比较了用化合物1和3以50mpk给药治疗28天后的总血浆胆固醇比率和得自对照动物的比率。出乎意料地,总胆固醇比率显著增加。图4-5显示,该总血浆胆固醇的增加与通过用化合物1和3以50mpk治疗动物所诱导的HDL-胆固醇部分的明显增加相对应。
图4-6和4-7比较了用化合物1和3以50mpk治疗28天后的血浆甘油三酯比率与游离脂肪酸比率和得自对照动物的比率。出乎意料地,通过治疗,循环甘油三酯比率和游离脂肪酸比率显著减少。
诵过定量RT-PCR分析基因表达
本发明人还证明,本发明的化合物是PPAR靶基因表达的体内调节剂。图4-8和4-9中所示的结果显示,化合物1和3以50mpk向db/db小鼠给药28天诱导编码PDK4的基因的肝脏表达的显著增加(图4-8),并诱导编码UCP2的基因在骨骼肌中的表达的减少(图4-9)。编码特别地参与脂质和糖代谢以及能量耗散的酶的所有基因以及它们的表达受到本发明化合物调节的事实加强这些化合物具有用于治疗代谢疾病的巨大潜力的观点。
结论
出乎意料地,所示的实验数据显示,本发明的化合物在体内诱导体重减少和胰岛素敏感性的改善、刺激HDL胆固醇合成而且具有降血脂质效力(导致血浆甘油三酯比率的降低)。而且,所公开的的实验数据显示,本发明的化合物调节受PPAR的激活的调节的基因的表达,这些基因编码特别地参与脂质和糖代谢以及能量耗散的酶。
实施例7:本发明化合物的抗炎性质的体外评价
原理
通过测量用本发明的化合物处理24小时并同时用PMA(佛波醇12-肉豆蔻酸酯13-乙酸酯,它促进细胞的炎症应答并促进它们分化为巨噬细胞)刺激的单核细胞的MCP1(单核细胞趋化蛋白-1)分泌,来评价本发明的化合物的抗炎效力。MCP-1分泌越少,则本发明的化合物就越抑制炎症反应。
实验方案
THP-1细胞的培养和处理
将THP-1人单核细胞系(ATCC来源)培养在具有25mM羟乙基哌嗪乙磺酸(Gibco;42401-018)、1%谷氨酰胺(Gibco;25030-24)、1%青霉素/链霉素(Biochrom AG;A2213)和10%去补体(decomplemented)胎牛血清(SVF.Gibco;26050-088)的RPMI1640培养基中。
将细胞以870000个细胞/孔的密度涂布在24孔板(Primaria BD Falcon)中,然后在37℃和5%CO2下于,含有0.2%胎牛血清的培养基中,在5ng/ml佛波醇12-肉豆蔻酸酯13-乙酸酯(PMA)和1μM本发明化合物3的存在下培养24小时。将本发明的化合物溶解在二甲基亚砜(DMSO,Fluka;41640)中。将本发明的化合物的效力与单独的DMSO的效力做比较。
MCP1分泌的测定
将处理培养基复原,使用ELISA试剂盒《Human MCP-1ELISA Set》(BD OptEIA;555179),根据生产商的建议,测定MCP1浓度。
将MCP1置于平板上,通过抗MCP1特异性抗体识别。该特异性抗体本身被用过氧化物酶偶联的第二抗体特异性地识别。由酶活性产生的染色与被固定的MCP1的量呈正比,并可通过分光光度法测定。从代表已知浓度的点进行一系列测定,并由此计算各个样品的MCP1浓度。
然后计算诱导因子,即本发明的化合物诱导的信号与由对照组诱导的信号的比率。该因子越小,则所述化合物就越抑制MCP1的分泌。最终结果表示为得自各个实验组的诱导值的平均值。
结果
本发明人已证明,本发明的化合物对体外单核细胞具有抗炎效力。图5所示的结果显示,1μM的本发明化合物3诱导单核细胞分泌的MCP1显著减少。
结论
出乎意料地,所公开的实验数据显示,本发明的化合物对被PMA刺激的单核细胞具有抗炎效力。
总结
本发明人已证明,本发明的化合物导致体重减少,具有降血脂的性质,降低胆固醇和血浆甘油三酯的水平,刺激HDL-胆固醇的合成并具有抗糖尿病的性质。而且,本发明人已证明,本发明的化合物能调节编码特别地参与脂质和糖代谢以及能量耗散的酶的基因的表达。
本发明人还证明,本发明的化合物具有抗炎性质。
这些得自体内和体外的结果证明,本发明的化合物用于治疗例如血脂异常、II型糖尿病和肥胖症的重要疾病的治疗潜力。
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序列表
<110>基恩菲特
<120>取代的1,3-二苯基丙烷衍生物、它们的制备及用途
<130>B0487PC00
<150>FR0605540
<151>2006-06-21
<160>10
<170>PatentIn version 3.3
<210>1
<211>22
<212>DNA
<213>artificial
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<223>sens primer PDK4
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Claims (18)
1.衍生自取代的1,3-二苯基丙烷的化合物,其具有以下通式(I):
其中:
X1代表卤素原子、R1或者G1-R1基团;
X2代表卤素原子、R2或者G2-R2基团;
X3代表R3或者G3-R3基团;
X4代表卤素原子、R4或者G4-R4基团;
X5代表R5或者G5-R5基团;
R1代表卤代烷基;
R2代表氢原子或者非卤代烷基;
R3、R4和R5相同或者不同,代表氢原子或者由一个或者多个组1或组2取代基取代的烷基或者非取代烷基;
G1、G2、G3、G4和G5相同或者不同,代表氧原子或者硫原子;
X3、X4或者X5中至少一个基团与R3、G3R3、R4、G4R4、R5或者G5R5式对应,其中:
G3、G4和G5如上所述,并且
R3、R4和R5相同或者不同,代表由一个或者多个组1或组2取代基取代的烷基;
A代表:
(i)-CR6R7基团,其中:
R6代表氢原子、烷基或者-OR8基团,
并且R7代表烷基、羟基或者-OR8基团,R8定义如下,
(ii)羰基(CO),
(iii)肟基(C=N-O-H)或者肟醚(C=N-O-R8),
R8相同或者不同,代表由芳基或者环烷基取代的烷基或者非取代烷基;
D代表:
(i)与两个氢原子连接的碳原子(CH2),
(ii)与氢原子和G2连接以形成氧化或者硫化杂环的碳原子;
组1取代基选自-COOR9和-CONR9R10;
组2取代基选自-SO3H和-SO2NR9R10;
R9和R10相同或者不同,代表氢原子或者由至少一个组1或组2取代基取代的烷基或者非取代烷基;
其纯立体异构体(非对映异构体、对映异构体)或者混合立体异构体、外消旋混合物、几何异构体、互变异构体、盐、水合物、溶剂合物、固体形式以及它们的混合物。
2.权利要求1的化合物,其特征在于,A代表羰基(CO)。
3.权利要求1或2的化合物,其特征在于,它们的X3、X4和X5基团中仅一个代表R3、R4、R5、G3R3、G4R4或者G5R5,其中
G3、G4和G5如权利要求1所述,并且
R3、R4和R5代表由一个或者多个如权利要求1中所定义的组1或组2取代基取代的烷基。
4.权利要求1-3之一的化合物,其特征在于,X3、X4和X5中仅X4代表R4或者G4R4基团,
G4如权利要求1所定义,并且
R4代表由一个或者多个如以上权利要求1中所定义的组1或组2取代基取代的烷基。
5.前述权利要求中任一项的化合物,其特征在于,G3、G4和/或G5代表氧原子。
6.前述权利要求中任一项的化合物,其特征在于,所述取代基选自如权利要求1中所定义的组1取代基。
7.前述权利要求中任一项的化合物,其特征在于,所述X3、X4和X5基团中仅一个与式-OC(CH3)2COOR9对应,R9如权利要求1中所定义。
8.前述权利要求中任一项的化合物,其特征在于,X3和X5相同或者不同,分别代表R3和R5基团,R3和R5代表由一个或者多个如权利要求1中所定义的组1或组2取代基取代的烷基或者非取代烷基。
9.前述权利要求任一项的化合物,其特征在于,X1代表R1或者G1R1基团,G1如权利要求1中所定义,且R1代表卤代烷基。
10.前述权利要求中任一项的化合物,其特征在于,X2代表氢原子。
11.前述权利要求中任一项的化合物,其特征在于,D代表-CH2基团。
12.前述权利要求中任一项的化合物,其特征在于,它们选自:
2-[2,6-二甲基-4-[3-[4-(三氟甲氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸,
2-[2,6-二甲基-4-[3-[4-(三氟甲硫基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸,
2-[2,6-二甲基-4-[3-[4-溴苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸,
2-[2,6-二甲基-4-[3-[4-(三氟甲基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸,
2-[4-[3-[4-氯-2-羟基苯基]-3-氧代丙基]苯硫基]-2-甲基丙酸,
2-[2-甲基-4-[3-[4-(3,3,3-三氟丙氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸,
2-[2,6-二甲基-4-[3-羟基-3-[4-(三氟甲硫基)苯基]丙基]苯氧基]-2-甲基丙酸,
2-[2,6-二甲基-4-[3-(吡啶-3-基甲氧基)-3-[4-(三氟甲氧基)苯基]丙基]苯氧基]-2-甲基丙酸,
2-[4-(3-(4-碘苄氧基)-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基]-2-甲基丙酸,
2-[4-(3-(4-甲氧基)-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基]-2-甲基丙酸,
2-[2,6-二甲基-4-[3-[4-(3,3,3-三氟丙氧基)苯基]-3-氧代丙基]苯氧基]-2-甲基丙酸,
2-(2,6-二甲基-4-(3-氧代-3-(4-(2,2,2-三氟乙氧基)苯基)丙基)苯氧基)-2-甲基丙酸,
2-(2,6-二甲基-4-(3-氧代-3-(4-(2,2,2-三氟乙硫基)苯基)丙基)苯氧基)-2-甲基丙酸,
2-(4-(3-(4-氯-2-(甲硫基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基)-2-甲基丙酸,
2-(4-(3-(2,4-双(三氟甲基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基)-2-甲基丙酸,
2-(4-(3-(2-氟-4-(三氟甲基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基)-2-甲基丙酸,
2-(4-(3-(2-氟-4-(2,2,2-三氟乙氧基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基)-2-甲基丙酸,
2-(2,6-二甲基-4-(3-(2-甲基-4-(2,2,2-三氟乙氧基)苯基)-3-氧代丙基)苯氧基)-2-甲基丙酸,
2-(4-(3-(2-甲氧基-4-(2,2,2-三氟乙氧基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基)-2-甲基丙酸,
2-(4-(3-(2-羟基-4-(三氟甲基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基)-2-甲基丙酸,
2-(4-(3-(2-甲氧基-4-(三氟甲基)苯基)-3-氧代丙基)-2,6-二甲基苯氧基)-2-甲基丙酸,
2-(2,6-二甲基-4-(3-(2-异丙氧基-4-(三氟甲基)苯基)-3-氧代丙基)苯氧基)-2-甲基丙酸,
2-(2,6-二甲氧基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2-甲基丙酸,
2-(4-(3-(2-氟-4-(三氟甲基)苯基)-3-氧代丙基)-2,6-二甲氧基苯氧基)-2-甲基丙酸,
2-甲基-2-(2-甲基-4-(3-氧代-3-(4-(三氟甲硫基)苯基)丙基)苯氧基)丙酸,
2-甲基-2-(2-甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)丙酸,
2-(4-(3-(2-氟-4-(三氟甲基)苯基)-3-氧代丙基)苯硫基)-2-甲基丙酸,
2-甲基-2-(3-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)丙酸,
2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)丙酸,
2-[4-(3-羟基-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基]-2-甲基丙酸,
2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2-甲基丙酰胺,
2-(4-(3-肟基-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基)-2-甲基丙酸,
2-(4-(3-甲氧亚胺基-3-(4-(三氟甲氧基)苯基)丙基)-2,6-二甲基苯氧基)-2-甲基丙酸,
4-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2,2-二甲基丁酸,
2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2-甲基丙酸叔丁酯,
2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)-2-甲基丙酸异丙酯,
2,2-二氟-2-(2,6-二甲基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯氧基)乙酸,
2-(2-甲氧基-4-(3-氧代-3-(4-(三氟甲氧基)苯基)丙基)苯硫基)-2-甲基丙酸。
13.权利要求1-12中任一项的化合物,其作为药物。
14.药物组合物,所述组合物在药学上可接受的载体中包含至少一种如权利要求1-12所定义的化合物,所述化合物可能与一种或者多种其它治疗和/或化妆活性组份结合。
15.药物组合物,所述组合物在药学上可接受的载体中包含至少一种如权利要求1-12中任一项所定义的化合物,所述化合物与下列所选的化合物中的一种或者多种结合:
-抗糖尿病药
-胰岛素
-降脂和/或降胆固醇分子
-抗高血压剂或降压剂
-抗血小板剂
-减肥药
-抗炎剂
-抗氧化剂
-用于治疗心功能不全的药剂
-用于治疗冠状动脉功能不全的药剂
-抗癌药
-平喘药
-平喘药
-用于治疗皮肤病的肾上腺皮质激素
-血管扩张剂和/或抗局部缺血药。
16.权利要求14或15的药物组合物,其用于治疗与代谢综合征相关的并发症、胰岛素抵抗、糖尿病、血脂异常、动脉粥样硬化、心血管疾病、肥胖症、高血压、炎性疾病、神经变性疾病或者癌症。
17.权利要求14或15的药物组合物,其用于治疗血脂异常。
18.权利要求14或15的药物组合物,其用于治疗与脂质和/或糖代谢异常相关的心血管风险因素。
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FR0605540A FR2902789A1 (fr) | 2006-06-21 | 2006-06-21 | Derives de 1,3-diphenylpropane substitues, preparations et utilisations |
FR0605540 | 2006-06-21 | ||
PCT/EP2007/056225 WO2007147880A1 (fr) | 2006-06-21 | 2007-06-21 | Derives de 1,3-diphenylpropane substitues, preparations et utilisations |
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Cited By (3)
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CN102647982A (zh) * | 2009-11-26 | 2012-08-22 | 基恩菲特公司 | 使用1,3-二苯基丙-2-烯-1-酮衍生物治疗肝脏疾患 |
CN103930406A (zh) * | 2011-11-14 | 2014-07-16 | 霍夫曼-拉罗奇有限公司 | 作为gpbar1激动剂的1-哒嗪基-羟基亚氨基-3-苯基-丙烷类 |
CN104185471A (zh) * | 2011-12-28 | 2014-12-03 | 基恩菲特公司 | 1,3-二苯基丙烷衍生物、其制备以及用途 |
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FR2902789A1 (fr) * | 2006-06-21 | 2007-12-28 | Genfit Sa | Derives de 1,3-diphenylpropane substitues, preparations et utilisations |
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US9221751B2 (en) * | 2009-11-26 | 2015-12-29 | Genfit | Use of 1,3-diphenylprop-2-en-1-one derivatives for treating liver disorders |
WO2011080276A1 (en) | 2009-12-29 | 2011-07-07 | Genfit | Pharmaceutical combinations comprising a dpp-4 inhibitor and a 1,3-diphenylprop-2-en-1-one derivative |
KR101860008B1 (ko) | 2010-05-17 | 2018-07-05 | 장피트 | 칼콘 유도체의 개선된 제조 |
ES2516165T3 (es) * | 2010-07-12 | 2014-10-30 | F. Hoffmann-La Roche Ag | 1-hidroxiimino-3-fenil-propanos |
EP3416629A4 (en) * | 2016-02-16 | 2019-08-07 | CoNCERT Pharmaceuticals, Inc. | DEUTERATED GFT-505 |
IT201600098338A1 (it) | 2016-09-30 | 2018-03-30 | Univ Degli Studi Padova | Composti 1-fenilpropanone e loro impiego |
RU186145U1 (ru) * | 2018-08-08 | 2019-01-11 | Общество с ограниченной ответственностью "Научно-производственное объединение "Центротех" (ООО "НПО "Центротех") | Каркас виброрамы вибросита |
US11634387B2 (en) | 2019-09-26 | 2023-04-25 | Abionyx Pharma Sa | Compounds useful for treating liver diseases |
WO2021160519A1 (en) | 2020-02-10 | 2021-08-19 | Genfit | Treatment of primary biliary cholangitis with elafibranor |
CN114901641A (zh) * | 2020-02-28 | 2022-08-12 | 四川科伦博泰生物医药股份有限公司 | 芳香族化合物及其药物组合物和用途 |
CA3176020A1 (en) | 2020-05-18 | 2021-11-25 | Alice Roudot | Elafibranor for the treatment of primary sclerosing cholangitis |
MX2023002159A (es) | 2020-08-26 | 2023-03-01 | Genfit | Composiciones y metodos para el tratamiento de la colangitis biliar primaria. |
EP4337184A1 (en) | 2021-05-11 | 2024-03-20 | Genfit | Ppar-agonists for use in the treatment of liver failure |
AU2022272414A1 (en) | 2021-05-11 | 2023-10-26 | Genfit | Elafibranor derivatives agonists of ppar for use in the treatment of sepsis |
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DE4121849A1 (de) * | 1991-07-02 | 1993-01-14 | Rhone Poulenc Rorer Gmbh | (4-((omega)-arylalkyl)-phenyl)alkansaeuren, ihre salze und/oder ihre derivate |
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HUP0201291A3 (en) * | 1999-04-28 | 2002-11-28 | Sanofi Aventis Deutschland | Di-aryl acid derivatives as ppar receptor ligands and pharmaceutical compositions containing them |
DE19933421A1 (de) * | 1999-07-16 | 2001-01-25 | Gruenenthal Gmbh | 2-Benzyl-3-dimethylamino-1-phenyl-propanderi- vate |
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FR2902789A1 (fr) | 2006-06-21 | 2007-12-28 | Genfit Sa | Derives de 1,3-diphenylpropane substitues, preparations et utilisations |
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Cited By (7)
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CN102647982A (zh) * | 2009-11-26 | 2012-08-22 | 基恩菲特公司 | 使用1,3-二苯基丙-2-烯-1-酮衍生物治疗肝脏疾患 |
CN102647982B (zh) * | 2009-11-26 | 2014-10-15 | 基恩菲特公司 | 使用1,3-二苯基丙-2-烯-1-酮衍生物治疗肝脏疾患 |
CN104434891A (zh) * | 2009-11-26 | 2015-03-25 | 基恩菲特公司 | 使用1,3-二苯基丙-2-烯-1-酮衍生物治疗肝脏疾患 |
CN104434891B (zh) * | 2009-11-26 | 2018-03-30 | 基恩菲特公司 | 1,3‑二苯基丙‑2‑烯‑1‑酮衍生物在制备用于治疗选自肝纤维变性、肝硬化和脂肪性肝病的肝脏疾患的药物中的应用 |
CN103930406A (zh) * | 2011-11-14 | 2014-07-16 | 霍夫曼-拉罗奇有限公司 | 作为gpbar1激动剂的1-哒嗪基-羟基亚氨基-3-苯基-丙烷类 |
CN104185471A (zh) * | 2011-12-28 | 2014-12-03 | 基恩菲特公司 | 1,3-二苯基丙烷衍生物、其制备以及用途 |
CN104185471B (zh) * | 2011-12-28 | 2018-03-30 | 基恩菲特公司 | 1,3‑二苯基丙烷衍生物、其制备以及用途 |
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