CN116693456A - 异喹啉酮类化合物及其制备方法和应用 - Google Patents
异喹啉酮类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明属药物化学技术领域，具体涉及如式(Ⅰ)所示的异喹啉酮类化合物、其药学上可接受的盐、前药分子以及它们的混合物，其制备方法、含此类化合物的药物组合物及作为FABP4/FABP5双靶向抑制剂的用途。本发明所涉及的芳基羧酸类化合物可用于制备治疗代谢性疾病(如糖尿病、胰岛素抵抗、高脂血症、动脉粥样硬化)、自身免疫性疾病和癌症的药物。
Description
技术领域
本发明属药物化学技术领域，涉及脂肪酸结合蛋白(FABP)4和/或5的抑制剂，具体涉及异喹啉酮类新型FABP4/5抑制剂，本发明还涉及该类化合物的制备方法及其作为FABP4/5抑制剂的医药用途。
背景技术
随着人类医学水平的发展和提高，世界上很多古老的传染性疾病已被成功治愈，而非传染病已经成为世界上许多国家发病率和死亡率的主要原因。在非传染性疾病中，代谢综合征正成为世界范围内的公共健康难题。代谢综合征描述的是一组代谢失调特征，即肥胖，糖尿病，胰岛素抵抗，高血脂，高血糖和高血压。这些因素直接增加心血管疾病的发生率和死亡率。
目前，代谢综合征的病因、分子和细胞水平的作用机制并未完全阐明清楚，肥胖相关的慢性炎症已经被确定是糖尿病和代谢综合征发病的病理生理基础。2014年，世界卫生组织研究表明，超过19亿成年人超重；其中超过6亿人患有肥胖症，这意味着39％的成年人超重，13％的人肥胖。此外，4100万5岁以下儿童超重或肥胖。肥胖，尤其是内脏脂肪组织的扩张，会导致机体处于“慢性低级别炎症状态”，简称代谢性炎症，其特征是脂肪因子分泌失调。研究发现，在脂肪细胞和巨噬细胞均表达的脂肪因子-脂肪酸结合蛋白4(Fatty acidbinding protein 4，FABP4)和脂肪酸结合蛋白5(Fatty acid binding protein 5，FABP5)在胰岛素抵抗和动脉粥样硬化等代谢性疾病中发挥着重要作用。
代谢性疾病的发生发展与体内的脂质代谢异常密切相关。游离脂肪酸(Freefatty acids)作为细胞中重要的脂质能量来源及信号分子，通过运输到达相关作用位点参与调节细胞内多种酶催化反应及信号传导，从而维持机体的代谢平衡。脂肪酸结合蛋白(FABPs)是一类脂质伴侣蛋白，在体内脂肪酸的摄取、运输和代谢调节中发挥着重要作用，影响着细胞内多种生物进程。
脂肪酸结合蛋白4(Fatty Acid Binding Protein 4，FABP4，也称aP2)是细胞内的脂质伴侣蛋白-脂肪酸结合蛋白家族中的一员，它主要表达于脂肪细胞、巨噬细胞及内皮细胞中。在细胞内，FABP4通过作用于多条信号通路调节细胞内的脂质代谢和炎症通路，削弱胰岛素的功能，促进葡萄糖的生成，降低胆固醇外排，是糖尿病、动脉粥样硬化等代谢性疾病的发病机制之一。除了在细胞内发挥功能，脂肪细胞还可以分泌FABP4进入血液循环，产生多种生物学效应。临床研究显示，不同人种血浆中FABP4的水平与多种疾病密切相互，血液水平中高表达的FABP4可以促进胰岛素抵抗，糖尿病，动脉粥样硬化，高血压和心脏功能障碍的发展，导致心血管疾病预后不良。此外，糖脂代谢紊乱和心血管疾病介导的交感神经系统激活以及炎症性细胞因子表达上调可能会促进脂肪细胞中的脂解作用，从而导致FABP4分泌的增加所引起的恶性循环。
脂肪酸结合蛋白5(Fatty acid binding protein 5)，又称表皮型脂肪酸结合蛋白(E-FABP)，银屑病相关脂肪酸结合蛋白(PA-FABP)或mal 1。FABP5主要分布于表皮细胞，在脂肪细胞、巨噬细胞和树突状细胞也有表达。FABP5与FABP4有52％的氨基酸序列同源性，并且对脂肪酸配体具有相似的亲和力和选择性，暗示着FABP5对FABP4发挥生物学功能的协同效应。在正常状态下，脂肪细胞中FABP4的含量是FABP5的100倍，但是在敲除了FABP4的脂肪细胞中FABP5的表达会代偿性增加。研究表明，FABP5敲除的脂肪细胞在胰岛素刺激下对葡萄糖的摄取显著增加；FABP5敲除的正常小鼠其血浆中的胆固醇和甘油三脂显著下降；与FABP4类似，分泌蛋白组学表明脂肪细胞也可以分泌FABP5，外源性FABP4和FABP5可以调节脂肪组织来源干细胞的转录和代谢功能。临床研究表明，FABP5通过抑制巨噬细胞的胆固醇外排功能促进动脉粥样硬化的进展，可以作为预测动脉粥样硬化的生物标志物。作为FABP4相关脂质蛋白，表达于脂肪细胞和巨噬细胞中的FABP5同样在胰岛素抵抗、糖尿病和动脉中样硬化等代谢性疾病中扮演的重要角色。
针对FABP4基因敲除的小鼠模型的研究发现，FABP4在代谢综合征中起着重要作用。敲除FABP4基因的小鼠可以明显改善高脂诱导的高胰岛素血症、胰岛素抵抗，有效控制小鼠血糖并减少脂肪组织炎症。最近的研究表明，全部敲出或者组织或器官特异性地敲除巨噬细胞中的FABP4可以明显减少载脂蛋白E缺陷模型小鼠体内的动脉粥样硬化斑块。除此之外，在FABP4基因敲除小鼠体内，包括肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)和单核细胞趋化蛋白-1(MCP-1)在内的炎症细胞因子的表达受到较强的抑制。在高脂饮食条件下，敲除FABP5可以改善肥胖小鼠的口服糖耐量和胰岛素敏感性，血浆中的胰岛素和血糖含量低于对照组；而FABP5过表达可以损害小鼠的糖耐受量。另一方面，在高脂饮食喂养8周后，与对照组相比，FABP5/低密度脂蛋白受体(LDLR-/-)双敲除小鼠动脉粥样硬化病变范围缩小了36％，巨噬细胞在病变斑块的聚集减少，炎症因子白介素-6(IL-6)、环氧合酶2(COX-2)的表达显著下降。
另一方面，FABP4/5双突变(FABP4-5-/-)小鼠可以避免高脂饮食诱导的肥胖，并且其对胰岛素敏感性和葡萄糖稳态的改善作用明显优于单独敲除FABP4/5的表型。此外，Fabp4-5-/-小鼠可以避免高脂饮食诱导的肝脂肪变性，增强肌肉AMPK激酶活性并降低肝中关键脂肪酸代谢酶Scd1的表达，由此减少脂质的积累。在瘦素基因缺乏(ob/ob-/-)的小鼠模型中，同时敲除FABP4/5同样可以改善小鼠的糖耐受量和胰岛素敏感性，改善效果优于单独敲除的小鼠模型，并抑制肝中硬脂酰去饱和酶SCD-1的活性，抑制小鼠脂肪肝的形成。在apoE-/-突变小鼠模型中，合并敲除FABP4/5可以明显抑制小鼠动脉粥样硬化病变的程度，改善小鼠的糖脂代谢异常并延长apoE-/-突变小鼠的生存期。综上所述，FABP4/5双靶向抑制剂能够更加有效地治疗2型糖尿病及动脉粥样硬化等代谢性疾病及银屑病、类风湿性关节炎等自身免疫性疾病。
脂肪来源的脂肪因子—FABP4和FABP5—在癌症的起始、发展和转移过程中发挥着重要作用。FABP4通过脂质转运、诱导脂肪酸氧化，促进肿瘤细胞增殖和转移，在癌症细胞与脂肪组织的相互沟通中发挥积极作用。在恶性胶质瘤中，过表达的FABP4可以调节血管内皮生长因子和成纤维细胞生长因子促进肿瘤组织血管生成。外源性的FABP4可以促进前列腺癌增殖，使用选择性的FABP4抑制剂BMS309403处理前列腺癌细胞，可以抑制细胞增殖和转移，促进细胞凋亡。在乳腺癌细胞中，外源性的FABP4可以活化Akt和MAPK信号通路，促进细胞增殖。流行病学研究表明，乳腺癌患者血清中FABP4的水平显着高于健康组。这些高表达的FABP4与肿瘤的大小和淋巴结受累呈正相关。非小细胞肺癌患者中的FABP4和FABP3表达上调。FABP4与FABP3的高表达与非小细胞肺癌的分级和患者生存期相关。FABP5可能通过调节脂肪酸代谢细胞信号通路的来抑制胃癌的增殖，凋亡和侵袭。敲除FABP5可以通过G0/G1的细胞周期阻滞来减少侵袭，增殖和细胞生长，并通过基因表达的改变来增加胃癌细胞的凋亡。肝癌组织中FABP5的过表达与肿瘤的发生，侵袭和转移有关。因此，FABP5可用作肝癌治疗策略的重要标志物和分子靶标。在前列腺癌组织中，FABP5作为与转移相关的特定癌基因被上调，通过核受体PPARβ/δ来诱导癌细胞增殖；利用FABP5-PPARr-VEGF信号转导通路增加前列腺癌细胞的血管生成从而促进癌细胞转移。这些研究表明，FABP4和FABP5既可以看作肿瘤相关的新型临床标志物，也可以作为治疗脂肪组织相关的癌症的新靶标。
有研究通过计算机虚拟筛选、高通量筛选或者基于结构的药物设计等手段，不同结构类型的FABP4、FABP5和FABP4/5小分子抑制剂被大量开发和报道，但是截至到目前为止，尚未有小分子抑制剂进入临床研究。其原因可能与化合物的理化性质差、选择性低(针对FABP3)，药代动力学性质不佳有关。因此迫切需要开发选择性高、理化性质优良、活性强度高的FABP4抑制剂、FABP5抑制剂尤其是FABP4/5双重抑制剂，用于治疗糖尿病、动脉粥样硬化等代谢性疾病和银屑病、类风湿性关节炎等自身免疫性疾病以及乳腺癌、胃癌、前列腺癌等恶性肿瘤。
发明内容
本发明的目的是针对现有技术存在的问题，提供一种具有FABP4/5抑制活性的异喹啉酮类化合物、其药学上可接受的盐、立体异构体、前药分子或它们的混合物及其制备方法、药物组合物及应用，尤其是用于治疗和/或预防FABP4/5密切相关的代谢性疾病、炎症和癌症等多种疾病。
本发明的第一方面提供了具有通式(Ⅰ)所示的异喹啉酮类化合物、其药学上可接受的盐、立体异构体(如对映异构体、非对映异构体或外消旋体)、前药分子或它们的混合物：
其中，
R1选自由取代的或非取代的苯基，含氧、氮和/或硫的C5-C12元芳杂环基，C3-C8的环烷基，和含1-3个氧、氮和/或硫原子的4-7元的杂环基组成的组；在R1基团为具有取代基(即“取代的”)的情况下，取代基各自独立地选自由卤素、羟基、羟甲基、巯基、氨基、氰基、硝基、羧基、酯基、三氟甲基、三氟甲氧基、C1-C6的直链或支链烷基、C1-C6的直链或支链卤代烷基、C1-C6的直链或支链烷氧基、C1-C6的直链或支链卤代烷氧基、C1-C6的直链或支链烷基羰氧基、C1-C6的直链或支链羟烷基组成的组；
R2选自羧基、氰基、羟基、磺酸基、磺酰胺基、酰胺基、四氮唑、方酸基、磷酸基、异羟肟酸基、羟基异恶唑；
R3选自取代或非取代的苯基；C6-C12的芳基；苄基；含氧、氮和硫的C5-C7的芳杂环；C3-C14的环烷基；4-8元的杂环基；在R3基团为具有取代基(即“取代的”)的情况下，取代基各自独立地选自由卤素、羟基、羟甲基、巯基、氨基、氰基、硝基、羧基、酯基、三氟甲基、三氟甲氧基、C1-C6的直链烷基或C3-C6的支链烷基、C1-C6的直链卤代烷基或C3-C6的支链卤代烷基、C1-C6的直链烷氧基或C3-C6的支链烷氧基、C1-C6的直链卤代烷氧基的组；
R4-R7各自独立地选自氢、卤素、羟基、氨基、氰基、巯基、三氟甲基、三氟甲氧基、硝基、酰胺基、磺酰胺基、C1-C3直链或支链烷基、C1-C3直链或支链烷氧基；
在某些优选的实施方案中，在本发明的式I所示的化合物、其药学上可接受的盐、立体异构体或前药分子或它们的混合物中：
R1选自C3-C8的环烷基、含1-3个氧、氮和/或硫原子的4-7元的杂环基、取代的或非取代的苯基组成的组；在R1基团为具有取代基(即“取代的”)的情况下，取代基各自独立地选自由卤素、羟基、羟甲基、巯基、氨基、氰基、硝基、羧基、酯基、三氟甲基、三氟甲氧基、C1-C3的直链或支链烷基、C1-C3的直链或直链烷氧基；
R2选自羧基、磺酸基、磺酰胺基、酰胺基、四氮唑、方酸基、羟基异恶唑；
R3选自取代或非取代的苯基；含氧、氮和硫的C5-C7的芳杂环；C3-C14的环烷基；4-8元的杂环基；在R3基团为具有取代基(即“取代的”)的情况下，取代基各自独立地选自由卤素、羟基、羟甲基、巯基、氨基、氰基、硝基、羧基、酯基、三氟甲基、三氟甲氧基；
R4-R7各自独立地选自氢、卤素、羟基、氨基、三氟甲基、三氟甲氧基、硝基、甲氧基。
在另外一些优选的实施方案中，R5如前定义所述，R2为-COOH，R3为苯基，R4，R6，R7独立地为氢或同时为氢。
在又一些优选的实施方案中，R5如前定义所述，R2为-COOH，R3为取代苯基或芳杂环基，R4，R6，R7独立地为氢或同时为氢)。
在另一些实施方案中，R1选自环己基、甲基环己基、环戊基、四氢吡喃基、环丙基、环丁基、环庚基、氯代苯基、哌啶基和环戊基组成的组；R2为羧基；R3选自苯基、氟代苯基、羟基苯基、羟甲基苯基、氯代氟代苯基、三氟甲基苯基、二氢苯并呋喃基、吡啶基、二甲基吡唑基组成的组；R4和R7独立地为H或同时为H，R5为Cl、Br或甲基；R6为H或Cl。
C5-C12元芳杂环基例如可以为具有5、6、7、8、9、10、11或12个碳原子的芳杂环基；
C3-C8的环烷基例如可以为环丙基、环丁基、环戊基或环己基；
卤素例如为F、Cl、Br或I。
4-7元的杂环基例如可以为带有数量为1、2或3个选自O、N和S的杂原子的4元杂环基、5元杂环基、6元杂环基或7元杂环基；
C1-C6的直链烷基或C1-C6的支链烷基为碳原子数为1、2、3、4、5或6个的直链烷基或C3-C6的支链烷基，例如可以为甲基、乙基、正丙基、异丙基、正丁基、正戊基、正己基、带有支链丁基(如仲丁基或叔丁基)、带有支链的戊基(异戊基)、带有支链的己基等；
上述基团具有本领域技术人员通常理解的意思，例如：
C1-C6的直链卤代烷基可以为碳原子数为1、2、3、4、5或6个的直链卤代烷基上取代有一个或多个(例如1、2或3个)卤素原子的基团；
C3-C6的支链卤代烷基可以为碳原子数为3、4、5或6个的支链卤代烷基上取代有一个或多个(例如1、2或3个卤素原子的基团)卤素原子的基团；
C1-C6的直链烷氧基为碳原子数为1、2、3、4、5或6个的直链烷氧基，例如甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或丁氧基等；
C3-C6的支链烷氧基为碳原子数为1、2、3、4、5或6个的带有支链的烷氧基；
C6-C12的芳基为碳原子数为6、7、8、9、10、11或12个的芳基，例如苯基、苯甲基、苯乙基等；
含氧、氮和硫的C5-C7的芳杂环例如可以为碳原子数为5、6或7个的带有一个或多个(例如1、2或3个)选自氧、氮和硫的杂原子的芳杂环。
C3-C14的环烷基例如可以为环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基等；
4-8元的杂环基例如可以为碳原子数为4、5、6、7或8个的含有杂原子例如O、N或S的杂环基；
C1-C3直链烷基或烷氧基例如可以为甲基、甲氧基、乙基、乙氧基、丙基、丙氧基等。
在某些最优选的实施方案中，本发明的化合物或其在药学上可接受的盐、立体异构体、前药分子选自如下化合物Y1-Y22：
本发明所述的药学上可接受的盐可以是阴离子与如通式I所示的化合物上带正电荷的基团形成的盐。合适的阴离子可以选自氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲基磺酸根、三氟乙酸根、乙酸根、苹果酸根、酒石酸根、富马酸根、谷氨酸根、葡萄糖醛酸根、乳酸根、戊二酸根、或马来酸根中的一种或多种。类似地，可以由阳离子与如通式I所示的化合物上带负电荷的基团形成的盐。合适的阳离子可以选自钠离子、钾离子、镁离子、钙离子、铵离子、四甲基铵离子中的一种或多种。
本发明的化合物也可以是酯、前药形式、N-氧化物形式组成的药物组合物。
本发明的另一个目的是提供本发明第一方面所述的如通式I所示的异喹啉酮类化合物在制备用于预防或治疗FABP4/5介导的疾病的药物中的用途。
所述FABP4/5介导的疾病可以例如为代谢性疾病和心脑血管疾病,包括但不限于：胰岛素抵抗、代谢综合征、2型糖尿病、高血脂症、肥胖症、动脉粥样硬化、心肌炎、心肌梗死、心律失常、冠心病、高血压、心衰、心肌肥大、糖尿病并发症(包括糖尿病心肌病、糖尿病肾病、糖尿病溃疡、视网膜病变和神经病变等)、非酒精性脂肪性肝病、非酒精性脂肪肝炎、肝硬化、高尿酸血症、骨质疏松、多囊卵巢综合征等。
所述FABP4/5介导的疾病，如炎症疾病、自身免疫性进步、器官纤维化疾病、神经损伤性疾病或病原体感染所致的继发性疾病，这些疾病可以包括：肺炎、肺结核、炎性肠病、哮喘、慢性阻塞性肺病、慢性支气管炎、肺气肿、闭塞性细支气管炎、过敏性鼻炎、鼻窦炎、系统性红斑狼疮、类风湿性关节炎、骨关节炎、胰腺炎、慢性肾炎、膀胱炎、多发性硬化症、肌萎缩侧索硬化病等。
所述FABP4/5介导的疾病，如肿瘤，可以包括：黑色素瘤、肺癌、乳腺癌、胃癌、肝癌、胰腺癌、结肠癌、肾癌、前列腺癌、骨癌、淋巴癌、间质细胞癌、急性骨髓性白血病、慢性骨髓性白血病、霍奇金是淋巴瘤、神经胶质瘤、星性细胞瘤等。
本发明还提供一种用于预防或治疗FABP4/5介导的疾病的药物组合物，其中含有治疗有效量的如通式I所示的异喹啉酮化合物、其药学上可接受的盐、立体异构体、前药分子或它们的混合物作为活性成分和药学上可接受的辅料。
在本发明的药物组合物中可混合的辅料可以根据剂型、给药方式等的改变而改变。辅料可以包括包括但不限于赋形剂、粘合剂、崩解剂、润滑剂、矫味剂、香味剂、着色剂和/或甜味剂等。所述药物组合物的给药途径可以为口服、舌下、经皮、经肌肉、皮下、皮肤黏膜或静脉等。所述药物组合物的制剂形式可以是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、霜及、软膏剂、栓剂或贴剂等制剂学上常规采用的制剂形式。
本发明的化合物的制备可参照以下合成路线或改进的方法进行。
合成路线1
当R2为-COOH，R3为苯基时，R4，R6，R7为氢时，R5如前定义所述，合成路线如下：
起始原料酸酐1与苯经过傅克反应生成中间体2，中间体2是一位置异构体，无需分离，直接进行下一步，与2-溴丙二酸二乙酯在碳酸钾/丙酮条件下生成中间体酯，在酸性条件下关环生成中间体4，中间体4与原料胺在乙醇中经氨解反应生成中间体5，后在酸性条件关环生成中间体6，中间体6仍然是位置异构体，中间体6在甲醇/氯化亚砜条件下生成甲酯，经过柱层析可以分得目标中间体7，中间体在碱性条件下水解生成目标化合物。
合成路线2
当R2为-COOH，R3为取代苯基或芳杂环基时，R4，R6，R7为氢时，R5如前定义所述，合成路线如下：
起始原料1与另一原料8室温条件下在四氢呋喃溶液中搅拌发生氨解反应生成中间体9，中间体9为位置异构体，无需纯化直接投下一步，中间体9随后与碘乙烷反应生成羧酸乙酯，后者在碱性条件经酯缩合反应生成中间体10，中间体10与1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺在DMF/三乙胺条件下反应生成关键中间体，经过柱层析纯化分离得到位于目标位置的中间体11，中间体11与不同取代的芳基或芳杂环硼酸酯经过suzuki反应生成中间体12，后在碱性条件下水解生成目标化合物。
本发明化合物可以单独给药，或者与其他治疗药物(如抗肿瘤药)联合给药。
附图说明
图1显示了不同化合物在3T3-L1细胞上对脂解(Lipolysis)的抑制作用图，其中，横坐标以FSK的倍数(fold of FSK)表征脂解，Control为空白对照处理，FSK表示佛司可林处理，BMS309403表示阳性对照处理，Y2和Y3分别表示采用本发明制得的化合物Y2和Y3进行的处理。
图2显示不同化合物对THP-1细胞MCP-1分泌的抑制作用图。在图2A至2C中，纵坐标为每mg细胞蛋白中所含的MCP-1的量(ng)；在图2D中，纵坐标为MCP-1的相对浓度(ng/mgcellularprotein％LPS)。其中，Control为空白对照处理，LPS表示脂多糖处理，BMS309403表示抑制剂阳性对照处理，RO6806051(RO)表示先导化合物处理，Y2、Y3、Y15、Y16和Y18分别表示采用本发明制得的化合物Y2、Y3、Y15、Y16和Y18进行的处理。
图3显示不同化合物对THP-1细胞IL-6分泌的抑制作用图。在图3中，纵坐标为每mg细胞蛋白中所含的MCP-1的量(ng)。其中，Control(Con)为空白对照处理，LPS表示脂多糖处理，BMS309403表示抑制剂阳性对照处理，RO6806051(RO)表示先导化合物处理，Y2、Y3、Y15、Y16和Y18分别表示采用本发明制得的化合物Y2、Y3、Y15、Y16和Y18进行的处理。
具体实施方式
下面通过实施例具体说明本发明的内容，在本发明中，以下所述的实施例是为了更好的阐述本发明，并不是用来限制本发明的范围。在不背离本发明的精神和范围的前提下，可以对本发明进行各种变化和修饰。下述实施例中所述的实验方法所采用的试剂，如无特殊说明，均为常规试剂；所述试剂和材料，如无特殊说明，均可以通过商业化途径获得。
实施例1
6-氯-2-环己基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y1)
合成路线如下：
将I-1(5.0g,27.29mmol)加入茄形瓶中，随后加入苯(20ml)和三氯化铝(7.3g,54.78mmol)，氩气保护下室温反应45min,随后回流反应2h,将反应液倒入冰水中，加入1N稀盐酸(50ml)后室温继续搅拌0.5h，分出有机层，乙酸乙酯萃取水相后与之前的有机相合并，然后有机相经过饱和氯化钠洗涤，无水硫酸钠干燥，旋干得粗品，向粗品中加入甲苯，经过重结晶得I-2 5g,收率70.03％。ESI-MS:259.0[M–H]-。
将I-2(4.7g,18.03mmol)溶于丙酮(30ml)中，随后加入碳酸钾(2.49g,18.03mmol)，有大量固体析出，将2-溴丙二酸二乙酯(5.17g,21.64mmol)混溶于DMF(10ml)中加入上述溶液，室温反应20h。旋干丙酮，将反应液倒入水中，乙酸乙酯萃取3次，依次经过饱和氯化钠洗涤，无水硫酸钠干燥，旋干后，加入等体积的醋酸(30ml)和浓盐酸(30ml)于120摄氏度回流反应过夜，旋干溶剂，利用石油醚和乙酸乙酯打浆得I-3 3.1g,收率57.8％。ESI-MS:299.0[M–H]-。
将I-3(0.5g,1.66mmol)和环己胺(2.47g,24.94mmol)加入封管中，加入乙醇(6ml)后，85摄氏度回流反应过夜，次日，LC-MS监测主要是产物I-4,旋干溶剂后，加入4N的HCl乙酸乙酯溶液(10ml)于封管中反应12h,次日有白色固体析出，LC-MS监测为目标产物I-5,得产物600mg，收率90.24％。ESI-MS:380.1[M–H]-。I-5为位置异构体混合物，所以用羧酸酯化的方法进行分离纯化。
将I-5(600mg，1.57mmol)溶于DMF(6mL)中，加入碘甲烷(446mg,3.14mmol)和碳酸钾(434mg,3.14mmol)，室温反应2h。反应结束后，将反应液倒入水中，乙酸乙酯萃取3次，依次经过饱和氯化钠洗涤，无水硫酸钠干燥，旋干得粗品，然后经硅胶柱层析纯化，分离I-6A(极性大)和I-6B(极性小)，得I-6A 340mg，收率54.66％。ESI-MS:380.1[M–H]-。1H NMR(400MHz,Chloroform-d)δ8.38(d,J＝8.6Hz,1H),7.49–7.41(m,4H),7.31–7.26(m,2H),7.10(s,1H),3.65–3.55(m,1H),3.51(s,3H),2.74–2.65(m,2H),1.90–1.86(m,4H),1.35–1.23(m,3H).
将I-6(340mg,0.858mmol)溶于甲醇(5ml)中，加入5N氢氧化钠溶液(5ml)，反应于70摄氏度加热反应过夜，次日反应结束后，旋干反应物中的甲醇，随后在冰浴条件下，将反应液调至pH为5，用乙酸乙酯萃取2次，依次经过饱和氯化钠洗涤，无水硫酸钠干燥，旋干得粗品，经硅胶柱层析得目标产物152mg,收率46.35％。ESI-MS:380.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.23(d,J＝8.6Hz,1H),7.45–7.37(m,4H),7.34–7.31(m,2H),7.10(d,J＝2.0Hz,1H),3.73(t,J＝11.8Hz,1H),2.67(d,J＝11.8Hz,2H),1.87(d,J＝9.4Hz,4H),1.24–1.15(m,2H)。
实施例2
6-氯-2-(环己基甲基)-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y2)
参照实施例1的合成方法制备，得目标产物132mg,收率34.45％。ESI-MS:394.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.31(d,J＝8.6Hz,1H),7.46–7.40(m,4H),7.34–7.31(m,2H),7.14(d,J＝2.0Hz,1H),3.98(d,J＝7.3Hz,2H),1.90–1.85(m,1H),1.71–1.66(m,2H),1.63–1.59(m,2H),1.13(d,J＝8.9Hz,2H),1.03–0.94(d,J＝11.7Hz,2H)。
实施例3
6-氯-2-环戊基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y3)
参照实施例1的合成方法制备，得目标产物85mg,收率23.16％。ESI-MS:366.1[M–H]–。1H NMR(400MHz,DMSO-d6)δ8.28(d,J＝8.6Hz,1H),7.58(d,J＝10.3Hz,1H),7.50–7.43(m,3H),7.34(d,J＝7.4Hz,2H),6.90(s,1H),4.26–4.20(m,1H),2.35–2.27(m,2H),2.01–1.92(m,2H),1.89–1.81(m2H),1.60–1.53(m,2H)。
实施例4
6-氯-1-氧代-4-苯基-2-(四氢-2H-吡喃-4-基)-1,2-二氢异喹啉-3-羧酸(Y4)
参照实施例1的合成方法制备，得目标产物35mg,收率9.14％。ESI-MS:382.1[M–H]–。1H NMR(400MHz,DMSO-d6)δ8.29(d,J＝8.0Hz,1H),7.59(d,J＝8.7Hz,1H),7.50–7.43(m,3H),7.33(d,J＝8.1Hz,2H),6.88(s,1H),3.98–3.90(m,3H),3.25(d,J＝11.9Hz,2H),2.96–2.86(m,2H),1.66(d,J＝16.0Hz,2H)。
实施例5
6-氯-2-环丙基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y5)
参照实施例1的合成方法制备，得目标产物109mg,收率19.29％。ESI-MS:338.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.35(d,J＝8.6Hz,1H),7.47–7.43(m,4H),7.33–7.28(m,2H),7.10(s,1H),3.21–3.17(m,1H),1.09–1.06(m,2H),0.95–0.93(m,2H)。
实施例6
6-氯-2-环丁基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y6)
参照实施例1的合成方法制备，得目标产物132mg,收率22.44％。ESI-MS:352.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.29(d,J＝8.6Hz,1H),7.46–7.41(m,4H),7.30–7.27(m,2H),7.08(s,1H),4.65–4.57(m,1H),2.72–2.62(m,2H),2.49–2.41(m,2H),1.90–1.79(m,1H),1.78–1.69(m,1H)。
实施例7
6-氯-2-环庚基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y7)
参照实施例1的合成方法制备，得目标产物75mg,收率11.39％。ESI-MS:394.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.26(d,J＝8.7Hz,1H),7.45–7.43(m,3H),7.40(dd,J＝8.7,1.9Hz,1H),7.36–7.32(m,2H),7.10(d,J＝2.0Hz,1H),3.87(s,1H),2.62(s,2H),2.00–1.93(m,2H),1.85–1.76(m,2H),1.66–1.54(m,4H),1.46–1.39(m,2H)。
实施例8
6-氯-2-(4-氯苯基)-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y8)
参照实施例1的合成方法制备，得目标产物31mg,收率24.66％。ESI-MS:408.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.25(d,J＝8.6Hz,1H),7.52–7.41(m,4H),7.34(d,J＝8.5Hz,2H),7.29(d,J＝6.7Hz,2H),7.21(d,J＝7.6Hz,3H)。
实施例9
6-氯-1-氧代-4-苯基-2-(哌啶-1-基)-1,2-二氢异喹啉-3-羧酸(Y9)
参照实施例1的合成方法制备，得目标产物20mg,收率18.85％。ESI-MS:381.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.37(d,J＝8.6Hz,1H),7.47–7.40(m,4H),7.36–7.34(m,2H),7.20(s,1H),3.90(t,J＝11.7Hz,2H),3.15(d,J＝10.8Hz,2H),1.75–1.63(m,3H),1.44–1.35(m,2H)。
实施例10
6-溴-2-环戊基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y10)
参照实施例1的合成方法制备，得目标产物121mg,收率24.29％。ESI-MS:410.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.21(d,J＝8.6Hz,1H),7.57(d,J＝8.7Hz,1H),7.47–7.42(m,3H),7.35–7.31(m,2H),7.27(s,1H),4.30–4.21(m,1H),2.49–2.41(m,2H),2.08–2.02(m,2H),1.99–1.89(m,2H),1.64–1.57(m,2H)。
实施例11
6,7-二氯-2-环戊基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y11)
参照实施例1的合成方法制备，得目标产物240mg,收率39.99％。ESI-MS:400.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.50(s,1H),7.48–7.43(m,3H),7.34–7.31(m,2H),7.21(s,1H),4.29–4.20(m,1H),2.48–2.40(m,2H),2.10–2.03(m,2H),1.99–1.91(m,2H),1.62–1.58(m,2H)。
实施例12
2-环戊基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y12)
参照实施例1的合成方法制备，得目标产物580mg,收率77.20％。ESI-MS:332.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.32(d,J＝8.0Hz,1H),7.55(t,J＝7.6Hz,1H),7.47(t,J＝8.0Hz,1H),7.41–7.38m,3H),7.37–7.34(m,2H),7.17(d,J＝8.0Hz,1H),4.36–4.26(m,1H),2.49–2.39(m,2H),2.09–2.02(m,2H),1.98–1.90(m,2H),1.58–1.54(m,2H)。
实施例13
2-环戊基-6-氟-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y13)
参照实施例1的合成方法制备，得目标产物136mg,收率22.00％。ESI-MS:350.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.31–8.25(m,1H),7.43–7.39(m,3H),7.33(dd,J＝6.6,3.0Hz,2H),7.14(td,J＝8.5,2.5Hz,1H),6.80(dd,J＝9.9,2.5Hz,1H),4.35–4.29(m,1H),2.44–2.37(m,2H),2.06–1.91(m,4H),1.62–1.50(m,2H)。
实施例14
2-环戊基-6-甲基-1-氧代-4-苯基-1,2-二氢异喹啉-3-羧酸(Y14)
参照实施例1的合成方法制备，得目标产物116mg,收率29.00％。ESI-MS:346.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.19(d,J＝8.3Hz,1H),7.44–7.39(q,J＝3.6Hz,3H),7.37–7.32(m,2H),7.28(d,J＝8.9Hz,1H),6.92(s,1H),4.34–4.24(m,1H),2.44–2.38(m,2H),2.35(s,3H),2.04–2.00(m,2H),1.97–1.89(m,2H),1.59–1.50(m,2H)。
实施例15
6-氯-2-环戊基-4-(4-氟苯基)-1-氧代-1,2-二氢异喹啉-3-羧酸(Y15)
合成路线如下：
将化合物II-1(4.40g,24.10mmol)溶于四氢呋喃溶液(20ml)中，随后将环戊基甘氨酸甲酯(4.17g,26.51mmol)溶于适量四氢呋喃溶液加入上述反应液，在室温条件搅拌1h,LC-MS监测反应结束后，将反应液倒入水中，用乙酸乙酯萃取水层3次，依次用饱和氯化钠洗涤，无水硫酸钠干燥，旋干得产物7.0g,无需纯化直接投下一步，收率85.48％。ESI-MS:340.1[M+H]+。
将化合物II-2(7.0g,20.60mmol)溶于DMF(15ml)中，随后加入碘乙烷(4.82g,30.90mmol)和碳酸钾(8.54g,61.81mmol)，该反应液在室温条件下反应三小时，LC-MS监测反应结束后，将反应液倒入水中，乙酸乙酯萃取水层三次，然后依次用饱和氯化钠洗涤，无水硫酸钠干燥，旋干后向瓶中加入甲醇(30ml)和甲醇钠(7.6ml，5mol/L甲醇钠/甲醇溶液)，在室温条件下反应2h后，LC-MS监测反应结束后，用1N盐酸溶液调反应液的pH至弱酸性，将反应液倒入水中，乙酸乙酯萃取2次，再使用饱和氯化钠洗涤，无水硫酸钠干燥，旋干得粗品5.60g,收率91.45％。ESI-MS:322.1[M+H]+。
将II-3(2.0g,6.22mmol)溶于DMF(10ml)中，依次加入三乙胺(2.59ml,18.65mmol)和1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰基)甲磺酰胺(2.66g,7.46mmol),室温反应过夜，LC-MS监测反应结束后，将反应液倒入水中，依次用乙酸乙酯洗涤，无水硫酸钠干燥，旋干得粗品，硅胶柱层析可以将两个位置异构体II-4A(极性大)和II-4B(极性小)成功分离，最终得到II-4A1.6g，收率56.72％。ESI-MS:454.0[M+H]+。1H NMR(400MHz,Chloroform-d)δ8.34(d,J＝8.8Hz,1H),7.73(s,1H),7.58(d,J＝9.3Hz,1H),4.13–4.04(m,1H),4.03(s,3H),2.43–2.35(m,2H),2.11–2.04(m,2H),1.97–1.90(m,2H),1.63–1.57(m,2H).
将II-4A(250mg,0.55mmol)、对氟苯硼酸(93mg,0.66mmol)、碳酸钾(152mg,1.10mmol)和PdCl2(dppf).CH2Cl2(27mg,0.027mmol)加入茄形瓶中，然后加入二氧六环和水，在氩气保护下于100℃加热反应过夜，反应结束后，将反应液旋干，加入乙酸乙酯，依次经过饱和氯化钠洗涤，无水硫酸钠干燥，旋干得粗品，硅胶柱层析得产物II-5 123mg,收率55.84％。ESI-MS:400.1[M+H]+。
将II-5(123mg,0.307mmol)溶于甲醇(5ml)中，加入5N氢氧化钠溶液(5ml)，反应于70℃加热反应过夜，次日反应结束后，旋干反应中的甲醇溶液，随后在冰浴条件下，将反应液调至pH为5,用乙酸乙酯萃取2次，依次经过饱和氯化钠洗涤，无水硫酸钠干燥，旋干得粗品，硅胶柱层析得产物63mg,收率53.08％。ESI-MS:384.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.24(d,J＝8.6Hz,1H),7.44(d,J＝8.6Hz,1H),7.35–7.32(m,2H),7.17–7.09(m,3H),4.34–4.26(m,1H),2.46–2.39(m,2H),2.07–2.00(m,2H),1.97–1.92(m,2H),1.64–1.56(m,2H).
实施例16
6-氯-2-环戊基-4-(4-羟基苯基)-1-氧代-1,2-二氢异喹啉-3-羧酸(Y16)
参照实施例15的合成方法制备，得目标产物157mg,收率65.10％。ESI-MS:382.1[M–H]–。1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),9.71(s,1H),8.27(d,J＝8.2Hz,1H),7.58(d,J＝8.2Hz,1H),7.12(d,J＝8.2Hz,2H),6.98(s,1H),6.85(d,J＝8.3Hz,2H),4.27–4.18(m,1H),2.34–2.27(m,2H),1.98–1.95(m,2H),1.87–1.84(m,2H),1.61–1.52(d,J＝8.7Hz,2H)。
实施例17
6-氯-2-环戊基-4-(4-(羟甲基)苯基)-1-氧代-1,2-二氢异喹啉-3-羧酸(Y17)
参照实施例1的合成方法制备，得目标产物83mg,收率52.08％。ESI-MS:396.1[M–H]–。1H NMR(400MHz,DMSO-d6)δ8.29(d,J＝8.6Hz,1H),7.59(d,J＝7.0Hz,1H),7.42(d,J＝7.8Hz,2H),7.30(d,J＝7.9Hz,2H),6.93(s,1H),5.31(s,1H),4.57(s,2H),4.29–4.21(m,1H),2.35–2.28(m,2H),1.99–1.93(m,2H),1.87–1.82(m,2H),1.58–1.54(m,2H)。
实施例18
6-氯-4-(3-氯-4-氟苯基)-2-环戊基-1-氧代-1,2-二氢异喹啉-3-羧酸(Y18)
参照实施例1的合成方法制备，得目标产物221mg,收率81.56％。ESI-MS:418.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.29(d,J＝10.6Hz,1H),7.44(t,J＝10.4Hz,2H),7.25–7.18(m,2H),7.07(s,1H),4.36–4.24(m,1H),2.47–2.42(m,2H),2.12–2.03(m,2H),1.98(s,2H),1.65–1.60(m,2H)。
实施例19
6-氯-2-环戊基-1-氧代-4-(4-(三氟甲基)苯基)-1,2-二氢异喹啉-3-羧酸(Y19)
参照实施例15的合成方法制备，得目标产物231mg,收率85.16％。ESI-MS:434.1[M–H]–。1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝8.6Hz,1H),7.87(d,J＝8.7Hz,2H),7.63–7.59(m,3H),6.91(s,1H),4.30–4.22(m,1H),2.36–2.28(m,2H),2.02–1.94(m,2H),1.91–1.84(m,2H),1.62–1.56(m,2H)。
实施例20
6-氯-2-环戊基-4-(2,3-二氢苯并呋喃-5-基)-1-氧代-1,2-二氢异喹啉-3-羧酸(Y20)
参照实施例15的合成方法制备，得目标产物185mg,收率83.19％。ESI-MS:408.1[M–H]–。1H NMR(600MHz,Chloroform-d)δ8.32(d,J＝8.6Hz,1H),7.45(d,J＝8.7Hz,1H),7.19(s,1H),7.16(s,1H),7.08(d,J＝8.1Hz,1H),6.84(d,J＝7.0Hz,1H),4.71–4.63(m,2H),4.32–4.26(m,1H),3.32–3.21(m,2H),2.52–2.47(m 2H),2.12–2.07(m,2H),2.04–1.94(m,2H),1.66–1.59(m,2H)。
实施例21
6-氯-2-环戊基-1-氧代-4-(吡啶-3-基)-1,2-二氢异喹啉-3-羧酸(Y21)
参照实施例15的合成方法制备，得目标产物137mg,收率64.64％。ESI-MS:367.1[M–H]–。1H NMR(600MHz,DMSO-d6)δ8.59(d,J＝4.8Hz,1H),8.52(s,1H),8.26(d,J＝8.6Hz,1H),7.78(d,J＝7.7Hz,1H),7.49–7.45(m,2H),6.86(s,1H),4.52–4.47(m,1H),2.33–2.28(m,2H),1.98–1.93(m,2H),1.83–1.78(m,2H),1.54–1.50(m,2H)。
实施例22
6-氯-2-环戊基-4-(1,3-二甲基-1H-吡唑-4-基)-1-氧代-1,2-二氢异喹啉-3-羧酸(Y22)
参照实施例15的合成方法制备，得目标产物160mg,收率52.31％。ESI-MS:384.1[M–H]–。1H NMR(400MHz,Chloroform-d)δ8.37(d,J＝8.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.37(s,1H),7.13(s,1H),2.56–2.46(m,1H),3.84(s,3H),2.56–2.46(m,2H),2.11(s,2H),2.06(s,3H),2.01(s,2H),1.68–1.64(m,2H)。
药理活性实验实施例
实施例23：分子水平活性测试
我们首先测试了本发明制得的化合物在25μM对FABP4的抑制率，考虑到抑制FABP3会导致心肌功能损伤，带来潜在的安全性问题，我们测试了部分化合物对FABP3的抑制活性。下面以FABP4活性测试体系为例进行举例说明。
实验原理和方法：游离的非共价荧光探针ANS与FABP4结合后，会导致ANS荧光强度增加和光谱蓝移。本实验通过测定ANS荧光信号值变化，来评价化合物对FABP4的抑制作用。对于FABP4抑制活性测试用ANS底物竞争的方法，我们采用了Kane和Bernlohr的方法(E.Marr,M.Tardie,M.Carty,T.Brown Phillips,I.K.Wang,W.Soeller,X.Qiu,G.Karam,Expression,purification,crystallization and structure of human adipocytelipid-binding protein(aP2).Acta Crystallogr.,Sect.F:Struct.Biol.Cryst.Commun.62(2006)1058-1060.)。带有His标签的人源FABP4在BL21(DE3)菌株中表达，然后用带有His标签的Ni柱进行纯化得到蛋白。检测体系中1,8-ANS底物的浓度为10μM，FABP4的终浓度为10μM,再加入所需浓度的本发明制得的化合物孵育3min，最后激发波长(EX)370nm/发射波长(EM)470nm检测荧光信号。根据体系的荧光吸收值计算受试样品对FABP4的抑制率(％)。抑制率(％)根据下式进行：
抑制率(％)＝[1-(FX-F背景)/(F0％-F背景)]*100％
在上式中：
FX表示在化合物x存在下，测定的体系的荧光值(fluorescence，F)；
F背景表示荧光底物ANS的荧光值；
F0％表示抑制率为0％时，即不加化合物时体系的荧光值。
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注：“/”表示没有检测。
实施例24
本实施例测定本发明制得的化合物对分化成熟的3T3-L1前脂肪细胞的脂解抑制活性。
在脂肪细胞中，FABP4扮演着脂肪酸伴侣的角色，使用基因敲除或药物抑制FABP4可抑制脂肪分解，促进脂肪细胞的脂质生成。因此脂解实验可作为化合物FABP4抑制活性的一个确证指标。本实验通过测定本发明制得的化合物对成熟脂肪细胞上清甘油含量的影响来衡量化合物的脂解活性。
实验材料：3T3-L1前脂肪细胞；小牛血清，胎牛血清，高糖H-DMEM培养基，3-异丁基-1-甲基黄嘌呤(IBMX)，地塞米松，胰岛素，Forskolin(佛司可林)，甘油测定试剂盒，BCA蛋白浓度测定试剂盒。
实验方法：
1.将3T3-L1前脂肪细胞接种于培养板，用含10％小牛血清的高糖DMEM在37℃、5％CO2培养箱中培养；
2.待细胞长满后，接触抑制两天；
3.加入终浓度为0.5mmol/L IBMX、终浓度为1umol/L地塞米松和终浓度为5ug/ml的胰岛素的含10％胎牛血清的高糖DMEM培养48h；
4.48h后换液为终浓度为5μg/ml的胰岛素的含10％胎牛血清的高糖DMEM培养液再培养48h，每2天换一次培养液，诱导分化8～12天，3T3-L1细胞90％多呈成熟脂肪细胞表型；
5.加化合物孵育24小时，用Krebs Ringer HEPES buffer洗两次，再用含终浓度为20μM的forskolin(佛司可林)刺激两小时；
6.收集细胞上清测甘油含量，BCA法测胞内蛋白浓度进行校准，最后利用GraphpadPrism进行结果分析。
细胞结果如图1所示，化合物Y2和Y3在80μM浓度下能够显著降低FSK(佛司可林)刺激下的上清甘油的含量。
实施例25
化合物对THP-1单核源性巨噬细胞单核细胞趋化因子-1(MCP-1)和白介素-6(IL-6)的影响。
首先，取对数生长期的单核细胞系THP-1，以5*105/ml细胞密度铺在96孔板上；随后加入100nM的佛波酯(PMA)诱导24小时时期分化成为巨噬细胞；接下来使用磷酸缓冲盐溶液(PBS)洗细胞1-2遍，加入不同浓度化合物(5、10/25μM)孵育18小时；最后，使用100ng/ml的脂多糖(LPS)刺激6小时后收取上清液并稀释一定倍数使用酶联免疫吸附测定法(ELISA)检测其对MCP-1和IL-6的含量，同时收取细胞蛋白使用BCA法测蛋白浓度进行校准。
如图2所示，化合物Y2、Y3、Y15、Y16和Y18在25μM、10μM、5μM浓度下均能显著降低THP-1单核巨噬细胞中炎症因子MCP-1的分泌，且化合物Y2、Y3的活性优于阳性对照FABP4抑制剂BMS309403和先导化合物RO6806051。
如图3所示，化合物Y18在25μM浓度下可以降低THP-1单核巨噬细胞中炎症因子IL-6的分泌，Y2、Y3、Y15和Y18有降低IL-6分泌的趋势，但无统计学差异。
以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (10)
1.如通式I所示的异喹啉酮类化合物、其药学上可接受的盐、立体异构体、前药分子或它们的混合物：
其中，
R1选自由取代的或非取代的苯基，含氧、氮和/或硫的C5-C12元芳杂环基，C3-C8的环烷基，和含1-3个氧、氮和/或硫原子的4-7元的杂环基组成的组；在R1基团为具有取代基的情况下，所述取代基各自独立地选自由卤素、羟基、羟甲基、巯基、氨基、氰基、硝基、羧基、酯基、三氟甲基、三氟甲氧基、C1-C6的直链或支链烷基、C1-C6的直链或支链卤代烷基、C1-C6的直链或支链烷氧基、C1-C6的直链或支链卤代烷氧基、C1-C6的直链或支链烷基羰氧基、C1-C6的直链或支链羟烷基组成的组；
R2选自羧基、氰基、羟基、磺酸基、磺酰胺基、酰胺基、四氮唑、方酸基、磷酸基、异羟肟酸基、羟基异恶唑；
R3选自取代或非取代的苯基；C6-C12的芳基；苄基；含氧、氮和硫的C5-C7的芳杂环；C3-C14的环烷基；4-8元的杂环基；在R3基团为具有取代基(即“取代的”)的情况下，取代基各自独立地选自由卤素、羟基、羟甲基、巯基、氨基、氰基、硝基、羧基、酯基、三氟甲基、三氟甲氧基、C1-C6的直链烷基或C3-C6的支链烷基、C1-C6的直链卤代烷基或C3-C6的支链卤代烷基、C1-C6的直链烷氧基或C3-C6的支链烷氧基、C1-C6的直链卤代烷氧基的组；
R4-R7各自独立地选自氢、卤素、羟基、氨基、氰基、巯基、三氟甲基、三氟甲氧基、硝基、酰胺基、磺酰胺基、C1-C3直链或支链烷基、C1-C3直链或支链烷氧基。
2.根据权利要求1所述的异喹啉酮类化合物、其药学上可接受的盐、立体异构体、前药分子或它们的混合物，其中：
R1选自C3-C8的环烷基、含1-3个氧、氮和/或硫原子的4-7元的杂环基、取代的或非取代的苯基组成的组；在R1基团为具有取代基(即“取代的”)的情况下，取代基各自独立地选自由卤素、羟基、羟甲基、巯基、氨基、氰基、硝基、羧基、酯基、三氟甲基、三氟甲氧基、C1-C3的直链或支链烷基、C1-C3的直链或直链烷氧基；
R2选自羧基、磺酸基、磺酰胺基、酰胺基、四氮唑、方酸基、羟基异恶唑；
R3选自取代或非取代的苯基；含氧、氮和硫的C5-C7的芳杂环；C3-C14的环烷基；4-8元的杂环基；在R3基团为具有取代基(即“取代的”)的情况下，取代基各自独立地选自由卤素、羟基、羟甲基、巯基、氨基、氰基、硝基、羧基、酯基、三氟甲基、三氟甲氧基；
R4-R7各自独立的选自氢、卤素、羟基、氨基、三氟甲基、三氟甲氧基、硝基、甲氧基；
优选的是，R2为-COOH，R3为苯基、取代苯基(例如氯代苯基、氟代苯基、甲基苯基、苄基、三氟甲基苯基)或芳杂环基，R4，R6，R7独立地为氢；
另外优选的是，R1选自环己基、甲基环己基、环戊基、四氢吡喃基、环丙基、环丁基、环庚基、氯代苯基、哌啶基和环戊基组成的组；R2为羧基；R3选自苯基、氟代苯基、羟基苯基、羟甲基苯基、氯代氟代苯基、三氟甲基苯基、二氢苯并呋喃基、吡啶基、二甲基吡唑基组成的组；R4和R7独立地为H或同时为H，R5为Cl、Br或甲基；R6为H或Cl。
3.根据权利要求1所述的异喹啉酮类化合物、其药学上可接受的盐、立体异构体、前药分子或它们的混合物，其中所述化合物选自由下列化合物组成的组：
4.根据权利要求1所述的异喹啉酮类化合物、其药学上可接受的盐、立体异构体、前药分子或它们的混合物在制备用于预防或治疗FABP4/5介导的疾病的药物中的用途。
5.根据权利要求5所述的用途，其特征在于，所述的FABP4/5介导的疾病是代谢性疾病、心脑血管疾病、炎性疾病、自身免疫性疾病、器官纤维化疾病、神经损伤性疾病、病原体感染所致的继发性疾病或肿瘤。
6.根据权利要求5所述的用途，其中，所述代谢性疾病选自胰岛素抵抗、2型糖尿病、动脉粥样硬化、高脂血症和非酒精性脂肪肝中的一种或多种；所述自身免疫性疾病选自银屑病和类风湿性关节炎中的一种或多种；所述急性炎症选自脓毒症、败血症、急性肾损伤、急性肺损伤、急性肝损伤中的一种或多种；所述癌症选自恶性黑色素瘤、肺癌、胃癌、乳腺癌、结肠癌、膀胱癌、胰腺癌、淋巴癌、白血病、前列腺癌、卵巢癌、肝癌、宫颈癌中的一种或多种。
7.一种药物组合物，其中，所述药物组合物包含治疗有效量的权利要求1至3中任一项所述的异喹啉酮化合物、其药学上可接受的盐、立体异构体、其前药分子或它们的混合物。
8.根据权利要求7所述的药物组合物，其中，所述异喹啉酮类化合物、其药学上可接受的盐、立体异构体、其前药分子或它们的混合物占该药物组合物的总重量的20％～99％。
9.根据权利要求7或8所述的药物组合物，其中，所述组合物进一步包含一种或多种药学上可接受的载体、气味剂、香味剂、赋形剂和/或稀释剂。
10.权利要求7～9中任一项所述的药物组合物在制备用于预防和治疗FABP4/5介导的疾病的药物中的应用，所述疾病为代谢性疾病、心脑血管疾病、炎性疾病、自身免疫性疾病、器官纤维化疾病、神经损伤性疾病、病原体感染所致的继发性疾病或肿瘤。
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| PCT/CN2023/083988 WO2023160726A1 (zh) | 2022-02-28 | 2023-03-27 | 异喹啉酮类化合物及其制备方法和应用 |
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