CN110121343B - 用作gpr120调节剂的双环化合物 - Google Patents
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- CN110121343B CN110121343B CN201780068712.9A CN201780068712A CN110121343B CN 110121343 B CN110121343 B CN 110121343B CN 201780068712 A CN201780068712 A CN 201780068712A CN 110121343 B CN110121343 B CN 110121343B
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Abstract
本发明提供了化合物,包含其的组合物,以及通过施用所述化合物和所述组合物来调节GPR120活性和治疗由GPR120介导的疾病的方法。
Description
相关专利申请的交叉引用
本申请要求2016年9月12日提交的美国临时申请序列号62/393,619的优先权,其全部内容通过引用并入本文。
技术领域
本发明提供了用于调节GPR120受体的组合物和方法,通常涉及药物化学、医学、药理学、分子生物学和生物学领域。调节GPR120受体的化合物可用于治疗各种代谢和炎性疾病,包括但不限于II型糖尿病、肥胖症、肝脂肪变性和阿尔茨海默症以及其各自的一种或多种症状。
背景技术
II型糖尿病(T2D)是一种由于身体低效使用其产生的胰岛素而导致的慢性疾病。在T2D中观察到的高血糖和胰岛素抵抗的状态通常是由于超重和缺乏体育锻炼引起的。由于肥胖和久坐不动的生活方式在世界范围内不断增加,T2D的发病率也在迅速增加。据世界卫生组织(WHO)统计,全球有超过3亿人患有T2D,每年有超过100万人死于T2D。世界卫生组织进一步预测,糖尿病相关死亡人数将在未来十年内增加50%。目前用于T2D的治疗策略包括针对胰岛素分泌和利用的靶向药物治疗。然而,这些策略并不对所有患者都奏效或完全奏效,因此需要新的策略和药剂来治疗T2D的多个病理方面。
GPR120,也被称为游离脂肪酸受体4(FFA4),是一种由包括ω-3脂肪酸在内的长链游离脂肪酸激活的7跨膜的G蛋白偶联受体。GPR120在多种组织中表达,并介导与能量平衡和炎症相关的多种作用。在肠内分泌细胞中,GPR120的激活导致肠降血糖素胰高血糖素样肽-1(GLP-1)和胃抑制肽(GIP)的分泌,其转而刺激胰岛β细胞释放胰岛素。脂肪细胞中GPR120的激活刺激葡萄糖摄取和脂肪生成,同时抑制脂解作用。巨噬细胞中GPR120的激活发挥抗炎作用,抑制细胞因子(包括TNF-α和IL-6)的释放。在肠内分泌细胞和脂肪细胞中,GPR120信号通过Gq/11进行转导,但在巨噬细胞中,GPR120信号通过β-抑制蛋白途径进行转导。在小鼠和人类中,糖尿病和肥胖症都与GPR120的功能紊乱有关。因此,GPR120激动剂已被测试用于治疗T2D和其他代谢疾病。(1-4)
肝脏脂肪变性是与肝脏中脂肪堆积相关的炎症和细胞损伤状态。在与酒精摄入无关的病例中,该疾病被称为非酒精性脂肪性肝炎(NASH)。NASH变得越来越普遍,其可导致肝硬化或肝功能衰竭,常见于肥胖、葡萄糖耐受不良或血脂异常的人群。最近利用野生型和GPR120缺陷小鼠的研究证实了GPR120在控制脂质代谢、甘油三酯和二酰基甘油水平以及炎症标志物中的积极作用。与这些结果一致的是,对施用GPR120激动剂二十二碳六烯酸(DHA)治疗的非酒精性脂肪肝患儿的研究结果显示了肝损伤和炎性巨噬细胞减少,GPR120肝细胞表达增加(5a)。
阿尔茨海默症(AD)是老年痴呆症的最常见原因,目前全世界估计有4700万例病例,预计到2050年将超过1.3亿例。最近已证实GPR120的激活在永生化的下丘脑神经元中发挥抗炎作用(6a),以及GPR120和另一种长链游离脂肪酸受体GPR40(FFA1)控制小鼠下丘脑的能量内稳态和炎症(7a)。NLRP3炎性体活性已显示对于APP/PS1小鼠的病理学有所贡献(8a)。ω-3脂肪酸阻断巨噬细胞中NLRP3炎性体的活化,从而抑制胱天蛋白酶-1的下游活化和白细胞介素-1β(IL-1β)的成熟和释放(9a)。NLRP1炎性体的表达也在APP/PS1小鼠的脑中上调,并且Aβ在来自这些动物的培养的皮质神经元中诱导NLRP1-和胱天蛋白酶-1依赖性细胞凋亡(10a)。在具有轻度认知障碍和AD的人类大脑中,炎性体激活的胱天蛋白酶-1的水平显著增强,并且培养的人神经元中NLRP1的激活诱导轴索变性(11a)。因此,GPR120激动剂有望用于AD、帕金森病、额颞叶痴呆(FTD)、肌萎缩侧索硬化症(ALS)、多系统萎缩(MSA)和其他与神经炎症相关疾病的疾病改良疗法。
本发明提供了新型的化合物、物质组合物,特别是药物组合物、合成或制备该化合物和组合物的方法,以及使用它们调节GPR120和治疗T2D、肝脂肪变性、阿尔茨海默氏症和其它与代谢功能紊乱和炎症相关的疾病的方法。
发明内容
在某些方面,本发明提供了化合物、物质组合物(特别是药物组合物)、合成或制备所述化合物和组合物的方法,以及使用它们调节GPR120的方法。
本发明提供了化合物、包含它们的组合物以及通过施用所述化合物和组合物来调节GPR120受体和治疗疾病的方法。
本发明的第一方面提供了式I化合物,其在各种实施方案中包含一个含有9-10个环原子、1-4个环氮原子和至多3个环取代基的双环核心元素:
及其互变异构体、同位素异构体和立体异构体,以及任何前述物的前药,以及所有前述物的药学上可接受的盐和溶剂化物,其中X各自独立地为CH、CR3或N;Y为SO2或CO;Z为-CH2-、-CH(CH3)-、-C(CH3)2-、-C(CH2CH2)-、CO、-(CO)CH2-、-CH2CH2-或-CHCH-;U为共价键、CH2、-CH(CH3)-、-C(CH3)2-、或-CH2CH2-;R1为任选地被取代的烷基、任选地被取代的3-7元环烷基或杂环基、任选地被取代的5元或6元芳基或杂芳基、或任选地被取代的5,6-元或6,6-元双环芳基或杂芳基;R2为氢、任选地被取代的3-7元环烷基或杂环基、任选地被取代的6元芳基、任选地被取代的5元或6元杂芳基、任选地被取代的5,6-元或6,6-元双环杂芳基、或任选地被取代的双环芳基;R3为卤素、或任选地被取代的烷基或烷氧基。
式I所示化合物预期可作为GPR120激动剂刺激GLP-1、GIP和/或胰高血糖素的释放、抑制胃饥饿素的释放、刺激葡萄糖摄取和/或发挥抗炎作用,从而在T2D治疗中发挥作用。在另一方面,本发明提供了激活GPR120的方法,其包含将GPR120与本发明提供或公开的化合物或其药物组合物接触。
另一方面,本发明提供了一种调节哺乳动物体内新陈代谢的方法,其包含将所述哺乳动物体内的GPR120与调节所述哺乳动物新陈代谢有效量的本发明提供的化合物接触。另一方面,本发明提供了一种调节哺乳动物体内新陈代谢的方法,其包含给所述哺乳动物施用调节所述哺乳动物新陈代谢有效量的本发明提供的组合物。
另一方面,本发明提供了一种减轻哺乳动物炎症的方法,其包含将所述哺乳动物体内的GPR120与减轻炎症有效量的本发明提供的化合物接触。另一方面,本发明提供了一种减轻哺乳动物炎症的方法,其包含给所述哺乳动物施用减轻炎症有效量的本发明提供的组合物。
另一方面,本发明提供了一种减轻哺乳动物神经炎症的方法,其包含将所述哺乳动物体内的GPR120与减轻神经炎症有效量的本发明提供的化合物接触。本发明中的神经炎症是指神经组织的炎症。另一方面,本发明提供了一种减轻哺乳动物神经炎症的方法,其包含给所述哺乳动物施用减轻神经炎症有效量的本发明提供的组合物。
另一方面,本发明提供了一种治疗哺乳动物的糖尿病、前驱糖尿病或代谢综合征或其各自的一种或多种症状的方法,其包含将所述哺乳动物体内的GPR120与治疗有效量的本发明提供的化合物接触。另一方面,本发明提供了一种治疗哺乳动物的糖尿病、前驱糖尿病或代谢综合征或其各自的一种或多种症状的方法,其包含给所述哺乳动物施用治疗有效量的本发明提供的组合物。
另一方面,本发明提供了一种治疗哺乳动物脂肪性肝炎的方法,其包含将所述哺乳动物体内的GPR120与治疗有效量的本发明提供的化合物接触。另一方面,本发明提供了一种治疗哺乳动物脂肪性肝炎的方法,其包含给所述哺乳动物施用治疗有效量的本发明提供的组合物。
另一方面,本发明提供了一种治疗哺乳动物的非酒精性脂肪性肝炎的方法,其包含将所述哺乳动物体内的GPR120与治疗有效量的本发明提供的化合物接触。另一方面,本发明提供了一种治疗哺乳动物的非酒精性脂肪性肝炎的方法,其包含给所述哺乳动物施用治疗有效量的本发明提供的组合物。
另一方面,本发明提供了一种治疗哺乳动物的与神经炎症有关、导致神经炎症或由神经炎症引起的疾病的方法,其包含将所述哺乳动物体内的GPR120与治疗有效量的本发明提供的化合物接触。另一方面,本发明提供了一种治疗哺乳动物的与神经炎症有关、导致神经炎症或由神经炎症引起的疾病的方法,其包含给所述哺乳动物施用治疗有效量的本发明提供的组合物。
另一方面,本发明提供了一种治疗阿尔茨海默症、帕金森病、额颞叶痴呆、肌萎缩侧索硬化或多系统萎缩或其各自的一种或多种症状的方法,其包含将患者体内的GPR120与治疗有效量的本发明提供的化合物接触。
另一方面,本发明提供了一种治疗阿尔茨海默症、帕金森病、额颞叶痴呆、肌萎缩侧索硬化或多系统萎缩或其各自的一种或多种症状的方法,其包含给患者施用治疗有效量的本发明提供的组合物。
为了帮助读者理解本发明如何制备、使用及其益处,本发明提供了以下用法和定义。
所有数字标号例如pH、温度、时间、浓度、分子量以及范围,均为以0.1或1的增量上(+)下(-)浮动的近似值。因此,所有数字标号之前可以由读者解释为术语“约”。类似地,本文描述的试剂仅是示例性的;通常,本领域普通技术人员将理解,这些的等同物在本领域中是已知的。除非上下文另有明确说明,说明书和权利要求书中所使用的单数形式“一”和“所述”应被解释为包括其复数形式。
“酰基”是指通式为-CO-Rx的基团,其中Rx为H,或任选地被取代的烷基、环烷基、杂环基、芳基或杂芳基。酰基的实例包括例如-CHO、-CO-Me和-CO-Ph。
给患者(和该短语的同义词)“施用”化合物或组合物药物是指直接施用,其可以由医学专业人员向患者施用或可以是自行施用,和/或间接施用,其可以是开具药物处方。例如,医生指示患者自行施用药物和/或向患者提供药物处方即是将药物施用于患者。
“烷氧基”是指与氧原子共价键合的烷基。也就是说,烷氧基具有-O-烷基的结构通式。C1-C6烷氧基包括例如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、2-戊氧基、3-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基和3-甲基戊氧基。
“烯基”是指含有至少一个碳碳双键的直链或支链烃基。C1-C6烯基包括例如乙烯基、烯丙基和丁烯基。
“烷基”是指直链或支链烃基。C1-C6烷基包括例如甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基、戊基、2-戊基、异戊基、新戊基、己基、2-己基、3-己基和3-甲基戊基。
“胺(氨)基”是指一价基团-NRaRb,其中Ra和Rb独立地为氢、烷基、芳基或杂芳基。术语“烷基胺基”是指基团-NRaRb,其中Ra是烷基,Rb为H或烷基。对于二烷基胺基,烷基部分可以相同或不同,也可以与各自连接的氮原子结合形成3至8元环。因此,表示为-NRaRb的基团意在包括杂环基,例如哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基等。
“芳基”指的是包含一个或多个含有6-20个环碳原子的单环或稠环芳族体系的环系,其包括具有一个或多个单环或双环稠合芳族体系的任何部分,包括但不限于苯基和萘基。
“(Cm-Cn),Cm-Cn或Cm-n”中任意一个符号置于某一基团前,表示其中的碳原子数。例如,C1-C6烷基是指含有1至6个碳原子的烷基。
“羧酰胺或甲酰胺基”是指一价基团-CO-NRaRb,其中NRaRb是如上定义的“氨基”基团。
“载体”是指预递送或捕获本发明化合物用于随后递送的固体或液体物质,例如聚合物、溶剂、悬浮剂、吸收剂或吸附剂。载体可以是液体或固体,其选择需考虑计划的给药方式。
当用于定义化合物、组合物和方法时,“包含”是指所列举的元素可以与其他材料或步骤一起存在。当用于定义化合物、组合物或方法时,“基本上由……组成”是指所述元素可以不与其他将实质影响要求保护的发明的基本和新颖性特征的元素一起存在。“由……组成”仅表示所述元素。由这些过渡项中的每一个定义的实施方案都在本发明的范围内。
除非另有说明,“环烷基”是指环状形式的“烷基”、“烯基”和“炔基”,其中所有环原子都是碳。“环烷基”是指单环或多环基团。“环烷基”可以形成桥环或螺环。环烷基可具有一个或多个双键或三键。典型的环烷基具有3至8个环原子。环烷基的实例包括环戊基、环己基、1-环己烯基、3-环己烯基和环庚基。
除非另有说明,“卤素”或“卤代”本身或作为另一取代基的一部分是指氟、氯、溴或碘原子。
“杂芳基”是指具有5或6个环原子的单环芳族体系,或具有8-20个原子的稠合双环芳族体系,其中环原子为C、O、S、SO、SO2或N,并且至少有一个环原子是杂原子,即O、S、SO、SO2或N。杂芳基包括例如吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯噻呋喃基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑、苯并咪唑啉、咔唑基、NH-咔唑基、咔啉基、色满基、色烯基、噌啉基、二噻嗪基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、吲唑基、吲哚烯基、二氢吲哚基、吲嗪基、吲哚基、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、萘啶基、八氢异喹啉基、噁二唑基、噁唑烷基、噁唑基、噁唑烷基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、苯氧基乙基、吩嗪基、酞嗪基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喔啉基、奎宁环基、四氢异喹啉基、四氢喹啉基、四唑基、噻二嗪基、噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基和吨基。除非另有说明,否则环内杂原子的排列可以是任何符合成环原子键合特性的排列。
“杂环基”或杂环是指单环或稠合多环环烷基,其至少一部分不是芳族的,并且其中环体系中的一个或多个碳原子被选自O、S、SO、SO2、P或N的杂原子取代。杂环基的实例包括但不限于咪唑啉基、吗啉基、哌啶基、哌啶-2-酮基、哌嗪基、吡咯烷基、吡咯烷-2-酮基、四氢呋喃基、四氢吡喃基和四氢咪唑并[4,5-c]吡啶基。
“药学上可接受的盐”是指根据本发明所述化合物的特定酸性或碱性,用相对无毒的酸或碱制备的活性化合物的盐。当本发明的化合物含有相对酸性的官能团时,碱加成盐可以通过使这些化合物的中性形式与足够量的所需碱在无溶剂或在合适的惰性溶剂中接触而获得。衍生自药学上可接受的无机碱的盐的实例包括铝盐、铵盐、钙盐、锂盐、镁盐、钾盐、钠盐等。衍生自药学上可接受的有机碱的盐包括伯、仲和叔胺的盐,包括取代的胺、环胺、天然存在的胺等,例如精氨酸、甜菜碱、咖啡因、胆碱、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡糖胺(glucamine)、葡糖胺(glucosamine)、组氨酸、水杨酸胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。当本发明的化合物含有相对碱性的官能团时,酸加成盐可以通过使这些化合物的中性形式与足够量的所需酸在无溶剂或在合适的惰性溶剂中接触而获得。药学上可接受的酸加成盐的实例包括那些衍生自无机酸的盐,如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸或磷酸等,以及衍生自相对无毒的有机酸的盐,如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等。还包括氨基酸盐如精氨酸等,以及有机酸盐如葡糖醛酸或半乳糖醛酸。本发明的某些特定化合物可以同时含有碱性和酸性官能团,使得化合物可转化成碱或酸加成盐。
“药学上可接受的赋形剂、载体或稀释剂”是指可用于制备药物组合物的赋形剂、载体或稀释剂,通常安全无毒、且不具有生物学或其他方面的不良性质,包括可供人类药物使用以及兽医使用的赋形剂、载体或稀释剂。“药学上可接受的赋形剂、载体或稀释剂”包括一种和多种所述的赋形剂、载体或稀释剂。
“减轻”或“抑制”病理状况或疾病的一种或多种症状(和该短语的同义词)是指降低该症状的严重程度或频率,或消除该症状。
本文中的“受试者”与“个体”和“患者”可互换使用,是指脊椎动物,通常是哺乳动物,通常是人。哺乳动物包括但不限于小鼠、大鼠、兔、猿猴、牛、绵羊、猪、犬科动物、猫科动物、农场动物、运动动物、宠物、马和灵长类动物。
“被取代的”是指如本文所定义的基团其中一个或多个连接至碳或氢的键被连接至非氢和非碳原子的键取代。所述的取代基包括但不限于卤素原子;羟基、烷氧基、芳氧基和酰氧基等基团中的氧原子;硫醇基团、烷基和芳基硫醚基团、砜基团、磺酰基和亚砜基团等中的硫原子;硝基、-NH2、烷基胺、二烷基胺、芳基胺、烷基芳基胺、二芳基胺、烷氧基胺基、羟基胺基、酰胺基、磺酰基胺基、N-氧化物、酰亚胺和烯胺中的氮原子;和其他各种基团中的其他杂原子。“取代基”还包括其中一个或多个连接至碳原子或氢原子的键被连接至杂原子的高阶键(例如双键或三键)取代的基团。所述的杂原子例如氧代基、酰基、酰胺基、烷氧基羰基、氨基羰基、羧基和酯基中的氧;亚胺、肟、腙和腈等基团中的氮。“取代基”还包括其中一个或多个连接至碳或氢原子的键被连接至环烷基、杂环基、芳基和杂芳基的键取代的基团。对于环烷基、杂环基、芳基和杂芳基,“取代基”还包括被取代和未被取代的烷基。其他取代基包括乙炔基、乙烯基、羧基及其酯和酰胺、羟甲基和甲基。另一种“取代基”是三氟甲基或其他氟代烷基和含有这些基团的其他基团。相同或相邻碳原子上的两个取代基可与它们所键合的碳原子一起形成杂环或环烷基。通常,特定基团可具有0(未被取代)、1、2或3个取代基。对于本领域技术人员显而易见的是,用取代基取代不会产生分子量大于1000的聚合物部分。
“磺酰胺或磺酰胺基”是指一价基团-SO2-NRaRb,其中NRaRb是如上定义的“胺基”。
“治疗有效量”是指给患有由GPR120介导的疾病的患者施用足以产生有益或期望的结果的药物的量。治疗有效量可以以一种或多种给药方案、应用或剂量施用。
“治疗”病症或患者是指采取步骤以获得有益或期望的结果,包括临床结果如症状的减轻。出于本发明的目的,有益或期望的临床结果包括但不限于减轻或改善由GPR120介导的疾病的一种或多种症状;减少此类疾病的扩张;延迟或减缓这种疾病进程;改善、缓解或稳定此类疾病;或其他有益的结果。
相应地,本发明在第一方面提供了式I化合物:
或其互变异构体、同位素异构体和立体异构体,以及任何前述物的前药,以及所有前述物的药学上可接受的盐和溶剂化物,其中X各自独立地为CH、CR3或N;Y为SO2或CO;Z为-CH2-、-CH(CH3)-、-C(CH3)2-、-C(CH2CH2)-、CO、-(CO)CH2-、-CH2CH2-或-CHCH-;U为共价键、CH2、-CH(CH3)-、-C(CH3)2-、或-CH2CH2-;R1为任选地被取代的烷基、任选地被取代的3-7元环烷基或杂环基、任选地被取代的6元芳基、任选地被取代的5元或6元杂芳基、任选地被取代的5,6-或6,6-双环杂芳基、或任选地被取代的双环芳基;R2为氢、任选地被取代的3-7元环烷基或杂环基、任选地被取代的6元芳基、任选地被取代的5元或6元杂芳基、任选地被取代的5,6-或6,6-双环杂芳基、或任选地被取代的芳基;R3为卤素、或任选地被取代的烷基或烷氧基。在一个实施方案中,R2是非氢取代基。
在一个优选的实施方案中,R1为任选地被取代的环烷基或杂环基。具体优选的环烷基和杂环基的实例如下所示,其中R11为核心骨架的连接点。R12和R13独立地为H、CH3、CF3或F。
在另一个优选的实施方案中,R1是任选地被取代的芳基或杂芳基。具体优选的芳基和杂芳基的实例如下所示,其中R11为核心骨架的连接点,R15为H、卤素、烷基、CF3、OCH3、OCF3或CN,R16为H、卤素、烷基、CF3、OCH3、OCF3、CN、NHCOR14或N(CH3)COR14,其中R14为烷基、环烷基、芳基或杂芳基。
在另一个优选的实施方案中,R1是任选地被取代的稠合双环基团。具体优选的稠合双环基团的实例如下所示,其中R11为核心骨架的连接点,R15和R17独立地为H、卤素、烷基、CF3、OCH3、OCF3或CN。
在另一个优选的实施方案中,U为共价键或CH2,R2为任选地被取代的5元或6元芳基或杂芳基,其中R18为与U的连接点,R15和R17独立地为H、卤素、烷基、CF3、OCH3、OCF3或CN。
另一方面,本发明提供的化合物选自:
一些本发明中的化合物的合成方法由下文示意性地描述。本发明的其他化合物可以通过采用下面实施例中举例说明的方法或本领域技术人员已知的方法,对原料、其他试剂和/或工艺条件(即反应温度、时间、反应物的摩尔比、溶剂、压力等)进行适当代替进行合成。
对于本发明中含有一个或多个手性中心的化合物,其可以制备或分离为纯立体异构体,即作为单一的对映异构体或非对映异构体或单一立体异构体的富集物。除非另有说明,否则所有这些立体异构体(和立体异构体的富集物)都包括在本发明提供和使用的化合物的范围内。纯立体异构体(或立体异构体的富集物)可以使用例如本领域熟知的光学活性原料或立体选择试剂性来制备。此外,这些化合物的外消旋混合物可以通过使用例如手性柱色谱法或手性拆分剂等来分离。
另一方面,本发明提供了包含本发明化合物和至少一种药学上可接受的赋形剂的组合物,即药物制剂。通常,本发明的化合物可以配制成通过任何可接受的给药方式向患者施用的制剂。因此,本发明提供了本发明化合物的固体和液体制剂。本领域还提供其他各种制剂和药物递送系统。参见例如:Gennaro,A.R.,ed.(1995)Remington’s PharmaceuticalSciences,18th ed.,Mack Publishing Co.。
通常,本发明的化合物作为药物组合物通过下列途径之一施用:口服、全身(例如透皮、鼻内或通过栓剂)、或肠胃外(例如肌肉内、静脉内或皮下)施用。组合物可以采取片剂、丸剂、胶囊、半固体、粉末、缓释制剂、溶液、悬浮液、酏剂、喷雾或任何其它合适的组合物的形式。
本发明的化合物的药物剂型可以通过任意本领域熟知的任何方法制备,例如通过常规混合、筛分、溶解、熔融、制粒、制糖衣、压片、悬浮、挤制、喷雾干燥、澄出、乳化、(纳米/微米)封装、包封或冻干等方法。如上所述,本发明的组合物可以包含一种或多种生理学可接受的非活性成分,从而有助于将活性分子加工为药用制剂。
基于通过增加表面积(即减小颗粒尺寸)来提高生物利用度的原则,药物制剂尤其是生物利用度差的药物正在被开发。例如美国专利号4,107,288描述了一种颗粒尺寸为10至1000nm的药物制剂,其中活性物质负载在大分子交联基质上。美国专利5,145,684号描述了一种药物制剂的制备,其中药物成分在表面改性剂的存在下被粉碎成纳米颗粒(平均颗粒尺寸400nm),并分散在液体介质中制成药剂,其表现出很好的生物利用度。在一些实施案中,所述化合物通过以上方法配制。
所述组合物通常包含本发明的化合物与至少一种药学上可接受的赋形剂。可接受的赋形剂无毒、有助于药物施用并且对要求保护的化合物的治疗效益无不良影响。所述赋形剂可以为本领域技术人员通常可获得的任何固体、液体、半固体或气溶胶组合物情况下的气体赋形剂。
固体药物赋形剂包括淀粉、纤维素、滑石、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、单硬脂酸甘油酯、氯化钠和脱脂奶粉等。液体和半固体赋形剂可选自甘油、丙二醇、水、乙醇和多种油类,包括石油、动物、植物或合成油,例如花生油、大豆油、矿物油和芝麻油等。优选的液体载体,特别是可以用于注射溶液的载体包括水、盐水、葡萄糖溶液和二醇类。其他合适的药学赋形剂及其制剂方法在E.W.Martin(MackPublishing Company,18th ed.,1990)出版的Remington's Pharmaceutical Sciences中详尽描述。
如有需要,本发明的组合物可以呈现为含有一或多个单位剂量的活性成分的包装或投放装置。例如,所述包装或投放装置可以包含金属或塑料薄膜(如泡罩包装)、玻璃及橡胶塞(如在小瓶中)。所述包装或投放装置可附有施药说明。与合适的药学载体配制的包含本发明化合物的组合物也可以在合适的容器中制备和放置,并标记用于治疗指定的病症。
制剂中所述化合物的量可以由本领域技术人员在全范围内改变。通常地,基于制剂总重量,以重量百分比(wt%)计,制剂将含有约0.01-99.99wt%的本发明化合物,余量为一种或多种合适的药物赋形剂。通常地,化合物的含量为约1-80wt%。
在另一方面,本发明提供了一种通过将治疗有效量的本发明的化合物或组合物与有此需求的GPR120接触而获得GPR120治疗效果的方法。在一个实施例中,治疗效果在细胞中产生。在另一个实施例中,所述接触在体内或体外进行。
在另一个方面,本发明提供了一种治疗有此需要的受试者的II型糖尿病的方法,其包含向所述受试者施用治疗有效量的本发明的化合物或组合物。在一个实施案中,所述受试者为人类。
本发明引用的所有技术和专利公开文本的全部内容均通过引用并入本文。
具体实施方式
本发明已有概述并经下述实施例进行了详尽说明,但并不受其限制。实施例1-46阐明了本发明的具体化合物及其合成方法。实施例47和48阐明了在生物学试验中测量本发明的化合物激活GPR120受体的能力的方法。
合成实施例
实施例1
化合物1的合成
步骤1
0℃下,向在CHCl3(500mL)中搅拌的1(50.0g,292mmol)溶液中加入氯磺酸(238g,2.05mol)。将反应混合物在0℃下搅拌0.5小时。当TLC显示反应完成时,将反应混合物倒入冰水(500mL)中,用CH2Cl2(3×500mL)萃取,经无水Na2SO4干燥并浓缩。粗品经石油醚(20mL)洗涤得到2(49.2g,59%)。
步骤2
0℃下,向在二噁烷(800mL)中搅拌的2(40.0g,148mmol)溶液中加入NH3.H2O(1.5L,15.58mol)。将反应混合物在0℃下搅拌1小时。当TLC显示反应完成时,将反应混合物用CH2Cl2(6×500mL)萃取,经无水Na2SO4干燥并浓缩。粗品经石油醚(100mL)洗涤得到3(36g,收率92%)。
步骤3
0℃下,向NaOH(24.0g,600mmol)的H2O(240mL)溶液中分批加入3(30.0g,120mmol)和KMnO4(94.8g,600mmol)。在N2下将反应混合物在60℃下搅拌12小时。当LCMS显示反应完成时,0℃下用Na2SO3(30g)将反应混合物淬灭并过滤。将滤液酸化至pH=2并过滤得到固体4(25.0g),其不需要经进一步纯化而使用。
步骤4
0℃下,向浓硫酸(100mL)中加入4(10.0g,35.7mmol),并将反应混合物在40℃下搅拌12小时。当LCMS显示反应完成时,将反应混合物倒入冰水(200mL)中,然后用乙酸乙酯(3×200mL)萃取。用H2O(3×20mL)洗涤有机层,无水Na2SO4干燥并浓缩得到5(9.1g)。
步骤5
0℃下,向在THF(200mL)中搅拌的5(9.1g,34.7mmol)溶液中分批加入NaBH4(13.1g,347mmol)和BF3.Et2O(49.3g,347mmol)。在N2下将反应混合物在70℃下搅拌12小时。当LCMS显示反应完成时,将反应混合物倒入冰水(250mL)中并用乙酸乙酯(3×200mL)萃取。用H2O(100mL)洗涤有机层,无水Na2SO4干燥并浓缩得到6(8.6g)。
步骤6
向6(50mg,0.20mmol)和苄基溴(52mg,0.30mmol)的DMF(2mL)溶液中加入碳酸铯(197mg,0.60mmol)。在惰性气氛下,将反应混合物在室温下搅拌12小时。完成后,将反应混合物减压浓缩并通过制备型TLC纯化得到7(30mg)。
步骤7
向7(31mg,0.092mmol)和吡啶-3-醇(8.8mg,0.092mmol)的二噁烷(2mL)溶液中加入碳酸铯(90mg,0.028mmol),CuI(7mg,0.037mmol)和2-(二甲基氨基)乙酸盐酸盐(2.6mg,0.018mmol)。在惰性气氛下,将反应混合物在90℃下搅拌12小时。完成后,将反应物浓缩并通过制备型HPLC(0.04%HCl/CH3CN/H2O体系)纯化得到白色固体化合物1(10mg,31%)。1HNMR(CD3OD,400MHz)δ8.26-8.24(d,1H),8.07-7.95(s,1H),7.96-7.93(d,1H),7.45-7.32(m,2H),4.43(s,2H),4.28(s,2H);LCMS(ESI):m/z 353.0(M+H)。
实施例2
化合物2的合成
使用与合成化合物1相似的方法合成化合物2。1H NMR(DMSO-d6,400MHz)δ7.91-7.89(d,1H),7.45-7.38(m,7H),7.25-7.23(m,1H),7.14-7.10(m,4H),4.36(s,2H),4.24(s,2H);LCMS(ESI):m/z 352.0(M+H)。
实施例3
化合物3的合成
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使用与合成化合物1相似的方法合成化合物3。1H NMR(DMSO-d6,400MHz)δ7.82-7.80(d,1H),7.44-7.43(d,2H),7.39-7.35(m,4H),7.21-7.20(m,2H),7.13-7.12(d,1H),7.04-7.02(m,2H),4.40(s,2H),4.21(s,2H);LCMS(ESI):m/z 386.0(M+H)。
实施例4
化合物4的合成
使用与合成化合物1相似的方法合成化合物4。1H NMR(DMSO-d6,400MHz)δ7.80-7.78(d,1H),7.44-7.31(m,7H),7.19-7.18(d,1H),7.08-7.06(d,2H),7.01(s,1H),4.39(s,2H),4.20(s,2H);LCMS(ESI):m/z 386.0(M+H)。
实施例5
化合物5的合成
使用与合成化合物1相似的方法合成化合物5。1H NMR(DMSO-d6,400MHz)δ7.94-7.92(d,1H),7.69-7.67(d,1H),7.51-7.50(d,1H),7.42-7.40(m,5H),7.39-7.37(d,1H),7.27(s,1H),7.20-7.16(d,1H),4.37(s,2H),4.24(s,2H);LCMS(ESI):m/z 420.0(M+H)。
实施例6
化合物6的合成
使用与合成化合物1相似的方法合成化合物6。1H NMR(DMSO-d6 400MHz)δ7.93-7.90(d,1H),7.68-7.66(d,1H),7.56-7.54(m,3H),7.45-7.43(m,2H),7.39-7.26(m,1H),4.58(s,2H),4.32(s,2H);LCMS(ESI):m/z 421.0(M+H)。
实施例7
化合物7的合成
使用与合成化合物1相似的方法合成化合物7。1H NMR(CD3OD,400MHz)δ8.79-8.68(d,1H),8.28-8.26(d,1H),8.06-8.04(m,1H),7.92-7.90(d,1H),7.43-7.32(m,4H),7.20-7.15(m,1H),4.61(s,2H),4.42(s,2H);LCMS(ESI):m/z 405.0(M+H)。
实施例8
化合物8的合成
使用与合成化合物1相似的方法合成化合物8。1H NMR(DMSO-d6 400MHz)δ8.52-8.48(t,2H),7.95-7.67(m,1H),7.53-7.51(m,1H),7.39-7.28(m,1H),7.28-7.20(m,1H),4.48(s,2H),4.37(s,2H);LCMS(ESI):m/z 387.0(M+H)。
实施例9
化合物9的合成
使用与合成化合物1相似的方法合成化合物9。1H NMR(CD3OD,400MHz)δ8.81-8.69(d,2H),8.31-8.29(d,1H),8.10-8.08(m,1H),7.97-7.95(d,1H),7.49-7.44(m,2H),7.39-7.33(m,4H),4.45(s,2H),4.33(s,2H);LCMS(ESI):m/z 387.0(M+H)。
实施例10
化合物10的合成
使用与合成化合物1相似的方法合成化合物10。1H NMR(CD3OD,400MHz)δ8.82(s,1H),8.70(s,1H),8.34-8.32(d,1H),8.11-8.08(m,1H),7.96-7.94(d,1H),7.46-7.36(m,6H),4.43(s,2H),4.31(s,2H);LCMS(ESI):m/z 387.0(M+H)。
实施例11
化合物11的合成
使用与合成化合物1相似的方法合成化合物11。1H NMR(CD3OD,400MHz)δ8.55-8.49(m,2H),7.95(d,1H),7.69(bs,2H),7.60-7.53(m,2H),7.51-7.47(m,1H),7.28(d,1H),7.20(s,1H),4.47(s,2H),4.38(s,2H);LCMS(ESI):m/z 421.0(M+H)。
实施例12
化合物12的合成
使用与合成化合物1相似的方法合成化合物12。1H NMR(CD3OD,400MHz)δ8.82(s,1H),8.70-8.68(d,1H),8.36-8.33(d,1H),8.12-8.10(d,1H),7.44-7.40(m,2H),4.40(s,2H),2.90(s,3H);LCMS(ESI):m/z 277.0(M+H)。
实施例13
化合物13的合成
使用与合成化合物1相似的方法合成化合物13。1H NMR(CD3OD,400MHz)δ8.78(d,2H),8.27-8.25(d,2H),7.92-7.90(d,1H),7.49-7.47(d,1H),7.38-7.29(m,8H),4.96-4.93(m,1H),4.36-4.32(d,1H),4.06-4.02(d,1H),1.79-1.77(d,3H);LCMS(ESI):m/z 367.0(M+H)。
实施例14
化合物14的合成
步骤1
向6(1.0g,4.03mmol)的DMF(15mL)溶液中加入Cs2CO3(2.63g,8.06mmol)和苄基溴(1.03g,6.05mmol)。将混合物在30℃下搅拌12小时,然后过滤。减压浓缩滤液得到残余物,并用水(80mL)稀释,CH2Cl2(3×60mL)萃取。将合并的有机层用水(3×60mL)和盐水(2×80mL)洗涤,无水Na2SO4干燥过滤并减压浓缩得到白色固体7(1.2g),其无需纯化,在下一步直接使用。
步骤2
将7(120mg粗品)、Pd2(dba)3(65mg,0.071mmol)、t-Bu Xphos(30mg,0.071mmol)和KOH(99.5mg,1.77mmol)在二噁烷(2mL)和H2O(2mL)中的混合物脱气,用N2(3X)吹扫,然后在85℃下搅拌12小时。减压浓缩反应混合物得到残余物,并用水(5mL)稀释。使用2M HCl将溶液调节至pH=3,然后用乙酸乙酯(3×15mL)萃取。将有机层用盐水(2×20mL)洗涤,经无水Na2SO4干燥过滤并减压浓缩得到黄色固体8(130mg),其无需纯化,在下一步直接使用。
步骤3
35℃下,在N2下,将8(50mg,0.18mmol)、3,3-二氟环丁醇(23.6mg,0.22mmol)、PPh3(95mg,0.36mmol)和DIAD(74mg,0.36mmol)在THF(2mL)溶液中搅拌12小时。当LCMS显示反应完成时,浓缩反应混合物得到残余物。通过制备型HPLC(0.04%HCl/ACN/H2O体系)纯化残余物得到白色固体化合物14(14mg,21%)。1H NMR(CD3OD,400MHz)δ7.74-7.46(d,1H),7.44-7.38(d,2H),7.36-7.32(m,2H),7.11-7.09(d,1H),6.93(s,1H),4.80(s,2H),4.21(s,2H),3.31-3.12(m,2H),2.76-2.69(m,2H);LCMS(ESI):m/z 366.0(M+H)。
实施例15
化合物15的合成
使用与合成化合物14相似的方法合成化合物15。1H NMR(DMSO-d6,400MHz)δ7.79-7.76(d,1H),7.43-7.37(m,4H),7.34-7.33(m,1H),7.04-7.02(m,1H),6.98(s,1H),4.77-4.70(m,1H),4.34(s,2H),4.21(s,2H),2.50-2.43(m,2H),2.05-2.00(m,2H),1.79-1.77(m,1H),1.61-1.64(m,1H);LCMS(ESI):m/z 330.1(M+H)。
实施例16
化合物16的合成
步骤1
向在DMF(2mL)中搅拌的6(300mg,1.21mmol)和PMBCl(284mg,1.81mmol)溶液中加入Cs2CO3(788mg,2.42mmol)。将反应混合物在35℃下搅拌12小时。当LCMS显示反应完成时,将反应混合物用H2O(10mL)淬灭并用乙酸乙酯(3×20mL)萃取。将有机层用H2O(3×20mL)洗涤,经无水Na2SO4干燥浓缩并通过制备型TLC(石油醚:乙酸乙酯=1:1)纯化得到9(335mg,64%)。
步骤2
向在二噁烷(15mL)中搅拌的9(1.50g,4.07mmol)和吡啶-3-醇(775mg,8.15mmol)溶液中加入CuI(620mg,3.26mmol)、Cs2CO3(3.32g,10.2mmol)和2-(二甲基氨基)乙酸盐酸盐(227mg,1.63mmol)。在N2下,将反应混合物在100℃下搅拌12小时。当LCMS显示反应完成时,过滤反应混合物。浓缩滤液并通过制备型TLC(石油醚:乙酸乙酯=1:1.5)纯化得到液体10(770mg,42%)。
步骤3
25℃下,将10(770mg,2.01mmol)在TFA/CH2Cl2(77mL)中的溶液搅拌12小时。当LCMS显示反应完成时,浓缩反应混合物。将粗品溶于甲基叔丁基醚(15mL)和H2O(10mL)中。将水层调节至pH=10并浓缩。将固体用CH2Cl2:MeOH=10:1(30mL)洗涤得到固体11(500mg,76%)。LCMS(ESI):m/z 263.1.(M+H)。
步骤4
向在THF(2mL)中搅拌的11(80mg,0.31mmol)、12(69mg,31mmol)和PPh3(80mg,0.31mmol)溶液中加入DIAD(62mg,0.31mmol)。在N2下,将反应混合物在40℃下搅拌12小时。当LCMS显示反应完成时,浓缩反应混合物。通过制备型HPLC纯化粗品得到化合物16(8.7mg,6%)。1H NMR(CD3OD 400MHz)δ8.443(s,2H),7.87-7.85(d,1H),7.85-7.67(d,1H),7.64-7.57(m,3H),7.50-7.29(d,2H),4.59(s,2H),4.42(s,2H);LCMS(ESI):m/z 471.1(M+H)。
实施例17
化合物17的合成
使用与合成化合物16相似的方法合成化合物17。1H NMR(CD3OD,400MHz)δ7.83-7.81(d,2H),7.33-7.28(s,6H),7.22-7.21(m,2H),4.34(d,2H),3.51-3.48(m,2H),3.05-3.01(s,2H);LCMS(ESI):m/z 367.1(M+H)。
实施例18
化合物18的合成
向11(80mg,0.18mmol)的CH3CN(3mL)溶液中加入Cs2CO3(149mg,046mmol)和13(38mg,0.22mmol)。将混合物在20℃下搅拌2小时,然后过滤。减压浓缩滤液得到残余物并通过制备型HPLC(HCl,0.05%HCl-ACN)纯化得到黄色油状物化合物18(24mg,收率36%)。1HNMR(CD3OD,400MHz)δ8.86-8.85(d,2H),8.72-8.71(d,1H),8.67-8.65(m,1H),8.24-8.22(d,1H),8.14-8.12(m,1H),8.05-7.99(m,2H),8.01-7.99(d,1H),7.48-7.51(m,2H),4.99(s,2H),4.70(s,2H);LCMS(ESI):m/z 354.0(M+H)。
实施例19
化合物19的合成
使用与合成化合物18相似的方法合成化合物19。1H NMR(CD3OD,400MHz)δ9.01(s,1H),8.88-8.87(d,2H),8.80-8.78(d,1H),8.73-8.72(d,1H),8.40-8.38(d,1H),8.18-8.12(m,2H),7.99-7.97(d,1H),7.51-7.46(m,2H),4.81(s,2H),4.59(s,2H);LCMS(ESI):m/z354.0(M+H)。
实施例20
化合物20的合成
使用与合成化合物18相似的方法合成化合物20。1H NMR(CD3OD,400MHz)δ8.88-8.87(m,3H),8.72-8.71(d,1H),8.40-8.38(d,1H),8.22-8.21(d,2H),8.15-8.11(m,1H),8.01-7.99(d,1H),7.51-7.47(m,2H),4.90(s,2H),4.62(s,2H);LCMS(ESI):m/z 354.0(M+H)。
实施例21
化合物21的合成
步骤1
将6(150mg,0.60mmol)、14(180mg,0.79mmol)和Cs2CO3(393mg,1.21mmol)在DMF(2mL)中的混合物脱气,用N2(3X)吹扫,然后在35℃下搅拌12小时。当LC-MS监测完成反应时,将其过滤并用乙酸乙酯(30mL)稀释。有机层用水(3×30mL)和盐水(30mL)洗涤,无水硫酸钠干燥,过滤并浓缩。粗品(180mg,白色固体)无需纯化,在下一步直接使用。
步骤2
将15(180mg,0.27mmol)、吡啶-3-醇(33mg,0.35mmol)、CuI(15mg,0.08mmol),Cs2CO3(174mg,0.53mmol)和2-(二甲基氨基)乙酸盐酸盐(11mg,0.08mmol)在二噁烷(2mL)中的混合物脱气,用N2(3X)吹扫,然后在100℃下搅拌24小时。冷却反应混合物,用水(20mL)稀释,并用乙酸乙酯(3×10mL)萃取。将合并的有机层用盐水(30mL)洗涤,无水硫酸钠干燥,过滤并浓缩。粗品通过制备型TLC(石油醚:乙酸乙酯=1:1)纯化得到浅黄色油状物16(80mg,0.15mmol)。
步骤3
向16(80mg,0.15mmol)的THF(1mL)和MeOH(1mL)溶液中加入NaOH(1mL,2M)。将混合物在15℃下搅拌0.5小时,用水(30mL)稀释,然后用2N HCl(aq)酸化至pH=6。用乙酸乙酯(3×10mL)萃取溶液。有机层用盐水(30mL)洗涤,无水硫酸钠干燥,过滤并浓缩。粗品通过制备型HPLC纯化得到白色固体化合物21(8.9mg,13%)。1H NMR(DMSO-d6,400MHz)δ8.54(d,2H),7.99-7.93(m,3H),7.73(d,1H),7.61-7.50(m,3H),7.29(d,1H),7.21(s,1H),4.47(s,2H),4.30(s,2H)。
实施例22
化合物22的合成
使用与合成化合物21相似的方法合成化合物22。1H NMR(DMSO-d6,400MHz)δ8.58(s,2H),8.02-7.94(m,2H),7.90(d,1H),7.78(d,1H),7.70-7.60(m,2H),7.56-7.48(m,1H),7.30(d,1H),7.22(s,1H),4.47(s,2H),4.28(s,2H);LCMS(ESI):m/z 397.0(M+H)。
实施例23
化合物23的合成
步骤1
0℃下,向17(15.0g,90.8mmol)的DMF(200mL)溶液中加入NBS(16.2g,90.8mmol)。加完后,将混合物升温至15℃并搅拌14小时。加入水(200mL)淬灭反应混合物,然后用乙酸乙酯(3×250mL)萃取。合并的有机相用水(3×250mL)和盐水(2×200mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩,得到灰色固体18(21.0g),其直接用于下一步反应。1H NMR(CDCl3,400MHz)δ7.90-7.89(d,1H),7.29-7.28(d,1H),5.84(s,2H),3.87(s,3H),2.15(s,3H);LCMS(ESI):m/z 246.0(M+H)。
步骤2
0℃下,向18(11.0g)的HCl(120mL)和AcOH(20mL)溶液中逐滴加入NaNO2(3.42g,49.6mmol)的H2O(20mL)溶液。将混合物在0℃下搅拌30分钟,然后分批加入SO2(17.3g,270mmol)和CuCl(1.34g,13.5mmol)的AcOH(200mL)溶液。0℃下30分钟后,将反应混合物倒入水(300mL)中并用CH2Cl2(3×300mL)萃取。有机层用饱和盐水(2×300mL)洗涤,无水Na2SO4干燥,过滤并减压浓缩,得到棕色油状物19(12.0g),其无需进一步纯化,直接使用。
步骤3
0℃下,向NH3.H2O(200mL)的二噁烷(100mL)溶液中加入19(11.0g,33.6mmol)的二噁烷(100mL)溶液。15℃下30分钟后,将反应混合物用水(100mL)稀释,然后用乙酸乙酯(3×300mL)萃取。合并的有机相用饱和盐水(2×300mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩,得到的残余物通过从甲基叔丁基醚(100mL)中重结晶纯化得到白色固体20(1.0g)。LCMS(ESI):m/z 276.0(M-H)。
步骤4
0℃下,向20(200mg,0.72mmol)的THF(10.0mL)溶液中分批加入NaBH4(274mg,7.24mmol)。加完后,分批加入BF3.Et2O(1.03g,7.24mmol)。将所得混合物在70℃下搅拌14小时。将反应混合物用水(40mL)淬灭,然后用乙酸乙酯(3×50mL)萃取。有机相用饱和盐水(2×50mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩,得到白色固体21(160mg,粗品),其无需进一步纯化,直接使用。LCMS(ESI):m/z 262.0(M-H)。
步骤5
向21(120mg,粗品)的DMF(6.0mL)溶液中加入Cs2CO3(298mg,0.92mmol)和BnBr(117mg,0.69mmol)。将混合物在30℃下搅拌14小时。过滤反应混合物,然后用水(20mL)稀释,乙酸乙酯(3×20mL)萃取。有机层用水(3×15mL)和饱和盐水(2×20mL)洗涤,无水Na2SO4干燥,过滤并减压浓缩,得到黄色油状物22(200mg),其无需纯化,在下一步直接使用。
步骤6
将22(140mg)、吡啶-3-醇(45mg,0.48mmol)、CuI(30mg,0.16mmol)、N,N-二甲基甘氨酸盐酸盐(11mg,0.079mmol)和Cs2CO3(259mg,0.79mmol)在二噁烷(6.0mL)中的混合物脱气,并用N2(3X)吹扫。将混合物在100℃下搅拌14小时,然后过滤。减压浓缩滤液得到残余物,其通过制备型HPLC纯化得到无色油状化合物23(72mg,91%)。1H NMR(MeOD,400MHz)δ8.79-8.78(d,1H),8.68-8.67(d,1H),8.33-8.31(m,1H),8.11-8.09(m,1H),7.46-7.44(m,2H),7.39-7.32(m,3H),7.26-7.25(d,1H),7.15-7.14(d,1H),4.44(s,2H),4.24(s,2H),2.63(s,3H);LCMS(ESI):m/z 486.2(M+H)。
实施例24
化合物24的合成
步骤1
向6(1.00g,3.63mmol)和碘苯(889mg,4.36mmol)的二噁烷(15.0mL)溶液中加入CuI(276mg,1.45mmol)、2-(二甲基氨基)乙酸盐酸盐(101mg,7.26mmol)和碳酸铯(2.36g,7.26mmol)。将所得混合物加热至90℃并在惰性气氛下搅拌12小时。完成后,将反应混合物过滤,减压浓缩,将得到的油状物用甲基叔丁基醚(10mL)打浆得到23(700mg)。LCMS(ESI):m/z 324.0(M+H).
步骤2
向在二噁烷(4.0mL)中搅拌的23(350mg,1.08mmol)和吡啶-3-醇(123mg,1.30mmol)溶液中加入CuI(82mg,0.43mmol)、碳酸铯(703mg,2.16mmol)和2-(二甲基氨基)乙酸盐酸盐(30mg,0.22mmol)。在N2下,将反应混合物在90℃下搅拌12小时。完成后,将反应混合物过滤,减压浓缩并通过HPLC(0.04%HCl/CH3CN/H2O体系)纯化得到化合物24(50mg,26%)。1H NMR(DMSO-d6,400MHz)δ8.59-8.58(d,2H),8.54-8.53(d,1H),8.04-8.02(m,1H),7.47-7.45(m,1H),7.42-7.41(m,4H),7.33-7.31(m,1H),7.28-7.20(m,1H),5.0(s,2H);LCMS(ESI):m/z 339.0(M+H)。
实施例25
化合物25的合成
使用与合成化合物24相似的方法合成化合物25。1H NMR:(DMSO-d6,400MHz)δ8.00-7.98(d,1H),7.50-7.40(m,6H),7.21-7.17(m,6H),4.99(s,2H);LCMS(ESI):m/z 338.0(M+H)。
实施例26
化合物26的合成
使用与合成化合物24相似的方法合成化合物26。1H NMR(DMSO,400MHz)δ8.17-8.15(d,1H),7.81(s,1H),7.74-7.72(d,2H),7.58-7.55(t,1H),7.49-7.48(m,4H),7.24-7.23(m,1H),6.55-6.53(d,1H),6.41-6.38(t,1H),5.11(s,2H);LCMS(ESI):m/z 339.0(M+H)。
实施例27
化合物27的合成
使用与合成化合物24相似的方法合成化合物27。1H NMR(DMSO-d6,400MHz)δ8.16-8.14(d,1H),7.74-7.72(d,1H),7.56-7.55(d,1H),7.49-7.48(m,3H),6.55-6.53(d,1H),6.41-6.39(m,1H),5.11(s,2H);LCMS(ESI):m/z 339.0(M+H)。
实施例28
化合物28的合成
使用与合成化合物24相似的方法合成化合物28。1H NMR(DMSO-d6 400MHz)δ8.03-8.01(d,1H),7.51-7.41(m,8H),7.34-7.18(m,3H),5.01(s,2H);LCMS(ESI):m/z 372.0(M+H)。
实施例29
化合物29的合成
使用与合成化合物24相似的方法合成化合物29。1H NMR(DMSO-d6 400MHz)δ8.03-8.01(d,1H),7.75-7.72(d,1H),7.58(s,1H),7.48-7.29(m,4H),7.23-7.20(m,4H),5.00(s,2H);LCMS(ESI):m/z 405.9(M+H)。
实施例30
化合物30的合成
使用与合成化合物24相似的方法合成化合物30。1H NMR(DMSO-d6 400MHz)δ7.88-7.86(d,1H),7.48-7.41(m,4H),7.20-7.16(m,1H),7.20-7.16(m,2H),4.96-4.87(d,2H),4.83-4.80(m,1H),2.41-2.11(m,2H),2.09-2.04(m,2H),1.83-1.81(m,1H),1.71-1.64(m,1H);LCMS(ESI):m/z 316.0(M+H)。
实施例31
化合物31的合成
使用与合成化合物24相似的方法合成化合物31。1H NMR(DMSO-d6,400MHz)δ8.71-8.69(d,2H),8.61-8.60(d,2H),8.15-8.13(d,2H),7.90-7.88(m,1H),7.72-7.37(m,2H),5.17(s,2H);LCMS(ESI):m/z 340.0(M+H)。
实施例32
化合物32的合成
使用与合成化合物24相似的方法合成化合物32。1H NMR(DMSO-d6 400MHz)δ8.57-8.54(d,2H),8.07-8.05(d,1H),7.72-7.59(d,1H),7.48-7.42(d,1H),7.40-7.38(m,1H),7.33-7.26(m,2H),5.05(s,2H);LCMS(ESI):m/z 373.0(M+H)。
实施例33
化合物33的合成
使用与合成化合物24相似的方法合成化合物33。1H NMR(DMSO-d6 400MHz)δ8.57-8.53(d,1H),8.08-8.06(d,1H),7.60-7.58(m,1H),7.45-7.26(m,2H),5.07(s,2H);LCMS(ESI):m/z 423.0(M+H)。
实施例34
化合物34的合成
使用与合成化合物24相似的方法合成化合物34。1H NMR(DMSO-d6,400MHz)δ8.58-8.48(m,2H),8.42(d,1H),8.06(d,1H),7.93-7.86(m,1H),7.70(dd,1H),7.55(dd,1H),7.37-7.29(m,3H),7.17(dd,1H),5.12(s,2H);LCMS(ESI):m/z 340.0(M+H)。
实施例35
化合物35的合成
使用与合成化合物24相似的方法合成化合物35。1H NMR(DMSO-d6 400MHz)δ8.82(s,1H),8.72-8.70(d,3H),8.22-8.14(d,1H),8.01-8.00(d,1H),7.99-7.86(m,1H),7.86-7.83(d,2H),5.28(s,2H);LCMS(ESI):m/z 340.0(M+H)。
实施例36
化合物36的合成
使用与合成化合物24相似的方法合成化合物36。1H NMR(CD3OD 400MHz)δ8.81(s,1H),8.68-8.67(d,1H),8.28-8.11(d,1H),8.06-8.00(m,2H),7.88-7.86(d,1H),7.56-7.48(d,1H),5.03(s,2H);LCMS(ESI):m/z 383.0(M+H)。
实施例37
化合物37的合成
使用与合成化合物24相似的方法合成化合物37。1H NMR(CD3OD,400MHz)δ7.85-7.83(d,1H),7.48-7.40(m,5H),7.20-7.17(m,4H),7.15-6.85(m,1H),4.560(s,2H);LCMS(ESI):m/z 372.0(M+H)。
实施例38
化合物38的合成
步骤1
向6(500mg,2.02mmol)和碘苯(453mg,2.22mmol)在二噁烷(10mL)中的混合物中加入CuI(39mg,0.20mmol)、N1,N2-二甲基乙烷-1,2-二胺(35.6mg,0.40mmol)和K3PO4(858mg,4.04mmol)。将混合物加热至100℃并搅拌12小时。将反应混合物倒入水(20mL)中并用乙酸乙酯(3×20mL)萃取。有机相用盐水(2×20mL)洗涤,无水Na2SO4干燥,过滤并减压浓缩。残留物通过制备型TLC(石油醚/乙酸乙酯)=1:1纯化残余物得到白色固体23(250mg,0.66mmol,33%)。
步骤2
25℃下,在N2下向23(80mg,0.25mmol)和KOH(69mg,1.23mmol)在二噁烷(1.0mL)和H2O(1.0mL)中的混合物中一次性加入Pd2(dba)3(22.6mg,0.025mmol)和t-BuXphos(11mg,0.025mmol)。将混合物加热至100℃并搅拌12小时,然后用1N HCl淬灭(至pH=6)。将反应混合物用EtOAc(3×5mL)萃取,有机相经Na2SO4干燥,过滤并减压浓缩得到24(35mg),其无需纯化,在下一步直接使用。
步骤3
向在DMF(2.0mL)中搅拌的24(15mg,0.057mmol)和溴甲基苯(9.8mg,0.057mmol)溶液中加入K2CO3(56mg,0.17mmol)。在N2下,将反应混合物在90℃下搅拌12小时。当LCMS显示反应完成时,将反应混合物浓缩,得到粗品并通过制备型HPLC纯化,得到化合物38(3mg)。1HNMR(DMSO-d6,400MHz)δ7.91-7.49(d,1H),7.48-7.44(m,9H),7.40-7.38(d,1H),5.26(s,2H),4.99(s,2H);LCMS(ESI):m/z 352.0(M+H).
实施例39
化合物39的合成
使用与合成化合物38相似的方法合成化合物39。1H NMR(DMSO-d6,400MHz)δ7.95-7.93(d,1H),7.61-7.59(d,2H),7.59-7.51(m,6H),7.49-7.45(d,1H),7.35-7.19(m,1H),5.38(s,2H),5.03(s,2H);LCMS(ESI):m/z 420.0(M+H)。
实施例40
化合物40的合成
使用与合成化合物38相似的方法合成化合物40。1H NMR(DMSO-d6,400MHz)δ8.24-8.22(d,1H),7.96-7.94(d,1H),7.74(s,1H),7.48-7.45(m,4H),7.34-7.22(m,3H),7.19-7.17(m,1H),5.39(s,2H),5.01(s,2H);LCMS(ESI):m/z 353.0(M+H)。
实施例41
化合物41的合成
步骤1
将6(120mg,0.48mmol)、25(140mg,0.58mmol)、Cu(OAc)2(88mg,0.48mmol)、Et3N(98mg,0.97mmol)和4A分子筛(250mg)在CH2Cl2(10.0mL)中的混合物脱气,并用O2(3X)吹扫。在15℃下搅拌1小时后,过滤反应混合物,用水(20mL)稀释,CH2Cl2(3×20mL)萃取。有机层用盐水(2×20mL)洗涤,无水Na2SO4干燥,过滤并减压浓缩,得到黄色固体26(220mg),其无需纯化,在下一步直接使用。
步骤2
将26(220mg,粗品)、吡啶-3-醇(48mg,0.51mmol)、CuI(32mg,0.17mmol)、N,N-二甲基甘氨酸盐酸盐(12mg,0.084mmol)和Cs2CO3(275mg,0.084mmol)在二噁烷(3.0mL)中的混合物脱气,并用N2(3X)吹扫。将混合物在100℃下搅拌12小时,然后过滤。减压浓缩滤液,得到残余物,将其通过制备型HPLC纯化,得到白色固体化合物41(2.6mg,1%)。1H NMR(CD3OD,400MHz)δ8.80(s,1H),8.66(s,1H),8.26-8.24(d,1H),8.02-7.99(d,2H),7.74-7.72(d,1H),7.67(s,1H),7.49-7.44(m,3H),4.95(s,2H);LCMS(ESI):m/z457.0(M+H)。
实施例42
化合物42的合成
使用与合成化合物41相似的方法合成化合物42。1H NMR(400MHz,CD3OD)δ8.37(d,J=8.53Hz,1H),8.16(s,1H),8.03(d,J=9.04Hz,1H),7.56-7.38(m,7H),4.99(s,2H);LCMS(ESI):m/z 457.0(M+H)。
实施例43
化合物43的合成
使用与合成化合物41相似的方法合成化合物43。1H NMR(400MHz,CD3OD)δ7.93(d,J=8.38Hz,1H),7.86(d,J=7.94Hz,2H),7.73-7.57(m,2H),7.50-7.32(m,3H),7.29(s,1H),4.88(s,2H);LCMS(ESI):m/z 457.0(M+H)。
实施例44
化合物44的合成
将11(40mg,0.15mmol)、溴代环丁烷(103mg,0.76mmol)、KI(25mg,0.15mmol)和Cs2CO3(99mg,0.31mmol)在DMF(2.0mL)中的混合物脱气,并用N2吹扫(3×)。在N2气氛下,将反应混合物在50℃下搅拌12小时,然后用H2O(10mL)淬灭。将溶液用乙酸乙酯(2×10mL)萃取,合并的有机层用盐水(2×10mL)洗涤,硫酸钠干燥,过滤减压浓缩并通过制备型HPLC纯化,得到浅黄色固体化合物44(33mg,59%)。1H NMR(DMSO-d6,400MHz)δ8.61(d,1H),8.55(d,1H),7.89(d,1H),7.80(d,1H),7.64(dd,1H),7.31-7.22(m,2H),4.43(s,2H),4.05(m,1H),2.37-2.24(m,2H),2.22-2.11(m,2H),1.78(m,2H);LCMS(ESI):m/z 317.1(M+H)。
实施例45
化合物45的合成
步骤1
向27(3.0g,14.0mmol)和CH3I(3.96g,27.9mmol)的DMF(30mL)溶液中加入K2CO3(2.89g,20.9mmol)。将反应混合物在25℃下搅拌12小时,然后用H2O(20mL)淬灭。溶液用乙酸乙酯(3×100mL)萃取,有机层用H2O(3×100mL)洗涤并浓缩,得到28(2.9g,82%)。
步骤2
向28(1.0g,4.37mmol)和NBS(0.93g,5.24mmol)的CCl4(10mL)溶液中加入BPO(106mg,0.44.00mmol)。将反应混合物在80℃下搅拌5小时。完成后,用H2O(10mL)淬灭反应,并用乙酸乙酯(3×20mL)萃取。将有机层用H2O(3×10mL)洗涤,浓缩,并通过制备型TLC(石油:乙酸乙酯=20:1)纯化,得到29(610mg,41%)。
步骤3
向29(500mg,1.62mmol)和苯胺(166mg,1.78mmol)的EtOH(2mL)溶液中加入二异丙基乙胺(230mg,1.78mmol)。将反应混合物在90℃下搅拌12小时,冷却至0℃,然后过滤。将粗品用EtOH洗涤,得到白色固体30(400mg,77%),其无需进一步纯化。
步骤4
向30(120mg,0.42mmol)和吡啶-3-醇(59mg,0.62mmol)的二噁烷(2mL)溶液中加入Cs2CO3(407mg,1.25mmol)、CuI(32mg,0.17mmol)和2-(二甲基氨基)乙酸盐酸盐(23mg,0.17mmol)。在N2下,将反应混合物在110℃搅拌12小时,然后过滤浓缩并通过制备型HPLC纯化,得到化合物45(100mg,72%)。1H NMR(DMSO-d6,400MHz)δ8.71(s,1H),8.71-8.62(d,1H),7.98-7.96(d,1H),7.88-7.84(m,4H),7.46-7.40(m,3H),7.31-7.29(m,1H),7.18(m,1H),5.00(s,2H);LCMS(ESI):m/z 303.1(M+H)。
实施例46
化合物46的合成
使用与合成化合物45相似的方法合成化合物46。1H NMR(DMSO-d6,400MHz)δ8.83-8.59(m,2H).7.99(d,1H),7.87-7.76(m,2H),7.38-7.32(m,3H),7.31-7.25(m,4H),4.72(s,2H),4.35(s,2H);LCMS(ESI):m/z 317.1(M+H)。
生物学实施例
实施例47
人GPR120β-抑制蛋白募集试验
该体外试验测试化合物通过β-抑制蛋白募集到异源表达的人GPR120来激活细胞内信号传导的能力。该功能性细胞试验利用与β-半乳糖苷酶(β-gal)互补的酶片段作为功能性报道分子(β-抑制蛋白试验平台)。将人GPR120受体(GenBank登录号NM_181745)与小酶片段ProLinkTM框内融合,并在CHO-K1细胞中与β-抑制蛋白2和较大的N末端缺失的β-gal突变体的融合蛋白共表达。GPR120激动剂的激活刺激β-抑制蛋白与ProLink标记的GPCR的结合,并迫使两个酶片段互补,导致活性β-gal酶的形成。这种相互作用导致酶活性的增加,酶活性可以使用化学发光/>检测试剂测量。
在试验前一天,将细胞以20μL生长培养基的总体积接种到白壁384孔微量培养板中,并在37℃/5%CO2下孵育过夜。在试验当天,除去生长培养基并向每个孔中加入20μL试验缓冲液(HBSS+10mM HEPES+0.1%热灭活的BSA)。
将待测化合物溶于100%DMSO中至浓度为10mM,得到储备溶液。将储备溶液在试验缓冲液中进行连续稀释,从而得到5倍于待测浓度的中间浓度。向细胞中加入5μL的5份化合物溶液,将试验板在37℃下孵育90分钟。在测定中测试的化合物的最终浓度范围为1.5nM至100μM。孵育后,向每个孔中加入12.5μL的检测试剂,并将板在室温下孵育60分钟。使用EnVision读板仪(PerkinElmer)读取化学发光,原始数据表示为相对光单位(RLU)。
为了确定激动剂效力(EC50值),使用可变Hill Slope四因子模型,在GraphPadPrism软件包中进行原始数据(RLU)的非线性最小二乘曲线拟合:
下面在表1中示出该试验中式I化合物的pEC50值(pEC50=-log(EC50)曲线拟合),β-Arr pEC50。
实施例48
人GPR120钙释放试验
该体外试验测试化合物通过G蛋白偶联导致肌醇1,4,5-三磷酸的产生和细胞内钙的活化来激活异源表达的人GPR120的能力。该功能性细胞试验基于细胞内Ca2+释放后线粒体水母发光蛋白(aequorin)的发光。水母发光蛋白是从水母Aequorea victoria分离的发光蛋白。活性蛋白质在来自脱辅基水母发光蛋白及其辅助因子腔肠素的分子氧存在下形成。Ca2+与活性蛋白质的结合诱导构象变化,导致腔肠素的氧化和随后的蓝色发光。
人GPR120受体的短变体(GenBank登录号AAI01176)在Gα16和线粒体脱辅基水母发光蛋白共表达的CHO-K1细胞系中稳定表达。
细胞在不含抗生素的培养基中生长至对数中期,用PBS/EDTA分离,离心并在试验缓冲液(含有15mM的HEPES pH 7.0和0.1%无蛋白酶BSA的DMEM-F12培养基)中重悬,至浓度为106个细胞/毫升。将细胞在室温下用5μM腔肠素孵育至少4小时。
将测试化合物溶于100%DMSO中至浓度为20mM,得到储备溶液。将储备溶液在100%DMSO中进行连续稀释,以得到200倍于待测浓度的中间浓度。将每个样品在试验缓冲液中稀释100倍。将50μL这些化合物溶液分配到96孔测定板的每个孔中。试验中待测试化合物的最终浓度范围为5nM至100μM。α-亚麻酸用作参比化合物。每个测试一式两份进行。
试验开始前,将50μL细胞悬浮液加入到试验板的每个孔中。使用HamamatsuFunctional Drug Screening System 6000(FDSS 6000)记录所得的发光,原始数据表示为相对光单位(RLU)。
为了确定激动剂效力(EC50值),使用可变Hill Slope四因子模型,在GraphPadPrism软件包中进行原始数据(RLU)的非线性最小二乘曲线拟合:
下面在表1中示出该试验中式I化合物的pEC50值(pEC50=-log(EC50)曲线拟合),Ca2+pEC50。
表1:式I化合物的体外试验活性
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上述结果表明,如上文实施例中所述及由式1一般定义的,本发明化合物是有效的GRP120激动剂,其可用于治疗T2D。虽然如上文说明书中所详细公开的,这些化合物可以通过任何给药途径并以各种频率给药,但在一个优选的实施方案中,它们以片剂或胶囊通过口服的方式每天一次施用于T2D患者以治疗和控制该病症。
实施例49
生物学实施例:GPR120 C57BL/6J小鼠口服葡萄糖耐受测试
用某些化合物进行口服葡萄糖耐量试验(OGTT)以确定它们对葡萄糖波动的急性作用。
将8-10周龄且保持常规饲料喂养的雄性C57BL/6J小鼠用于该研究。每个治疗组使用10只小鼠,研究当天每只小鼠体重在24-30克之间,并且每个治疗组的平均体重为27.2-27.3克。
通过混合和超声处理,将供试品以10mg/mL的浓度在给药载体(0.5%羟丙基甲基纤维素和2%Tween-20水溶液)中制成悬浮液。
小鼠禁食6小时后,通过口服灌胃法以100mg/kg(10mL/kg)施用载体或测试品。在施用测试品30分钟后,以3g/kg施用葡萄糖(PO)。通过尾部剪切将动物放血以在葡萄糖激发之前30分钟确定基础葡萄糖水平,并且在葡萄糖激发之后0、15、30、60、90和120分钟再次确定基础葡萄糖水平。使用Johnson&Johnson OneTouch血糖仪测定所有血液样品中的葡萄糖水平。
将葡萄糖值输入Excel表中,并在GraphPad Prism中绘制平均值±平均值的标准误差的曲线。通过双因素方差分析法分析(RM ANOVA)研究时间段组间差异的显著性。P值小于0.05被认为具有统计学意义。
通过使用在用脂多糖(LPS)刺激时合成和分泌TNFα的人外周血单核细胞(hPBMC)评估本发明化合物抑制TNFα产生的能力。
使用由Key Biologics采购的单核细胞组制备hPBMC。简而言之,将细胞产品从电泳袋中无菌取出,小心地铺在预热的Ficoll(Histopaque 1077)上,并关闭制动器,在室温下以1,800×g离心15分钟。离心后,去除界面并加入无菌Dulbecco's磷酸盐缓冲盐水(DPBS)中。然后将细胞在室温下以300×g沉淀10分钟。将细胞重新悬浮在新鲜的DPBS中,然后重新沉淀以最小化血小板污染。将随后的沉淀重悬于DPBS中并将细胞计数。将细胞重新沉淀,然后以1×108个细胞/mL在DMEM/30%FBS/10%DMSO中冷冻保存。对于所有hPBMC制剂,供体在整个过程中各自保持分离。对于该试验,将hPBMC以80μL试验培养基(DMEM,0.1%FBS,1%青霉素/链霉素)500,000个细胞/孔接种到平底96孔板中,并且在加入化合物前,将其在37℃培养箱中恢复1小时。
将化合物从粉末中溶解为具有100%DMSO的20mM原液,然后连续稀释到测定培养基中以制备10x原液以在测定中达到5种浓度(100μM,30μM,10μM,3μM和1μM)。将所有化合物稀释液加入含有hPBMC(最终测定体积100μL中含有10μL)的平板中,并在加入刺激物之前于37℃温育1小时。对照孔接受10μL载体(含有5%DMSO的培养基)。
对于LPS刺激,将1mg/mL脂多糖(LPS)储备溶液稀释1000倍至试验培养基(10μLLPS+10mL培养基)中。除“未刺激的”对照孔外的所有孔中均加入10μL LPS。“未刺激的”对照孔中加入10μL培养基。将板在37℃下孵育4小时。4小时后,将板以1,200rpm离心5分钟,并将培养基上清液收集到新鲜的96孔板中。
使用Meso Scale Diagnostics电化学发光免疫测定系统通过免疫测定法测定培养物上清液中的TNFα水平。使用Meso Scale V-plex 96孔板(Meso Scale Diagnostics,Rockville,MD)按照制造商的指导检测TNFα(过夜孵育方案)。将样品稀释100倍。通过标准曲线内插法然后乘以100来确定TNFα浓度,以得到“pg/mL”值。TNFα的释放通过载体处理过的LPS刺激细胞的百分比表示。
虽然已经说明和描述了某些实施例,但是应该理解,在不偏离本发明的权利要求所限定的更广泛的方面下,本领域普通技术人员可以在其中进行改变和修改。
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Claims (19)
1.如下式所示的化合物:
其中
U为CH2、-CH(CH3)-、-C(CH3)2-、或-CH2CH2-;
R1为其中R11为核心骨架的连接点,R12和R13独立地为H或F,R15为H或卤素,R16为H或卤素;和
R2为其中R18为与U的连接点,R15和R17独立地为H、卤素或OCF3。
2.如下结构的化合物:
或前述各自的药学上可接受的盐。
3.一种药物组合物,其包含如权利要求1-2中任意一项所述的化合物和药学上可接受的赋形剂。
4.如权利要求1-2中任意一项所述的化合物在制备哺乳动物体内新陈代谢调节剂中的应用。
5.如权利要求3所述的组合物在制备哺乳动物体内新陈代谢调节剂中的应用。
6.如权利要求1-2中任意一项所述的化合物在制备减轻哺乳动物炎症的药物中的应用。
7.如权利要求3所述的组合物在制备减轻哺乳动物炎症的药物中的应用。
8.如权利要求1-2中任意一项所述的化合物在制备减轻哺乳动物神经炎症的药物中的应用。
9.如权利要求3所述的组合物在制备减轻哺乳动物神经炎症的药物中的应用。
10.如权利要求1-2中任意一项所述的化合物在制备治疗哺乳动物的糖尿病、前驱糖尿病或代谢综合征或其各自的一种或多种症状的药物中的应用。
11.如权利要求3所述的组合物在制备治疗哺乳动物的糖尿病、前驱糖尿病或代谢综合征或其各自的一种或多种症状的药物中的应用。
12.如权利要求1-2中任意一项所述的化合物在制备治疗哺乳动物脂肪性肝炎的药物中的应用。
13.如权利要求3所述的组合物在制备治疗哺乳动物脂肪性肝炎的药物中的应用。
14.如权利要求1-2中任意一项所述的化合物在制备治疗哺乳动物的非酒精性脂肪性肝炎的药物中的应用。
15.如权利要求3所述的组合物在制备治疗哺乳动物的非酒精性脂肪性肝炎的药物中的应用。
16.如权利要求1-2中任意一项所述的化合物在制备治疗哺乳动物的与神经炎症有关、导致神经炎症或由神经炎症引起的疾病的药物中的应用。
17.如权利要求3所述的组合物在制备治疗哺乳动物的与神经炎症有关、导致神经炎症或由神经炎症引起的疾病的药物中的应用。
18.如权利要求1-2中任意一项所述的化合物在制备治疗阿尔茨海默症、帕金森病、额颞叶痴呆、肌萎缩侧索硬化或多系统萎缩或其各自的一种或多种症状的药物中的应用。
19.如权利要求3所述的组合物在制备治疗阿尔茨海默症、帕金森病、额颞叶痴呆、肌萎缩侧索硬化或多系统萎缩或其各自的一种或多种症状的药物中的应用。
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US10865201B2 (en) | 2020-12-15 |
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US11919891B2 (en) | 2024-03-05 |
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