CN101821227A - 激素敏感性脂酶调节剂及使用方法 - Google Patents
激素敏感性脂酶调节剂及使用方法 Download PDFInfo
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- CN101821227A CN101821227A CN200880107763A CN200880107763A CN101821227A CN 101821227 A CN101821227 A CN 101821227A CN 200880107763 A CN200880107763 A CN 200880107763A CN 200880107763 A CN200880107763 A CN 200880107763A CN 101821227 A CN101821227 A CN 101821227A
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- heteroaryl
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- alkyl
- hydrogen
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Abstract
本文公开了可用于抑制激素敏感性脂酶的通式(I)的化合物或其盐、这些化合物的药物组合物、以及使用这些化合物的治疗方法。其中:Ar为芳基或杂芳基;X为-OC(O)-、-NR6C(O)-、-(CH2)m-、-O(CH2)m、-S(O)(CH2)m或-S(O)O(CH2)m,其中m为1或2;R1选自氢、OH、C1-10烷基、芳基、杂芳基、OC1-10烷基、O-芳基、O-杂芳基、OC1-10亚烷基芳基、OC1-10亚烷基杂芳基和N(R4)R5;R2、R3、R4、R5和R6各自独立地选自氢、C1-10烷基、C(O)C1-10烷基、C(O)C(O)C1-10烷基、C(O)NR7R8和C(O)C1-10卤代烷基;和R7和R8独立地选自氢、C1-10烷基、芳基和杂芳基。
Description
相关申请的交叉引用
本申请要求2007年7月12日提交的美国临时申请60/949,325的权益,该申请通过全文引用结合到本文中来。
发明领域
本发明涉及化合物、包含所述化合物的组合物及其在治疗需要调节激素敏感性脂酶活性的医学病症中的用途。
背景
需要高度调节哺乳动物体系的总能量体内平衡,以确保在适当的时间利用适当的底物。在餐后状态血浆葡萄糖水平上升,在2-3小时内返回至餐前水平。在这2-3小时期间,胰岛素促进骨骼肌和脂肪组织摄取葡萄糖,且降低游离脂肪酸(FFA)从脂肪细胞释放,以确保两种底物互不竞争。当血浆葡萄糖水平下降时,需要升高血浆FFA以使各种组织从利用葡萄糖切换为利用脂肪。
在患有胰岛素抵抗的个体中,FFA水平不响应胰岛素下降(而在正常个体中,FFA水平响应胰岛素下降),这样妨碍了骨骼肌、脂肪和肝对葡萄糖的正常利用。此外,在胰岛素敏感性与血浆FFA水平之间存在负性关联。
激素敏感性脂酶(HSL)为主要表达于脂肪细胞中的酶,其催化甘油三酯向甘油和脂肪酸的转化。通过该酶的调节作用来调节循环FFA的水平。胰岛素导致HSL失活,继发在餐后状态血浆FFA水平下降,随后当在吸收后阶段胰岛素浓度下降且儿茶酚胺上升时,该酶被激活。HSL的激活导致血浆FFA上升,这时血浆FFA变为在空腹期间的主要能量来源。
HSL的激活-失活主要通过cAMP-蛋白质激酶A和AMP依赖性激酶路径介导。存在如烟酸及其衍生物的化合物,通过这些路径降低HSL的激活,并引起脂肪分解降低,这导致FFA水平下降。在FFA升高患者中可见,这些药物对葡萄糖的利用和过量甘油三酯合成的正常化具有有益效果。但是,因为这些路径被体内其他过程使用,因此这些药物具有严重的副作用。本申请感兴趣的是共同拥有、共同待审的美国申请11/650,912和国际申请PCT/US07/00284,这些申请各自通过引用结合到本文中来。存在对抑制HSL的化合物的需求。
发明概述
本发明涉及具有式(I)结构的化合物、其药物组合物以及使用这些化合物和组合物来治疗、预防或改善其中涉及激素敏感性脂酶(HSL)的各种疾病和病症的方法。抑制HSL可导致血浆游离脂肪酸(FFA)水平降低,且本文所公开的化合物可用于治疗其中需要降低血浆FFA水平的病症和/或疾病,例如胰岛素抵抗、代谢综合征X、血脂异常和脂蛋白代谢异常。
因此,一方面提供了式(I)化合物及其盐、溶剂合物和水合物、外消旋物、外消旋混合物和纯对映异构体、非对映异构体、同系物、类似物和混合物,
其中:Ar为芳基或杂芳基;X为-OC(O)-、-N-R6C(O)-、-(CH2)m-、-O(CH2)m、-S(O)(CH2)m或-S(O)O(CH2)m,其中m为1或2;R1选自氢、OH、C1-10烷基、芳基、杂芳基、OC1-10烷基、O-芳基、O-杂芳基、OC1-10亚烷基芳基、OC1-10亚烷基杂芳基和N(R4)R5;R2、R3、R4、R5和R6各自独立地选自氢、C1-10烷基、C(O)C1-10烷基、C(O)C(O)C1-10烷基、C(O)NR7R8和C(O)C1-10卤代烷基;和R7和R8独立地选自氢、C1-10烷基、芳基和杂芳基。
在一些实施方案中,R2和R3均不为氢。在各种实施方案中,X为OC(O)或NR6C(O)。在具体的实施方案中,Ar为苯基、4-乙酰基苯基、4-羟基苯基、4-吡啶基、2-噻吩基或2-呋喃基。在一些具体的实施方案中,R2为氢、甲基、乙基、丙基或苄基,R3为C(O)C(O)OCH3、C(O)CH3、C(O)CF3或C(O)NR7R8。在各种实施方案中,R1为OH、甲氧基、乙氧基、丙氧基、苯氧基、苄氧基、N(CH3)OCH3、任选取代的芳基或任选取代的杂芳基。
在具体的实施方案中,式(I)化合物如下所示或为其盐、溶剂合物或水合物、外消旋物、外消旋混合物或纯对映异构体,或其混合物:
另一方面提供了本文所公开的式(I)化合物和药学上可接受的载体的组合物。
又一方面提供了在有此需要的患者中抑制激素敏感性脂酶的方法,所述方法包括给予治疗有效量的本文所公开的式(I)化合物,所述化合物抑制HSL的IC50高达约10mM。在一些实施方案中,式(I)化合物的IC50高达约1mM或高达约100nM。在具体的实施方案中,所述化合物为
或其盐。在各种实施方案中,所述方法还包括给予治疗有效量的一种或多种对代谢障碍或紊乱具有有利效果的活性剂。在一些情况下,活性剂与式(I)化合物同时给予。在一些实施方案中,所述方法还包括给予治疗有效量的一种或多种抗糖尿病药物。
本发明的再一方面提供了一种治疗、预防或改善有需要的患者与脂肪酸代谢病症或葡萄糖利用病症关联的一种或多种症状的方法,所述方法包括给予所述患者治疗有效量的抑制HSL的IC50高达约10mM的本文所公开的化合物。在一些实施方案中,式(I)化合物的IC50高达约1mM或高达约100nM。在具体的实施方案中,所述化合物为
或其盐。在各种实施方案中,所述方法还包括给予治疗有效量的用于治疗或预防脂肪酸代谢病症、葡萄糖利用病症或二者的活性剂。在具体的实施方案中,活性剂与本文所公开的式(I)化合物同时给予。
又一方面提供了一种治疗、预防或改善涉及胰岛素抵抗的病症的方法,所述方法包括给予有此需要的患者治疗有效量的抑制HSL的IC50高达约10mM的本文所公开的式(I)化合物。在一些实施方案中,式(I)化合物的IC50高达约1mM或高达约100nM。在具体的实施方案中,所述化合物为
或其盐。在具体情况下,患者患有糖尿病。在各种实施方案中,所述方法还包括给予治疗有效量的用于治疗、预防或改善其中涉及胰岛素抵抗的病症的活性剂。在具体的实施方案中,活性剂与本文所公开的式(I)化合物同时给予。
另一方面提供了一种治疗、预防或改善血脂异常或血脂异常并发症的方法,所述方法包括给予有此需要的患者治疗有效量的本文所公开的式(I)化合物。在一些实施方案中,式(I)化合物的IC50高达约1mM或高达约100nM。在具体的实施方案中,所述化合物为
或其盐。
再一方面提供了一种治疗、预防或改善与代谢综合征X关联的病症的方法,所述方法包括给予有此需要的患者治疗有效量的本文所公开的式(I)化合物。在一些实施方案中,式(I)化合物的IC50高达约1mM或高达约100nM。在具体的实施方案中,所述化合物为
或其盐。
附图概述
图1、2和3说明在不同浓度的本文所公开的几种化合物和已知抑制HSL的参照化合物存在下,激素敏感性脂酶(HSL)的活性。
发明详述
定义
本文使用的术语“烷基”是指直链和支链烃基,其非限制性实例包括甲基、乙基、直链和支链的丙基和丁基。术语“烷基”包括“桥连烷基”,即,二环或多环烃基,例如降冰片烷基、金刚烷基、双环[2.2.2]辛基、双环[2.2.1]庚基、双环[3.2.1]辛基或十氢萘基。烷基可任选被取代,例如被羟基(OH)、卤素、芳基、杂芳基、环烷基、杂环烷基和氨基取代。
本文使用的术语“亚烷基”是指具有取代基的烷基。例如术语“亚烷基芳基(alkenylenearyl)”是指被芳基取代的烷基。亚烷基任选被一个或多个前面所列作为任选的烷基取代基的取代基取代。
本文使用的术语“芳基”是指单环或多环芳族基团,优选单环或二环芳族基团,例如苯基或萘基。除非另外说明,否则芳基可未被取代或被一个或多个特别是1-4个基团取代。示例性芳基包括但不限于苯基、萘基、四氢萘基、氯苯基、甲基苯基、甲氧基苯基、三氟甲基苯基、硝基苯基、2,4-甲氧基氯苯基等等。
本文使用的术语“杂芳基”是指包含一个或两个芳环且在芳环中包含至少一个氮、氧或硫原子的单环或二环环系。除非另外说明,否则杂芳基可未被取代或被一个或多个特别是1-4个取代基取代。杂芳基的实例包括但不限于噻吩基(thienyl)、呋喃基、吡啶基、噁唑基、喹啉基、噻吩基(thiophenyl)、异喹啉基、吲哚基、三嗪基、***基、异噻唑基、异噁唑基、咪唑基、苯并噻唑基、吡嗪基、嘧啶基、噻唑基和噻二唑基。
合适的脂族或芳族取代基包括但不限于-F、-Cl、-Br、-I、-OH、被保护的羟基、脂族醚、芳族醚、氧代、-NO2、-CN、任选被卤素取代的-C1-C12-烷基(例如全卤代烷基)、任选被卤素取代的C2-C12烯基、任选被卤素取代的-C2-C12炔基、-NH2、被保护的氨基、-NH-C1-C12烷基、-NH-C2-C12烯基、-NH-C2-C12炔基、-NH-C3-C12环烷基、-NH芳基、-NH-杂芳基、-NH-杂环烷基、-二烷基氨基、-二芳基氨基、-二杂芳基氨基、-OC1-C12-烷基、-OC2-C12烯基、-OC2-C12炔基、-OC3-C12环烷基、-O芳基、-O杂芳基、-O-杂环烷基、-C(O)C1-C12烷基、-C(O)C2-C12烯基、-C(O)C2-C12炔基、-C(O)C3-C12环烷基、-C(O)芳基、-C(O)杂芳基、-C(O)杂环烷基、-CONH2、-CONHC1-C12烷基、-CONHC2-C12烯基、-CONHC2-C12炔基、-CONHC3-C12环烷基、-CONH芳基、-CONH杂芳基、-CONH杂环烷基、-CO2C1-C12烷基、-CO2C2-C12烯基、-CO2C2-C12炔基、-CO2C3-C12环烷基、-CO2芳基、-CO2杂芳基、-CO2杂环烷基、-OCO2C1-C12烷基、-OCO2C2-C12烯基、-OCO2C2-C12炔基、-OCO2C3-C12环烷基、-OCO2芳基、-OCO2杂芳基、-OCO2杂环烷基、-OCONH2、-OCONHC1-C12烷基、-OCONHC2-C12烯基、-OCONHC2-C12炔基、-OCONHC3-C12环烷基、-OCONH芳基、-OCONH杂芳基、-OCONH杂环烷基、-NHC(O)C1-C12烷基、-NHC(O)C2-C12烯基、-NHC(O)C2-C12炔基、-NHC(O)C3-C12环烷基、-NHC(O)芳基、-NHC(O)杂芳基、 -NHC(O)杂环烷基、 -NHCO2C1-C12烷基、-NHCO2C2-C12烯基、-NHCO2C2-C12炔基、-NHCO2C3-C12环烷基、-NHCO2芳基、-NHCO2杂芳基、-NHCO2杂环烷基、-NHC(O)NH2、NHC(O)NHC1-C12烷基、-NHC(O)NHC2-C12烯基、-NHC(O)NHC2-C12炔基、-NHC(O)NHC3-C12环烷基、-NHC(O)NH芳基、-NHC(O)NH杂芳基、-NHC(O)NH杂环烷基、NHC(S)NH2、NHC(S)NHC1-C12烷基、-NHC(S)NHC2-C12烯基、-NHC(S)NHC2-C12炔基、-NHC(S)NHC3-C12环烷基、-NHC(S)NH芳基、-NHC(S)NH杂芳基、-NHC(S)NH杂环烷基、-NHC(NH)NH2、-NHC(NH)NHC1-C12烷基、-NHC(NH)NHC2-C12烯基、-NHC(NH)NHC2-C12炔基、-NHC(NH)NHC3-C12环烷基、-NHC(NH)NH芳基、-NHC(NH)NH杂芳基、-NHC(NH)NH杂环烷基、NHC(NH)C1-C12烷基、-NHC(NH)C2-C12烯基、-NHC(NH)C2-C12炔基、-NHC(NH)C3-C12环烷基、-NHC(NH)芳基、-NHC(NH)杂芳基、-NHC(NH)杂环烷基、-C(NH)NHC1-C12烷基、-C(NH)NHC2-C12烯基、-C(NH)NHC2-C12炔基、-C(NH)NHC3-C12环烷基、-C(NH)NH芳基、-C(NH)NH杂芳基、-C(NH)NH杂环烷基、-S(O)C1-C12烷基、-S(O)C2-C12烯基、-S(O)C2-C12炔基、-S(O)C3-C12环烷基、-S(O)芳基、-S(O)杂芳基、-S(O)杂环烷基、-SO2NH2、-SO2NHC1-C12烷基、-SO2NHC2-C12烯基、-SO2NHC2-C12炔基、-SO2NHC3-C12环烷基、-SO2NH芳基、-SO2NH杂芳基、-SO2NH杂环烷基、-NHSO2C1-C12烷基、-NHSO2C2-C12烯基、-NHSO2C2-C12炔基、-NHSO2C3-C12环烷基、-NHSO2芳基、-NHSO2杂芳基、-NHSO2杂环烷基、-CH2NH2、-CH2SO2CH3、-芳基、-芳基烷基、-杂芳基、-杂芳基烷基、-杂环烷基、-C3-C12环烷基、聚烷氧基烷基、聚烷氧基、-甲氧基甲氧基、-甲氧基乙氧基、-SH、-SC1-C12烷基、-SC2-C12烯基、-SC2-C12炔基、-SC3-C12环烷基、-S芳基、-S杂芳基、-S杂环烷基或甲基硫代甲基。应理解的是,芳基、杂芳基、烷基等等可被进一步取代。
本文使用的术语“药学上可接受的盐”是指在合理的医学判断范围内、适合与人类和低等动物的组织接触而没有过度毒性、刺激、过敏反应等等,且与合理的收益/风险比匹配的那些盐。药学上可接受的盐为本领域众所周知的。例如S.M.Berge等人在J.PharmaceuticalSciences,66:1-19(1977)中详细描述了药学上可接受的盐。所述盐可在本发明化合物的最终的分离和纯化过程中原位制备,或者通过游离碱官能团与合适的有机酸或无机酸反应而单独制备。药学上可接受的无毒酸加成盐的实例包括但不限于与无机酸(例如盐酸、氢溴酸、磷酸、硫酸和高氯酸)或与有机酸(例如乙酸、马来酸、酒石酸、柠檬酸、琥珀酸、乳糖酸或丙二酸)形成的或使用本领域使用的其他方法(例如离子交换)形成的氨基的盐。其他药学上可接受的盐包括但不限于己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫代氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等等。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁等等。其他药学上可接受的盐包括在适当的情况下使用反荷离子形成的无毒铵、季铵和胺阳离子,所述反荷离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、具有1-6个碳原子的烷基、磺酸根和芳基磺酸根。
本文使用的术语“药学上可接受的酯”是指体内水解的酯,包括在人体中容易分解以留下母体化合物或其盐的那些。合适的酯基包括例如衍生自药学上可接受的脂族羧酸(特别是链烷酸、链烯酸、环烷酸和链烷双酸)的那些,其中每个烷基或烯基部分具有不超过6个碳原子是有利的。具体酯的实例包括但不限于甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯和乙基琥珀酸酯。
本文使用的“药学上可接受的载体”意欲包括与给药相容的任何和所有的溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等张和吸收延迟剂等等,例如无菌不含热原物的水。合适的载体描述于最新版的Remington′s Pharmaceutical Sciences,其为本领域标准教科书,该文献通过引用结合到本文中来。所述载体或稀释剂的优选的实例包括但不限于水、盐水、finger′s溶液、葡萄糖溶液和5%人血清白蛋白。也可使用脂质体和非含水赋形剂,例如非挥发性油类。用于药学上活性物质的这些介质和试剂的使用为本领域众所周知的。除非与活性化合物不配伍,任何常规介质或试剂均考虑用于所述组合物。补充活性化合物也可掺入所述组合物中。
本文使用的术语“治疗有效量”是指依据给定的给予模式,获得期望效果的活性化合物的量。所述化合物的毒性和疗效可通过在细胞培养物或实验动物中以标准药学程序来测定,例如测定LD50(群体中50%致命的剂量)和ED50(群体中50%治疗有效的剂量)。毒性剂量与治疗有效剂量之比称为治疗指数。优选表现出大治疗指数的化合物。这些数据可用于调配用于人类或其他动物的剂量范围。优选所述化合物的剂量落入循环浓度范围内,包括ED50,毒性很小或无毒性。根据使用的剂型和采用的给药途径,剂量可在该范围内变化。
本文所公开的化合物可抑制HSL。HSL的抑制通常用IC50表示,IC50为50%的酶被抑制时的浓度。IC50越低,则抑制剂越有效。可使用标准技术来测量IC50。本文所公开的化合物对HSL的IC50可高达约10mM,高达约5mM,高达约3mM,高达约2mM,高达约1mM,高达约0.5mM,高达约0.3mM,高达约0.2mM,高达约0.1mM,高达约50nM,高达约40nM,高达约30nM,高达约25nM,高达约20nM,高达约15nM,高达约10nM或高达约5nM。
本发明还提供了治疗、预防或改善其中降低和抑制激素敏感性脂酶(HSL)有益于患者治疗期望FFA血浆水平降低的病症的方法,所述病症例如胰岛素抵抗、代谢综合征X、血脂异常和脂蛋白代谢异常。
通式(I)的本发明化合物对于HSL可具有强抑制效果,HSL为脂肪细胞中的一种变构酶,其被胰岛素抑制并起分解脂肪细胞中的脂肪的作用并从而将脂肪成分转移至血流中。因此,该酶的抑制等同于本发明的化合物和衍生物的类胰岛素效果,最终导致血液中的游离脂肪酸和血液中的葡萄糖下降。因此,式(I)化合物可用于代谢紊乱,例如非胰岛素依赖性糖尿病、糖尿病性综合征和直接胰腺损害。
式(I)化合物可为其盐、溶剂合物和水合物、外消旋物、外消旋混合物和纯对映异构体以及其非对映异构体、同系物、类似物和混合物形式。在一些情况下,式(I)化合物为外消旋混合物或(R)和(S)对映异构体的不等混合物。在各种情况下,式(I)化合物主要为(S)对映异构体或主要为(R)对映异构体。例如
通式(I)的本发明化合物对于HSL可具有强抑制效果,HSL为脂肪细胞中的一种变构酶,其被胰岛素抑制并起分解脂肪细胞中的脂肪的作用并从而将脂肪成分转移至血流中。因此,该酶的抑制等同于本发明的化合物和衍生物的类胰岛素效果,最终导致血液中的游离脂肪酸和血液中的葡萄糖下降。因此,式(I)化合物可用于代谢紊乱,例如非胰岛素依赖性糖尿病、糖尿病性综合征和直接胰腺损害。
化合物的合成
可使用本领域已知的技术和在2007年1月5日提交的国际申请PCT/US07/00284中所公开的那些技术来合成本文所公开的化合物,该申请通过全文引用结合到本文中来。一种合成方法描述于以下流程1。
流程1
通过改变原料可制备其他式(I)化合物,例如使用甲基碘代替甲氧基甲基胺以提供甲基酯和/或使用烷基化试剂代替二醇酯以提供烷基胺。对以上合成流程的其他修改以及其他合适的合成方式对于合成领域技术人员来说是显而易见的。
治疗应用
式(I)化合物对于激素敏感性脂酶(HSL)具有强抑制效果,HSL为脂肪细胞中的一种变构酶,其被胰岛素抑制并起分解脂肪细胞中的脂肪的作用并从而将脂肪成分转移至血流中。因此,该酶的抑制等同于本发明的化合物和衍生物的类胰岛素效果,最终导致血液中的游离脂肪酸和血液中的葡萄糖下降。因此,式(I)化合物可用于代谢紊乱,例如非胰岛素依赖性糖尿病、糖尿病性综合征和直接胰腺损害。
式(I)化合物特别适合治疗和/或预防脂肪酸代谢的改变和葡萄糖利用病症,涉及胰岛素抵抗的病症,例如糖尿病,特别是II型糖尿病,包括预防与其关联的并发症。关于这一点的具体方面为高血糖症、改进胰岛素抵抗、改进葡萄糖耐受、保护胰腺β-细胞和预防大脉管和微脉管病症。式(I)化合物也适合治疗和/或预防血脂异常及其并发症,例如动脉粥样硬化、冠心病、脑血管病症等,特别是(但不限于)特征为一种或多种以下因素的那些:血浆甘油三酯浓度高、餐后血浆甘油三酯浓度高、HDL胆固醇浓度低、ApoA脂蛋白浓度低、LDL胆固醇浓度高、密集LDL胆固醇颗粒少和ApoB脂蛋白浓度高。
各种其他病症可与代谢综合征X关联,例如:肥胖,包括中枢肥胖、血栓症、心衰例如(但不限于)心肌梗塞后的心衰、高血压性心脏病或心肌病。
再一方面,一种或多种式(I)化合物可用于治疗高血糖症、升高的HbAlc水平、高胰岛素血症、II型糖尿病、成人潜伏性自身免疫糖尿病、成年发病糖尿病、β-细胞凋亡、血色病诱发的糖尿病、葡萄糖耐受受损、空腹葡萄糖受损、代谢综合征X、胰岛素抵抗、脂质耐受受损、与囊性纤维变性相关的糖尿病、多囊性卵巢综合征和妊娠期糖尿病。
再一方面,一种或多种式(I)化合物可用于治疗肝病,例如肝脂肪变性和肝硬化。
再一方面,一种或多种式(I)化合物可用于治疗各种症状,例如重量减轻和与AIDS关联的恶病质或与AIDS相关的疾病。一种或多种式(I)化合物也可用于治疗各种状况或病症,例如骨关节炎;红斑狼疮(LE)或炎性风湿病,例如类风湿性关节炎;血管炎;消瘦(恶病质);痛风;局部缺血/多次灌注综合征;急性呼吸窘迫综合征(ARDS);脂肪代谢障碍和脂肪代谢障碍状态,以及用于治疗治各种病症的其他药物的不利影响(例如在用于治疗HIV或肿瘤的药物之后)。
再一方面,一种或多种式(I)化合物可用于预防或治疗肥胖、血脂异常、糖尿病性血脂异常、高脂质血症、高甘油三酯血症、高脂蛋白血症、高胆固醇血症、高血压、原发性高血压、急性高血压性急症、动脉硬化、动脉粥样硬化、支架内再狭窄、间歇性跛行、心血管病、心肌病、心脏肥大、左心室肥大、冠状动脉疾病、早期冠状动脉疾病、心力不足、锻炼耐受、慢性心衰、轻度慢性心衰、心律失常、心脏节律障碍、晕厥、心脏病发作、心肌梗塞、Q-波心肌梗塞、中风、急性冠状动脉综合征、心绞痛、不稳定绞痛、心脏支路再闭塞、舒张机能障碍、收缩机能障碍、非Q-波心脏坏死、术后分解代谢变化、急性胰腺炎和过敏性肠综合征。
再一方面,一种或多种式(I)化合物可用于预防或治疗糖尿病性视网膜病、本底视网膜病、增殖性前视网膜病、增殖性视网膜病、斑点水肿、白内障、肾病、肾病综合征、糖尿病性肾病、微蛋白尿、大量蛋白尿、神经病、糖尿病性神经病、多神经病和糖尿病性自发性神经病。
再一方面,一种或多种式(I)化合物可用于预防或治疗其中可能涉及炎性反应或细胞分化的其他病症或状况。例如动脉粥样硬化,例如(但不限于)冠状动脉硬化,包括心绞痛或心肌梗塞、中风脉管支架内再狭窄或再闭塞;慢性炎性肠病,例如局限性回肠炎和溃疡性结肠炎、胰腺炎;和其他炎性状态。
再一方面,一种或多种式(I)化合物可用于预防或治疗其中胆固醇为前体的疾病、状况或病症。所述疾病、状况或病症可涉及睾酮,例如男性节育、过度睾酮水平和***癌。所述疾病、状况或病症还可涉及氢化可的松或促肾上腺皮质激素,例如库欣病。
本文所公开的化合物也可用于预防或治疗癌症。因此,一种或多种式(I)化合物可用于治疗胰岛瘤(胰腺岛细胞肿瘤),例如恶性胰岛瘤和多发性胰岛瘤、脂肪细胞癌,例如脂瘤癌脂肪细胞肿瘤;pomatous癌,例如脂肪肉瘤;实体肿瘤和新生物,例如(但不限于)胃肠道癌、肝癌、胆道癌和胰脏癌;内分泌肿瘤;肺癌、肾癌、尿道癌、生殖道癌和***癌。
本文所公开的化合物也可用于预防或治疗phaechromocytoma和儿茶酚胺内分泌上升的其他疾病。
本文所公开的化合物可用于预防或治疗***癌,例如腺癌、急性和慢性成髓增殖性病症和淋巴瘤;血管形成、癌症关联的噁病质;神经变性病症,例如阿尔茨海默病、多发性硬化和帕金森病;红斑-鳞状皮肤病,例如银屑病、寻常痤疮;和受PPAR调节的其他皮肤病和皮肤状况,包括但不限于湿疹和神经性皮炎;皮炎,例如皮脂溢性皮炎或光照性皮炎;角膜炎和角化症,例如皮脂溢性角化症、老年性角化症、光化性角化症、光诱发的角化症或角化症卵泡、瘢痕和瘢痕预防;疣,包括湿疣或***;人***瘤病毒(HPV)感染,例如性病***瘤、病毒疣,例如***、粘膜白斑、丘疹皮肤病,例如扁平苔癣;皮肤癌,例如基础-细胞癌、黑素瘤或皮肤T-细胞淋巴瘤、局部良性表皮肿瘤,例如角皮病、表皮痣、高血压、代谢综合征X;多囊性卵巢综合征(PCOS);和哮喘。
联合治疗
本文所公开的化合物可单独给予或与一种或多种例如对通常与其关联的代谢障碍或紊乱具有有利效果的其他药理学上活性物质联用。所述药物的实例为降低血糖的药物、抗糖尿病药物、用于治疗血脂异常的活性成分、抗动脉粥样硬化药物、抗肥胖药、抗炎活性成分、用于治疗恶性肿瘤的活性成分、抗血栓形成活性成分、用于治疗高血压的活性成分、用于治疗心衰的活性成分和用于治疗和/或预防由糖尿病引起或与糖尿病关联的并发症的活性成分。
此外,本发明化合物可与一种或多种抗高血压药联合给药。抗高血压药的实例为β-阻滞药,例如阿普洛尔、阿替洛尔、噻吗洛尔、吲哚洛尔、***和美托洛尔;ACE(血管紧张素转化酶)抑制剂,例如贝那普利、卡托普利、alatriopril、依那普利、福辛普利、赖诺普利、喹那普利和雷米普利;钙通道阻滞药,例如硝苯地平、非洛地平、尼卡地平、伊拉地平、尼莫地平、地尔硫卓和维拉帕米;和α-阻滞药,例如多沙唑嗪、乌拉地尔、哌唑嗪和特拉唑嗪。认为本发明化合物与一种或多种上述化合物和任选的一种或多种其他药理学上活性物质的任何合适的组合在本发明的范围内。
具体而言,一种或多种其他药理学上活性物质可与一种或多种式(I)化合物联用以具有协同改进效果。活性成分组合的给予可通过对患者单独给予活性成分或采用联用产品的形式给予。
在本发明的一种实施方案中,一种或多种式(I)化合物与抗糖尿病药联合给予(例如,参见Rote Liste 2001,第12章,或USAN的USPDictionary和International Drug Names,US药典,Rockvile 2001)。抗糖尿病药包括所有胰岛素和胰岛素衍生物和其他空腹起作用的胰岛素、GLP-1受体调节剂。
口服有效低血糖活性成分可包括但不限于磺脲类(例如甲苯磺丁脲、格列苯脲、格列吡嗪或格列美脲)、双胍类(例如二甲双胍)、美格列奈类(例如瑞格列奈)、噁唑烷二酮类、噻唑烷二酮类(例如环格列酮、吡格列酮、罗格列酮)、普糖苷酶抑制剂、胰高血糖素拮抗剂、GLP-1激动剂、DPP-IV抑制剂、钾通道开启剂、胰岛素敏化剂、涉及刺激葡糖异生和/或糖原分解的肝酶的抑制剂、葡萄糖摄取调节剂、改变脂质代谢且导致血脂组成改变的化合物、减少食物摄取的化合物、PPAR和PXR调节剂以及作用于β细胞的ATP依赖性钾通道的活性成分。
在一种实施方案中,一种或多种式(I)化合物与PPARγ激动剂例如罗格列酮或吡格列酮联合给予。
在一种实施方案中,一种或多种式(I)化合物与α-普糖苷酶抑制剂例如米格列醇或阿卡波糖联合给予。
在一种实施方案中,一种或多种式(I)化合物与多于一种上述化合物联合给予,例如与磺酰脲和二甲双胍、磺酰脲和阿卡波糖、瑞格列奈和二甲双胍、胰岛素和磺酰脲、胰岛素和二甲双胍、胰岛素和曲格列酮、胰岛素和洛伐他汀,等联用。
在一种实施方案中,一种或多种式(I)化合物与一种或多种脂质调节剂联合给予。示例性脂质调节剂包括但不限于HMGCoA还原酶抑制剂(例如洛伐他汀、氟伐他汀、普伐他汀、辛伐他汀、ivastatin、伊伐他汀、阿托伐他汀、罗苏伐他汀);胆汁酸再吸收抑制剂;聚合物胆汁酸吸附剂(例如考来烯胺、考来维仑);胆固醇吸收抑制剂(例如依泽替米贝、替奎安、帕马苷);和LDL受体诱导剂。
在一种实施方案中,一种或多种式(I)化合物与PPARα激动剂联合给予。
在一种实施方案中,一种或多种式(I)化合物与混合型PPARα/γ激动剂例如AZ 242和/或替格列扎(Tesaglitazar)联合给予。
在一种实施方案中,一种或多种式(I)化合物与贝特类药物例如非诺贝特、吉非贝齐、氯贝丁酯或苯扎贝特联合给予。
在一种实施方案中,一种或多种式(I)化合物与烟酸(nicotinic acid)或烟酸(niacin)联合给予.
在一种实施方案中,一种或多种式(I)化合物与单独的CETP抑制剂如CP-529,4 1 4(托彻普(torcetrapib))联合给予,以及进行多重联合治疗,包括但不限于与HMGCoA还原酶抑制剂,例如洛伐他汀、氟伐他汀、普伐他汀、辛伐他汀、ivastatin、阿托伐他汀或罗苏伐他汀联合给予。
在一种实施方案中,一种或多种式(I)化合物与ACAT抑制剂联合给予。
在一种实施方案中,一种或多种式(I)化合物与MTP抑制剂例如英普他派联合给予。
在一种实施方案中,一种或多种式(I)化合物与抗氧化剂联合给予。
在一种实施方案中,一种或多种式(I)化合物与脂蛋白脂酶抑制剂联合给予。
在一种实施方案中,一种或多种式(I)化合物与ATP柠檬酸裂合酶抑制剂联合给予。
在一种实施方案中,一种或多种式(I)化合物与角鲨烯合成酶抑制剂联合给予。
在一种实施方案中,一种或多种式(I)化合物与脂蛋白拮抗剂联合给予。
在另一实施方案中,一种或多种式(I)化合物与抗肥胖药联合给予。在本发明的一种实施方案中,式(I)或(II)的化合物与脂酶抑制剂例如奥利司他联合给予。
在一种实施方案中,其他活性成分或药物为芬氟拉明、右芬氟拉明或***。
在其他实施方案中,一种或多种式(I)化合物与CART调节剂、NPY拮抗剂、MC4激动剂、食欲素(orexin)拮抗剂、H3激动剂、TNF激动剂、CRF拮抗剂、CRF BP拮抗剂、尿皮质激素(urocortin)激动剂、β3激动剂、MSH(黑素细胞-刺激激素)激动剂、CCK-A激动剂、5-羟色胺重摄取抑制剂(例如右芬氟拉明)、混合型血清素激活和去甲肾上腺素能化合物、5HT激动剂、韩蛙皮素激动剂、神经节肽(galanin)拮抗剂、生长激素(例如人生长激素)、释放生长激素的化合物、TRH激动剂、解偶联蛋白质2或3调节剂、瘦蛋白激动剂、DA激动剂(溴隐亭、Doprexin)、脂酶/淀粉酶抑制剂、PPAR调节剂、RXR调节剂或TR-β激动剂联合给予。
在一种实施方案中,其他活性成分或药物为瘦蛋白、右***、***、马吲哚或芬特明。
在一种实施方案中,一种或多种式(I)化合物与对冠状动脉循环和脉管体系具有影响的药物如ACE抑制剂(例如雷米普利)、对血管紧张素-肾素体系起作用的药物、钙拮抗剂、β阻滞药等联合给予。
在一种实施方案中,一种或多种式(I)化合物与具有抗炎效果的药物联合给予。
在一种实施方案中,一种或多种式(I)化合物与用于癌症治疗和癌症预防的药物联合给予。
应理解的是,认为本发明化合物与一种或多种上述化合物和任选的一种或多种其他药理学上活性物质的每个合适的组合落入本发明的保护范围内。
药物组合物
本发明包括药物组合物,所述组合物包含上述本发明化合物的药学上可接受的盐或其衍生物、类似物、同系物。本发明还包括包含本发明化合物的水合物的药物组合物。术语“水合物”包括但不限于半水合物、一水合物、脱水物、三水合物等等。本发明还包括包含本发明化合物的任何固体或液体物理形式的药物组合物。例如所述化合物可为晶体形式、无定形形式,且具有任何粒度。所述颗粒可为微粒化的、或可为附聚的、粒状颗粒、粉末、油状、油状混悬液或固体或液体物理形式的任何其他形式。
可将本发明化合物及其衍生物、片段(fragment)、类似物、同系物、药学上可接受的盐或水合物掺入适合与药学上可接受的载体或赋形剂一起给予的药物组合物中。所述组合物通常包含治疗有效量的任一种上述化合物以及药学上可接受的载体。优选,当治疗癌症时,有效量为有效选择性引发合适的肿瘤细胞的末端分化的量且小于在患者中引起毒性的量。
式(I)化合物可通过任何合适的方式给予,包括但不限于胃肠外、静脉内、肌内、皮下、植入、口服、舌下、口颊、经鼻、经肺、经皮、局部、经***、经直肠和经粘膜给予等等。药物制剂包括适合所选给予模式的包含式(I)化合物作为活性成分的固体、半固体或液体制剂(片剂、丸剂、锭剂、胶囊剂、栓剂、霜剂、软膏剂、气溶胶、散剂、液体剂、乳剂、混悬剂、糖浆剂、注射剂等)。在一种实施方案中,所述药物组合物口服给予,因此,配制成适合口服给予的形式,即,固体或液体制剂。合适的固体口服制剂包括片剂、胶囊剂、丸剂(pills)、颗粒剂、丸剂(pillet)、扁囊剂和泡腾剂、散剂等等。合适的液体口服制剂包括溶液剂、混悬剂、分散剂、乳剂、油剂等等。在一种实施方案中,将所述组合物配制成胶囊剂。根据该实施方案,除了活性化合物和惰性载体或稀释剂以外,本发明组合物还包含硬明胶胶囊剂。
常用作载体或稀释剂的任何惰性赋形剂可用于本发明的制剂,例如树胶,淀粉,糖,纤维素材料,丙烯酸酯或其混合物。优选的稀释剂为微晶纤维素。所述组合物还可包含崩解剂(例如交联羧甲基纤维素钠)和润滑剂(例如硬脂酸镁),此外,所述组合物可包含一种或多种选自以下的添加剂:粘合剂、缓冲剂、蛋白酶抑制剂、表面活性剂、增溶剂、增塑剂、乳化剂、稳定剂、粘度提高剂、甜味剂、成膜剂或其任何组合。此外,本发明组合物可为受控释放或立即释放制剂形式。
对于液体制剂,药学上可接受的载体可为含水或非含水溶液剂、混悬剂、乳剂或油剂。非含水溶剂的实例为丙二醇、聚乙二醇和注射用有机酯如油酸乙酯。含水载体包括水、醇/含水溶液剂、乳剂或混悬剂,包括盐水和缓冲介质。油剂的实例为石油、动物油、植物油或合成来源的那些,例如花生油、豆油、矿物油、橄榄油、葵花油和鱼肝油。溶液剂或混悬剂还可包括以下组分:无菌稀释剂,例如注射用水、盐水溶液、非挥发性油类、聚乙二醇、甘油、丙二醇或其他合成溶剂;抗菌剂,例如苄醇或对羟基苯甲酸甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸(EDTA);缓冲剂,例如乙酸盐、柠檬酸盐或磷酸盐,以及用于调节张度的试剂,例如氯化钠或葡萄糖。可用酸或碱来调节pH,例如用盐酸或氢氧化钠。
此外,所述组合物还可包含粘合剂(例如***胶、玉米淀粉、明胶、卡波姆、乙基纤维素、瓜耳胶、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮)、崩解剂(例如玉米淀粉、马铃薯淀粉、藻酸、二氧化硅、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、瓜耳胶、淀粉羟乙酸钠、Primogel)、各种pH和离子强度的缓冲剂(例如tris-HCl、乙酸盐、磷酸盐)、添加剂(例如白蛋白或明胶,以防止吸收至表面)、洗涤剂(例如Tween 20、Tween 80、Pluronic F68、胆汁酸盐)、蛋白酶抑制剂、表面活性剂(例如十二烷基硫酸钠)、渗透增强剂、增溶剂(例如甘油、聚乙烯甘油)、助流剂(例如胶态二氧化硅)、抗氧化剂(例如抗坏血酸、焦亚硫酸钠、丁基化羟基苯甲醚)、稳定剂(例如羟丙基纤维素、羟丙基甲基纤维素)、粘度提高剂(例如卡波姆、胶态二氧化硅、乙基纤维素、瓜耳胶)、甜味剂(例如蔗糖、阿司帕坦、柠檬酸)、矫味剂(例如薄荷、水杨酸甲酯或橙味调味剂)、防腐剂(例如硫柳汞、苄醇、对羟基苯甲酸酯)、润滑剂(例如硬脂酸、硬脂酸镁、聚乙二醇、十二烷基硫酸钠)、流动助剂(例如胶态二氧化硅)、增塑剂(例如邻苯二甲酸二乙酯、柠檬酸三乙酯)、乳化剂(例如卡波姆、羟丙基纤维素、十二烷基硫酸钠)、聚合物包衣(例如泊洛沙姆或poloxamines)、包衣和成膜剂(例如乙基纤维素、丙烯酸酯、聚甲基丙烯酸酯)和/或佐剂。
在一种实施方案中,将活性化合物与保护化合物避免从身体快速消除的载体一起配制,例如控释制剂,包括植入物和微囊包封的递药体系。可使用可生物降解的生物相容的聚合物,例如乙烯-乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。制备所述制剂的方法对于本领域技术人员来说是显然的。各种材料也可市售得自AlzaCorporation和Nova Pharmaceuticals,Inc。也可使用脂质体混悬剂(包括靶向被感染细胞的具有针对病毒抗原的单克隆抗体的脂质体)作为药学上可接受的载体。这些可根据本领域技术人员已知的方法来制备,例如描述于美国专利4,522,811中的方法。
特别有利的是配制易给予且剂量均匀的剂量单位形式的口服组合物。本文使用的剂量单位形式是指适用于待治疗对象的单位剂量的物理离散单位;每个单位包含经计算产生期望治疗效果的预定量的活性化合物以及所需的药物载体。本发明的剂量单位形式的说明受制于并直接取决于活性化合物的独特特性和要达到的具体治疗效果以及混配这种活性化合物用于个体治疗的领域的固有限制。
所述药物组合物可包括在容器、包或分配器中,同时含有给药说明。
含有活性组分的药物组合物的制备为本领域众所周知的,例如通过混合、造粒或形成片剂的方法。通常将活性治疗成分与药学上可接受且与活性成分相容的赋形剂混合。对于口服给予,将活性剂与常用于该目的添加剂的混合,所述添加剂例如赋形剂、稳定剂或惰性稀释剂,且通过常规方法转化为适于给予的形式,例如以上详述的片剂、包衣的片剂、硬或软明胶胶囊剂、含水、醇或油性溶液剂等等。
本领域普通技术人员能确定适合具体疾病状态的不同化合物的服药和服药方案,且这种服药方案可凭经验确定。获得期望生物效应所需的本发明化合物的量取决于多种因素,例如所选择的特定化合物、预定用途、给予方式以及患者的临床状况。
日剂量通常在每天每公斤体重0.3mg-500mg范围内(通常为3mg-50mg),例如3-10mg/kg/天。静脉内剂量可例如在0.3mg-1.0mg/kg范围内,其可适宜以缓慢输液形式给予。单剂量可例如含有1mg-10g的活性成分。因此,注射用安瓿可例如含有1mg-100mg,可口服给予的单剂量制剂(例如片剂或胶囊剂)可例如含有0.05-1000mg活性成分,通常含有0.5-500mg活性成分。
随后每日给予,连续重复几天至几年的时间。口服治疗可持续一周至患者的整个生命之间的时间。优选该给予连续进行5天,随后可评价患者,以确定是否需要进一步给予。给予可为连续或间歇的,即,连续治疗几天,然后歇息一段时间。本发明化合物可在治疗的第一天静脉内给予,在第二天和随后的全部连续日子中口服给予。
给予患者的所述化合物的量低于在患者中会引起毒性的量。在某些实施方案中,给予患者的所述化合物的量低于该化合物在患者血浆中的浓度等于或超过化合物的毒性水平的量。
对于上述病症的治疗,式(I)化合物可使用该化合物本身,但优选为与可接受的载体的药物组合物形式。当然,载体必须是可接受的,意味着其与组合物的其他成分相容且对患者的健康无害。所述载体可为固体或液体或二者,并优选与化合物配制成单剂量,例如为片剂形式,其可含有0.05%-95%重量的活性成分。同样可存在其他药学上活性物质,包括本发明的其他化合物。本发明的药物组合物可通过已知的制药方法中的一种来生产,该方法基本上由将各种成分与药理学上可接受的载体和/或赋形剂混合组成。
本发明的药物组合物为适合口服、直肠、局部、经口(例如舌下)、腹膜内和胃肠外(例如皮下、肌内、皮内或静脉内)给予的那些,但是,在每个个体的情况中,最合适的给予模式取决于待治疗状况的性质和严重性以及用于每种情况的式(I)化合物的性质。包衣的制剂和包衣的缓慢释放的PEG脂质体制剂也在本发明的范围中。
适合口服给予的药物化合物可为单独的单位形式,例如为以下形式:胶囊剂、扁囊剂、***片或片剂,各自含有指定量的式(I)化合物;散剂或颗粒剂;在含水或非水液体中的溶液剂或混悬剂;水包油型或油包水型乳剂。如已提及的,这些组合物可通过任何合适的制药方法来制备,所述方法包括其中使活性成分与载体(可由一种或多种附加的成分组成)接触的步骤。所述组合物通常通过将活性成分与液体和/或细固体载体均一和均匀混合,随后在必要时将产物成型而生产。
适合经口(舌下)给予的药物组合物包括***片和锭剂,***片含有式(I)化合物以及矫味剂(通常为蔗糖和***胶),锭剂在惰性基质(如明胶和甘油或蔗糖和***胶)中包含所述化合物。
适合胃肠外给予的药物组合物优选包含一种或多种式(I)化合物的无菌含水制剂,其优选与接受目标的血液等张。这些制剂优选静脉内给予,但也可通过皮下、肌内或皮内注射给予。这些制剂可优选通过将化合物与水混合、使所得溶液无菌并与血液等张而制备。本发明的注射用组合物通常含有0.1-5%重量的活性化合物。
适合直肠给予的药物组合物优选为单剂量栓剂形式。它们可通过将一种或多种式(I)化合物与一种或多种常规固体载体(例如可可脂)混合并将所得混合物成型而制备。
适合局部给予皮肤的药物组合物优选为软膏剂、霜剂、洗剂、糊剂、喷雾剂、气雾剂或油剂形式。可用的载体有凡士林、羊毛脂、聚乙二醇、醇类以及两种或更多种上述物质的组合。活性成分通常以组合物重量的0.1%-15%,例如0.5%-2%的浓度存在。
经皮给予也是可能的。使用适合于经皮使用的药物组合物。活性成分的适宜浓度为约1%-35%,优选约3%-15%。
式(I)化合物的区别之处在于对代谢病症的有利效果。式(I)化合物有利地影响脂质和葡萄糖代谢,特别是降低甘油三酯水平,且适合预防和治疗II型糖尿病和动脉硬化及其各种并发症。
结合以下实施例可更好地理解本发明的化合物和方法,这些实施例仅用于举例说明,而不是要限制本发明的范围。对所公开的实施方案的各种变化和修改对于本领域技术人员来说是显然的,且在不偏离本发明的精神和所附权利要求的范围的情况下,可进行这些变化和修改,包括但不限于关于本发明的化学结构、取代基、衍生物、制剂和/或方法的那些。
实施例
将化合物1-7溶解于20%DMSO中成10mg/mL的储备液,用于与重组体HSL进行测定,以测试抑制HSL活性的效能,测定方法描述于国际专利申请PCT/US07/00284,该申请通过全文引用结合到本文中来。每种化合物对HSL的抑制效果示于图1和2,其中化合物1的IC50为约0.1-约0.2mg/mL,化合物5在0.4mg/mL时显示约40%的抑制。
表1
测试另一组5种化合物(化合物8-12)对HSL的抑制活性,结果示于表2和图3,其中化合物A为HSL抑制活性的参照化合物。
表2
本说明书中涉及的所有的以上美国专利、美国专利申请公开、美国专利申请、外国专利、外国专利申请和非专利公开通过全文引用结合到本文中来。
由前述可理解的是,虽然就说明的目的已描述了本发明的具体实施方案,但是在不偏离本发明的精神和范围的情况下,可进行各种修改。
Claims (67)
1.一种式(I)化合物或其盐
其中:
Ar为芳基或杂芳基;
X为-OC(O)-、-NR6C(O)-、-(CH2)m-、-O(CH2)m、-S(O)(CH2)m或-S(O)O(CH2)m,其中m为1或2;
R1选自氢、OH、C1-10烷基、芳基、杂芳基、OC1-10烷基、O-芳基、O-杂芳基、OC1-10亚烷基芳基、OC1-10亚烷基杂芳基和N(R4)R5;
R2、R3、R4、R5和R6各自独立地选自氢、C1-10烷基、C(O)C1-10烷基、C(O)C(O)C1-10烷基、C(O)NR7R8和C(O)C1-10卤代烷基;和
R7和R8独立地选自氢、C1-10烷基、芳基和杂芳基。
2.权利要求1的化合物,其中R2和R3均不为氢。
3.权利要求1的化合物,其中X为OC(O)。
4.权利要求1的化合物,其中X为NR6C(O)。
5.权利要求1的化合物,其中Ar选自苯基、4-乙酰基苯基、4-羟基苯基、4-吡啶基、2-噻吩基和2-呋喃基。
6.权利要求1的化合物,其中R2选自氢、甲基、乙基、丙基和苄基,R3选自C(O)C(O)OCH3、C(O)CH3、C(O)CF3和C(O)NR7R8。
7.权利要求1的化合物,其中R1选自OH、甲氧基、乙氧基、丙氧基、苯氧基、苄氧基、N(CH3)OCH3、任选取代的芳基和任选取代的杂芳基。
9.一种组合物,所述组合物包含权利要求1-8中任一项的化合物和药学上可接受的载体。
10.一种在有此需要的患者中抑制激素敏感性脂酶的方法,所述方法包括给予治疗有效量的式(I)化合物或其盐:
其中:
Ar为芳基或杂芳基;
X为-OC(O)-、-NR6C(O)-、-(CH2)m-、-O(CH2)m、-S(O)(CH2)m或-S(O)O(CH2)m,其中m为1或2;
R1选自氢、OH、C1-10烷基、芳基、杂芳基、OC1-10烷基、O-芳基、O-杂芳基、OC1-10亚烷基芳基、OC1-10亚烷基杂芳基和N(R4)R5;
R2、R3、R4、R5和R6各自独立地选自氢、C1-10烷基、C(O)C1-10烷基、C(O)C(O)C1-10烷基、C(O)NR7R8和C(O)C1-10卤代烷基;和
R7和R8独立地选自氢、C1-10烷基、芳基和杂芳基,
其中所述式(I)化合物抑制激素敏感性脂酶(HSL)的IC50高达约10mM。
11.权利要求10的方法,其中R2和R3均不为氢。
12.权利要求10的方法,其中X为OC(O)。
13.权利要求10的方法,其中X为NR6C(O)。
14.权利要求10的方法,其中Ar选自苯基、4-乙酰基苯基、4-羟基苯基、4-吡啶基、2-噻吩基和2-呋喃基。
15.权利要求10的方法,其中R2选自氢、甲基、乙基、丙基和苄基,R3选自C(O)C(O)OCH3、C(O)CH3、C(O)CF3和C(O)NR7R8。
16.权利要求10的方法,其中R1选自OH、甲氧基、乙氧基、丙氧基、苯氧基、苄氧基、N(CH3)OCH3、任选取代的芳基和任选取代的杂芳基。
18.权利要求10的方法,其中所述式(I)化合物的IC50高达约1mM。
19.权利要求10的方法,其中所述式(I)化合物的IC50高达约100nM。
20.权利要求10的方法,所述方法还包括给予治疗有效量的一种或多种对代谢障碍或紊乱具有有利效果的活性剂。
21.权利要求20的方法,其中所述式(I)化合物与所述活性剂同时给予。
22.权利要求10的方法,所述方法还包括给予治疗有效量的一种或多种抗糖尿病药物。
23.一种治疗、预防或改善有需要的患者与脂肪酸代谢病症或葡萄糖利用病症关联的一种或多种症状的方法,所述方法包括给予所述患者治疗有效量的式(I)化合物或其盐:
其中:
Ar为芳基或杂芳基;
X为-OC(O)-、-NR6C(O)-、-(CH2)m-、-O(CH2)m、-S(O)(CH2)m或-S(O)O(CH2)m,其中m为1或2;
R1选自氢、OH、C1-10烷基、芳基、杂芳基、OC1-10烷基、O-芳基、O-杂芳基、OC1-10亚烷基芳基、OC1-10亚烷基杂芳基和N(R4)R5;
R2、R3、R4、R5和R6各自独立地选自氢、C1-10烷基、C(O)C1-10烷基、C(O)C(O)C1-10烷基、C(O)NR7R8和C(O)C1-10卤代烷基;和
R7和R8独立地选自氢、C1-10烷基、芳基和杂芳基,
其中所述式(I)化合物对激素敏感性脂酶(HSL)的IC50高达约10mM。
24.权利要求23的方法,其中R2和R3均不为氢。
25.权利要求23的方法,其中X为OC(O)。
26.权利要求23的方法,其中X为NR6C(O)。
27.权利要求23的方法,其中Ar选自苯基、4-乙酰基苯基、4-羟基苯基、4-吡啶基、2-噻吩基和2-呋喃基。
28.权利要求23的方法,其中R2选自氢、甲基、乙基、丙基和苄基,R3选自C(O)C(O)OCH3、C(O)CH3、C(O)CF3和C(O)NR7R8。
29.权利要求23的方法,其中R1选自OH、甲氧基、乙氧基、丙氧基、苯氧基、苄氧基、N(CH3)OCH3、任选取代的芳基和任选取代的杂芳基。
30.权利要求23的方法,其中所述式(I)化合物选自
及其盐。
31.权利要求23的方法,其中所述式(I)化合物的IC50高达约1mM。
32.权利要求23的方法,其中所述式(I)化合物的IC50高达约100nM。
33.权利要求23的方法,所述方法还包括给予治疗有效量的用于治疗或预防脂肪酸代谢病症、葡萄糖利用病症或二者的活性剂。
34.权利要求33的方法,其中所述式(I)化合物与所述活性剂同时给予。
35.一种治疗、预防或改善涉及胰岛素抵抗的病症的方法,所述方法包括给予有此需要的患者治疗有效量的式(I)化合物或其盐:
其中:
Ar为芳基或杂芳基;
X为-OC(O)-、-NR6C(O)-、-(CH2)m-、-O(CH2)m、-S(O)(CH2)m或-S(O)O(CH2)m,其中m为1或2;
R1选自氢、OH、C1-10烷基、芳基、杂芳基、OC1-10烷基、O-芳基、O-杂芳基、OC1-10亚烷基芳基、OC1-10亚烷基杂芳基和N(R4)R5;
R2、R3、R4、R5和R6各自独立地选自氢、C1-10烷基、C(O)C1-10烷基、C(O)C(O)C1-10烷基、C(O)NR7R8和C(O)C1-10卤代烷基;和
R7和R8独立地选自氢、C1-10烷基、芳基和杂芳基,
其中所述式(I)化合物对激素敏感性脂酶(HSL)的IC50高达约10mM。
36.权利要求35的方法,其中R2和R3均不为氢。
37.权利要求35的方法,其中X为OC(O)。
38.权利要求35的方法,其中X为NR6C(O)。
39.权利要求35的方法,其中Ar选自苯基、4-乙酰基苯基、4-羟基苯基、4-吡啶基、2-噻吩基和2-呋喃基。
40.权利要求35的方法,其中R2选自氢、甲基、乙基、丙基和苄基,R3选自C(O)C(O)OCH3、C(O)CH3、C(O)CF3和C(O)NR7R8。
41.权利要求35的方法,其中R1选自OH、甲氧基、乙氧基、丙氧基、苯氧基、苄氧基、N(CH3)OCH3、任选取代的芳基和任选取代的杂芳基。
42.权利要求35的方法,其中所述式(I)化合物选自
及其盐。
43.权利要求35的方法,其中所述式(I)化合物的IC50高达约1mM。
44.权利要求35的方法,其中所述式(I)化合物的IC50高达约100nM。
45.权利要求35的方法,其中所述涉及胰岛素抵抗的病症为糖尿病。
46.权利要求35的方法,所述方法还包括给予用于治疗、预防或改善涉及胰岛素抵抗的病症的活性剂。
47.权利要求46的方法,其中所述式(I)化合物与所述活性剂同时给予。
48.一种治疗、预防或改善血脂异常或血脂异常并发症的方法,所述方法包括给予有此需要的患者治疗有效量的式(I)化合物或其盐:
其中:
Ar为芳基或杂芳基;
X为-OC(O)-、-NR6C(O)-、-(CH2)m-、-O(CH2)m、-S(O)(CH2)m或-S(O)O(CH2)m,其中m为1或2;
R1选自氢、OH、C1-10烷基、芳基、杂芳基、OC1-10烷基、O-芳基、O-杂芳基、OC1-10亚烷基芳基、OC1-10亚烷基杂芳基和N(R4)R5;
R2、R3、R4、R5和R6各自独立地选自氢、C1-10烷基、C(O)C1-10烷基、C(O)C(O)C1-10烷基、C(O)NR7R8和C(O)C1-10卤代烷基;和
R7和R8独立地选自氢、C1-10烷基、芳基和杂芳基,
其中所述式(I)化合物对激素敏感性脂酶(HSL)的IC50高达约10mM。
49.权利要求48的方法,其中R2和R3均不为氢。
50.权利要求48的方法,其中X为OC(O)。
51.权利要求48的方法,其中X为NR6C(O)。
52.权利要求48的方法,其中Ar选自苯基、4-乙酰基苯基、4-羟基苯基、4-吡啶基、2-噻吩基和2-呋喃基。
53.权利要求48的方法,其中R2选自氢、甲基、乙基、丙基和苄基,R3选自C(O)C(O)OCH3、C(O)CH3、C(O)CF3和C(O)NR7R8。
54.权利要求48的方法,其中R1选自OH、甲氧基、乙氧基、丙氧基、苯氧基、苄氧基、N(CH3)OCH3、任选取代的芳基和任选取代的杂芳基。
56.权利要求48的方法,其中所述式(I)化合物的IC50高达约1mM。
57.权利要求48的方法,其中所述式(I)化合物的IC50高达约100nM。
58.一种治疗、预防或改善与代谢综合征X关联的病症的方法,所述方法包括给予有此需要的患者治疗有效量的式(I)化合物或其盐:
其中:
Ar为芳基或杂芳基;
X为-OC(O)-、-NR6C(O)-、-(CH2)m-、-O(CH2)m、-S(O)(CH2)m或-S(O)O(CH2)m,其中m为1或2;
R1选自氢、OH、C1-10烷基、芳基、杂芳基、OC1-10烷基、O-芳基、O-杂芳基、OC1-10亚烷基芳基、OC1-10亚烷基杂芳基和N(R4)R5;
R2、R3、R4、R5和R6各自独立地选自氢、C1-10烷基、C(O)C1-10烷基、C(O)C(O)C1-10烷基、C(O)NR7R8和C(O)C1-10卤代烷基;和
R7和R8独立地选自氢、C1-10烷基、芳基和杂芳基,
其中所述式(I)化合物对激素敏感性脂酶(HSL)的IC50高达约10mM。
59.权利要求58的方法,其中R2和R3均不为氢。
60.权利要求58的方法,其中X为OC(O)。
61.权利要求58的方法,其中X为NR6C(O)。
62.权利要求58的方法,其中Ar选自苯基、4-乙酰基苯基、4-羟基苯基、4-吡啶基、2-噻吩基和2-呋喃基。
63.权利要求58的方法,其中R2选自氢、甲基、乙基、丙基和苄基,R3选自C(O)C(O)OCH3、C(O)CH3、C(O)CF3和C(O)NR7R8。
64.权利要求58的方法,其中R1选自OH、甲氧基、乙氧基、丙氧基、苯氧基、苄氧基、N(CH3)OCH3、任选取代的芳基和任选取代的杂芳基。
66.权利要求58的方法,其中所述式(I)化合物的IC50高达约1mM。
67.权利要求58的方法,其中所述式(I)化合物的IC50高达约100nM。
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US94932507P | 2007-07-12 | 2007-07-12 | |
US60/949,325 | 2007-07-12 | ||
PCT/US2008/067987 WO2009009287A2 (en) | 2007-07-12 | 2008-06-24 | Hormone sensitive lipase modulators and methods of use |
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US (1) | US20090018189A1 (zh) |
EP (1) | EP2178821A2 (zh) |
CN (1) | CN101821227A (zh) |
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WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
EP2760862B1 (en) | 2011-09-27 | 2015-10-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
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US5578606A (en) * | 1992-10-30 | 1996-11-26 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors |
CN1798735A (zh) * | 2003-06-12 | 2006-07-05 | 诺沃挪第克公司 | 用作激素敏感性脂肪酶的抑制剂的1-芳基-4-(芳氧基羰基)-哌嗪衍生物 |
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US6326396B1 (en) * | 1998-11-20 | 2001-12-04 | Alteon, Inc. | Glucose and lipid lowering compounds |
DE19942354A1 (de) * | 1999-09-04 | 2001-03-08 | Aventis Pharma Gmbh | Substituierte 3-Phenyl-5-alkoxi-1,3,4-oxdiazol-2-one, ihre Herstellung und Verwendung in Arzneimitteln |
US6756402B2 (en) * | 2000-05-04 | 2004-06-29 | Aventis Pharma Deutschland Gmbh | Cyclipostins, process for their preparation and use thereof |
US20050271755A1 (en) * | 2004-05-12 | 2005-12-08 | Ilya Raskin | Phytomedicinal compositions for the control of lipid accumulation and metabolism in mammals |
AU2007205147A1 (en) * | 2006-01-05 | 2007-07-19 | Deviris Inc. | Compounds and derivatives for the treatment of medical conditions by modulating hormone-sensitive lipase activity |
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2008
- 2008-06-24 EP EP08771794A patent/EP2178821A2/en not_active Withdrawn
- 2008-06-24 CN CN200880107763A patent/CN101821227A/zh active Pending
- 2008-06-24 WO PCT/US2008/067987 patent/WO2009009287A2/en active Application Filing
- 2008-06-26 US US12/146,985 patent/US20090018189A1/en not_active Abandoned
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US5578606A (en) * | 1992-10-30 | 1996-11-26 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors |
CN1798735A (zh) * | 2003-06-12 | 2006-07-05 | 诺沃挪第克公司 | 用作激素敏感性脂肪酶的抑制剂的1-芳基-4-(芳氧基羰基)-哌嗪衍生物 |
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US20090018189A1 (en) | 2009-01-15 |
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