CN101679326B - 作为雌激素相关α受体调节剂的取代的苯氧基N-烷基化的噻唑烷二酮 - Google Patents
作为雌激素相关α受体调节剂的取代的苯氧基N-烷基化的噻唑烷二酮 Download PDFInfo
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- CN101679326B CN101679326B CN2008800153616A CN200880015361A CN101679326B CN 101679326 B CN101679326 B CN 101679326B CN 2008800153616 A CN2008800153616 A CN 2008800153616A CN 200880015361 A CN200880015361 A CN 200880015361A CN 101679326 B CN101679326 B CN 101679326B
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Abstract
本发明涉及式(I)化合物,制备这些化合物、组合物、中间体及其衍生物的方法,以及用于治疗病症的方法,所述病症包括但不限于强直性脊柱炎、动脉粥样硬化、关节炎(如类风湿性关节炎、感染性关节炎、儿童关节炎、牛皮癣性关节炎、反应性关节炎)、骨相关疾病(包括那些与骨形成相关的疾病)、乳腺癌(包括那些对抗激素疗法无效的疾病)、心血管疾病、软骨相关疾病(如软骨损伤/损失、软骨退化和那些与软骨形成有关的疾病)、软骨发育不全、软骨肉瘤、慢性背部损伤、慢性支气管炎、慢性炎性呼吸道疾病、慢性阻塞性肺病、糖尿病、能量体内稳态紊乱、痛风、假痛风、血脂异常、代谢综合征、多发性骨髓瘤、肥胖症、骨关节炎、成骨不全、溶骨性骨转移、骨软化症、骨质疏松症、Paget氏病、牙周病、风湿性多肌病、Reiter氏综合征、重复应力损伤、高血糖症、血糖水平升高和胰岛素抵抗。
Description
发明领域
本发明涉及某些新化合物、制备化合物、组合物、中间体及其衍生物的方法以及治疗病症如癌症、关节炎、炎性呼吸道疾病和代谢紊乱的方法。更特别是,本发明化合物为雌激素相关α受体(ERR-α)调节剂,其用于治疗、改善活抑制由ERR-α活性所介导的疾病状态、紊乱和病症的发作。
发明背景
核受体是转录因子超家族的成员。该家族各成员具有类似的结构,并调节多种生物效应(Olefsky,J.M.J.Biol.Chem.2001,276(40),36863-36864)。配体激活或抑制这些控制参与代谢、分化和复制的基因的转录因子(Laudet,V.和H.Gronmeyer.The Nuclear ReceptorFactbooks.2002,San Diego:Academic Press)。现在,人类基因组工程已经鉴别出该家族中的约48个成员,并鉴别出了其中约28个成员的同源配体(Giguere,V.Endocrine Rev.1999,20(5),689-725)。该蛋白质家族由可以在该家族成员中互换而不丧失功能的模块结构区域组成。典型的核受体含有高变的N-末端、保守的DNA结合区域(DBD)、铰链区域和保守的配体结合区域(LBD)。DBD的功能是使受体靶向特定的DNA序列(NHR应答元件或各种NRE),LBD的功能是识别其同源配体。在核受体的序列内,存在参与转录激活的区域。AF-1区域位于N-末端,组成性地激活转录(Rochette-Egly,C.等Cell 1997,90,97-107;Rochette-Egly,C.等Mol.Endocrinol.1992,6,2197-2209);而AF-2区域嵌在LBD内,其转录激活依赖于配体(Wurtz,J.M.等Nat.Struct.Biol.1996,3,87-94)。核受体可以以单体、同型二聚体或异源二聚体存在,并与同向重复序列或反向重复序列结合(Laudet和Gronmeyer,2002;Aranda,A.和A.Pascual.Physiol.Rev.2001,81(3),1269-1304)。
该家族各成员以被激活的基础生物状态或被抑制的基础生物状态存在。基因激活的基本机制包含辅调蛋白的配体依赖性交换。这些辅调蛋白是指辅激活物或辅抑制物(McKenna,L.J.等Endocrine Rev.1999,20,321-344)。抑制状态的核受体与其DNA应答元件结合,并与募集组蛋白脱乙酰基酶(HDAC)的辅抑制物蛋白联接(Jones,P.L.和Y.B.Shi.Curr.Top.Microbiol.Immunol.2003,274,237-268)。在激动剂存在时,辅抑制物和辅激活物交换,辅激活剂转而募集转录因子,转录因子装配入ATP依赖型染色质重塑复合物。组蛋白是高乙酰化的,使核小体解叠,抑制被缓解。AF-2区域作为辅调蛋白交换的配体依赖型分子开关。在激动剂存在时,AF-2区域经历构象转变,在LBD上产生与辅激活蛋白相互作用的表面。在没有激动剂时或存在拮抗剂时,AF-2区域产生促进与辅抑制蛋白相互作用的表面。LBD上辅激活物的相互作用表面重叠,辅抑制物的相互作用表面也重叠,为基因的激活或抑制提供保守的分子机制,该机制适用于该家族转录因子的各成员(Xu,H.E.等Nature 2002,415(6873),813-817)。
仅鉴别出约半数的已知核受体的调节其生物活性的天然配体。尚未鉴别出天然配体的受体被称为“孤儿受体”。与孤儿受体相互作用的配体或化合物的发现,将加速对核受体在生理学和疾病中作用的理解,促进新治疗方法的寻求,这些尚未鉴别出天然配体的受体的一个亚型是雌激素相关受体(ERR)。
ERR-α(也称为ERR-1)是一种孤儿受体,是孤儿核受体的雌激素受体相关亚族中已鉴别出的三个成员(ERR-α、ERR-β、ERR-γ)中最先被鉴别的。ERR亚族与雌激素受体(ER-α和ER-β)密切相关。ERR-α和ERR-β是通过低严格性杂交筛检最先分离的(Giguere,V.等Nature 1988,331,91-94),后来又发现了ERR-γ(Hong,H.等J.Biol.Chem.1999,274,22618-22626)。ERR和ER具有序列相似性,其DBD的同源性最高,约为60%,并且ERRs和Ers都与典型的DNA雌激素应答元件相互作用。最近的生物化学证据表明,ERR和ER具有共同的靶基因,包括pS2、乳铁蛋白(lactoferin)、芳香酶和骨桥蛋白,还具有共同的辅调蛋白(Giguere,V.Trends in Endocrinol.Metab.2002,13,220-225;Vanacker,J.M.等EMBO J.1999,18,4270-4279;Kraus,R.J.等J.Biol.Chem.2002,272,24286-24834;Hong等,1999;Zhang,Z.和C.T.Teng.J.Biol.Chem.2000,275,20387-20846)。因此,ERR的主要功能之一是调节雌激素应答基因的应答。类固醇激素雌激素的作用主要在乳腺、骨和子宫内膜中介导。因此,鉴别出与ERR相互作用的化合物,将有助于治疗骨相关疾病、乳腺癌和生殖疾病。
ERR-α在正常组织和乳腺癌组织中都存在(Ariazi,E.A.等Cancer Res.2002,62,6510-6518)。已报道,ERR-α在正常乳腺组织中的主要功能是起到雌激素应答基因抑制物的作用。已报道,在乳腺癌中或非雌激素应答(ER-α阴性)细胞系中,ERR-α处于激活状态(Ariazi等,2002)。因此,与ERR-α相互作用的化合物,对于ER-α阴性、且对传统的抗雌激素疗法不反应的乳腺癌的治疗而言,可能是有用的药物;或者可用作抗雌激素应答型乳腺癌治疗的辅助药物。这些药物可用作拮抗剂,降低这些特定组织中ERR-α的生物活性。
许多绝经后的妇女会出现骨质疏松,这是一种由于雌激素生成减少所导致的病症。雌激素水平的下降会导致骨损失增加(Turner,R.T.等Endocrine Rev.1994,15(3),275-300)。对绝经后的骨质疏松患者给予雌激素,发现对于骨生长具有同化作用(Pacifici,R.J.BoneMiner.Res.1996,11(8),1043-1051),但是由于ER-α和ER-β敲除动物的骨骼缺陷轻微,雌激素的作用通常是介导的,所以该同化作用的分子机制未明。(Korach,K.S.Science 1994,266,1524-1527;Windahl,S.H.等J.Clin.Invest.1999,104(7),895-901)。雌激素调节骨骼中ERR-α的表达(Bonnelye,E.等Mol.Endocrin.1997,11,905-916;Bonnelye,E.等J.Cell Biol.2001,153,971-984)。ERR-α在整个成骨细胞分化期都有存在。大鼠颅顶造骨细胞中ERR-α的过度表达这种公认的骨分化模型,导致骨小结的形成增加,而用ERR-α反义物处理大鼠颅顶造骨细胞,导致骨小结的形成减少。ERR-α还调节骨桥蛋白,骨桥蛋白被认为是参与骨基质形成的一种蛋白质。因此,通过提高ERR-α活性来对其进行调节的化合物,可能对于骨密度再生具有同化作用,相对于目前防止骨损失,但不具同化作用的方法更有益。这样的化合物可以通过两种可能的机制增强受体的活性:I)增强受体与蛋白质的联接,所述蛋白质能增强受体的活性或提高受体的稳定性;和II)增加细胞内的受体浓度,从而增强受体活性。相反,就骨生长异常造成的骨疾病而言,与ERR-α相互作用的,降低其生物活性的化合物可能通过阻止骨生长而有益于这些疾病的治疗。用辅激活蛋白对抗受体的联接,能降低受体的活性。
ERR-α还存在于心脏、脂肪和肌肉组织中,并与PGC-1辅激活物家族形成转录活性复合物,所述辅激活物与能量稳态、线粒体生物发生、肝脏糖异生相关,且涉及参与脂肪酸β-氧化的基因的调节(Kamei,Y.等Proc.Natl.Acad.Sci.USA 2003,100(21),12378-12383)。ERR-α调节中链酰基-CoA脱氢酶启动子(MCAD)的表达。中链酰基-CoA脱氢酶是参与脂肪酸β-氧化的初期反应的一种基因。人们相信,在脂肪组织中,ERR-α通过调节MCAD来调节能量的消耗(Sladek,R.等Mol.Cell.Biol.1997,17,5400-5409;Vega,R.B.和DP.Kelly.J.Biol.Chem.1997,272,31693-31699)。在对大鼠颅顶造骨细胞的反义试验中,除了抑制了骨小结的形成,还使脂肪细胞分化的标记物包括aP2和PPAR-γ增加(Bonnelye,E.等Endocrinology 2002,143,3658-3670)。近来有人描述,ERR-α敲除模型相对于野生型显示出脂肪质量的下降以及DNA芯片的分析数据表明,参与脂肪生成和能量代谢的基因的表达水平有变化(Luo,J.等Mol.Cell.Biol.2003,23(22),7947-7956)。更近来,已表明ERR-α能调节内皮一氧化氮合酶的表达,所述内皮一氧化氮合酶是一种具有抗动脉硬化保护机制的基因(Sumi,D.和L.J.Ignarro.Proc Natl.Acad.Sci.2003,100,14451-14456)。生物化学证据表明,在代谢稳态中和细胞分化成脂肪细胞的过程中,涉及ERR-α。因此,与ERR-α相互作用的化合物能影响能量稳态,因而可能有益于肥胖症和代谢综合征相关疾病的治疗,所述疾病包括动脉硬化和糖尿病(Grundy,S.M.等Circulation 2004,109(3),433-438)。
Lion Bioscience AG已揭示了某些吡唑衍生物作为ERR-α拮抗剂,用于治疗癌症、骨质疏松、肥胖症、血脂异常和心血管疾病和用于调节生育力(欧洲已公布的第1398029号专利申请)。
仍需要一种新ERR-α反向激动剂。还需要用于治疗包括但不限于以下病症的ERR-α反向激动剂:强直性脊柱炎、动脉粥样硬化、关节炎(如类风湿性关节炎、感染性关节炎、儿童关节炎、牛皮癣性关节炎、反应性关节炎)、骨相关疾病(包括那些与骨形成相关的疾病)、乳腺癌(包括那些对抗雌激素疗法无效的疾病)、心血管疾病、软骨相关疾病(如软骨损伤/损失、软骨退化和那些与软骨形成有关的疾病)、软骨发育不全、软骨肉瘤、慢性背部损伤、慢性支气管炎、慢性炎性呼吸道疾病、慢性阻塞性肺病、糖尿病、能量体内稳态紊乱、痛风、假痛风、血脂异常、代谢综合征、多发性骨髓瘤、肥胖症、骨关节炎、成骨不全、溶骨性骨转移、骨软化症、骨质疏松症、Paget氏病、牙周病、风湿性多肌病、Reiter氏综合征、重复应力损伤、高血糖症、血糖水平升高和胰岛素抵抗。
发明概述
在许多实施方案中,本发明提供了新的用作例如ERR-α反向激动剂的化合物、制备这些化合物的方法;包含一种或多种该化合物的药物组合物、制备包含一种或多种该化合物的药物组合物的方法;以及使用该化合物或药物组合物治疗、预防、抑制或改善一种或多种与ERR-α有关的疾病的方法。
本发明的一个方面涉及式(I)化合物
其中
X为S或O;
n为1-4;
R1为卤素、任选取代的C1-4烷基、任选取代的C1-4烷氧基或羟基;
R2选自卤素取代的C1-3烷基、氰基、卤素、-C(O)NH2和-C(O)O-C1-4烷基,或者R2与R3连接在一起形成与R2和R3所连接的苯环稠合的芳基;
R3为H,或者R3与R2连接在一起形成与R3和R2所连接的苯环稠合的芳基环;
R4为卤素、氰基、卤素取代的C1-3烷基、-C≡CH、-C(O)O-C1-4烷基、-C(O)NH2或-S(O2)-C1-4烷基;和
R5和R6独立为H或任选取代的C1-4烷基,或者R5和R6与它们所连接的氮原子一起形成任选取代的5-9元含氮杂芳基或任选取代的5-7元含氮杂环基;
或者其旋光异构体、对映异构体、非对映异构体、顺反异构体、外消旋体、前药或药学上可接受的盐。
本发明的另一方面涉及药物组合物,所述药物组合物包含至少一种式(I)化合物和至少一种药学上可接受的载体。
本发明还涉及一种治疗患有或诊断患有由ERR-α活性介导的疾病、紊乱或病症的患者的方法,所述方法包括给予患者治疗有效量的至少一种式(I)化合物。这些疾病、紊乱或病症可包括但不限于强直性脊柱炎、动脉粥样硬化、关节炎(如类风湿性关节炎、感染性关节炎、儿童关节炎、牛皮癣性关节炎、反应性关节炎)、骨相关疾病(包括那些与骨形成相关的疾病)、乳腺癌(包括那些对抗雌激素疗法无效的疾病)、心血管疾病、软骨相关疾病(如软骨损伤/损失、软骨退化和那些与软骨形成有关的疾病)、软骨发育不全、软骨肉瘤、慢性背部损伤、慢性支气管炎、慢性炎性呼吸道疾病、慢性阻塞性肺病、糖尿病、能量体内稳态紊乱、痛风、假痛风、血脂异常、代谢综合征、多发性骨髓瘤、肥胖症、骨关节炎、成骨不全、溶骨性骨转移、骨软化症、骨质疏松症、Paget氏病、牙周病、风湿性多肌病、Reiter氏综合征、重复应力损伤、高血糖症、血糖水平升高和胰岛素抵抗。式(I)化合物的治疗有效量可为约0.1mg/天至约5000mg/天。
本发明进一步涉及一种制备药物组合物的方法,所述方法包括将任一种式(I)化合物与药学上可接受的载体混合。
通过以下详细讨论、流程、实施例和权利要求书,本发明的其他实施方案和优点将变得显而易见。
发明详述
本发明涉及新的用于治疗、改善、预防或抑制多种病症的ERR-α调节剂及其组合物,所述病症包括但不限于癌症、关节炎、炎性呼吸道疾病、骨相关疾病、代谢紊乱及其相关症状或并发症。
本发明的一个方面涉及式(I)化合物
其中
X为S或O;
n为1-4;
R1为卤素、任选取代的C1-4烷基、任选取代的C1-4烷氧基或羟基;
R2选自卤素取代的C1-3烷基、氰基、卤素、-C(O)NH2和-C(O)O-C1-4烷基,或者R3与R2连接在一起形成与R3和R2所连接的苯环稠合的芳基;
R3为H,或者R3与R2连接在一起形成与R3和R2所连接的苯环稠合的芳基环;
R4为卤素、氰基、卤素取代的C1-3烷基、-C≡CH、-C(O)O-C1-4烷基、-C(O)NH2或-S(O2)-C1-4烷基;和
R5和R6独立为H或任选取代的C1-4烷基,或者R5和R6与它们所连接的氮原子一起形成任选取代的5-9元含氮杂芳基或任选取代的5-7元含氮杂环基;
或者其旋光异构体、对映异构体、非对映异构体、顺反异构体、外消旋体、前药或药学上可接受的盐。
特别是,本发明包括式(I)化合物的顺反异构体,其具有以下结构,其中X、n、R1、R2、R3、R4、R5和R6如上所述:
特别是,R1为未取代的C1-4烷氧基。更特别是,R1为-O-CH3。
特别是,R2为CF3。
特别是,R3为H。
特别是,R2与R3连接在一起形成与R2和R3所连接的苯环稠合的芳基。更特别是,R2与R3连接在一起形成与R2和R3所连接的苯环稠合的苯基。
特别是,R2为CF3,R3为H。
特别是,R4为氰基。更特别是,R4为氰基,R2为CF3。
特别是,X为S。
特别是,本发明包括式(I)化合物,其中
R1为-O-CH3;
R2为CF3;
R3为H;
R4为CN;
X为S;
或其旋光异构体、对映异构体、非对映异构体、外消旋体、顺反异构体、前药或药学上可接受的盐。
更特别是,本发明的实例包括式(I)化合物,其中R5和R6为-CH3,或者R5和R6与它们所连接的氮原子一起形成选自以下的任选取代的成员:
本发明的一个实施方案提供了选自以下的化合物:
1)4-{2-甲氧基-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈;
2)4-{4-[3-(2-二甲基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
3)4-{4-[2,4-二氧代-3-(2-吡咯烷-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
4)4-(2-甲氧基-4-{3-[2-(4-甲基-哌嗪-1-基)-乙基]-2,4-二氧代-噻唑烷-5-亚基甲基}-苯氧基)-3-三氟甲基-苄腈;
5)4-{4-[3-(2-二甲基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-氟-苯氧基}-3-三氟甲基-苄腈;
6)4-{2-氟-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈;
7)4-{4-[3-(2-二乙基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
8)4-{4-[3-(2-咪唑-1-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
9)4-{4-[2,4-二氧代-3-(2-哌啶-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
10)4-{4-[2,4-二氧代-3-(2-吡唑-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
11)4-{4-[2,4-二氧代-3-(2-[1,2,4]三唑-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
12)4-{4-[3-(2-氮杂环庚烷-1-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
13)4-{4-[2,4-二氧代-3-(2-吡咯-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;和
14)4-{4-[2,4-二氧代-3-(2-吡咯烷-1-基-乙基)-噻唑烷-5-亚基甲基]-2-氟-苯氧基}-3-三氟甲基-苄腈。
更特别是,所述化合物为
更特别是,所述化合物为
更特别是,所述化合物为
更特别是,所述化合物为
本发明的另一个方面涉及一种药物组合物,所述组合物包含至少一种式(I)化合物和至少一种药学上可接受的载体。特别是,本发明的药物组合物还可包含至少一种用于治疗、改善或预防ERR-α介导疾病的其他药物(agent)、药品(drug)、药剂(medicament)、抗体和/或抑制剂。更特别是,本发明的药物组合物包括选自以下的化合物:
1)4-{2-甲氧基-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈;
2)4-{4-[3-(2-二甲基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
3)4-{4-[2,4-二氧代-3-(2-吡咯烷-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;和
4)4-(2-甲氧基-4-{3-[2-(4-甲基-哌嗪-1-基)-乙基]-2,4-二氧代-噻唑烷-5-亚基甲基}-苯氧基)-3-三氟甲基-苄腈;
5)4-{4-[3-(2-二甲基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-氟-苯氧基}-3-三氟甲基-苄腈;
6)4-{2-氟-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈;
7)4-{4-[3-(2-二乙基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
8)4-{4-[3-(2-咪唑-1-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
9)4-{4-[2,4-二氧代-3-(2-哌啶-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
10)4-{4-[2,4-二氧代-3-(2-吡唑-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
11)4-{4-[2,4-二氧代-3-(2-[1,2,4]三唑-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
12)4-{4-[3-(2-氮杂环庚烷-1-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
13)4-{4-[2,4-二氧代-3-(2-吡咯-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;和
14)4-{4-[2,4-二氧代-3-(2-吡咯烷-1-基-乙基)-噻唑烷-5-亚基甲基]-2-氟-苯氧基}-3-三氟甲基-苄腈。
更特别是,本发明的药物组合物至少包含:
本发明还涉及(features)一种治疗患有或诊断患有由ERR-α活性介导的疾病、紊乱或病症的患者的方法,所述方法包括给予患者治疗有效量的至少一种式(I)化合物。
本发明还涉及一种在需要此等治疗患者中预防或抑制ERR-α-介导病症进展的方法,所述方法包括给予所述患者治疗有效量的至少一种式(I)化合物。
本发明还涉及一种在需要此等治疗患者中治疗前驱糖尿病症状的方法,所述方法包括给予所述患者治疗有效量的至少一种式(I)化合物。
这些疾病、紊乱或病症可包括但不限于强直性脊柱炎、动脉粥样硬化、关节炎(如类风湿性关节炎、感染性关节炎、儿童关节炎、牛皮癣性关节炎、反应性关节炎)、骨相关疾病(包括那些与骨形成相关的疾病)、乳腺癌(包括那些对抗雌激素疗法无效的疾病)、心血管疾病、软骨相关疾病(如软骨损伤/损失、软骨退化和那些与软骨形成有关的疾病)、软骨发育不全、软骨肉瘤、慢性背部损伤、慢性支气管炎、慢性炎性呼吸道疾病、慢性阻塞性肺病、糖尿病、能量体内稳态紊乱、痛风、假痛风、血脂异常、代谢综合征、多发性骨髓瘤、肥胖症、骨关节炎、成骨不全、溶骨性骨转移、骨软化症、骨质疏松症、Paget氏病、牙周病、风湿性多肌病、Reiter氏综合征、重复应力损伤、高血糖症、血糖水平升高和胰岛素抵抗。
根据本发明的一个方面,所公开的化合物和组合物被用于与以下病症和疾病相关症状的改善、以下病症和疾病的治疗、以及以下病症和疾病进程的预防或抑制:骨相关疾病、骨形成、软骨形成、软骨损失、软骨退化、软骨损伤、强直性脊柱炎、慢性背部损伤、痛风、骨质疏松症、溶骨性骨转移、多发性骨髓瘤、软骨肉瘤、软骨发育不全、成骨不全、骨软化症、Paget氏病、风湿性多肌病、假痛风、关节炎、类风湿性关节炎、感染性关节炎、骨关节炎、牛皮癣性关节炎、反应性关节炎、儿童关节炎、Reiter氏综合征和重复应力损伤。
根据本发明的另一个方面,所公开的化合物和组合物被用于与以下病症和疾病相关症状的改善、以下病症和疾病的治疗、以及以下病症和疾病进程的预防和/或抑制:牙周病、慢性炎性呼吸道疾病、慢性支气管炎和慢性阻塞性肺病。
本发明的又一个方面,所公开的化合物和组合物被用于与乳腺癌相关症状的改善、乳腺癌的治疗、以及乳腺癌进展的预防和/或抑制。
本发明的再一个方面,所公开的化合物和组合物被用于与以下病症和疾病相关症状的改善、以下病症和疾病的治疗、以及以下病症和疾病进程的预防和/或抑制:代谢综合征、肥胖症、能量体内稳态紊乱、糖尿病、血脂异常、心血管疾病、动脉粥样硬化、高血糖症、血糖水平升高和胰岛素抵抗。
特别是,本发明的方法包括给予患者治疗有效量的(a)至少一种式(I)化合物;和(b)至少一种选自以下的其他药物:第二ERR-α反向激动剂、ERR-α拮抗剂、葡萄糖激酶调节剂、抗糖尿病剂、抗肥胖症药、降脂药、抗血栓药、直接凝血酶抑制剂和降压药,以任何顺序进行所述给药。更特别是,(b)中的其他药物为不同于(a)中化合物的第二ERR-α反向激动剂。更特别是,在(b)中的其他药物为选自CB1拮抗剂、单胺重摄取抑制剂和脂肪酶抑制剂的抗肥胖症药。更特别是,在(b)中的其他药物选自利莫那班、西布曲明和奥利司他。
本发明还涉及治疗或抑制一种或多种ERR-α-介导病症进程的方法,所述方法包括给予需要此等治疗患者药学上有效量的本发明组合物。
本发明的另一实施方案提供了一种制备药物组合物的方法,所述方法包括将任一种式(I)化合物与药学上可接受的载体混合。
本发明还涉及药物组合物,所述药物组合物,包含但不限于,一种或多种所公开的化合物和药学上可接受的载体或赋形剂。
在本发明的另一实施方案中,一种在需要此等治疗患者中用于治疗或改善ERR-α-介导病症的方法,所述方法包括给予患者治疗有效量的至少一种式(I)化合物,其中式(I)化合物的治疗有效量为约0.1mg/剂至约5g/剂。特别是,式(I)化合物的治疗有效量为约0.5mg/剂至约1000mg/剂。更特别是,式(I)化合物的治疗有效量为约1mg/剂至约100mg/剂。在本发明的另一个实施方案中,式(I)化合物的每日剂次为1至3剂。在本发明的另一个实施方案中,式(I)化合物的治疗有效量为约0.001mg/kg/天至约30mg/kg/天。更特别是,式(I)化合物的治疗有效量为约0.01mg/kg/天至约2mg/kg/天。
在本发明的又一个实施方案中,一种在需要此等治疗患者中预防或抑制ERR-α-介导病症进展的方法,所述方法包括给予患者治疗有效量的至少一种式(I)化合物,其中式(I)化合物的治疗有效量为约0.1mg/剂至约5g/剂。特别是,式(I)化合物的治疗有效量为约1mg/剂至约100mg/剂。在本发明的另一个实施方案中,式(I)化合物的每日剂次为1至3剂。在本发明的另一个实施方案中,式(I)化合物的治疗有效量为约0.001mg/kg/天至约30mg/kg/天。更特别是,式(I)化合物的治疗有效量为约0.01mg/kg/天至约2mg/kg/天。
在本发明的又一个实施方案中,一种在需要此等治疗患者中治疗前驱糖尿病症状的方法,所述方法包括给予所述患者治疗有效量的至少一种式(I)化合物,其中式(I)化合物的治疗有效量为约0.1mg/剂至约5g/剂。更特别是,式(I)化合物的治疗有效量为约1mg/剂至约100mg/剂。在本发明的另一个实施方案中,式(I)化合物的每日剂次为1至3剂。在本发明的另一个实施方案中,式(I)化合物的治疗有效量为约0.001mg/kg/天至约30mg/kg/天。更特别是,式(I)化合物的治疗有效量为约0.01mg/kg/天至约2mg/kg/天。
下面进一步描述本发明。
A)术语
以下定义了一些术语并在该公开各处使用。
除非另有说明,否则文中所用“烷基”,不论单独或作为取代基的一部分使用,是指通过从母体烷烃的单个碳原子上除去一个氢而衍生的支链或直链的饱和一价烃基。典型的烷基基团包括但不限于甲基;乙基如乙烷基;丙基如丙-1-基、丙-2-基、环丙-1-基;丁基如丁-1-基、丁-2-基、2-甲基-丙-1-基、2-甲基-丙-2-基、环丁-1-基等。在优选实施方案中,所述烷基基团为C1-6烷基,特别优选C1-3烷基。“烷氧基”基团为由上述直链或支链烷基形成的氧醚。在一些实施方案中,所述烷基或烷氧基独立被1-5个、优选1-3个基团取代,基团包括但不限于氧代基、氨基、烷氧基、羧基、杂环基、羟基和卤素(F、Cl、Br或I)。
术语“烯基”是指通过从母体烯烃的单个碳原子上除去一个氢而衍生的支链、直链或环状的不饱和一价烃基,其含有至少一个碳-碳双键。该基团对于双键可存在顺式或反式构型。典型的烯基基团包括但不限于乙烯基;丙烯基如丙-1-烯-1-基、丙-1-烯-2-基、丙-2-烯-1-基、丙-2-烯-2-基、环丙-1-烯-1-基;环丙-2-烯-1-基;丁烯基如丁-1-烯-1-基、丁-1-烯-2-基、2-甲基-丙-1-烯-1-基、丁-2-烯-1-基、丁-2-烯-1-基、丁-2-烯-2-基、丁-1,3-二烯-1-基、丁-1,3-二烯-2-基、环丁-1-烯-1-基、环丁-1-烯-3-基、环丁-1,3-二烯-1-基等;等。在一些实施方案中,所述烯基被1-5个、优选1-3个基团取代,基团包括但不限于氧代、氨基、烷氧基、羧基、杂环基、羟基和卤素。
术语“炔基”是指通过从母体炔烃的单个碳原子上除去一个氢而衍生的支链、直链或环状的不饱和一价烃基,其含有至少一个碳-碳叁键。典型的炔基基团包括但不限于乙炔基;丙炔基如丙-1-炔-1-基、丙-2-炔-1-基等;丁炔基如丁-1-炔-1-基、丁-1-炔-3-基、丁-3-炔-1-基等;等。在一些实施方案中,所述炔基被1-5个、优选1-3个基团取代,基团包括但不限于氧代、氨基、烷氧基、羧基、杂环基、羟基和卤素。
术语“杂芳基”是指通过从母体杂芳环系的单个原子上除去一个氢而衍生的一价杂芳基团。典型的杂芳基基团包括其中一个或两个环为杂芳环的单环和二环系统。杂芳环可包含1-4个选自O、N和S的杂原子。实例包括但不限于衍生自咔唑、咪唑、吲唑、吲哚、吲嗪、异吲哚、异喹啉、异噻唑、异噁唑、萘啶、噁二唑、噁唑、嘌呤、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、双吡咯烷(pyrrolizine)、喹唑啉、喹啉、喹嗪、喹噁啉、四唑、噻二唑、噻唑、噻吩、三唑、呫吨等的基团。在一些实施方案中,“杂芳基”被取代。例如,“杂芳基”可被例如任选取代的C1-6烷基、C2-6烯基、C2-6炔基、卤素、羟基、-CN、-C(O)OH、-C(O)O-C1-4烷基、-C(O)NR’R”-OR′、-SR’-C(O)R′、-N(R′)(R”)、-S(O)2-R′和-S(O)2-N(R′)(R”)取代,其中R′和R”独立选自H、C1-6-烷基、芳基、杂芳基和/或杂环基。
文中所用术语“芳基”是指由碳原子组成的含稳定的6元单环或10元二环或14元三环芳族环系的芳族基团。芳基基团的实例包括但不限于苯基或萘基。在一些实施方案中,“芳基”被取代。例如,“芳基”可被例如任选取代的C1-6烷基、C2-6烯基、C2-6炔基、卤素、羟基、-CN、-C(O)OH、-C(O)O-C1-4烷基、-C(O)NR’R”、-SR’、-OR′、-C(O)R′、-N(R′)(R”)、-S(O)2-R′和-S(O)2-N(R′)(R”)取代,其中R′和R”独立选自H、C1-6-烷基、芳基、杂芳基和/或杂环基。
术语“杂环基”或“杂环”为由碳原子和1-6个选自N、O和S的杂原子组成的3-至8-元饱和或部分饱和单环或稠环系。所述杂环基基团可在任何导致产生稳定结构的杂原子或碳原子上连接。杂环基基团的实例包括但不限于2-咪唑啉、咪唑烷;吗啉、噁唑啉、2-吡咯啉、3-吡咯啉、吡咯烷、吡啶酮、嘧啶酮、哌嗪、哌啶、二氢吲哚、四氢呋喃、2-吡咯啉、3-吡咯啉、2-咪唑啉、2-吡唑啉和吲哚啉酮。在一些实施方案中,“杂环基”或“杂环”独立地被取代。例如“杂环基”或“杂环”可被例如任选取代的C1-6烷基、C2-6烯基、C2-6炔基、卤素、羟基、-CN、-C(O)OH、-C(O)O-C1-4烷基、-C(O)NR’R”-OR′、-SR’-C(O)R′、-N(R′)(R”)、-S(O)2-R′和-S(O)2-N(R′)(R”)取代,R’和R”独立选自H、C1-6-烷基、芳基、杂芳基和/或杂环基。
术语“氧代”,无论是单独使用还是作为取代基的一部分,是指连接在碳或硫原子上的O=。如,酞酰亚胺和糖精为具有氧代取代基的实例。
术语“顺反异构体”是指相对于参考平面,原子(或基团)位置不同的立体异构的烯烃或环烷烃(或杂-类似物):在顺式异构体中原子在同侧;在反式异构体中原子处于对侧。
术语“取代的”是指其中一个或多个氢原子各自独立被相同或不同的取代基置换的基团。
就取代基而言,术语“独立地”意指当可能为多个这些取代基时,这些取代基可相同或互不相同。
术语“组合物”是指包含特定量的特定成分的产品和直接或间接得自特定量的特定成分的组合的任何产品。
本文所用术语“患者”是指作为治疗、观察或实验目标的动物,优选哺乳动物,更优选人类。
应了解在分子中特定位置的任何取代基或变量的定义独立于其在那个分子其他位置的定义。应明白本领域普通技术人员可选择本发明化合物上的取代基和取代方式以提供化学稳定的并可容易地由本领域已知技术和本文提到的方法合成的化合物。
本文所用术语″反向激动剂″是指在没有激动剂存在下具有降低受体激活作用构成水平能力的化合物或物质,而不是仅仅阻滞由于激动剂与受体结合而导致的激活作用。
代谢性疾病、病症或症状包括但不限于,糖尿病、肥胖症及其相关综合征或并发症。它们包括如下病症:IDDM(胰岛素依赖型糖尿病)、NIDDM(非胰岛素依赖型糖尿病)、IGT(葡萄糖耐量损伤)、IFG(空腹血糖损伤)、综合征X(或代谢综合征)、高血糖、血糖水平升高和胰岛素抵抗。IGT或IFG还被称为“前驱糖尿病”或“糖尿病前期”。
本领域已知确定所公开的药物组合物或公开的药物组合(无论是否配制在同一组合物中)的治疗和预防有效剂量的方法。对于治疗目的,本文所用术语“治疗有效量”是指研究者、兽医、医学博士或其他临床医生寻求的单独或联合使用时每种活性化合物或药物在组织系统、动物或人类中产生生物学或医学反应的量,所述生物学或医学反应包括所治疗的疾病或病症症状的减轻。对于预防目的(即抑制病症的发作和发展),术语“治疗有效量”是指研究者、兽医、医学博士或其他临床医生寻求的单独或联合使用时每种活性化合物或药物在患者中治疗或抑制病症的发作和发展的量。因此,本发明提供了两种或更多种药物的组合,其中,如,(a)每种药物以独立的治疗有效量或预防有效量用药;(b)所述组合中至少一种药物在单独给予时为亚治疗量或亚预防量用药、但是当按照本发明结合第二种或另外的药物给予时为治疗量或预防量用药;或者(c)两种(或更多种)药物在单独给予时为亚治疗量或亚预防用药量、但是当一起给予时为治疗量或预防量用药。
术语“药学可接受盐”是指无毒药学可接受盐(参考International J.Pharm.,1986,33,201-217;J.Pharm.Sci.,1997(Jan),66,1,1)。但是,本领域中其他众所周知的盐也可用于制备本发明的化合物或其药学可接受盐。代表性的有机或无机酸包括但不限于,盐酸、氢溴酸、氢碘酸、高氯酸、硫酸、硝酸、磷酸、乙酸、丙酸、羟乙酸、乳酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、羟基乙磺酸、苯磺酸、草酸、双羟萘酸、2-萘磺酸、对甲苯磺酸、环己烷氨基磺酸、水杨酸、糖精酸或三氟乙酸。代表性的有机或无机碱包括但不限于,碱性或阳离子盐如苄星(benzathine)、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺、普鲁卡因、铝、钙、锂、镁、钾、钠和锌。
B)化合物
在下表I中列出了本发明代表性的化合物:
表I
C)合成
本发明提供了根据传统的有机合成方法以及基本(matrix)或组合的合成方法制备所公开化合物的方法。流程1介绍了建议的合成路线。使用该流程、以下指导原则和实施例,本领域的技术人员可研究出在本发明内所给化合物的类似方法。这些方法为代表性的合成流程,但这不被解释为限制本发明的范围。
如果本发明化合物具有至少一个手性中心,则它们可相应地存在对映异构体。如果该化合物具有两个或更多个手性中心,则它们还可存在非对映异构体。如果用于制备本发明化合物的方法产生立体异构体的混合物,这些异构体可通过常规技术如制备色谱来分离。可以外消旋形式或通过立体定向合成或拆分这些化合物以单个对映异构体或非对映异构体形式制备。通过标准技术如通过与旋光性碱成盐形成立体异构体对,随后通过分步结晶和游离酸再生,这些化合物例如可拆分成这些组分的对映异构体或非对映异构体。这些化合物还可被拆分,做法是:通过形成立体异构的酯或酰胺,随后色谱分离并除去手性助剂。或者,这些化合物可使用手性HPLC柱拆分。应当理解的是,所有其立体异构体、外消旋混合物、非对映异构体、几何异构体和对映异构体均包括在本发明范围内。
此外,化合物的一些晶型可为多晶型且这也被包括在本发明范围内。而且,化合物中的一些可与水(即水合物)或普通有机溶剂形成溶剂化物且这些溶剂化物也意欲包括在本发明范围内。
所述合成路线的实例包括流程1和实施例1-4。与这些实施例的目标化合物类似的化合物可采用类似的路径制备。这些公开的化合物用作如文中所述的药物。
文中所用的缩写或首字母缩写包括:
AIBN(2,2′-偶氮二异丁腈)
Boc(氨基甲酸叔丁酯)
BOP(六氟磷酸(苯并三唑-1-基氧基)三(二甲基氨基)鏻)
BuLi(丁基锂)
DIBAL-H(二异丁基氢化铝)
DMAP(4-(二甲基氨基)吡啶)
DME(乙二醇二甲醚)
DMF(二甲基甲酰胺)
DMPU(1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮)
DMSO(二甲亚砜)
EDC(N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺)
EDCI(1-(3-二甲基氨基丙基)-3-乙基碳二亚胺·盐酸盐)
Et(乙基)
EtOAc(乙酸乙酯)
h或hr(小时)
HATU(六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓)
HMPA(六甲基磷酰胺)
HOBt(1-羟基苯并三唑一水合物)
LCMS(高压液相-质谱仪)
LDA(二异丙基氨基锂)
LHMDS(六甲基二甲硅烷基氨基锂)
Me(甲基)
Mg(毫克)
MOM(甲氧基甲基)
NaHMDS(六甲基二甲硅烷基氨基钠)
NaOtBu(叔丁醇钠)
NBS(N-溴代琥珀酰亚胺)
NMP(N-甲基吡咯烷酮)
rt或RT(室温)
SPE(固相萃取)
TBTU(六氟磷酸O-苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓)
TEMPO(2,2,6,6-四甲基-1-哌啶基氧基,自由基)
TFA(三氟乙酸);
THF(四氢呋喃)
TLC(薄层色谱)
通用指导原则
流程1
其中n、X、R1、R2、R3、R4、R5和R6如本文所定义的式I化合物可按照流程1中所述的通用合成路线合成。用碱如K2CO3在溶剂如DMF中、在优选25-150℃的温度下处理合适的羟基苯甲醛II和芳基氟III(两者均可为市售或可由市售的起始原料制备),可得到苯氧基醛IV。在催化量的碱如哌啶和酸如苯甲酸存在下醛IV与环状二酮V进行Knoevenagel反应,可得到苯氧基环状二酮VI。Knoevenagel反应通常在非质子溶剂如甲苯中、在优选100-200℃的温度下进行。醛IV和环状二酮V间的反应还可用碱如乙酸钠在以下条件下进行:在溶剂如乙腈中、优选50-150℃的温度下;或在醋酸铵/乙酸存在下、优选50-150℃的温度下。在下列条件下用合适的胺VII(其中LG为离去基团如氯、溴、碘或甲磺酸根)处理二酮VI可得到式I化合物:在碱如K2CO3存在下、在溶剂如DMF中、在优选25-150℃的温度下。
实施例
实施例1
4-{2-甲氧基-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈
A.4-(4-甲酰基-2-甲氧基-苯氧基)-3-三氟甲基-苄腈
用K2CO3(2.83g,21.72mmol)处理香草醛(1.65g,10.86mmol)和4-氟-3-三氟甲基-苄腈(10.26mmol)在DMF(15mL)中的溶液,随后在80℃的油浴中将该混合物加热12小时。将该反应冷却至室温并在EtOAc和H2O间分配。有机相用水(3x)洗涤,经Na2SO4干燥并真空干燥。硅胶层析(EtOAc/己烷),得到标题化合物。
1H NMR(400Hz,CDCl3)δ10.00(s,1H),8.00(m,1H),7.68(dd,1H),7.58-7.53(m,2H),7.29(d,1H),6.75(d,1H),3.83(s,3H);
LC/MS(m/z)[M+1]+322.1(C16H11F3NO3的计算值,322.06).
B.4-[4-(2,4-二氧代-噻唑烷-5-亚基甲基)-2-甲氧基-苯氧基]-3-三氟甲基-苄腈
将噻唑烷-2,4-二酮(2.55g,21.79mmol)和4-(4-甲酰基-2-甲氧基-苯氧基)-3-三氟甲基-苄腈(21.79mmol)溶解在甲苯(150mL)中并用苯甲酸(3.27mmol)和哌啶(2.83mmol)处理。该烧瓶装有Dean-Stark阱(Dean-Stark trap),随后将该反应在130℃的油浴中回流12小时。在冷却至室温后,通过过滤收集产物并与己烷研磨,得到标题化合物。
1H NMR(400Hz,DMSO-d6)δ12.68(NH),8.32(d,1H),8.00(dd,1H),7.83(s,1H),7.49(d,1H),7.36(d,1H),7.26(dd,1H),6.90(d,1H),3.77(s,3H);
LC/MS(m/z)[M+1]+ 421.0(C19H12F3N2O4S的计算值,421.04).
C.4-{2-甲氧基-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈
用K2CO3(33mg,0.24mmol)处理4-[4-(2,4-二氧代-噻唑烷-5-亚基甲基)-2-甲氧基-苯氧基]-3-三氟甲基-苄腈(40mg,0.095mmol)和4-(2-氯-乙基)-吗啉(0.095mmol)在DMF(1.5mL)中的溶液并在铝热块(aluminum heating block)中加热至80℃。在12小时后,将该反应冷却至室温并在EtOAc(5mL)和H2O(5mL)间分配。有机相用H2O(2×5mL)洗涤,经Na2SO4干燥并真空干燥。硅胶层析(MeOH/CH2Cl2),得到标题化合物。
1H NMR(400Hz,CDCl3)δ7.97(d,1H),7.87(s,1H),7.68(dd,1H),7.19(m,3H),6.76(d,1H),3.90(t,2H),3.82(s,3H),3.67(bs,4H),2.64(t,2H),2.51(bs,4H);
LC/MS(m/z)[M+1]+ 534.2(C25H23F3N3O5S的计算值,534.12).
实施例2
4-{4-[3-(2-二甲基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈
基本上如在实施例1C中所述制备标题化合物,不同之处在于使用(2-氯-乙基)-二甲基-胺代替4-(2-氯-乙基)-吗啉。
1H NMR(400Hz,CDCl3)δ7.97(d,1H),7.87(s,1H),7.68(dd,1H),7.19(m,3H),6.78(d,1H),3.90(t,2H),3.81(s,3H),2.61(bt,2H),2.31(bs,6H);
LC/MS(m/z)[M+1]+ 492.1(C23H21F3N3O4S的计算值,492.11).
实施例3
4-{4-[2,4-二氧代-3-(2-吡咯烷-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈
基本上如在实施例1C中所述制备标题化合物,不同之处在于使用1-(2-氯-乙基)-吡咯烷代替4-(2-氯-乙基)-吗啉。
1H NMR(400Hz,CDCl3)δ7.90(d,1H),7.80(s,1H),7.61(dd,1H),7.11(m,3H),6.68(d,1H),3.92(t,2H),3.72(s,3H),2.87(bs,2H),2.72(bs,4H),1.80(bs,4H);
LC/MS(m/z)[M+1]+ 518.1(C25H23F3N3O4S的计算值,518.13).
实施例4
4-(2-甲氧基-4-{3-[2-(4-甲基-哌嗪-1-基)-乙基]-2,4-二氧代-噻唑烷-5-亚基甲基}-苯氧基)-3-三氟甲基-苄腈
基本上如在实施例1C中所述制备标题化合物,不同之处在于使用1-(2-氯-乙基)-4-甲基-哌嗪代替4-(2-氯-乙基)-吗啉。
1H NMR(400Hz,CDCl3)δ7.88(d,1H),7.69(s,1H),7.59(dd,1H),7.25(d,1H),7.21(d,1H),7.09(d,1H),6.70(d,1H),3.93(br s,2H),3.76-3.67(m,5H),3.42(br s,2H),3.10(t,2H),2.53(br s,4H),2.34(s,3H);
LC/MS(m/z)[M+1]+ 547.4(C26H26F3N4O4S的计算值,547.15).
实施例5
4-{4-[3-(2-二甲基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-氟-苯氧基}-3-三氟甲基-苄腈
如实施例1中所述使用4-[4-(2,4-二氧代-噻唑烷-5-亚基甲基)-2-氟-苯氧基]-3-三氟甲基-苄腈和(2-氯-乙基)-二甲基-胺制备标题化合物。
1H NMR(400Hz,CDCl3)δ7.95(s,1H),7.76(s,1H),7.69(dd,1H),7.27(m,3H),6.84(d,1H),3.91(t,2H),2.76(bt,2H),2.40(s,6H);
LC/MS(m/z)[M+1]+480.1(C22H18F4N3O3S的计算值,480.45).
实施例6
4-{2-氟-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈
如实施例1中所述使用4-[4-(2,4-二氧代-噻唑烷-5-亚基甲基)-2-氟-苯氧基]-3-三氟甲基-苄腈和4-(2-氯-乙基)-吗啉制备标题化合物。
1H NMR(400Hz,CDCl3)δ8.01(s,1H),7.83(s,1H),7.74(dd,1H),7.34(m,3H),6.91(d,1H),3.92(t,2H),3.69(bt,2H),2.69(bt,2H),2.57(bs,2H);
LC/MS(m/z)[M+1]+522.2(C24H20F4N3O4S的计算值,522.49).
实施例7
4-{4-[3-(2-二乙基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈
如实施例1中所述使用(2-氯-乙基)-二乙基-胺制备标题化合物。
1H NMR(400Hz,CDCl3)δ7.97(s,1H),7.89(s,1H),7.68(dd,1H),7.18(m,3H),6.77(d,1H),3.98(bs,2H),3.81(s,3H),2.89(bs,4H),1.61(bs,3H),1.18(bs,5H);
LC/MS(m/z)[M+1]+520.1(C25H25F3N3O4S的计算值,520.54).
实施例8
4-{4-[3-(2-咪唑-1-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈
如实施例1中所述使用1-(2-氯-乙基)-1H-咪唑制备标题化合物。
1H NMR(400Hz,CDCl3)δ9.49(bs,1H),7.97(s,1H),7.87(s,1H),7.68(d,1H),7.39(s,1H),7.19(m,4H),6.77(d,1H),4.71(t,2H),4.34(t,2H),3.82(s,3H);
LC/MS(m/z)[M+1]+ 515.0(C24H18F3N4O4S的计算值,515.48).
实施例9
4-{4-[2,4-二氧代-3-(2-哌啶-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈
如实施例1中所述使用1-(2-氯-乙基)-哌啶制备标题化合物。
1H NMR(400Hz,CDCl3)δ7.97(s,1H),7.89(s,1H),7.69(d,1H),7.17(m,3H),6.77(d,1H),4.12(bs,2H).3.81(s,3H),1.62(bs,8H);
LC/MS(m/z)[M+1]+532.3(C26H25F3N3O4S的计算值,532.55).
实施例10
4-{4-[2,4-二氧代-3-(2-吡唑-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈
如实施例1中所述使用1-(2-氯-乙基)-1H-吡唑制备标题化合物。
1H NMR(400Hz,CDCl3)δ7.97(s,1H),7.84(s,1H),7.68(dd,1H),7.58(d,1H),7.43(d,1H),7.18(m,3H),6.76(d,1H),6.32(m,1H),4.55(t,2H),4.21(t,2H),3.81(s,3H);
LC/MS(m/z)[M+1]+ 515.1(C24H18F3N4O4S的计算值,515.48).
实施例11
4-{4-[2,4-二氧代-3-(2-[1,2,4]三唑-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈
如实施例1中所述使用1-(2-氯-乙基)-1H-[1,2,4]三唑制备标题化合物。
1H NMR(400Hz,CDCl3)δ8.93,8.80(bs,1H),8.13,8.08(s,1H),7.97(s,1H),7.85(s,1H),7.69(dd,1H),7.18(m,3H),6.77(d,1H),4.64(t,1H),4.60(t,1H),4.27(t,1H),3.93(t,1H),3.81(s,3H);
LC/MS(m/z)[M+1]+516.1(C23H17F3N5O4S的计算值,516.47).
实施例12
4-{4-[3-(2-氮杂环庚烷-1-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈
如实施例1中所述使用1-(2-氯-乙基)-氮杂环庚烷制备标题化合物。
LC/MS(m/z)[M+1]+546.3(C27H27F3N3O4S的计算值,546.57).
实施例13
4-{4-[2,4-二氧代-3-(2-吡咯-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈
如实施例1中所述使用1-(2-氯-乙基)-1H-吡咯制备标题化合物。
1H NMR(400Hz,CDCl3)δ8.32(s,1H),8.01(d,1H),7.93(s,1H),7.51(d,1H),7.36(d,1H),7.26(d,1H),6.91(d,1H),6.66(d,2H),5.93(d,2H),4.17(m,2H),3.94(t,1H),3.85(t,1H),3.75(s,3H);
LC/MS(m/z)[M+1]+514.1(C25H19F3N3O4S的计算值,514.49).
实施例14
4-{4-[2,4-二氧代-3-(2-吡咯烷-1-基-乙基)-噻唑烷-5-亚基甲基]-2-氟-苯氧基}-3-三氟甲基-苄腈
如实施例1中所述使用4-[4-(2,4-二氧代-噻唑烷-5-亚基甲基)-2-氟-苯氧基]-3-三氟甲基-苄腈和1-(2-氯-乙基)-吡咯烷制备标题化合物。
1H NMR(400Hz,DMSO-d6)δ8.49(s,1H),8.21(dd,1H),8.05(s,1H),7.87(d,1H),7.64(m,2H),7.31(d,1H),3.86(t,2H),2.76(bs,2H),2.60(bs,4H),1.73(bs,4H);
LC/MS(m/z)[M+1]+506.2(C24H20F4N3O3S的计算值,506.49).
D)通用给药方法、制剂和剂量
本发明的化合物为ERR-α反向激动剂,因此可用于治疗、预防或抑制ERR-α介导的病症的发展,所述病症包括但不限于强直性脊柱炎、动脉粥样硬化、关节炎(如类风湿性关节炎、感染性关节炎、儿童关节炎、牛皮癣性关节炎、反应性关节炎)、骨相关疾病(包括与骨形成有关的疾病)、乳腺癌(包括那些对抗雌激素疗法无效的疾病)、心血管疾病、软骨相关疾病(如软骨损伤/损失、软骨退化和与软骨形成有关的疾病)、软骨发育不全、软骨肉瘤、慢性背部损伤、慢性支气管炎、慢性炎性呼吸道疾病、慢性阻塞性肺病、糖尿病、能量体内稳态紊乱、痛风、假痛风、血脂异常、代谢综合征、多发性骨髓瘤、肥胖症、骨关节炎、成骨不全、溶骨性骨转移、骨软化症、骨质疏松、Paget氏病、牙周病、风湿性多肌病、Reiter氏综合征、重复劳损、高血糖、血糖水平升高和胰岛素抵抗和其他相关紊乱、疾病或病症。
本发明涉及一种治疗患有ERR-α介导的疾病的患者的方法,所述方法包括给予所述患者治疗有效量的包含本发明化合物的药物组合物。特别是,本发明还提供了治疗或抑制患者的下列病症发展的方法:乳腺癌、关节炎、炎性呼吸道疾病或代谢性疾病及其相关症状或并发症,其中所述方法包括给予所述患者治疗有效量的包含本发明化合物的药物组合物。
本发明的范围包括本发明化合物的前药。通常,这些前药为本发明化合物的功能性衍生物,其在体内很容易转化为所需化合物。因此,在本发明的治疗方法中,术语“给药”应包括用明确公开的化合物或用可能未明确公开但给予患者后可在体内转化为特定化合物的化合物来治疗所述各种病症。如,在“前药设计(Ddsign of Prodrugs)”,H.Bundgaard编辑,Elsevier,1985中描述了选择和制备合适的前药衍生物的常规方法。
本发明化合物的一些晶型可为多晶型,这也包含在本发明的范围内。此外,一些本发明化合物可与水或普通有机溶剂形成溶剂合物(如水合物),这些溶剂合物也包含在本发明的范围内。
制备本发明化合物的方法会产生立体异构体混合物,这些异构体可通过常规技术如制备色谱法分离。本发明化合物可被制备为外消旋形式,或通过立体合成或拆分制备为单个对映体或非对映体。如,所述化合物可通过标准技术被拆分为其组分对映体或非对映体,如通过与旋光活性的碱形成盐得到立体异构体对,再分步结晶,并重新产生游离酸。所述化合物还可通过形成立体异构酯或酰胺,然后用色谱法分离,再除去手性助剂而被拆分。或者,所述化合物可采用手性HPLC柱来拆分。应了解所有其立体异构体、外消旋混合物、非对映体异构体、顺反异构体和对映异构体都包含在本发明的范围内。
E)用途
1.用量
治疗由ERR-α介导的紊乱、疾病或病症的熟练技术人员可从后面提出的试验结果和其他信息决定有效日用量。确切的剂量和给药频率取决于本发明所用的特定化合物、所治疗的特定病症、所治疗的病症的严重性、特定患者的年龄、体重和综合身体健康情况以及患者服用的其他药物,这都是本领域熟练技术人员众所周知的。另外,很明显,根据所治疗患者的反应和/或根据开本发明化合物处方的医生的评价,可减少或增加所述日用量。因此,本文提到的有效日用量范围仅作为实施本发明的指导方针。
优选地,采用任何本文定义的化合物治疗本发明描述的ERR-α病症的方法中,所用剂型将包含药学可接受载体,其包含约0.1mg-约5000mg;特别是约0.5mg-约1000mg;和更特别是,约1mg-约100mg所述化合物,并可制成适于所选给药模式的任何形式。但是,根据患者需要、所治疗病症的严重性和所用的化合物,剂量可有所不同。可采取每日给药或后-定期给药(post periodic dosing)。
本发明的药物组合物包含每单位剂量单位,如片剂、胶囊剂、散剂、注射剂、栓剂、一茶匙的量(teaspoonful)等等,约0.001mg/kg/天-约10mg/kg/天-(特别是约0.01mg/kg/天-约1mg/kg/天;和更特别是,约0.1mg/kg/天-约0.5-mg/kg/天),和以约0.001mg/kg/天约30mg/kg/天-(特别是约0.01mg/kg/天-约2mg/kg/天,更特别是约0.1mg/kg/天-约1mg/kg/天和甚至更特别是,约0.5mg/kg/天-约1mg/kg/天)的剂量给药。
优选地,这些组合物为单位剂型,如用于口服、鼻内给药、舌下给药、眼内给药、经皮给药、胃肠外给药、直肠给药、阴道给药、干粉吸入或其他吸入或吹入方式给药的片剂、丸剂、胶囊剂、用于重构或吸入的干散剂、颗粒剂、锭剂、无菌注射溶液或混悬液、计量气雾剂或液体喷雾剂、滴剂、安瓿剂、带自动注射器装置的剂型或栓剂。或者,所述组合物可为适于每周或每月给药一次的形式;如,活性化合物的不溶性盐,如癸酸盐,可被制成用于肌内注射的长效制剂。
对于固体药物组合物如片剂的制备,将主要活性成分与药用载体如普通片剂成分如稀释剂、结合剂、粘合剂、崩解剂、润滑剂、抗粘着剂和助流剂(gildants)混合。合适的稀释剂包括但不限于,淀粉(即玉米、小麦或马铃薯淀粉,其可被水解)、乳糖(颗粒的、喷雾干燥的或无水的)、蔗糖、蔗糖为基础的稀释剂(蔗糖和玉米淀粉磨制而成的药片赋形剂(Confectioner’s sugar)、蔗糖加上约7-10%重量的转化糖;蔗糖加上约3%重量的改良糊精;蔗糖加上转化糖,约4%重量的转化糖、约0.1-0.2%重量的玉米淀粉和硬脂酸镁)、右旋糖、肌醇、甘露醇、山梨糖醇、微晶纤维素(如得自FMC Corp.的AVICEL TM微晶纤维素)、磷酸二钙、硫酸钙二水合物、乳酸钙三水合物等。合适的结合剂和粘合剂包括但不限于阿拉伯胶、瓜尔胶、西黄蓍胶、蔗糖、明胶、葡萄糖、淀粉和纤维素(如甲基纤维素、羧甲基纤维素钠、乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素等)、水溶性或可分散的结合剂(如海藻酸及其盐、硅酸镁铝、羟乙基纤维素[如得自Hoechst Celanese的TYLOSE TM]、聚乙二醇、多糖酸、膨润土、聚乙烯吡咯烷酮、聚甲基丙烯酸酯和预胶化淀粉)等。合适的崩解剂包括但不限于,淀粉(玉米、马铃薯等)、淀粉羟乙酸钠、预胶化淀粉、粘土(硅酸镁铝)、纤维素(如交联羧甲基纤维素钠和微晶纤维素)、海藻酸盐、预胶化淀粉(如玉米淀粉等)、树胶(如琼脂、瓜尔胶、刺槐豆胶、梧桐胶、果胶和西黄蓍胶)、交联聚乙烯吡咯烷酮等。合适的润滑剂和抗粘着剂包括但不限于,硬脂酸盐(镁、钙和钠)、硬脂酸、滑石粉、蜂蜡、stearowet、硼酸、氯化钠、DL-亮氨酸、碳蜡4000、碳蜡6000、油酸钠、苯甲酸钠、乙酸钠、月桂硫酸钠、月桂硫酸镁等。合适的助流剂包括但不限于,滑石粉、玉米淀粉、硅胶(如得自Cabot的CAB-O-SILTM硅胶、得自W.R.Grace/Davison的SYLOIDTM硅胶和得自Degussa的AEROSILTM硅胶)等。可向咀嚼固体剂型中加入甜味剂和矫味剂以改善口服剂型的风味。此外,固体剂型中可加入或采用着色剂和包衣以便识别药物或为了美观。这些载体和活性药物一起制成具有治疗学释放曲线的活性药物的精确、合适的剂量。
通常,将这些载体与活性药物混合形成包含本发明药学活性形式或其药学可接受盐的均质混合物的固体预制剂组合物。所述预制剂组合物通常由三种常用方法之一制备:(a)湿法制粒,(b)干法制粒,和(c)干法混合。当提到这些预制剂组合物为均质时,是指活性成分均匀地分散于组合物中,以至于该组合物可容易地被再分为等效剂型如片剂、丸剂和胶囊剂。然后将这种固体预制剂组合物再分为包含约0.1mg-约500mg本发明活性成分的上述单位剂型。包含新型组合物的片剂或丸剂还可被制成多层片剂或丸剂以得到缓释或双释放产品。例如,双释放片剂或丸剂可包含内剂量和外剂量组分,后者可为包裹前者的外壳(envelope)形式。可通过肠衣层分离两种组分,肠衣层在胃中可抗崩解,允许内层组分完整通过进入十二指肠或被延迟释放。可用各种材料制备这种肠溶层或包衣,所述材料包括许多聚合材料如虫胶、乙酸纤维素(如醋酞纤维素、乙酸偏苯三酸纤维素)、聚醋酸乙烯邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、甲基丙烯酸酯和乙基丙烯酸酯共聚物、甲基丙烯酸酯和甲基丙烯酸甲酯共聚物等。缓释片剂还可通过薄膜包衣,或采用在溶液中微溶或不溶性物质(其在湿法制粒中作为结合剂)或低熔点固体的熔化形式(其在湿法制粒中可与活性成分混合)进行湿法制粒。这些材料包括天然和合成高分子蜡、氢化油、脂肪酸和醇(如蜂蜡、巴西棕榈蜡、十六醇、十六烷基十八醇等)、脂肪酸金属皂酯和其他可用于制粒、包衣、包埋或其他限制活性成分的溶解度的可接受材料以得到延长或持续释放产品。
用于口服或注射给药的其中含有本发明的新型组合物的液体形式包括但不限于水溶液剂;适当调味的糖浆剂;水或油混悬剂和用食用油如棉籽油、芝麻油、椰子油或花生油调味的乳剂;以及酏剂和类似的药用载体。用于水性混悬剂的合适的悬浮剂包括合成和天然树胶如阿拉伯胶、琼脂、海藻酸盐(即藻酸羟丙酯、海藻酸钠等)、瓜尔胶、梧桐胶、刺槐豆胶、果胶、西黄蓍胶和黄原胶、纤维素如羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素和羟丙基甲基纤维素及其混合物,合成聚合物如聚乙烯吡咯烷酮、卡波姆(即羧基聚乙烯)和聚乙二醇;粘土如膨润土、锂蒙脱石、活性白土或海泡石;其他药学可接受悬浮剂如卵磷脂、明胶等。合适的表面活性剂包括但不限于多库酯钠、月桂基硫酸钠、聚山梨醇酯、辛苯昔醇-9、壬苯醇醚-10、聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、泊洛沙姆(polyoxamer)188、泊洛沙姆(polyoxamer)235及其混合物。合适的反絮凝或分散剂包括药用级别的卵磷脂。合适的絮凝剂包括但不限于简单中性电解质(即氯化钠、氯化钾等)、高电荷不溶性聚合物和聚电解质类、水溶性二价或三价铁(即钙盐、明矾或硫酸盐、柠檬酸盐和磷酸盐(其可在制剂中作为pH缓冲剂和絮凝剂共同使用)。合适的防腐剂包括但不限于尼泊金酯类(即甲酯、乙酯、正丙酯和正丁酯)、山梨酸、硫柳汞、季铵盐、苯甲醇、苯甲酸、葡萄糖酸洗必太、苯乙醇等。有许多可用于液体药物剂型的液体载体,但是,在特定剂型中所用的液体载体必须与悬浮剂相容。例如,非极性液体载体如脂肪酯和油脂液体载体最好与悬浮剂如低HLB(亲水-亲脂平衡)表面活性剂、司拉氯铵锂蒙脱石、水不溶性树脂、形成水不溶性薄膜的聚合物等一起使用。相反,极性液体如水、醇、多元醇和乙二醇最好与悬浮剂如高HLB表面活性剂、硅酸盐粘土、树胶、水溶性纤维素、水溶性聚合物等一起使用。对于胃肠外给药,需要无菌混悬液和溶液。用于胃肠外给药的液体形式包括灭菌溶液、乳剂和混悬液。当需要静脉给药时,采用通常包含合适的防腐剂的等渗制剂。
此外,本发明的化合物可通过局部使用合适的鼻内载体而以鼻内给药剂型给药,或通过透皮贴剂给药,本领域普通技术人员熟知这样的组合物。以透皮给药系统形式给药时,治疗剂量的给药当然会比与间断的给药方案相比更连续。
本发明的化合物还可以脂质体递药系统形式给药,如小单层脂质体、大单层脂质体、多层脂质体等。脂质体可由多种磷脂形成,如胆固醇、硬脂酰胺、磷酸卵磷脂等。
本发明的药物组合物的日剂量可在较大范围内变化,所述范围为约0.1mg-约5000mg;优选地,对普通人来说,所述剂量范围为约1mg-约100mg/天。对于口服给药,所述组合物优选为片剂形式,所述片剂包含0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、150、200、250或500mg的活性成分,对所治疗的患者针对症状调整剂量。方便地,本发明的化合物可以每日一剂或总剂量被分为每日两次、三次或四次的方式给药。
本领域熟练技术人员还明显了解,根据所需的效果,本发明活性化合物或其药物组合物的治疗有效剂量会有所不同。因此,本领域熟练技术人员很容易确定给药的最佳剂量,并根据所用特定化合物、给药方式、制剂浓度和疾病症状的进展情况而改变。此外,与所治疗的特定患者有关的因素,包括患者的年龄、体重、饮食和给药时间,也会导致需要将剂量调整至合适的治疗水平。因此,上述剂量为普通病例的示例。当然也可以根据个体实例增加或减少剂量,这都在本发明的范围内。
当有需要的患者需要本发明的化合物作为ERR-α反向激动剂使用时,本发明的化合物可以任何前述组合物和给药方案给药,或通过本领域制定的组合物和给药方案的方式给药。
2.制剂
为了制备本发明的药物组合物,将作为活性成分的一种或多种式(I)化合物或其盐与药用载体按照常规药物配混技术充分混合,根据给药(如口服或胃肠外给药)所需剂型,载体可为各种形式。合适的药学上可接受载体为本领域众所周知的。在由美国药学会和英国药学会出版的The Handbook of Pharmaceutical Excipients(药用赋形剂手册)中可发现对一些此类药学可接受载体的描述。
本发明化合物可被制成用于各种给药目的的各种剂型。在许多公开出版物中都有描述制备药物组合物的方法,如Pharmaceutical Dosage Forms:Tablets(药物剂型:片剂),第二版,修订增补版,1-3卷,由Lieberman等编辑;Pharmaceutical Dosage Forms:Parenteral Medications(药物剂型:胃肠外药物),1-2卷,由Avis等编辑;和Pharmaceutical Dosage Forms:Disperse Systems(药物剂型:分散体系),1-2卷,由Lieberman等编辑;Marcel Dekker公司出版。
3.联合疗法
本发明的化合物可用于与一种或多种药学活性药物联合使用。这些药物包括ERR-α拮抗剂、葡萄糖激酶调节剂、抗糖尿病药、其他降脂药物、直接凝血酶抑制剂(DTI),以及降脂药物如他汀类药物和贝特类药物。
ERR-α拮抗剂包括,如,公开于US 2006 0014812A1中的所有化合物,特别是具有下式的化合物
其中:
n为0或1;
Z为-O-、-S-、>NH或>NRa,其中Ra为烷基、环烷基、苯基或杂环烷基;
X为芳基或杂芳基;
R3为-H或未取代或被一个或多个独立选自下列的取代基取代的O-烷基:-OH、卤素、-CN、-O-烷基和-N(Rw)Rx,其中Rw和Rx各自独立为-H或烷基;
R4选自-H、卤素、-O-烷基、-CN、-NO2和-COOH;和
R5和R6各自独立为-CN;-COOH;或为选自下列基团的部分:-COO-烷基、-(C=O)烷基、-(S=(O)m)-芳基,其中m为0、1或2、环烷基、杂环烷基、-(C=O)苯基、杂芳基和-(C=O)杂环烷基;或R5和R6与连接它们的碳原子一起形成任选苯并稠合的杂环烷基或环烷基部分;
其中每个所述部分为未取代的或被一个或多个独立选自下列的取代基取代:-OH;=O;=S;任选被-OH、-O-烷基、苯基、-NH2、-NH(烷基)、-N(烷基)2、卤素、-CF3、-COOH或-COO-烷基取代的烷基;-O-烷基;苯基;-O-苯基;苄基;-O-苄基;环烷基;-O-环烷基;-CN;-NO2;-N(Ry)Rz,其中Ry和Rz各自独立为-H、烷基或-(C=O)烷基,或Ry和Rz与连接它们的氮原子一起形成杂环烷基,其中一个碳环原子被>O、>NH或>N-烷基任选取代,且其中一个碳环原子被-OH或=O任选取代;-(C=O)N(Ry)Rz;-(N-Rt)SO2烷基,其中Rt为-H或烷基;-(C=O)烷基;-(S=(O)n)烷基,其中n为0、1或2;-SO2N(Ry)Rz,其中Ry和Rz如上定义;-SCF3;卤素;-CF3;-OCF3;-COOH;和-COO烷基;
或所述化合物的药学上可接受的盐、药学上可接受的前药或药学上的活性代谢物。
根据作用机制,抗肥胖症药物可被分为几种类型。这些药物包括选择性5-羟色胺重摄取抑制剂(SSRIs)、5-羟色胺激动剂、5-羟色胺和降肾上腺素重摄取抑制剂、胰脂酶抑制剂、β3-肾上腺素受体激动剂、NPY-拮抗剂、黑皮质素受体激动剂、来普汀靶向药物、CB1-拮抗剂(如利莫那班)、单胺重摄取抑制剂(如西布曲明)和脂肪酶抑制剂(如奥利司他)。
据报道,当以规定剂量与芬特明联用时,5-羟色胺激动剂药物如右芬氟拉明和芬氟拉明会引起心脏瓣膜异常。选择性5-羟色胺重摄取抑制剂(SSRIs)通常用于抑郁症的治疗。这些药物包括氟西汀(Prozac)、帕罗西汀、氟伏沙明和舍曲林。
下面列出了有代表性的5-羟色胺调节剂:
(A)选择性5-羟色胺重摄取抑制剂(SSRIs)
1.西酞普兰(1-(3-(二甲基氨基)丙基)-1-(4-氟苯基)-1,3-二氢-5-异苯并呋喃甲腈,也被称为氢溴酸西酞普兰(USAN)、nitalopram、氰酞氟苯胺(nitalapram)、ZD 211、LU 10171、Lu10-171、LU 10171-B、喜普妙(CIPRAMIL)、SEROPRAM、CIPRAM、ELOPRAM、LUPRAM、SEPRAM、PRISDAL或CELEXA);
2.氟西汀(苯丙胺、N-甲基-γ-[4-(三氟甲基)苯氧基]-、(±)盐酸盐,也被称为LY 110140、RENEURON、SARAFEM或PROZAC);
3.氟伏沙明(5-甲氧基-1-(4-(三氟甲基)苯基)-1-戊酮(E)-O-(2-氨基乙基)肟,也被称为马来酸氟伏沙明(USAN)、DU 23000、MK 264、SME 3110、FEVARIN、FLOXYFRAL、LUVOX、DUMYROX、DUMIROX、FLAVOXYL、FAVERIN或DEPROMEL);
4.茚洛嗪((+,-)-2-((茚(indel)-7-基氧基)甲基)吗啉,也被称为ideloxazine、YM 08054、CI 874、ELEN或NOIN);
5.盐酸帕罗西汀((3S,4R)-3-((1,3-苯并二氧戊环-5-基氧基)甲基)-4-(4-氟苯基)哌啶盐酸盐或哌啶,3-((1,3-苯并二氧戊环-5-基氧基)甲基)-4-(4-氟苯基)-,(3S-反式)-,也被称为FR 7051、FG-7051、BRL29060、BRL 29060A、NNC 207051、SI 211103、CASBOL、SEROXAT、AROPAX、PAXIL、TAGONIS、FROSINOR、DEROXAT、SEREUPIN、MOTIVAN或PAXIL CR);
6.舍曲林(1-萘胺、4-(3,4-二氯苯基)-1,2,3,4-四氢-N-甲基-、(1S-顺式)-;或1-萘胺,4-(3,4-二氯苯基)-1,2,3,4-四氢-N-甲基-、(1S-顺式),也被称为CP 51974、CP 5197401、AREMIS、BESITRAN、GLADEM、LUSTRAL、SERAD、SERLAIN、SERLIFT、TATIG或ZOLOFT);
7.噻萘普汀(7-((3-氯-6,11-二氢-6-甲基二苯并(c,f)(1,2)硫杂氮杂环庚烯-11-基)氨基)庚酸S、S-二氧化物,也被称为S 1574或STABLON);
8.桑普罗帕嗪(1-(p-丙酰基苯氧基)-3-(Nsup(4)-henylpiperazynyl)-丙-2-醇);
9.帕罗西汀(GEOMATRIX给药体系)(哌啶,3-((1,3-苯并二氧戊环-5-基氧基)甲基)-4-(4-氟苯基)-、(3S-反式)-,也被称为帕罗西汀、GEOMATRIX、PAXIL CR);
10.依他普仑((1S)-1-(3-(二甲基氨基)丙基)-1-(4-氟苯基)-1,3-二氢-5-异苯并呋喃甲腈;或5-异苯并呋喃家腈,1-(3-(二甲基氨基)丙基)-1-(4-氟苯基)-1,3-二氢-(S)-,也被称为依他普仑、xalate(USAN)、西酞普兰、(S)(+)-西酞普兰、LU 26042、LU 26054、Lu26-054或CIPRALEX);
11.利托西汀(4-[(2-萘基)甲氧基]哌啶,也被称为SL 810385);
12.(S)-氟西汀((S)-N-甲基-γ-(4-(三氟甲基)苯氧基)苯丙胺);
13.西克拉明((+,-)-3,4-二氯-β-(二甲基氨基)-β-甲基苯丙醇,也被称为JO 1017(+,-)、JO 1239(-)或JO 1240(+));
14.达泊西汀((+)-(S)-N,N-二甲基-α-(2-(1-萘基-氧基)乙基)苄胺盐酸盐,也被称为LY-210448或LY-243917);
15.6-硝基喹哌嗪衍生物;
16.一系列取代6-硝基喹哌嗪(Pharmaprojects No.3391);
17.AAL 13(2-(4-(3-氯丙基)-1-哌嗪基)喹啉e);
18.抑郁疗法(Depression therapy)(Vita Invest、Spain);
19.DUP 631(C13H23NO2S);
20.FI 4503(Ferrer,Spain);
21.一系列吲哚基环己胺化合物(Pharmaprojects No.6443,American Home Products);
22.LY 280253(N-甲基-N-[3-[4-(甲硫基)苯氧基)-3-苯基丙基]胺);
23.LY 285974(Lilly);
24.奥米西汀(乙酮,2-((3R,4S)-3-((1,3-苯并二氧戊环-5-基氧基)甲基)-4-(4-氟苯基)-1-哌啶基)-1-(4-氟苯基)-,rel-,也被称为FI-4500、FI-4501、FI-4503);和
25.WF 31(8-甲基-2β-丙酰基-3β-(4-(1-甲基乙基)-苯基)-8-氮杂二环[3.2.1]);
(B)5-羟色胺激动剂和部分激动剂
1.右芬氟拉明;和
2.芬氟拉明;
(C)具有5-羟色胺激动剂活性的5-羟色胺重摄取抑制剂
1.EMD-68843(2-苯并呋喃甲酰胺,5-(4-(4-(5-氰基-1H-吲哚-3-基)丁基)-1-哌嗪基)-,也被称为SB-659746-A);
2.OPC-14523(2(1H)-喹啉酮,1-(3-(4-(3-氯苯基)-1-哌嗪基)丙基)-3,4-二氢-5-甲氧基);
3.维拉佐酮(5-{4-[4-(5-氰基-3-吲哚基)-丁基]-1-哌嗪基}-苯并呋喃-2-甲酰胺,也被称为EMD 68843或SB 659746A);
4.一系列缩合噻唑化合物(3-(苯并(b)噻吩-3-基)-5,6-二氢咪唑并(2,1-b)噻唑一氢溴酸盐二水合物,Pharmaprojects No.5274,Abbott);和
5.VN-2222(VN-8522,Vita Invest,Spain)。
优选的5-羟色胺调节剂的实例包括选择性5-羟色胺重摄取抑制剂如西酞普兰、氟西汀、氟伏沙明、茚洛嗪、盐酸帕罗西汀、舍曲林、噻萘普汀、桑普罗帕嗪、帕罗西汀、依他普仑和利托西汀。
下面也是可用于本发明的联合疗法的抗肥胖症药物:
(A)胰淀素(Amylin)和胰淀素类似物
1.普兰林肽(1-赖氨酰-1-半胱氨酰-1-天冬酰胺酰-1-苏氨酰-1-丙氨酰-1-苏氨酰-1-半胱氨酰-1-丙氨酰-1-苏氨酰-1-谷氨酰胺酰-1-精氨酰-1-亮氨酰-1-丙氨酰-1-天冬酰胺酰-1-苯丙氨酰-1-亮氨酰-1-缬氨酰-1-组氨酰-1-丝氨酰-1-丝氨酰-1-天冬酰胺酰-1-天冬酰胺酰-1-苯丙氨酰甘氨酰-1-脯氨酰-1-异亮氨酰-1-亮氨酰-1-脯氨酰-1-脯氨酰-1-苏氨酰-1-天冬酰胺酰-1-缬氨酰甘氨酰-1-丝氨酰-1-天冬酰胺酰-1-苏氨酰-1-酪氨酰胺环状(2-7)-二硫化物,也被称为醋酸普兰林肽、AC 137、ACO 137、AC 0137、SYMLIN、Tripro-胰淀素或NORMYLIN);
2.胰淀素激动剂;
3.ACO 253(AC 253、GG 747、GR 1150747A或ANTAM);
(B)睫状神经营养因子(CNTF)
1.AXOKINE;
2.PEG-AXOKINE;
3.睫状神经营养因子的模拟肽(模拟CNTF,也被称为MYELOS);
4.睫状神经营养因子(CNTF,Fidia,Italy);
(C)高血糖素样肽-1
1.AC-2993(也被称为毒蜥外泌肽(exendin)-4、AC-2993LAR、Medisord毒蜥外泌肽、AC-2993、Medisorb或毒蜥外泌肽(extendin)-4、Amylin);
2.毒蜥外泌肽4
(His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-V-al-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-酰胺,也被称为AC 2993、AC 2993LAR、Medisord毒蜥外泌肽或AC-2993、Medisorb);
3.GLP-1(高血糖素样肽-17-36酰胺);
4.高血糖素样肽-1口腔经粘膜制剂;
5.毒蜥外泌肽3
(His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-V-al-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-酰胺);
(D)来普汀&来普汀模拟物
1.来普汀(第二代);
2.来普汀激动剂;
3.来普汀表达调节剂;
4.来普汀信号通路调节剂;
5.来普汀调节剂;
6.来普汀(IC Innovations,UK);
7.来普汀受体、单克隆抗体;
8.重组天然来普汀;
9.LY-355101;
10.来普汀、Amylin
(E)黑皮质素受体激动剂(MC4)
1.HP-228(甘氨酰胺,N-乙酰基-L-正亮氨酰-L-谷氨酰胺酰-L-组氨酰-D-苯丙氨酰-L-精氨酰-D-色氨酰-);
2.黑皮质素-4受体激动剂(Palatin,USA);
3.黑皮质素4激动剂(Pharmacopeia,Roche);
4.MC-4激动剂(Millennium,Chiron)
5.黑皮质素-4激动剂(Melacure Therapeutics,Sweden);
6.黑皮质素受体调节剂(Pharmaprojects No.5224,NeurocrineBiosciences,US);
7.Pharmaprojects No.5967,Trega/Novartis;
(F)NPY拮抗剂
1.AXC 0216;
2.AXC 1829;
3.SA-0204(神经肽Y拮抗剂、细胞凋亡刺激剂、脂类代谢调节剂);
4.α-trinositol(D-肌-肌醇,1,2,6-三(二氢磷酸酯),也被称为PP-56);
5.H 40922(H 409/22);
6.BMS-192548(1,11(4H,5H)-萘并萘二酮,2-乙酰基-4a,12a-二氢-3,4a,10,12,12a-五羟基-8-甲氧基-,TAN 1612异构体);
7.Alanex(1,4-二{(4-氨基-6-甲氧基苯基氨基-1,2-二氢-1,3,5-三嗪-2-基)-4-苯氧基甲基}苯,神经肽Y衍生物);
8.PD-160170(6-(2-异丙基-苯磺酰基)-5-硝基-喹啉-8-基胺);
9.2,4-二氨基吡啶衍生物(6-(5-乙基-1,3,4-噻二唑-2-基甲硫基)-4-吗啉代-2-(3-(2-丙烯基氧基羰基氨基)苄基氨基)吡啶,PharmaprojectsNo.5618,Banyu/Merck);
10.阿普米定类似物;
11.神经肽Y拮抗剂(Pharmaprojects No.4990,Pfizer);
12.4甲基取代的苯并咪唑类化合物(NPY-1拮抗剂、NPY-2拮抗剂);
13.LY-366337(神经肽Y1拮抗剂);
14.S-2501、S-25579、S-25584、S-25585、S-19528、S-34354(所有神经肽Y1/5拮抗剂);
15.神经肽Y拮抗剂(亚型1和5)和促生长激素神经肽受体拮抗剂(Pharmaprojects No.4897,Bristol-Myers Squibb);
16.苄基胺衍生物(1-芳基哌嗪基-1-烷基氧基苯基-4-烷基环烷烃类化合物);
17.J-104870(神经肽Y1拮抗剂、食欲抑制剂);
18.LY-357897(神经肽Y1拮抗剂);
19.神经肽Y1拮抗剂(Pfizer/Neurogen);
20.SR-120107A(神经肽Y1拮抗剂);
21.BIBO-3304((R)-N-((4-(氨基羰基氨基甲基)-苯基)甲基)-N2-(二苯基乙酰基)-精氨酰胺三氟乙酸盐);
22.BIBP 3226((R)-N-(4-((氨基亚氨基甲基)氨基)-1-((((4-羟基苯基)甲基)氨基)羰基)丁基)-α-苯基苯乙酰胺,或苯乙酰胺,N-((1R)-4-((氨基亚氨基甲基)氨基)-1-((((4-羟基苯基)甲基)氨基)羰基)丁基)-α-苯基-);
23.SR 120819A(苯丙酰胺,N-(1-((4-((((4-((二甲基氨基)甲基)环己基)甲基)氨基)亚氨基甲基)苯基)甲基)-2-氧代-2-(1-吡咯烷基)乙基)-α-((2-萘磺酰基)氨基)-,(αR-(N(R*(顺式))、αR*))-);
24.NGD-95-1(CP-422935、NGD 951);
25.具有苯并氮杂环庚烯母核的化合物(神经肽Y1拮抗剂);
26.神经肽Y1拮抗剂(Yamanouchi Pharmaceutical);
27.GI-264879A(神经肽Y1拮抗剂);
28.GW-1229(Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-Arg-Tyr-CONH2的[2′,4],[2,4′]同型二聚体,其中Dpr为二氨基丙酸,也被称为1229U91、MN-24、GR-231118);
29.BIIE-0246(环戊烷乙酰胺,N-[(1S)-4-[(氨基亚氨基甲基)氨基]-1-[[[2-(3,5-二氧代-1,2-二苯基-1,2,4-三唑烷-4-基)乙基]氨基]羰基]丁基]-1-[2-[4-(6,11-二氢-6-氧代-5H-二苯并[b,e]氮杂环庚烯-11-基)-1-哌嗪基]-2-氧代乙基]-);
30.神经肽Y2拮抗剂(Neurogen,USA);
31.酰胺衍生物(神经肽Y5拮抗剂);
32.神经肽Y激动剂和拮抗剂-亚型1和5(Schering-Plough)
33.N-(磺酰氨基)烷基-[3a,4,5,9b-四氢-1H-苯并[e]吲哚-2-基]胺(RWJPRI);
34.神经肽Y5拮抗剂(Novartis);
35.神经肽Y5拮抗剂(Pfizer/Neurogen);
36.吡咯并[3,2-d]嘧啶为基础的神经肽Y5拮抗剂;
37.CGP-71683(Pharmaprojects No.5651,CGP-71683A);
38.神经肽Y5激动剂/拮抗剂(Pharmaprojects No.5664,Bayer);
(G)组胺H3受体拮抗剂
1.GT-2331(3-((1R,2R)-2-(5,5-二甲基-1-己炔基)环丙基)-1H-咪唑,也被称为PERCEPTIN);
2.环丙沙芬(环丙基-(4-(3-1H-咪唑-4-基)丙基氧基)苯基)甲酮,也被称为BP 2359或化合物359);
3.化合物421(咪唑甲酰基丙醇衍生物,INSERM(France)/Bioprojet);
4.FUB 181(3-(4-氯苯基)丙基-3-(1H-咪唑-4-基)丙基醚);
5.GR 175737(3-((4-氯苯基)甲基)-5-(2-(1H-咪唑-4-基)乙基)-1,2-噁二唑);
6.GT 2227(4-(6-环己基-3(Z)-己烯基)咪唑马来酸盐);
7.GT 2394((1R,2R)-(反式-2-咪唑-4-基环丙基)-(环己基甲氧基)甲酰胺);
8.GT-2016(哌啶,1-(5-环己基-1-氧代戊基)-4-(1H-咪唑-4-基)-);
9.Imoproxifan(1-(4-(3-(1H-咪唑-4-基)丙氧基)苯基)乙-1-酮肟);
10.Impentamine(Berlin Free University);
11.雅培公司的用于注意缺陷障碍(ADHD)的H3拮抗剂;
12.Gliatech(USA)的用于进食障碍的H3拮抗剂;
13.一系列新型氨基甲酸酯类化合物,如具有N-烷基链的3-(1H-咪唑-4-基)丙醇的衍生物;
14.具有连接4-(1H-咪唑-4-基甲基)苯的中性连接基的一系列类似物;
15.脲,N-4-(1H-咪唑-4-基甲基)苯基甲基-N′-(3,5-二氯苯基)-,一盐酸盐;
16.Sch-50971(1H-咪唑,4-[(3R,4R)-4-甲基-3-吡咯烷基]-);
17.噻普酰胺(N-环己基-4-(1H-咪唑-4-基)-1-哌啶硫代甲酰胺,也被称为MR 12842);
18.UCL-1283(University College London);
19.UCL-1390(4-(3-(1H-咪唑-4-基)丙氧基)苯基氰);
20.UCL-1409((苯氧基烷基)咪唑);
21.UCL-1972(University College London);
22.Verongamine(苯丙酰胺,3-溴-α-(羟基亚氨基)-N-[2-(1H-咪唑-4-基)乙基]-4-甲氧基-,(E)-);
23.VUF-9153(氨基亚氨代甲硫代酸(Carbamimidothioic acid),[(4-氯苯基)甲基]-,3-(1H-咪唑-4-基)丙基酯,也被称为Clobenpropit);
(H)胰脂酶抑制剂
1.奥利司他(L-亮氨酸,N-甲酰基-,1-((3-己基-4-氧代-2-氧杂环丁烷基)甲基)十二烷基酯,(2S-(2α(R*),3β))-,或N-甲酰基-L-亮氨酸(2S-(2α(R*),3β))-1-((3-己基-4-氧代-2-氧杂环丁烷基)甲基)十二烷基酯,也被称为Orlipastat、RO 180647、Tetrahydrolipstatin(THL)、XENICAL或ZENICAL);
2.ATL 962(也被称为AZM 119或Alizyme);
3.GelTex(抗肥胖症疗法);
4.AZM-131(Yakurigaku Chuo Kenkyusho/Institute of FoodResearch);
5.RED 103004(XiMed Group(United Kingdom)/BioClin);
(I)α促黑激素类似物
1.Melanotan II(乙酰基-正亮氨酰-天冬氨酰-组氨酰-D-苯丙氨酰-精氨酰-色氨酰-赖氨酰胺C-4.2-N-6.7-内酰胺,也被称为MT II);
2.MBU-23、MBU-23、MBU-24、MBU-27、MBU-28和MBU-29(都在WO 009827113中有描述);
3.MSH融合毒素(也被称为DAB389MSH、antimelanoma、嵌合体(chimaera))
4.SHU-9119(L-赖氨酰胺,N-乙酰基-L-正亮氨酰-L-.α.-天冬氨酰-L-组氨酰-3-(2-萘基)-D-丙氨酰-L-精氨酰-L-色氨酰-,(2.fwdarw.7)-内酰胺,也被称为MBX 36)
5.SHU-9005(α-MSH的取代衍生物)
6.ZYC-200(α-MSH、Schepens/ZYCOS with BIOTOPE expressioncassette system)
(J)混合5-羟色胺重摄取抑制剂和5-羟色胺或α肾上腺素能拮抗剂活性
1.奈法唑酮(2-(3-(4-(3-氯苯基)-1-哌嗪基)丙基)-5-乙基-2,4-二氢-4-(2-苯氧基乙基)-3H-1,2,4-三唑-3-酮,也被称为MJ 13754、MS13754、BMY 13754、BMY 137541、SERZONE、DUTONIN、RESERIL、NEFADAR、NIFEREL、MENFAZONA、RULIVAN、DEPREFAX或SERZONIL);
2.YM 992((S)-2-(((7-氟-2,3-二氢-1H-茚-4-基)氧基)甲基)吗啉盐酸盐或(S)-2-(((7-氟-2,3-二氢-1H-茚-4-基)氧基)甲基)吗啉盐酸盐,也被称为YM 35992);
3.A 80426((R)-N-甲基-N-((1,2,3,4-四氢-5-甲氧基-1-萘基)甲基)-6-苯并呋喃乙胺);
4.5-HT1A拮抗剂(Vita-Invest,Spain);
5.奈法唑酮代谢产物(Sepracor,USA);
6.5-羟色胺重摄取抑制剂/5-羟色胺1A拮抗剂(Wyeth-Ayerst)
(K)通过肾上腺素能机制起作用的食欲抑制剂
1.苄非他明;
2.芬美曲秦;
3.芬特明;
4.安非拉酮;
5.马吲哚;
6.西布曲明;
7.苯丙醇胺;
8.麻黄碱
(L)混合5-羟色胺&多巴胺重摄取抑制剂
1.BL-1834(1-丙胺,3-二苯并(b,e),氧杂环庚烯-11(6H)-基亚基-N,N-二甲基);
2.NS-2389或NS-2347(GW-650250A、GW 650250);
3.(R)-西布曲明;
4.NS-2359(NeuroSearch,Denmark);
5.RTI-112或RTI-113或RTI-177(8-氮杂二环(3.2.1)辛烷-2-羧酸,3-(4-氯-3-甲基苯基)-8-甲基-,甲基酯,盐酸盐,(1R,2S,3S,5S));
6.BSF-74681(Abbott);
7.贯叶金丝桃素三甲氧基苯甲酸酯(IDN-5491);
(M)混合5-羟色胺重摄取抑制剂和多巴胺拮抗剂
1.SLV-310(Solvay,Belgium);
2.EMD 86006(3-(2-(3-(4-氟苯基)苄基氨基)乙氧基)苯基氰);
3.SLV 301(Solvay);
(N)去甲肾上腺素&5-羟色胺重摄取抑制剂(NSRI)
1.米那普仑(环丙烷甲酰胺,2-(氨基甲基)-N,N-二乙基-1-苯基-,顺式-(+/-)-,或(±)-顺式-2-(氨基甲基)-N-二乙基-1-苯基环丙烷甲酰胺盐酸盐,也被称为F-2207、F-2641、TN-912、DALCIPRAN、IXEL、MIDACIPR AN、MID ALCIPRAN、MILNACIPRAN SR、TOLEDOMIN);
2.曲马多、Purdue(环己醇,2-((二甲基氨基)甲基)-1-(3-甲氧基苯基)-,顺式-(+/-),也被称为TRAMADOL、Tramadol、CR或Toray);
3.米那普仑(持续释放给药体系);
4.度洛西汀((S)-N-甲基-γ-(1-萘氧基)-2-噻吩丙胺,或(+)-(S)-N-甲基-γ-(1-萘氧基)-2-噻吩-丙胺盐酸盐,也被称为LY 248686、草酸度洛西汀、LY-223332、LY-223743、LY-223994、LY-227750、LY-227942、LY-228993、LY-248686、LY-264452、LY-264453、LY-267826″
5.纳曲酮+曲马多(吗啡喃-6-酮,17-(环丙基甲基)-4,5-环氧-3,14-二羟基-,(5α)-,与环己醇混合(mixt withcyclohexanol),2-((二甲基氨基)甲基)-1-(3-甲氧基苯基)-,顺式-(+/-)-,也被称为PTI-601、曲马多+纳曲酮、Pain T)
6.(S)西布曲明((S)-1-(4-氯苯基)-N,N-二甲基-α-(2-甲基丙基)环丁烷甲胺);
7.曲马多,Labopharm(环己醇,2-((二甲基氨基)甲基)-1-(3-甲氧基苯基)-,顺式-(+/-),也被称为曲马多,Contramid);
8.F 98214TA(FAES,Spain);
9.S 33005((-)-1-(1-二甲基氨基甲基-5-甲氧基苯并环丁-1-基)环戊醇);
10.他克林类似物,SIDR;
(O)5-羟色胺、去甲肾上腺素和多巴胺重摄取抑制剂
1.西布曲明(环丁甲胺,1-(4-氯苯基)-N,N-二甲基-α-(2-甲基丙基)-,或1-(4-氯苯基)-N,N-二甲基-α-(2-甲基丙基)环丁甲胺盐酸盐一水合物,也被称为盐酸西布曲明一水合物、BTS-54354、BTS-54505、BTS-54524、KES-524、MERIDIA、REDUCTIL、RADUCTIL、REDUCTASE、PLENTY、ECTIVA);
2.文拉法辛(环己醇,1-[2-(二甲基氨基)-1-(4-甲氧基苯基)乙基],也被称为WY 45030、WY 45651、WY 45655、DOBUPAL、EFECTIN、EFEXOR、EFFEXOR、ELAFAX、VANDRAL、TREVILOR);
3.文拉法辛XR(环己醇,1-(2-(二甲基氨基)-1-(4-甲氧基苯基)乙基)-,盐酸盐,也被称为EFFEXOR XR,1EFFEXOR ER、EFFEXOR XL、EFFEXOR LP、DOBUPAL RETARD、VANDRAL RETARD、EFFEXOR-EXEL 75、EFEXOR XR、EFEXOR DEPOT、ELAFAXXR);
4.文拉法辛(给药体系,OROS口腔控制释放,也被称为文拉法辛,OROS或EFEXOR XR)
5.(+)-去甲基西布曲明(还被称为DDMS、二去甲基西布曲明-Sepracor);
6.BTS-74398(1-[1-(3,4-二氯苯基)环丁基]-2-(3-二甲基氨基丙基硫基)乙酮,Abbott Pharmaprojects No.6247);
7.去甲基文拉法辛(Sepracor);
(P)通过多巴胺机制起作用的抑郁抑制剂
1.阿扑吗啡;
(Q)选择性降肾上腺素(去甲肾上腺素)重摄取抑制剂
1.瑞波西汀((2S)-rel-2-((R)-(2-乙氧基苯氧基)苯基甲基)吗啉,或吗啉,2-[(2-乙氧基苯氧基)苯基甲基]-,(R,S)-,甲磺酸盐,也被称为甲磺酸瑞波西汀(USAN)、FCE 20124、FCE 21684、PNU 155950E、EDRONAX、PROLIFT、VESTRA、IRENON、NOREBOX);
2.托莫西汀((γR)-N-甲基-γ-(2-甲基苯氧基)苯丙胺或(-)-N-甲基-3-苯基-3-(o-甲苯氧基)-丙胺盐酸盐,也被称为LY 139603、LY135252、LY 139602);
3.羟基去甲替林((E)-10-11-二氢-5-(3-(甲基氨基)丙叉基)-5H-二苯并-(a,d)环庚烯-10-醇);
4.LY 368975((R)-N-甲基-3-[2-(甲硫基)苯氧基]-3-苯基-丙胺盐酸盐);
(R)混合的降肾上腺素和多巴胺重摄取抑制剂
1.丁氨苯丙酮(1-(3-氯苯基)-2-((1,1-二甲基乙基)氨基)-1-丙酮,也被称为盐酸丁氨苯丙酮(USAN)、安非他酮(bupropin)、安非他酮(amfebutamone)、BW 323U、WELLBUTRIN、QUOMEM或ZYBAN);
2.GW 320659((2S-(2α,3α,5α))-2-(3,5-二氟苯基)-3,5-二甲基-2-吗啉醇盐酸盐,也被称为1555、1555U88、BW 1555U88);
3.羟基丁氨苯丙酮(还被称为丁氨苯丙酮、R-或R-丁氨苯丙酮);
4.(-)二去甲基西布曲明(还被称为(S)-二去甲基西布曲明、去甲基西布曲明、(-)-DDMS或MERIDIA(urogenital));
(S)混合降肾上腺素重摄取抑制剂和其他神经递质拮抗剂
1.佐替平(2-((8-氯二苯并(b,f)硫杂环庚烯-10-基)氧基)-N,N-二甲基乙基胺,也被称为LODOPIN、NIPOLEPT、ZOLEPTIL、ZOPITE、SETOUS、MAJORPIN);
2.MCI 225(4-(2-氟苯基)-2-甲基-6-(哌嗪-1-基)-3a,7a-二氢噻吩并(2,3-d)嘧啶,或4-(2-氟苯基)-6-甲基-2-哌嗪基噻吩并[2,3-d]嘧啶盐酸盐水合物);
3.A 75200((R*,R*)-(+,-)-3-苯基-1-((6,7,8,9-四氢萘并(1,2-d)-1,3-二氧杂环戊烯-6-基)甲基)吡咯烷);
(T)混合5-羟色胺重摄取抑制剂和σ受体拮抗剂
1.E-5296(Esteve,Spain);
2.E-6276(Esteve,Spain);
3.E-5842(吡啶,4-(4-氟苯基)-1,2,3,6-四氢-1-(4-(1H-1,2,4-三唑-1-基)丁基)-,2-羟基-1,2,3-丙烷三羧酸盐(1∶1));
4.E 5826(E-5842的柠檬酸盐);
(U)其他具有5-羟色胺或降肾上腺素摄取抑制剂活性的神经递质调节剂
1.吡吲哚(1H-吡嗪并(3,2,1-jk)咔唑,2,3,3a,4,5,6-六氢-8-甲基-,也被称为CAS-125、Pyrazidol、吡吲哚、LIFRIL、IMPLEMENTOR);
2.NS-2330(NeuroSearch,Denmark);
3.VAN-H36(Vita-Invest,Spain);
4.UR 1827(2-(1-苄基哌啶-4-基)-1-[4-(5-甲基嘧啶-4-基氨基)苯基]-1-乙酮);
(V)C-75(脂肪酸合成酶抑制剂)
(W)S 15261(L-4-(2-(2-(9-芴基)乙酰氨基)乙基)苯甲酸2-(2-甲氧基-2-(3-(三氟甲基)苯基)乙基氨基)乙基酯)
(X)S 100B(神经营养因子)
(Y)解偶联蛋白功能刺激剂
(Z)缩胆囊素激动剂
(AA)雄激素
1.缩胆囊素;
2.脱氢表雄酮衍生物(如本胆烷二酮);
(BB)睾酮
(CC)促同化激素类(如氧雄龙)
(DD)甾体激素
(EE)淀粉酶抑制剂
(FF)肠抑素激动剂/模拟物
(GG)食欲素/下视丘分泌素拮抗剂
(HH)尿皮质素拮抗剂
(II)蛙皮素激动剂
(JJ)蛋白激酶A调节剂
(KK)促肾上腺皮质激素释放因子模拟物
(LL)可卡因-和安非他命-调节的转录物模拟物
(MM)降钙素基因相关肽模拟物
(NN)尼扎替丁(Axid)
其他用于本发明的联合疗法的药物包括葡萄糖激酶调节剂,包括:
Ro-28-1675
Banyu/Merck葡萄糖激酶激活剂
Novo Nordisk IV
Astra Zeneca葡萄糖激酶激活剂
抗糖尿病药包括RXR调节剂如:
(1)贝沙罗汀(4-(1-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)乙烯基)苯甲酸,也被称为TARGRETIN、TARGRETYN、TARGREXIN;还被称为LGD 1069、LG 100069、LG 1069、LDG 1069、LG 69、RO264455);
(2)9-顺式-维甲酸;
(3)AGN-4326(还被称为ALRT-4204、AGN-4204、ALRT-326、ALRT-324或LGD 1324);
(4)LGD 1324(ALRT 324);
(5)LG 100754;
(6)LY-510929;
(7)LGD 1268(6-(1,1,4,4,6-五甲基-1,2,3,4-四氢-萘-7-基环丙-1-基)烟酸,也被称为ALRT 268或LG 100268);和
(8)LG 100264。
抗糖尿病药还包括噻唑烷二酮和非-噻唑烷二酮胰岛素增敏剂,其通过增强胰岛素在靶器官和组织的效应而降低外周胰岛素抵抗。
下面的药物已知可结合并激活细胞核受体过氧化物酶体增生物激活受体-γ(PPARγ),其可增强特异性胰岛素敏感性基因的转录。PPAR-γ激动剂的实例为噻唑烷二酮类化合物如:
(1)罗格列酮(2,4-噻唑烷二酮,5-((4-(2-(甲基-2-吡啶基氨基)乙氧基)苯基)甲基)-,(Z)-2-丁烯二醇酯(1∶1)或5-((4-(2-(甲基-2-吡啶基氨基)乙氧基)苯基)甲基)-2,4-噻唑烷二酮,也被称为AVANDIA;还被称为BRL 49653、BRL 49653C、BRL 49653c、SB 210232或马来酸罗格列酮);
(2)吡格列酮(2,4-噻唑烷二酮,5-((4-(2-(5-乙基-2-吡啶基)乙氧基)苯基)甲基)-,一盐酸盐,(+-)-或5-((4-(2-(5-乙基-2-吡啶基)乙氧基)苯基)甲基)-2,4-噻唑烷二酮,也被称为ACTOS、ZACTOS或GLUSTIN;还被称为AD 4833、U 72107、U 72107A、U 72107E、盐酸吡格列酮(USAN));
(3)曲格列酮(5-((4-((3,4-二氢-6-羟基-2,5,7,8-四甲基-2H-1-苯并吡喃-2-基)甲氧基)苯基)甲基)-2,4-噻唑烷二酮,也被称为NOSCAL、REZULIN、ROMOZIN或PRELAY;还被称为CI 991、CS 045、GR92132、GR 92132X);
(4)isaglitazone((+)-5-[[6-[(2-氟苯基)甲氧基]-2-萘基]甲基]-2,4-噻唑烷二酮或5-((6-((2-氟苯基)甲氧基)-2-萘基)甲基-2,4-噻唑烷二酮或5-(6-(2-氟苄基氧基)萘-2-基甲基)噻唑烷-2,4-二酮,也被称为MCC-555或neoglitazone);和
(5)5-BTZD。
此外,用作胰岛素增敏剂的非-噻唑烷二酮类化合物包括但不限于:
(1)JT-501(JTT 501、PNU-1827、PNU-716-MET-0096或PNU182716:异噁唑烷-3,5-二酮,4-((4-(2-苯基-5-甲基)-1,3-噁唑基)乙基苯基-4)甲基-);
(2)KRP-297(5-(2,4-二氧代噻唑烷-5-基甲基)-2-甲氧基-N-(4-(三氟甲基)苄基)苯甲酰胺或5-((2,4-二氧代-5-噻唑烷基)甲基)-2-甲氧基-N-((4-(三氟甲基)苯基)甲基)苯甲酰胺);和
(3)法格立他扎(L-酪氨酸,N-(2-苯甲酰基苯基)-o-(2-(5-甲基-2-苯基-4-噁唑基)乙基)-或N-(2-苯甲酰基苯基)-O-(2-(5-甲基-2-苯基-4-噁唑基)乙基)-L-酪氨酸或GW2570或GI-262570)。
其他抗糖尿病药还显示具有PPAR调节剂活性如PPARγ、SPPARγ、和/或PPAR δ/γ激动剂活性。下面列出了其实例:
(1)AD 5075;
(2)R 119702((+-)-5-(4-(5-甲氧基-1H-苯并咪唑-2-基甲氧基)苄基)噻唑啉-2,4-二酮盐酸盐,或CI 1037或CS 011);
(3)CLX-0940(过氧化物酶体增生物激活受体α激动剂/过氧化物酶体增生物激活受体γ激动剂);
(8)GW-409890(PPAR激动剂);
(11)LG-101280(PPAR激动剂);
(13)利沙司他(CT-112);
(16)GW 0072(4-(4-((2S,5S)-5-(2-(二(苯基甲基)氨基)-2-氧代乙基)-2-庚基-4-氧代-3-噻唑烷基)丁基)苯甲酸);
(17)GW 409544(GW-544或GW-409544);
(18)NN 2344(DRF 2593);
(19)NN 622(DRF 2725);
(20)AR-H039242(AZ-242);
(21)GW 9820(贝特类(fibrate));
(23)SB 219994((S)-4-(2-(2-苯并噁唑基甲基氨基)乙氧基)-α-(2,2,2-三氟乙氧基)苯丙酸,或3-(4--(2-(N-(2-苯并噁唑基)-N-甲基氨基)乙氧基)苯基)-2(S)-(2,2,2-三氟乙氧基)丙酸或苯丙酸,4-(2-(2-苯并噁唑基甲基氨基)乙氧基)-α-(2,2,2-三氟乙氧基)-,(αS)-,PPAα/γ激动剂);
(31)NID525-209(NID-525);
(32)VDO-52(VDO-52);
(33)LG 100754(过氧化物酶体增生物激活受体激动剂);
(34)LY-510929(过氧化物酶体增生物激活受体激动剂);
(35)贝沙罗汀(4-(1-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)乙烯基)苯甲酸,也被称为TARGRETIN、TARGRETYN、TARGREXIN;还被称为LGD 1069、LG 100069、LG 1069、LDG 1069、LG 69、RO264455);和
(36)GW-1536(PPAR α/γ激动剂)。
其他胰岛素增敏剂包括但不限于:
(1)INS-1(D-手性肌醇或D-1,2,3,4,5,6-六羟基环己烷);
(2)蛋白酪氨酸磷酸酶1B(PTP-1B)抑制剂;
(3)糖原合酶激酶-3(GSK3)抑制剂;
(4)β3肾上腺素受体激动剂如ZD 2079((R)-N-(2-(4-(羧基甲基)苯氧基)乙基)-N-(2-羟基-2-苯乙基)氯化铵,也被称为ICI D 2079)或AZ40140;
(5)糖原磷酸化酶抑制剂;
(6)果糖-1,6-二磷酸酶抑制剂;
(7)吡啶甲酸铬、硫酸氧钒(vanadyl sulfate)(硫酸氧钒);
(8)KP 102(有机钒化合物);
(9)多聚烟酸铬;
(10)钾通道激动剂NN 414;
(11)YM 268(5,5′-亚甲基-二(1,4-苯撑)二亚甲基二(噻唑烷-2,4-二酮);
(12)TS 971;
(13)T 174((+-)-5-(2,4-二氧代噻唑烷-5-基甲基)-2-(2-萘基甲基)苯噁唑);
(14)SDZ PGU 693((+)-反式-2(S-((4-氯苯氧基)甲基)-7α-(3,4-二氯苯基)四氢吡咯并(2,1-b)噁唑-5(6H)-酮);
(15)S 15261((-)-4-(2-((9H-芴-9-基乙酰基)氨基)乙基)苯甲酸2-((2-甲氧基-2-(3-(三氟甲基)苯基)乙基)氨基)乙基酯);
(16)AZM 134(Alizyme);
(17)ARIAD;
(18)R 102380;
(19)PNU 140975(1-(肼基亚氨基甲基)肼基)乙酸;
(20)PNU 106817(2-(肼基亚氨基甲基)肼基)乙酸;
(21)NC 2100(5-((7-(苯基甲氧基)-3-喹啉基)甲基)-2,4-噻唑烷二酮;
(22)MXC 3255;
(23)MBX 102;
(24)ALT 4037;
(25)AM 454;
(26)JTP 20993(2-(4-(2-(5-甲基-2-苯基-4-噁唑基)乙氧基)苄基)-丙二酸二甲基二酯);
(27)Dexlipotam(5(R)-(1,2-二硫杂环戊烷-3-基)戊酸,也被称为(R)-α-硫辛酸或(R)-硫代辛酸(thioctic acid));
(28)BM 170744(2,2-二氯-12-(p-氯苯基)正十二烷酸);
(29)BM 152054(5-(4-(2-(5-甲基-2-(2-噻吩基)噁唑-4-基)乙氧基)苯并噻吩-7-基甲基)噻唑烷-2,4-二酮);
(30)BM 131258(5-(4-(2-(5-甲基-2-苯基噁唑-4-基)乙氧基)苯并噻吩-7-基甲基)噻唑烷-2,4-二酮);
(31)CRE 16336(EML 16336);
(32)HQL 975(3-(4-(2-(5-甲基-2-苯基噁唑-4-基)乙氧基)苯基)-2(S)-(丙基氨基)丙酸);
(33)DRF 2189(5-((4-(2-(1-吲哚基)乙氧基)苯基)甲基)噻唑烷-2,4-二酮);
(34)DRF 554158;
(35)DRF-NPCC;
(36)CLX 0100、CLX 0101、CLX 0900或CLX 0901;
(37)IkappaB激酶(IKK B)抑制剂
(38)丝裂原活化蛋白激酶(MAPK)抑制剂
p38MAPK刺激剂
(39)三磷酸磷脂酰肌醇酯
(40)胰岛素再循环受体抑制剂
(41)葡萄糖运载体4调节剂
(42)TNF-α拮抗剂
(43)浆细胞分化抗原-1(PC-1)拮抗剂
(44)脂细胞脂质结合蛋白(ALBP/aP2)抑制剂
(45)磷酸聚糖类化合物(phosphoglycans)
(46)Galparan;
(47)Receptron;
(48)胰岛细胞成熟因子;
(49)胰岛素强化因子(IPF或胰岛素强化因子-1);
(50)与结合蛋白偶合的生长介素C(还被称为IGF-BP3、IGF-BP3、SomatoKine);
(51)Diab II(也被称为V-411)或Glucanin,由Biotech Holdings Ltd.或Volque Pharmaceutical生产;
(52)葡萄糖-6磷酸酶抑制剂;
(53)脂肪酸葡萄糖转运蛋白;
(54)糖皮质激素受体拮抗剂;和
(55)谷氨酰胺:果糖-6-磷酸酰胺转移酶(GFAT)调节剂。
抗糖尿病药还可包括双胍类化合物,其可降低肝葡萄糖生成并增强葡萄糖的吸收。双胍类化合物的实例包括二甲双胍如:
(1)1,1-二甲基双胍(如二甲双胍-DepoMed、二甲双胍-BiovailCorporation或二甲双胍GR(二甲双胍胃潴留聚合物));和
(2)盐酸二甲双胍(N,N-二甲基亚氨基氨基亚氨代碳酰二胺(dicarbonimidic diamide)一盐酸盐,也被称为LA 6023、BMS 207150、GLUCOPHAGE或GLUCOPHAGE XR。
此外,抗糖尿病药还包括α-葡萄糖苷酶抑制剂,其可抑制α-葡萄糖苷酶。α-葡萄糖苷酶可将果糖转化为葡萄糖,从而延迟碳水化合物的消化。然后,未消化的碳水化合物在肠中降解,降低食后葡萄糖高峰。α-葡萄糖苷酶抑制剂包括但不限于:
(1)阿卡波糖(D-葡萄糖,O-4,6-二脱氧-4-(((1S-(1α,4α,5β,6α))-4,5,6-三羟基-3-(羟基甲基)-2-环己烯-1-基)氨基)-α-D-吡喃葡萄糖基-(1-4)-O-α-D-吡喃葡萄糖基-(1-4)-,也被称为AG-5421、Bay-g-542、BAY-g-542、GLUCOBAY、PRECOSE、GLUCOR、PRANDASE、GLUMIDA或ASCAROSE);
(2)米格列醇(3,4,5-哌啶三醇,1-(2-羟基乙基)-2-(羟基甲基)-,(2R(2α、3β、4α、5β))-或(2R,3R,4R,5S)-1-(2-羟基乙基)-2-(羟基甲基-3,4,5-哌啶三醇,也被称为BAY 1099、BAY M 1099、BAY-m-1099、BAYGLITOL、DIASTABOL、GLYSET、MIGLIBAY、MITOLBAY、PLUMAROL);
(3)CKD-711(0-4-脱氧-4-((2,3-环氧-3-羟基甲基-4,5,6-三羟基环己烷-1-基)氨基)-α-b-吡喃葡萄糖基-(1-4)-α-D-吡喃葡萄糖基-(1-4)-D-吡喃葡萄糖);
(4)乙格列酯(4-(2-((2R,3R,4R,5S)-3,4,5-三羟基-2-(羟基甲基)-1-哌啶基)乙氧基)苯甲酸乙酯,也被称为BAY o 1248或MKC 542);
(5)MOR 14(3,4,5-哌啶三醇,2-(羟基甲基)-1-甲基-,(2R-(2α,3β,4α,5β))-,也被称为N-甲基脱氧野尻霉素或N-甲基脱二氧亚氨基葡糖醇);和
(6)伏格列波糖(3,4-二脱氧-4-((2-羟基-1-(羟基甲基)乙基)氨基)-2-C-(羟基甲基)-D-表-肌醇或D-表-肌醇,3,4-二脱氧-4-((2-羟基-1-(羟基甲基)乙基)氨基)-2-C-(羟基甲基)-,也被称为A 71100、AO128、BASEN、GLUSTAT、VOGLISTAT。
抗糖尿病药还包括胰岛素类如正规胰岛素或短效、中效和长效胰岛素、非注射型或吸入胰岛素、组织选择性胰岛素、glucophosphokinin(D-手性肌醇),胰岛素类似物如在天然氨基酸序列上有小差异的胰岛素分子和胰岛素小分子模拟物(胰岛素模拟物)以及内体调节剂。其实例包括但不限于:
(1)Biota;
(2)LP 100;
(3)(SP-5-21)-氧代二(1-吡咯烷carbodithioato-S,S′)钒,
(4)门冬胰岛素(人胰岛素(28B-L-天门冬氨酸)或B28-Asp-胰岛素,也被称为胰岛素X14、INA-X14、NOVORAPID、NOVOMIX或NOVOLOG);
(5)地特胰岛素(人29B-(N6-(1-氧代十四烷基)-L-赖氨酸)-(1A-21A),(1B-29B)-胰岛素或NN 304);
(6)赖脯胰岛素(″28B-L-赖氨酸-29B-L-脯氨酸人胰岛素,或Lys(B28)、Pro(B29)人胰岛素类似物,也被称为lys-pro胰岛素、LY275585、HUMALOG、HUMALOG MIX 75/25或HUMALOG MIX50/50);
(7)甘精胰岛素(人(A21-甘氨酸、B31-精氨酸、B32-精氨酸)胰岛素HOE 901,也被称为LANTUS、OPTISULIN);
(8)胰岛素锌混悬液,长效(Ultralente),也被称为HUMULIN U或ULTRALENTE;
(9)胰岛素锌混悬液(慢),70%结晶和30%无定形胰岛素混悬液,也被称为LENTE ILETIN II、HULINL或NOVOLINL;
(10)HUMULIN 50/50(50%低精蛋白胰岛素和50%胰岛素注射液);
(11)HUMULIN 70/30(70%低精蛋白胰岛素NPH和30%胰岛素注射液),也被称为NOVOLIN70/30、NOVOLIN70/30PenFill、NOVOLIN 70/30Prefilled;
(12)低精蛋白胰岛素混悬液NPH ILETIN II、NOVOLIN N、NOVOLIN N PenFill、NOVOLIN N Prefilled、HUMULIN N;
(13)正规胰岛素注射液如ILETINII Regular、NOVOLINR、VELOSULIN BR、NOVOLIN R PenFill、NOVOLIN R Prefilled、HUMULIN R或Regular U-500(Concentrated);
(14)ARIAD;
(15)LY 197535;
(16)L-783281;和
(17)TE-17411。
抗糖尿病药还包括胰岛素分泌调节剂如:
(1)高血糖样肽-1(GLP-1)及其模拟物;
(2)葡萄糖-促胰岛素肽(GIP)及其模拟物;
(3)毒蜥外泌肽及其模拟物;
(4)二肽基蛋白酶(dipeptyl protease)(DPP或DPPIV)抑制剂如
(4a)DPP-728或LAF 237(2-吡咯烷甲腈,1-(((2-((5-氰基-2-吡啶基)氨基)乙基)氨基)乙酰基),也被称为NVP-DPP-728、DPP-728A、LAF-237);
(4b)Sitagliptin,也被称为Januvia;
(4c)P 3298或P32/98(二-(3N-((2S,3S)-2-氨基-3-甲基-戊酰基)-1,3-噻唑烷)富马酸盐);
(4d)TSL 225(色氨酰-1,2,3,4-四氢异喹啉-3-羧酸);
(4e)Valine pyrrolidide(valpyr);
(4f)1-氨基烷基异喹啉酮-4-羧酸酯及其类似物;
(4g)SDZ 272-070(1-(L-缬氨酰)吡咯烷);
(4h)TMC-2A、TMC-2B或TMC-2C;
(4i)二肽腈(2-氰基pyrrolodides);
(4j)CD26抑制剂;和
(4k)SDZ 274-444;
(5)高血糖素拮抗剂如AY-279955;和
(6)胰淀素激动剂,包括但不限于普兰林肽(AC-137、醋酸普兰林肽制剂、tripro-amylin或醋酸普兰林肽)。
众所周知的抗糖尿病药包括胰岛素、磺酰脲类、双胍类、氯茴苯酸类、AGI’s(A-葡萄糖苷酶抑制剂;如Glyset)、PPARα激动剂和PPARγ激动剂和双重PPAR α/γ激动剂。
降脂药物的实例包括胆汁酸多价螯合剂、fibric acid衍生物、烟酸和HMGCoA还原酶抑制剂。其具体实例包括他汀类药物如和以及匹伐他汀(nisvastatin)(Nissan、Kowa Kogyo、Sankyo、Novartis)及其缓释剂型,如ADX-159(缓释洛伐他汀),以及Colestid、Locholest、Questran、Atromid、Lopid和Tricor。
降压药物的实例包括抗高血压药如血管紧张素转化酶(ACE)抑制剂(Accupril、Altace、Captopril、Lotensin、Mavik、Monopril、Prinivil、Univasc、Vasotec和Zestril)、肾上腺素能受体阻滞剂(如可多华、台苯齐林、Hylorel、Hytrin、Minipress和Minizide)α/β肾上腺素能受体阻滞剂(如Coreg、Normodyne和Trandate)、钙通道阻滞剂(如Adalat、Calan、Cardene、Cardizem、Covera-HS、Dilacor、DynaCirc、Isoptin、Nimotop、Norvace、Plendil、Procardia、Procardia XL、Sula、Tiazac、Vascor和Verelan)、利尿剂、血管紧张素II受体拮抗剂(如Atacand、Avapro、Cozaar和Diovan)、β肾上腺素能受体阻滞剂(如Betapace、Blocadren、Brevibloc、Cartrol、Inderal、Kerlone、Lavatol、Lopressor、Sectral、Tenormin、Toprol-XL和Zebeta)、血管舒张剂(如Deponit、Dilatrate、SR、Imdur、Ismo、Isordil、Isordil Titradose、Monoket、Nitro-Bid、Nitro-Dur、Nitrolingual Spray、Nitrostat and Sorbitrate)及其组合(如Lexxel、Lotrel、Tarka、Teczem、Lotensin HCT、Prinzide、Uniretic、Vaseretic、Zestoretic)。
此外,第二ERR-α调节剂,如在上面的B)和E)部分中所描述,还可用作第三抗糖尿病药物,条件是其与第一ERR-α调节剂不同。
F)生物学实施例
TR-FRET测定
时间分辨荧光共振能量转移(TR-FRET)实验用于检测ERR1(还被称为ERR-α或ERR-1)配体功能应答。本文所描述的TR-FRET测定依赖于ERR1与辅激活因子肽结合的构象:当试验化合物与ERR1结合并改变其构象时,其可破坏辅激活因子肽的结合。这种同源辅助分析(homogeneous secondary assay)的组分包括:6His-标记的-ERR1 LBD、GST-标记的-hSRC2辅激活因子多肽和得自CIS bio internationalhtrf/bioassays(Bedford,MA)的采用α-GST铕穴合物(Eu)标记和α6His-XL665(别藻蓝蛋白)荧光团的荧光供体/受体对。
对于TR-FRET测定,将反应用25mM Tris pH 8、2.5mM Hepes、20mM KCl、1mM DTT和0.05mg/mL BSA(-脂类)缓冲。试剂的终浓度为6nM ERR1 LBD、6nM GST-SRC-2肽、30nM铕穴合物和7.5nMXL665。在25℃下反应4-18小时使反应达到平衡,然后,在得自LJLBiosystems(Molecular Devices Sunnyvale,CA)的Analyst上收集数据。作为时间分辨方法,样品在340nM处受激,分别在615nm和665nm延迟400和75μs收集发射1ms。用双曲线方程拟合剂量响应曲线,所记录数据为3次独立实验的平均值。
对下表II中列出的化合物进行了如上测定,这些化合物都是ERR1的活性调节剂。
表II.TR-FRET数据
化合物# | TR-FRET EC50(μM) |
1 | 0.02 |
2 | 0.039 |
3 | 0.042 |
4 | 0.32 |
5 | 0.36 |
6 | 0.32 |
7 | 0.059 |
8 | 0.032 |
9 | 0.033 |
10 | 0.059 |
11 | 0.024 |
12 | 0.044 |
13 | 0.086 |
14 | 0.23 |
前面的说明书教导了本发明的原理,为了示例的目的还提供了实施例,应了解本发明的实施包括所有在下面权利要求及其等同方案范围内的常规变化、改变和/或修改。
Claims (31)
3.权利要求1或2的化合物,其中R1为C1-4烷氧基。
4.权利要求3的化合物,其中R1为-O-CH3。
5.权利要求1或2的化合物,其中R2为CF3。
6.权利要求1或2的化合物,其中R2为CF3和R3为H。
7.权利要求1或2的化合物,其中R2为CF3和R4为氰基。
12.权利要求1的化合物,所述化合物选自
1)4-{2-甲氧基-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈;
2)4-{4-[3-(2-二甲基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
3)4-{4-[2,4-二氧代-3-(2-吡咯烷-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
4)4-(2-甲氧基-4-{3-[2-(4-甲基-哌嗪-1-基)-乙基]-2,4-二氧代-噻唑烷-5-亚基甲基}-苯氧基)-3-三氟甲基-苄腈;
5)4-{4-[3-(2-二甲基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-氟-苯氧基}-3-三氟甲基-苄腈;
6)4-{2-氟-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈;
7)4-{4-[3-(2-二乙基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
8)4-{4-[3-(2-咪唑-1-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
9)4-{4-[2,4-二氧代-3-(2-吡唑-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
10)4-{4-[2,4-二氧代-3-(2-[1,2,4]三唑-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
11)4-{4-[2,4-二氧代-3-(2-吡咯-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;和
12)4-{4-[2,4-二氧代-3-(2-吡咯烷-1-基-乙基)-噻唑烷-5-亚基甲基]-2-氟-苯氧基}-3-三氟甲基-苄腈。
19.一种药物组合物,所述药物组合物包括至少一种权利要求1-18任一项的化合物和至少一种药学上可接受的载体。
20.权利要求19的药物组合物,所述药物组合物包括至少一种选自以下的化合物:
1)4-{2-甲氧基-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈;
2)4-{4-[3-(2-二甲基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
3)4-{4-[2,4-二氧代-3-(2-吡咯烷-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;和
4)4-(2-甲氧基-4-{3-[2-(4-甲基-哌嗪-1-基)-乙基]-2,4-二氧代-噻唑烷-5-亚基甲基}-苯氧基)-3-三氟甲基-苄腈;
5)4-{4-[3-(2-二甲基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-氟-苯氧基}-3-三氟甲基-苄腈;
6)4-{2-氟-4-[3-(2-吗啉-4-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-苯氧基}-3-三氟甲基-苄腈;
7)4-{4-[3-(2-二乙基氨基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
8)4-{4-[3-(2-咪唑-1-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
9)4-{4-[2,4-二氧代-3-(2-哌啶-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
10)4-{4-[2,4-二氧代-3-(2-吡唑-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
11)4-{4-[2,4-二氧代-3-(2-[1,2,4]三唑-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
12)4-{4-[3-(2-氮杂环庚烷-1-基-乙基)-2,4-二氧代-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;
13)4-{4-[2,4-二氧代-3-(2-吡咯-1-基-乙基)-噻唑烷-5-亚基甲基]-2-甲氧基-苯氧基}-3-三氟甲基-苄腈;和
14)4-{4-[2,4-二氧代-3-(2-吡咯烷-1-基-乙基)-噻唑烷-5-亚基甲基]-2-氟-苯氧基}-3-三氟甲基-苄腈。
22.权利要求1-18任一项的化合物在制备用于治疗患者患有或诊断患有由ERR-α活性介导的疾病、紊乱或病症的药物中的用途。
23.权利要求22的用途,其中所述疾病、紊乱或医学病症是骨质疏松症。
24.权利要求22的用途,其中所述疾病、紊乱或病症为乳腺癌。
25.权利要求22的用途,其中所述疾病、紊乱或病症选自代谢综合征、肥胖症、能量体内稳态紊乱、糖尿病、动脉粥样硬化、高血糖症和胰岛素抵抗。
26.权利要求1-18任一项的化合物在制备用于在需要此等治疗患者中预防或抑制ERR-α介导病症发展的药物中的用途。
27.权利要求1-18任一项的化合物在制备用于在需要此等治疗患者中预防或抑制前驱糖尿病症状发病的药物中的用途。
28.权利要求22、26或27的用途,其中权利要求1-18任一项的化合物的治疗有效量为0.1mg/剂至5g/剂。
29.权利要求28的用途,其中权利要求1-18任一项的化合物的治疗有效量为0.5mg/剂至1000mg/剂。
30.权利要求28的用途,其中权利要求1-18任一项的化合物的治疗有效量为1mg/剂至100mg/剂。
31.一种制备药物组合物的方法,所述方法包括将权利要求1-18任一项中的任一种化合物与药学上可接受的载体混合。
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PCT/US2008/056018 WO2008109731A2 (en) | 2007-03-07 | 2008-03-06 | Substituted phenoxy n-alkylated thiazoledinedione as estrogen related receptor-alpha modulators |
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Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR059898A1 (es) | 2006-03-15 | 2008-05-07 | Janssen Pharmaceutica Nv | Derivados de 3-ciano-piridona 1,4-disustituida y su uso como moduladores alostericos de los receptores mglur2 |
TW200900065A (en) | 2007-03-07 | 2009-01-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives |
TW200845978A (en) | 2007-03-07 | 2008-12-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
EP2129668A1 (en) * | 2007-03-07 | 2009-12-09 | Janssen Pharmaceutica N.V. | Substituted phenoxy thiazolidinediones as estrogen related receptor-alpha modulators |
MX2010002537A (es) | 2007-09-14 | 2010-08-10 | Ortho Mcneil Janssen Pharm | 4-fenil-1h-piridin-2-onas 1,3-disubstituidas. |
CA2697399C (en) | 2007-09-14 | 2016-01-19 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc. | 1,3-disubstituted 4-(aryl-x-phenyl)-1h-pyridin-2-ones |
NZ584145A (en) | 2007-09-14 | 2012-03-30 | Ortho Mcneil Janssen Pharm | 1',3'-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2h, 1'h-[1,4'] bipyridinyl-2'-ones |
EP2220083B1 (en) | 2007-11-14 | 2017-07-19 | Janssen Pharmaceuticals, Inc. | Imidazo[1,2-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
EP2254576B1 (en) * | 2008-02-22 | 2013-08-28 | The Ohio State University Research Foundation | Androgen receptor-ablative agents |
JP5547194B2 (ja) | 2008-09-02 | 2014-07-09 | ジャンセン ファーマシューティカルズ, インコーポレイテッド. | 代謝型グルタミン酸受容体の調節因子としての3−アザビシクロ[3.1.0]ヘキシル誘導体 |
MX2011003691A (es) | 2008-10-16 | 2011-09-06 | Ortho Mcneil Janssen Pharm | Derivados de indol y benzomorfolina como moduladores de los receptores de glutamato metabotropico. |
ES2401691T3 (es) | 2008-11-28 | 2013-04-23 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc. | Derivados de indol y de benzoxacina como moduladores de los receptores metabotrópicos de glutamato |
CN102439008B (zh) | 2009-05-12 | 2015-04-29 | 杨森制药有限公司 | 1,2,4-三唑并[4,3-a]吡啶衍生物及其用于治疗或预防神经和精神病症的用途 |
MY153913A (en) | 2009-05-12 | 2015-04-15 | Janssen Pharmaceuticals Inc | 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
NZ596053A (en) | 2009-05-12 | 2013-05-31 | Janssen Pharmaceuticals Inc | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
JP2011057644A (ja) * | 2009-09-14 | 2011-03-24 | Sumitomo Chemical Co Ltd | 3型17β−ヒドロキシステロイドデヒドロゲナーゼを阻害するための化合物の使用およびそのための医薬組成物 |
JP2011057643A (ja) * | 2009-09-14 | 2011-03-24 | Sumitomo Chemical Co Ltd | 3型17β−ヒドロキシステロイドデヒドロゲナーゼを阻害するための化合物の使用およびそのための医薬組成物 |
RU2012139463A (ru) * | 2010-02-17 | 2014-03-27 | Янссен Фармацевтика Нв | Аминотиазолоны как модуляторы активности белков, родственных рецептору эстрогена альфа |
CA2815002C (en) | 2010-11-08 | 2019-10-22 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
CN103261195B (zh) | 2010-11-08 | 2015-09-02 | 杨森制药公司 | 1,2,4-三唑并[4,3-a]吡啶衍生物及其作为MGLUR2受体的正变构调节剂的用途 |
WO2012062750A1 (en) | 2010-11-08 | 2012-05-18 | Janssen Pharmaceuticals, Inc. | 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS |
WO2012153775A1 (ja) * | 2011-05-10 | 2012-11-15 | 国立大学法人神戸大学 | Ras機能阻害作用を有するチオキソチアゾリジン誘導体 |
WO2013018929A1 (en) | 2011-08-04 | 2013-02-07 | Takeda Pharmaceutical Company Limited | Nitrogen-containing heterocyclic compound |
CN102949364A (zh) * | 2011-08-30 | 2013-03-06 | 天津药物研究院 | 一种含有效成分盐酸维拉佐酮的缓释片 |
NZ700872A (en) | 2012-03-26 | 2016-09-30 | Nippon Chemiphar Co | Prophylactic or therapeutic agent for giant cell tumors occurring in bone and soft tissue or for chondrosarcoma |
US20160169896A1 (en) * | 2012-10-17 | 2016-06-16 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods for Predicting and Treating Bone Metastases in Prostate Cancer Patients |
JO3368B1 (ar) | 2013-06-04 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2 |
GB201311888D0 (en) | 2013-07-03 | 2013-08-14 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
GB201311891D0 (en) | 2013-07-03 | 2013-08-14 | Glaxosmithkline Ip Dev Ltd | Novel compound |
JO3367B1 (ar) | 2013-09-06 | 2019-03-13 | Janssen Pharmaceutica Nv | مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2 |
JP6527822B2 (ja) | 2013-09-25 | 2019-06-05 | 日本ケミファ株式会社 | 骨・軟部に発生する巨細胞性腫瘍、軟骨肉腫または骨肉腫の予防、治療または転移の予防のための薬剤、動脈塞栓術用局所注入剤、および、人工骨 |
KR20220049612A (ko) | 2014-01-21 | 2022-04-21 | 얀센 파마슈티카 엔.브이. | 대사 조절형 글루탐산 작동성 수용체 제2아형의 양성 알로스테릭 조절제 또는 오르토스테릭 작동제를 포함하는 조합 및 그 용도 |
ES2748633T3 (es) | 2014-01-21 | 2020-03-17 | Janssen Pharmaceutica Nv | Combinaciones que comprenden moduladores alostéricos positivos del receptor glutamatérgico metabotrópico de subtipo 2 y su uso |
US10071164B2 (en) * | 2014-08-11 | 2018-09-11 | Yale University | Estrogen-related receptor alpha based protac compounds and associated methods of use |
MX2018005340A (es) | 2015-11-02 | 2018-05-17 | Univ Yale | Proteolisis de direccionamiento a compuestos de quimera y metodos de preparacion y uso de los mismos. |
EP3840749B1 (en) | 2018-08-22 | 2023-08-09 | The J. David Gladstone Institutes, A Testamentary Trust Established under The Will of J. David Gladstone | Compounds for treating cardiac valve disease |
CN112538038B (zh) * | 2019-09-20 | 2022-05-20 | 暨南大学 | 2-吲哚酮类ERRα反向激动剂及其药物组合物和应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5037842A (en) * | 1990-06-05 | 1991-08-06 | Pfizer Inc. | Oxa- and thiazolidinedione hypoglycemic and hypocholesterolemic agents |
US6518268B1 (en) * | 1999-07-01 | 2003-02-11 | Geron Corporation | Telomerase inhibitors and methods of their use |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003507473A (ja) * | 1999-07-01 | 2003-02-25 | ジェロン コーポレイション | テロメラーゼインヒビターおよびその使用の方法 |
JP2003530437A (ja) | 2000-04-13 | 2003-10-14 | マヨ ファウンデーション フォー メディカル エデュケーション アンド リサーチ | Aβ42低下物質 |
DE10131899A1 (de) | 2001-07-04 | 2003-02-27 | Boehringer Ingelheim Pharma | In vitro-Screening-Assay für gamma-Secretase |
EP1501509A4 (en) * | 2002-04-30 | 2009-07-15 | Merck & Co Inc | THIAZOLIDINE-DIONE AND OXAZOLIDINE-DIONE WITH ARYL-ARYL-ARYLON SUBSTITUTION USEFUL AS BLOCKERS OF SODIUM CHANNELS |
EP1398029A1 (en) | 2002-09-10 | 2004-03-17 | LION Bioscience AG | NR3B1 nuclear receptor binding 3-substituted pyrazole derivatives |
WO2006004555A1 (en) | 2004-06-30 | 2006-01-12 | Paysetter Pte Ltd | System and method for facilitating transfer of physical money and/or credit |
MX2007000606A (es) | 2004-07-14 | 2007-06-25 | Johnson & Johnson | Arilidenos para el tratamiento de enfermedades mediadas por receptor alfa relacionado con estrogeno. |
JP4931824B2 (ja) | 2004-10-22 | 2012-05-16 | エグゼリクシス, インコーポレイテッド | 薬学的組成物 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5037842A (en) * | 1990-06-05 | 1991-08-06 | Pfizer Inc. | Oxa- and thiazolidinedione hypoglycemic and hypocholesterolemic agents |
US6518268B1 (en) * | 1999-07-01 | 2003-02-11 | Geron Corporation | Telomerase inhibitors and methods of their use |
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ATE537157T1 (de) | 2011-12-15 |
CY1112778T1 (el) | 2016-02-10 |
EP2132188B1 (en) | 2011-12-14 |
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MX2009009519A (es) | 2009-11-18 |
PL2132188T3 (pl) | 2012-05-31 |
CN101679326A (zh) | 2010-03-24 |
BRPI0808662B1 (pt) | 2020-09-29 |
SI2132188T1 (sl) | 2012-04-30 |
US20080286265A1 (en) | 2008-11-20 |
KR20090118103A (ko) | 2009-11-17 |
HRP20120160T1 (hr) | 2012-03-31 |
BRPI0808662A2 (pt) | 2014-08-26 |
JP2010520307A (ja) | 2010-06-10 |
RS52247B (en) | 2012-10-31 |
ZA200906953B (en) | 2010-12-29 |
US8119669B2 (en) | 2012-02-21 |
AU2008222749A1 (en) | 2008-09-12 |
AR065656A1 (es) | 2009-06-24 |
WO2008109731A2 (en) | 2008-09-12 |
BRPI0808662B8 (pt) | 2021-05-25 |
ES2377165T3 (es) | 2012-03-23 |
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