CN112752576A - 包含罗丹宁衍生物作为活性成分的用于预防、减轻或治疗骨关节炎的药物组合物 - Google Patents
包含罗丹宁衍生物作为活性成分的用于预防、减轻或治疗骨关节炎的药物组合物 Download PDFInfo
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- CN112752576A CN112752576A CN201980062769.7A CN201980062769A CN112752576A CN 112752576 A CN112752576 A CN 112752576A CN 201980062769 A CN201980062769 A CN 201980062769A CN 112752576 A CN112752576 A CN 112752576A
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- thioxothiazolidin
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Abstract
本发明涉及罗丹宁衍生物用于预防、减轻或治疗骨关节炎的用途。根据本发明的罗丹宁衍生物具有修复软骨基质损伤和减轻滑膜炎症的优异作用，因此可有效地用于预防、减轻或治疗骨关节炎。
Description
技术领域
本公开内容涉及用于预防、改善或治疗骨关节炎的药物组合物，所述药物组合物包含罗丹宁衍生物作为活性成分。
背景技术
在现代社会中，患有退行性疾病(例如痴呆、关节炎和动脉硬化)的患者随着群体的老龄化而增加，并且由于这些退行性疾病的老年人群体社会活动的限制不仅对患者本身而且对其家庭造成了经济和精神上的困难，从而导致社会问题。其中，骨关节炎(其是由于群体老龄化趋势而可在临床实践中常见的老年病)是一种慢性退行性疾病，其由于构成关节软骨的胞外基质的退化导致的关节软骨的渐进性损伤而引起，并涉及炎症和疼痛。
骨关节炎的发病率随年龄而提高，并且已报道软骨异常在多于60％的年龄为60岁或更大的人中出现(Bjelle(1982)Scand.J.Rheumatol.增刊，43：35-48)。已知，随着韩国最近进入老龄化社会，约80％的年龄超过55岁的人和几乎大多数年龄超过75岁的人患有骨关节炎疾病。
目前，用于治疗骨关节炎的有效方法是未知的，并且提供了减轻由骨关节炎引起的疼痛并通过防止关节的破坏和变形来维持正常关节的治疗。例如，当骨关节炎的疼痛相对较轻时，使用药物例如对乙酰氨基酚，但如果甚至当施用对乙酰氨基酚时疼痛持续或者是严重的或伴有炎症，则主要开非甾体抗炎药(NSAID)处方。然而，非甾体抗炎药的使用由于严重的胃肠并发症的高风险而受限。同时，欧洲抗风湿病联盟已推荐使用葡糖胺或软骨素(chondroitin)用于控制骨关节炎患者的疼痛，但是关于其安全性仍存在许多争议。
因此，本发明人进行了研究以发现用于治疗骨关节炎的有效治疗剂，从而完成了本公开内容。
发明内容
技术问题
一个方面旨在提供用于预防、改善或治疗骨关节炎的组合物，所述组合物包含罗丹宁衍生物化合物或其可药用盐作为活性成分。
另一个方面旨在提供使用罗丹宁衍生物化合物来预防、改善或治疗骨关节炎的方法。
技术方案
一个方面提供了用于预防或治疗骨关节炎的药物组合物，所述药物组合物包含由下式1表示的化合物或其可药用盐：
[式1]
其中R1是H、C1-5烷基、C1-5烷氧基、-C1-5烷基-羧酸、-C1-5烷基-C(＝O)-C1-3烷基、-C(＝O)-C1-5烷基、-C1-2烷基-SO2-C1-2烷基、-C1-2烷基-四氢呋喃、-苯基、-C1-2烷基-苯基、-环己基、-二氧代四氢噻吩、-吡唑、-C1-3烷基-呋喃或-CH(CO2H)-CH2-CO2H，其中所述苯基未经取代或经选自以下的至少一个取代基取代：C1-3烷基、经一个或更多个C1-2烷基取代的氨基、卤素、-CF3和-NO2；R2是H、卤素、C1-3烷基或-NO2，或者与R3连接以形成环；R3是H、卤素、C1-3烷基、C1-3烷氧基、-C1-5烷基-羧酸、-C(＝O)-O-R4、-NO2和吗啉中的任一种，或者是位于R2的邻位并与R2连接以形成环的-C(＝O)-NH-C(＝O)-、-CH2-O-C(＝O)-或-C＝C-C＝C-；R4是C1-4烷基，以及C1是sp3杂化碳或sp2杂化碳。
烷基可以是直链或支链的。
骨关节炎是一种伴随有关节软骨的渐进性破坏和与之相关的继发性症状的疾病。具体地，骨关节炎可由于保护关节的软骨的渐进性损伤或退行性变化而损伤构成关节的骨骼和韧带，并且可引起炎症和疼痛。由式1表示的化合物可有效地改善骨关节炎的症状，例如软骨基质的损失和滑膜炎，并且因此可有效地用于预防或治疗骨关节炎。
在一个实施方案中，R1可具有羧酸和/或酮基。
在一个实施方案中，R1可以是-CH2CH2C(＝O)CH3。
在一个实施方案中，R2可在呋喃的对位。
根据一个实施方案，由式1表示的化合物可以是选自以下的化合物：
1)3-{5-[5-(4-氯苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-丙酸，
2)4-(5-((5-(4-(异丙氧基羰基)苯基)呋喃-2-基)亚甲基)-4-氧代-2-硫代噻唑烷-3-基)丁酸，
3)3-(5-((5-(4-氯苯基)呋喃-2-基)甲基)-2，4-二氧代噻唑烷-3-基)丙酸，
4)3-(2，4-二甲基苯基)-5-[5-(3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
5)5-[5-(4-吗啉-4-基-3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
6)5-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-异吲哚-1，3-二酮，
7)3-(2-甲磺酰基乙基)-5-[5-(3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
8)5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-3-(四氢呋喃-2-基甲基)-2-硫代噻唑烷-4-酮，
9)3-(4-二乙基氨基苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
10)5-[5-(2，4-二氯苯基)-呋喃-2-基亚甲基]-3-(3-氟苯基)-2-硫代噻唑烷-4-酮，
11)3-苯乙基-5-(5-苯基-呋喃-2-基亚甲基)-2-硫代噻唑烷-4-酮，
12)5-[5-(3-氯-4-甲基苯基)-呋喃-2-基亚甲基]-3-乙基-2-硫代噻唑烷-4-酮，
13)5-(萘-1-基)-呋喃-2-基亚甲基-3-(2-氧代丙基)-2-硫代噻唑烷-4-酮，
14)3-环己基-5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
15)3-(3-氟苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
16)3-(1，1-二氧代四氢噻吩-3-基)-5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
17)5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-3-(4-氧代戊基)-2-硫代噻唑烷-4-酮，
18)5-[5-(2-溴-5-硝基苯基)呋喃-2-基亚甲基]-3-(4-碘苯基)-2-硫代噻唑烷-4-酮，
19)5-[5-(2-氯-4-硝基苯基)呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基苯基)-噻唑烷-4-酮，
20)3-苄基-5-[5-(4-乙氧基-2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
21){5-[5-(2-甲基-5-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸，
22){5-[5-(4-乙氧基-2-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-乙酸，
23){5-[5-(4-甲氧基-2-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸，
24)3-(4-硝基苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
25)4-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸异丙酯，
26)5-[5-(2，5-二氯苯基)呋喃-2-基亚甲基]-3-(1，5-二甲基-3-氧代-2-苯基-2，3-二氢-1H-吡唑-4-基)-2-硫代噻唑烷-4-酮，
27)5-[5-(1-氧代-1，3-二氢异苯并呋喃-5-基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
28)3-(呋喃-2-基甲基)-5-[5-(2-硝基苯基)呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
29)5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-3-苯乙基-2-硫代噻唑烷-4-酮，
30)3-(3-氯苯基)-5-[5-(2，3-二氯苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
31)2-氯-5-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸丙酯，
32)4-{5-[5-(3，4-二氯苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丁酸，
33)2-{5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-琥珀酸，
34)5-[5-(4-氯苯基)呋喃-2-基亚甲基]-3-(呋喃-2-基甲基)-2-硫代噻唑烷-4-酮，
35)5-[5-(2，4-二氯苯基)呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基苯基)-噻唑烷-4-酮，
36)3-(呋喃-2-基甲基)-5-[5-(4-硝基苯基)呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
37)3-{5-[5-(3-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丙酸，
38)3-{5-[5-(4-氯苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丙酸，
39)4-{5-[3-(2，4-二甲基苯基)-4-氧代-2-硫代噻唑烷-5-亚基甲基]-呋喃-2-基}苯甲酸，
40){5-[5-(3-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸，以及
41)5-[5-(4-溴苯基)-呋喃-2-基亚甲基]-3-(3-氧代丁基)-2-硫代噻唑烷-4-酮(在下文中，这些化合物可被称为化合物1至41)。
在下表1中示出了化合物1至41的式。
[表1]
根据一个实施方案，所述化合物可挽救软骨基质的损失。
根据一个实施方案，所述化合物可减轻滑膜炎。
通过由在小鼠软骨和关节组织中过表达ZIP8而诱导的骨关节炎的新动物模型，确定了本公开内容的化合物用于改善或治疗骨关节炎的活性。ZIP8是位于软骨细胞膜中并促进锌离子导入的转运蛋白(载体)。当ZIP8的表达提高时，可提高锌离子向软骨细胞中的导入，并且可提高软骨基质降解酶的表达，从而导致骨关节炎。新的动物模型示出了由于ZIP8的过表达导致的软骨基质损失和滑膜炎，并且因此可有效地用于确定候选药物对骨关节炎治疗的作用或改善由ZIP8表达提高而引起的骨关节炎的作用(Regulation of thecatabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis.Cell 156，730-743(2014))。
根据本公开内容的一个实例，作为向ZIP8过表达的动物模型施用化合物1至3(AVIX-7、MA3001和MA6004)中的每一种的结果，确定了每种化合物均表现出挽救软骨基质损失并减轻滑膜炎的活性。因此，在本公开内容中，化合物1至3以及与其共享结构特征的由式1表示的化合物可有效地用于预防或治疗骨关节炎。
根据一个实施方案，骨关节炎可以是由ZIP8表达提高引起的关节炎。由于该化合物可抑制由ZIP8导入的锌引起的软骨破坏和关节中的炎症，因此它可表现出针对由ZIP8表达提高引起的骨关节炎的治疗性作用。
对于骨关节炎的治疗，根据本公开内容的一个实施方案的药物组合物可单独使用或与手术、激素治疗、药物治疗、放射治疗和/或使用生物应答调节剂的方法组合使用。
由式1表示的化合物可通过本领域技术人员已知的方法来产生。例如，其可根据韩国专利No.10-1159000或美国专利No.8,759,536中描述的方法来产生。
术语“罗丹宁衍生物”是指具有罗丹宁结构的化合物。由于由式1表示的化合物具有罗丹宁结构，因此在本说明书中可将其称为罗丹宁衍生物。
由式1表示的化合物可根据本领域中已知的常规方法作为可药用盐或溶剂合物来产生。
可药用盐有利地是与游离酸形成的酸加成盐。酸加成盐以常规方式来制备，例如通过将化合物溶解在过量的酸水溶液中并用与水混溶的有机溶剂(例如甲醇、乙醇、丙酮或乙腈)使该盐沉淀。也可将等摩尔量的化合物和酸在水或醇(例如，乙二醇单甲醚)中加热，并随后可将混合物蒸发至干燥，或者可将沉淀的盐通过抽吸过滤出。
作为游离酸，可使用有机酸和无机酸。无机酸的一些实例包括盐酸、磷酸、硫酸、硝酸、酒石酸等，并且有机酸的一些实例包括甲磺酸、对甲苯磺酸、乙酸、三氟乙酸、柠檬酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、乳酸、乙醇酸、葡糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸、氢碘酸等。
另外，可使用碱来制备可药用金属盐。例如，通过将化合物溶解在过量的碱金属或碱土金属氢氧化物溶液中、过滤出未溶解的化合物盐并将滤液蒸发至干燥来获得碱金属或碱土金属盐。此时，作为金属盐，钠盐、钾盐或钙盐是药学上合适的盐。另外，通过使碱金属盐或碱土金属盐与合适的银盐(例如，硝酸银)反应来获得相应的银盐。
除非另有说明，否则由式1表示的化合物的可药用盐包括可存在于罗丹宁衍生物中的酸性或碱性基团的盐。可药用盐的一些实例包括羟基的钠盐、钙盐和钾盐，并且氨基的其他可药用盐的一些实例包括氢溴酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、乙酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、甲基磺酸盐(甲磺酸盐)和对甲苯磺酸盐(甲苯磺酸盐)。可使用本领域中已知的盐制备方法或工艺来制备盐。
本公开内容的药物组合物可包含可药用载体。本公开内容的药物组合物中包含的可药用载体的一些实例包括但不限于药物制造中常用的乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、藻酸类、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物质油。本公开内容的药物组合物除以上组分之外还可包含润滑剂、润湿剂、甜味剂、矫味剂、乳化剂、助悬剂、防腐剂等。合适的可药用载体和制剂在Remington’s PharmaceuticalSciences(第22版，2013)中进行了详细描述。
本公开内容的药物组合物可包含对于其制剂必需且适合的多种碱和/或添加剂，并且可被制备以进一步包含不损害其作用的范围内的已知组分，例如非离子表面活性剂、硅氧烷聚合物、体质颜料、芳香剂、抗菌剂、消毒剂、氧化稳定剂、有机溶剂、离子或非离子增稠剂、软化剂、抗氧化剂、自由基破坏剂、乳浊剂、稳定剂、润肤剂(emollient)、硅氧烷、α-羟基酸、消泡剂、保湿剂、维生素、驱虫剂、芳香剂、防腐剂、表面活性剂、抗炎剂、P物质拮抗剂、填充剂、聚合物、抛射剂、碱化剂或酸化剂、或着色剂。
本公开内容的药物组合物的合适剂量可根据以下因素而变化：例如配制方法、施用模式、患者的年龄、体重、性别、疾病状况和饮食、施用的持续时间、施用途径、排泄率和响应敏感性。对于成人，本公开内容的药物组合物的剂量可以是0.001至1,000mg/kg。
本公开内容的药物组合物可肠胃外施用。例如，可通过以下方法来施用药物组合物，例如关节内注射、皮下注射、静脉内注射、肌内注射或胸内注射，但是施用方法不限于此。
例如，为了配制成肠胃外剂型，可将本公开内容的药物组合物与稳定剂或缓冲剂在水中混合以制备溶液剂或混悬剂，然后将其制备成安瓿或小瓶单位剂型。另外，所述组合物可以是经灭菌的，或者还可包含辅料，例如防腐剂、稳定剂、水合剂或乳化促进剂、用于控制渗透压的盐、或缓冲剂，以及其他治疗有益物质，并且可根据常规方法进行配制。
本公开内容的另一个方面提供了用于治疗骨关节炎的方法，所述方法包括向骨关节炎患者施用包含选自由式1表示的化合物的化合物作为活性成分的组合物的步骤。
对由式1表示的化合物的描述如上所述。
根据一个实施方案，由式1表示的化合物可以是选自以下的化合物：1)3-{5-[5-(4-氯-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-丙酸；2)4-(5-((5-(4-(异丙氧基羰基)苯基)呋喃-2-基)亚甲基)-4-氧代-2-硫代噻唑烷-3-基)丁酸；3)3-(5-((5-(4-氯苯基)呋喃-2-基)甲基)-2，4-二氧代噻唑烷-3-基)丙酸；4)3-(2，4-二甲基苯基)-5-[5-(3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；5)5-[5-(4-吗啉-4-基-3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；6)5-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-异吲哚-1，3-二酮；7)3-(2-甲磺酰基乙基)-5-[5-(3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；8)5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-3-(四氢呋喃-2-基甲基)-2-硫代噻唑烷-4-酮；9)3-(4-二乙基氨基苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；10)5-[5-(2，4-二氯苯基)-呋喃-2-基亚甲基]-3-(3-氟苯基)-2-硫代噻唑烷-4-酮；11)3-苯乙基-5-(5-苯基-呋喃-2-基亚甲基)-2-硫代噻唑烷-4-酮；12)5-[5-(3-氯-4-甲基苯基)-呋喃-2-基亚甲基]-3-乙基-2-硫代噻唑烷-4-酮；13)5-(萘-1-基)呋喃-2-基亚甲基-3-(2-氧代丙基)-2-硫代噻唑烷-4-酮；14)3-环己基-5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；15)3-(3-氟苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；16)3-(1，1-二氧代四氢噻吩-3-基)-5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；17)5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-3-(4-氧代戊基)-2-硫代噻唑烷-4-酮；18)5-[5-(2-溴-5-硝基苯基)呋喃-2-基亚甲基]-3-(4-碘苯基)-2-硫代噻唑烷-4-酮；19)5-[5-(2-氯-4-硝基苯基)呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基苯基)-噻唑烷-4-酮；20)3-苄基-5-[5-(4-乙氧基-2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；21){5-[5-(2-甲基-5-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸；22){5-[5-(4-乙氧基-2-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-乙酸；23){5-[5-(4-甲氧基-2-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸；24)3-(4-硝基苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；25)4-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸异丙酯；26)5-[5-(2，5-二氯苯基)呋喃-2-基亚甲基]-3-(1，5-二甲基-3-氧代-2-苯基-2，3-二氢-1H-吡唑-4-基)-2-硫代噻唑烷-4-酮；27)5-[5-(1-氧代-1，3-二氢异苯并呋喃-5-基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；28)3-(呋喃-2-基甲基)-5-[5-(2-硝基苯基)呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；29)5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-3-苯乙基-2-硫代噻唑烷-4-酮；30)3-(3-氯苯基)-5-[5-(2，3-二氯苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；31)2-氯-5-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸丙酯；32)4-{5-[5-(3，4-二氯苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丁酸；33)2-{5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-琥珀酸；34)5-[5-(4-氯苯基)呋喃-2-基亚甲基]-3-(呋喃-2-基甲基)-2-硫代噻唑烷-4-酮；35)5-[5-(2，4-二氯苯基)呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基苯基)-噻唑烷-4-酮；36)3-(呋喃-2-基甲基)-5-[5-(4-硝基苯基)呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；37)3-{5-[5-(3-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丙酸；38)3-{5-[5-(4-氯苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丙酸；39)4-{5-[3-(2，4-二甲基苯基)-4-氧代-2-硫代噻唑烷-5-亚基甲基]-呋喃-2-基}苯甲酸；40){5-[5-(3-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸；以及41)5-[5-(4-溴苯基)-呋喃-2-基亚甲基]-3-(3-氧代丁基)-2-硫代噻唑烷-4-酮。
根据本公开内容的由式1表示的化合物具有改善骨关节炎症状的优异作用，并且因此可有效地用于治疗骨关节炎患者。
本公开内容的另一个方面提供了用于预防或改善骨关节炎的食品组合物，所述食品组合物包含由式1表示的化合物。
对由式1表示的化合物的描述如上所述。
根据一个实施方案，由式1表示的化合物可以是选自以下的化合物：1)3-{5-[5-(4-氯-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-丙酸；2)4-(5-((5-(4-(异丙氧基羰基)苯基)呋喃-2-基)亚甲基)-4-氧代-2-硫代噻唑烷-3-基)丁酸；3)3-(5-((5-(4-氯苯基)呋喃-2-基)甲基)-2，4-二氧代噻唑烷-3-基)丙酸；4)3-(2，4-二甲基苯基)-5-[5-(3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；5)5-[5-(4-吗啉-4-基-3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；6)5-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-异吲哚-1，3-二酮；7)3-(2-甲磺酰基乙基)-5-[5-(3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；8)5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-3-(四氢呋喃-2-基甲基)-2-硫代噻唑烷-4-酮；9)3-(4-二乙基氨基苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；10)5-[5-(2，4-二氯苯基)-呋喃-2-基亚甲基]-3-(3-氟苯基)-2-硫代噻唑烷-4-酮；11)3-苯乙基-5-(5-苯基-呋喃-2-基亚甲基)-2-硫代噻唑烷-4-酮；12)5-[5-(3-氯-4-甲基苯基)-呋喃-2-基亚甲基]-3-乙基-2-硫代噻唑烷-4-酮；13)5-(萘-1-基)呋喃-2-基亚甲基-3-(2-氧代丙基)-2-硫代噻唑烷-4-酮；14)3-环己基-5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；15)3-(3-氟苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；16)3-(1，1-二氧代四氢噻吩-3-基)-5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；17)5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-3-(4-氧代戊基)-2-硫代噻唑烷-4-酮；18)5-[5-(2-溴-5-硝基苯基)呋喃-2-基亚甲基]-3-(4-碘苯基)-2-硫代噻唑烷-4-酮；19)5-[5-(2-氯-4-硝基苯基)呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基苯基)-噻唑烷-4-酮；20)3-苄基-5-[5-(4-乙氧基-2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；21){5-[5-(2-甲基-5-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸；22){5-[5-(4-乙氧基-2-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-乙酸；23){5-[5-(4-甲氧基-2-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸；24)3-(4-硝基苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；25)4-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸异丙酯；26)5-[5-(2，5-二氯苯基)呋喃-2-基亚甲基]-3-(1，5-二甲基-3-氧代-2-苯基-2，3-二氢-1H-吡唑-4-基)-2-硫代噻唑烷-4-酮；27)5-[5-(1-氧代-1，3-二氢异苯并呋喃-5-基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；28)3-(呋喃-2-基甲基)-5-[5-(2-硝基苯基)呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；29)5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-3-苯乙基-2-硫代噻唑烷-4-酮；30)3-(3-氯苯基)-5-[5-(2，3-二氯苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；31)2-氯-5-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸丙酯；32)4-{5-[5-(3，4-二氯苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丁酸；33)2-{5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-琥珀酸；34)5-[5-(4-氯苯基)呋喃-2-基亚甲基]-3-(呋喃-2-基甲基)-2-硫代噻唑烷-4-酮；35)5-[5-(2，4-二氯苯基)呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基苯基)-噻唑烷-4-酮；36)3-(呋喃-2-基甲基)-5-[5-(4-硝基苯基)呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮；37)3-{5-[5-(3-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丙酸；38)3-{5-[5-(4-氯苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丙酸；39)4-{5-[3-(2，4-二甲基苯基)-4-氧代-2-硫代噻唑烷-5-亚基甲基]-呋喃-2-基}苯甲酸；40){5-[5-(3-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸；以及41)5-[5-(4-溴苯基)-呋喃-2-基亚甲基]-3-(3-氧代丁基)-2-硫代噻唑烷-4-酮。
根据本公开内容的由式1表示的化合物可挽救软骨基质的损失并减轻滑膜炎的症状，并且因此包含该化合物的食品组合物可预防骨关节炎症状的发生并改善已发生的骨关节炎症状。
本公开内容的食品组合物可通过除包含由式1表示的化合物作为活性成分之外，还添加本领域中惯常添加的原料和成分来制备。另外，与常规食品组合物一样，本公开内容的食品组合物可包含多种矫味剂或天然碳水化合物作为另外的成分。
根据本公开内容的一个实施方案，天然碳水化合物可以是常规的糖，例如单糖(例如，葡萄糖、果糖等)、二糖(例如，麦芽糖、蔗糖等)和多糖(例如，糊精、环糊精等)以及糖醇(例如，木糖醇、山梨糖醇或赤藓糖醇)。矫味剂的一些实例可包括天然矫味剂(奇异果甜蛋白)、甜叶菊提取物(例如，莱鲍迪苷A、甘草皂苷等)和/或合成矫味剂(糖精、阿斯巴甜等)。
本公开内容的食品组合物可被配制为除上述活性成分之外还包含一种或更多种食品可接受或可药用的载体的食品组合物。可将食品组合物配制成以下形式：片剂、胶囊剂、散剂、颗粒剂、液体剂、丸剂、溶液剂、糖浆剂、果汁剂、混悬剂、乳剂或滴剂。例如，对于为片剂或胶囊剂形式的制剂，可将活性成分与经口、无毒性的可药用惰性载体(例如乙醇、甘油或水)组合。
本公开内容的食品组合物可包含由以下组成的维生素混合物：乙酸维生素A、维生素E、维生素B1、维生素B2、维生素B6、维生素B12、维生素C、生物素、烟酰胺、叶酸和泛酸钙以及一种或更多种矿物质，例如硫酸亚铁、氧化锌、碳酸镁、磷酸二氢钾、磷酸氢二钾、柠檬酸钾、碳酸钙和氯化镁，其在本领域中可惯常添加。
如果需要的话，也可包含合适的黏合剂、润滑剂、崩解剂和着色剂作为混合物。合适的黏合剂的一些实例可包括天然糖(例如淀粉、明胶、葡萄糖或β-乳糖)、天然和合成的胶(例如玉米甜味剂、阿拉伯胶、黄蓍胶)或者油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂的一些实例可包括淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
这些组分可单独或组合使用，并且基于100重量份的本公开内容的食品组合物，这些添加剂的比例可在0至约20重量份的范围内选择，但是不限于此。
同时，通过将本领域技术人员已知的用于制备多种制剂的方法应用于本公开内容的食品组合物可制备多种食品。例如，本公开内容的食品组合物可被制备为常见的健康功能食品制剂，例如饮料、丸剂或散剂，但不限于此。
本公开内容的食品组合物具有改善由骨关节炎引起的症状的优异作用，并且因此可有效地用于预防或改善骨关节炎。
有益效果
本公开内容的化合物具有挽救软骨基质的损失和减轻滑膜炎的优异作用，并且因此可有效地用于预防、改善或治疗骨关节炎。
附图简述
图1描绘了示出观察AVIX-7对由ZIP8基因过表达而诱导的骨关节炎的治疗性作用的结果的组织图像。将载剂和不同浓度的AVIX-7中的每一种施用于小鼠，并通过用番红-O进行染色来观察小鼠的整个关节、软骨和滑膜组织。图1A中的Ad-C是正常组，且图1B中的Ad-ZIP8是患有由ZIP8过表达诱导的骨关节炎的小鼠组。载剂是不含药物的对照。
图2A是示出了在施用AVIX-7的骨关节炎诱导小鼠中，根据经修改的Mankin评分对软骨破坏程度进行分级的图。图2B示出了在将不同浓度的AVIX-7施用于患有由ZIP8过表达而诱导的骨关节炎的小鼠之后评价滑膜炎的程度的结果。
图3描绘了示出观察MA3001对由表达ZIP8基因而诱导的骨关节炎的治疗性作用的结果的组织图像。具体地，图3示出了在将载剂和不同浓度的根据本公开内容的一个实施方案的化合物(MA3001)中的每一种施用于骨关节炎诱导小鼠之后，通过用番红-O进行染色观察到的整个关节、软骨和滑膜组织。
图4A是示出了在施用MA3001的骨关节炎诱导小鼠中，根据经修改的Mankin评分对软骨破坏程度进行分级的图。图4B示出了在通过将不同浓度的MA3001施用于患有由ZIP8过表达而诱导的骨关节炎的小鼠之后评价滑膜炎的程度的结果。
图5描绘了示出观察MA6004对由表达ZIP8基因而诱导的骨关节炎的治疗性作用的结果的组织图像。具体地，图5示出了在将载剂(A)和不同浓度的根据本公开内容的一个实施方案的化合物(AVIX-7)中的每一种施用于骨关节炎诱导小鼠之后，通过用番红-O进行染色观察到的整个关节、软骨和滑膜组织。
图6A是示出了在施用MA6004的骨关节炎诱导小鼠中，根据经修改的Mankin评分对软骨破坏程度进行分级的图。图6B示出了在将不同浓度的MA6004施用于患有由ZIP8过表达而诱导的骨关节炎的小鼠之后评价滑膜炎的程度的结果。
图7示出了观察在将AVIX-7施用于患有由内侧半月板(DMM)不稳定而诱导的骨关节炎的小鼠之后AVIX-7的治疗性作用的结果。具体地，图7A和7B分别是示出了在将不同浓度的AVIX-7施用于正常小鼠(假手术组(sham))和患有由DMM诱导的骨关节炎的小鼠之后，通过用番红-O进行染色观察整个关节、软骨和滑膜组织的结果的图像。
图8A是示出了在将不同浓度的AVIX-7施用于患有由DMM诱导的骨关节炎的小鼠之后，根据OARSI分级方法进行分级的骨关节炎的图，并且图8B是示出了在将不同浓度的AVIX-7施用于患有由DMM诱导的骨关节炎的小鼠之后测量软骨下骨板厚度的结果的图。
图9示出了观察MA3001对由内侧半月板(DMM)的不稳定而诱导的骨关节炎的治疗性作用的结果。具体地，图9A和9B分别是示出了在将不同浓度的MA3001施用于正常小鼠(假手术组)和患有由DMM诱导的骨关节炎的小鼠之后，通过用番红-O进行染色观察整个关节、软骨和滑膜组织的结果的图像。
图10A是示出了在将不同浓度的MA3001施用于患有由DMM诱导的骨关节炎的小鼠之后，根据OARSI分级方法进行分级的骨关节炎的图，并且图10B是示出了在将不同浓度的MA3001施用于患有由DMM诱导的骨关节炎的小鼠之后测量软骨下骨板厚度的结果的图。
图11示出了观察MA6004对由内侧半月板(DMM)的不稳定而诱导的骨关节炎的治疗性作用的结果。具体地，图11A和11B分别是示出了在将不同浓度的MA6004施用于正常小鼠(假手术组)和患有由DMM诱导的骨关节炎的小鼠之后，通过用番红-O进行染色观察整个关节、软骨和滑膜组织的结果的图像。
图12A是示出了在将不同浓度的MA6004施用于患有由DMM诱导的骨关节炎的小鼠之后，根据OARSI分级方法进行分级的骨关节炎的图，并且图12B是示出了在将不同浓度的MA6004施用于患有由DMM诱导的骨关节炎的小鼠之后测量软骨下骨板厚度的结果的图。
具体实施方式
在下文中，将参照一个或更多个实施例来详细描述本公开内容。然而，这些实施例仅用于举例说明本公开内容，并且本公开内容的范围不限于这些实施例。
实施例1.在小鼠中通过ZIP8过表达来诱导骨关节炎并用治疗剂进行治疗
通过在小鼠的软骨和关节组织中过表达锌导入物ZIP8来制备骨关节炎诱导小鼠。
具体地，用正常对照腺病毒(Ad-C)或表达ZIP8的腺病毒(Ad-Slc39a8)对约12周龄的雄性C57/BL6小鼠的软骨和关节组织进行关节内注射。载剂组仅用不含载体的载剂进行处理。每种腺病毒均以1×109PFU的浓度注射，总共3次(每周一次)。
同时，为了评价治疗剂AVIX-7、MA3001和MA6004中的每一种对由ZIP8过表达诱导的骨关节炎的改善的作用，在注射每种腺病毒时将AVIX-7、MA3001或MA6004共注射到关节中。
AVIX-7的结构对应于上表1中的化合物1，MA3001的结构对应于上表1中的化合物2，并且MA6004的结构对应于上表1中的化合物3。
每种治疗剂以0.0075mg/kg、0.015mg/kg和0.03mg/kg小鼠体重的剂量使用。每种治疗剂通过每周一次的注射施用，并且在每个时间点所施用的每种治疗剂的量为10μl。在总共三次注射的最后一次注射那天之后一周，将小鼠处死并分析软骨破坏的程度和滑膜炎发生的程度。
实施例2.在小鼠中通过DMM诱导骨关节炎并用治疗剂进行治疗
制备了患有由内侧半月板(DMM)的不稳定诱导的骨关节炎的小鼠。作为对照组，使用了在手术期间半月板未损伤的组(假手术组)。
具体地，通过使约12周龄的雄性C57/BL6小鼠的关节半月板损伤来诱导骨关节炎，并且关节内注射每种治疗剂(AVIX-7、MA3001或MA6004)。
每种治疗剂以0.0075mg/kg、0.015mg/kg和0.03mg/kg小鼠体重的剂量使用。每种治疗剂通过每周一次的注射施用，并且在每个时间点所施用的每种治疗剂的量为10μl。在总共三次注射的最后一次注射那天之后一周，将小鼠处死并评价每种治疗剂对改善骨关节炎的作用。
实施例3.在由基因表达诱导的骨关节炎模型中治疗剂对改善软骨破坏的作用的评价
为了评价AVIX-7、MA3001或MA6004在ZIP8过表达的小鼠中对骨关节炎的治疗性作用，用番红-O对整个关节和软骨组织进行染色，并检查软骨破坏程度。
参照图1、3和5中的载剂组(未施用药物)，与正常组(Ad-C)中的相比，在其中诱导了ZIP8过表达的小鼠(Ad-Sic39a8)中的番红-O红色染色区域减少(在黑白图中红色由深色表示)。这是因为由于骨关节炎，整个关节变薄并且软骨基质损失。在另一方面，确定了在用AVIX-7、MA3001或MA6004处理的组中，软骨基质的损失被浓度依赖性地挽救(参见图1、3和5中的整个关节和软骨)。
另外，根据下表2观察番红-O染色的程度(反映软骨破坏的程度)，并且其根据经修改的Mankin评分(Mankin，Henry J.，and Louis Lippiello.JBJS 52.3(1970)：424-434.)降级，并以图表方式对等级进行量化。Mankin评分是指示关节炎程度的指标，并且可通过小鼠中番红-O染色的程度来确定，并且Mankin评分越低，越接近正常。经修改的Mankin评分在图2A、4A和6A中示出。
[表2]
| 番红-O染色的程度 | 经修改的Mankin评分 |
| 正常 | 0 |
| 略微降低 | 1 |
| 适度降低 | 2 |
| 显著降低 | 3 |
| 未被染色 | 4 |
作为结果，可以确定，在ZIP8过表达的小鼠中，载剂组的经修改的Mankin评分是2或更高，但是用AVIX-7、MA3001或MA6004处理的组的Mankin评分低于载剂组的评分，并且还以浓度依赖性方式降低。因此，确定了AVIX-7、MA3001和MA6004具有改善由骨关节炎引起的软骨破坏的作用(图2A、4A和6A)。
实施例4.对改善滑膜炎的作用的评价
为了评价在本公开内容中开发的每种治疗剂的骨关节炎改善作用，用AVIX-7、MA3001或MA6004处理ZIP8过表达的动物模型，并将动物模型的软骨和关节组织用苏木精-伊红/番红-O进行染色，并检查滑膜炎的存在或不存在。ZIP8过表达的动物模型通过实施例1中所述的方法来制备。
参照图1、3和5中的滑膜和载剂组，与正常组(Ad-C)中的相比，ZIP8过表达的小鼠(Ad-Sic39a8)中的炎性细胞向滑膜中的透入提高。在另一方面，确定了在用AVIX-7、MA3001或MA6004处理的组中炎性应答减轻(参见图1、3和5)。
另外，根据下表3中描述的“Synovitis score：discrimination between chroniclow-grade and high-grade synovitis.Histopathology 49，358-364”对滑膜炎的程度进行评分，并以图表方式进行量化。滑膜炎的评分在图2B、4B和6B中示出。
[表3]
| 滑膜炎的程度 | 等级 |
| 正常 | 0 |
| 位于血管周围的淋巴细胞或浆细胞 | 1 |
| 大量的淋巴细胞或浆细胞，一些滤泡样(follicle-like)聚集体的形成 | 2 |
| 密集的炎性浸润带或大量的大滤泡样聚集体的形成 | 3 |
参照图2B、4B和6B，确定了在ZIP8过表达的小鼠中，在软骨和关节组织中发生滑膜炎并且滑膜炎的评分高(2或更高)，但在用AVIX-7、MA3001或MA6004处理的组中，滑膜炎评分显著降低，表明AVIX-7、MA3001或MA6004具有改善滑膜炎症状的作用。
实施例5.在由内侧半月板的不稳定诱导的骨关节炎模型中对骨关节炎改善作用的评价
为了评价本公开内容的化合物对改善骨关节炎的作用，使小鼠内侧半月板(DMM)不稳定以诱导骨关节炎，并用AVIX-7、MA3001或MA6004进行处理。另外，用苏木精-伊红/番红-O对软骨和关节组织进行染色，并病理学地评价AVIX-7、MA3001或MA6004对骨关节炎改善的作用。在染色之后，通过OARSI(Osteoarthritis Research Society International(国际骨关节炎研究协会))建议的分级方法来评价关节表面的磨损状态和骨赘的存在。下表4中描述了OARSI分级方法。
[表4]
参照图7、9和11中的载剂组，与正常组(假手术组)中的相比，在患有由DMM诱导的骨关节炎的小鼠中炎性细胞向整个关节和软骨组织中的透入显著提高。然而，确定了在用AVIX-7、MA3001或MA6004处理的组中炎症应答减轻(参见图7B、9B和11B中的图像以及图8A、10A和12A中的OARSI等级)。
另外，作为测量患有由DMM诱导的骨关节炎的小鼠中软骨下骨板(subchondralbone plate，SBP)厚度的结果，确定了未向其施用药物的载剂组中的SBP厚度显著提高，但是向其施用了AVIX-7、MA3001或MA6004的组中的SBP厚度降低(参见图8B、10B和12B)。从这些结果，确定了AVIX-7、MA3001和MA6004均具有改善骨关节炎的作用。
迄今为止，已参照一些实施方案描述了本公开内容。本公开内容所属领域的普通技术人员将理解，在不脱离本公开内容的本质特征的情况下，可以以经修改的形式实施本公开内容。因此，应当从举例说明性的角度而不是限制性的角度来考虑所公开的实施方案。本公开内容的范围由权利要求书而不是以上描述来限定，并且与之等同的范围内的所有差异应被解释为包含在本公开内容中。
Claims (6)
1.用于预防或治疗骨关节炎的药物组合物，所述药物组合物包含由下式1表示的化合物或其可药用盐：
[式1]
其中R1是H、C1-5烷基、C1-5烷氧基、-C1-5烷基-羧酸、-C1-5烷基-C(＝O)-C1-3烷基、-C(＝O)-C1-5烷基、-C1-2烷基-SO2-C1-2烷基、-C1-2烷基-四氢呋喃、-苯基、-C1-2烷基-苯基、-环己基、-二氧代四氢噻吩、-吡唑、-C1-3烷基-呋喃或-CH(CO2H)-CH2-CO2H，其中所述苯基未经取代或经选自以下的至少一个取代基取代：C1-3烷基、经一个或更多个C1-2烷基取代的氨基、卤素、-CF3和-NO2；
R2是H、卤素、C1-3烷基或-NO2，或者与R3连接以形成环；
R3是H、卤素、C1-3烷基、C1-3烷氧基、-C1-5烷基-羧酸、-C(＝O)-O-R4、-NO2和吗啉中的任一种，或者是位于R2的邻位并与R2连接以形成环的-C(＝O)-NH-C(＝O)-、-CH2-O-C(＝O)-或-C＝C-C＝C-；
R4是C1-4烷基，以及
C1是sp3杂化碳或sp2杂化碳。
2.权利要求1所述的药物组合物，其中R3在所述呋喃的对位。
3.权利要求1所述的药物组合物，其中所述由式1表示的化合物是选自以下的化合物：
1)3-{5-[5-(4-氯-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-丙酸，
2)4-(5-((5-(4-(异丙氧基羰基)苯基)呋喃-2-基)亚甲基)-4-氧代-2-硫代噻唑烷-3-基)丁酸，
3)3-(5-((5-(4-氯苯基)呋喃-2-基)甲基)-2，4-二氧代噻唑烷-3-基)丙酸，
4)3-(2，4-二甲基苯基)-5-[5-(3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
5)5-[5-(4-吗啉-4-基-3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
6)5-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-异吲哚-1，3-二酮，
7)3-(2-甲磺酰基乙基)-5-[5-(3-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
8)5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-3-(四氢呋喃-2-基甲基)-2-硫代噻唑烷-4-酮，
9)3-(4-二乙基氨基苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
10)5-[5-(2，4-二氯苯基)-呋喃-2-基亚甲基]-3-(3-氟苯基)-2-硫代噻唑烷-4-酮，
11)3-苯乙基-5-(5-苯基-呋喃-2-基亚甲基)-2-硫代噻唑烷-4-酮，
12)5-[5-(3-氯-4-甲基苯基)-呋喃-2-基亚甲基]-3-乙基-2-硫代噻唑烷-4-酮，
13)5-(萘-1-基)呋喃-2-基亚甲基-3-(2-氧代丙基)-2-硫代噻唑烷-4-酮，
14)3-环己基-5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
15)3-(3-氟苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
16)3-(1，1-二氧代四氢噻吩-3-基)-5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
17)5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-3-(4-氧代戊基)-2-硫代噻唑烷-4-酮，
18)5-[5-(2-溴-5-硝基苯基)呋喃-2-基亚甲基]-3-(4-碘苯基)-2-硫代噻唑烷-4-酮，
19)5-[5-(2-氯-4-硝基苯基)呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基苯基)-噻唑烷-4-酮，
20)3-苄基-5-[5-(4-乙氧基-2-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
21){5-[5-(2-甲基-5-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸，
22){5-[5-(4-乙氧基-2-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-乙酸，
23){5-[5-(4-甲氧基-2-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸，
24)3-(4-硝基苯基)-5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
25)4-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸异丙酯，
26)5-[5-(2，5-二氯苯基)呋喃-2-基亚甲基]-3-(1，5-二甲基-3-氧代-2-苯基-2，3-二氢-1H-吡唑-4-基)-2-硫代噻唑烷-4-酮，
27)5-[5-(1-氧代-1，3-二氢异苯并呋喃-5-基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
28)3-(呋喃-2-基甲基)-5-[5-(2-硝基苯基)呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
29)5-[5-(2-硝基苯基)-呋喃-2-基亚甲基]-3-苯乙基-2-硫代噻唑烷-4-酮，
30)3-(3-氯苯基)-5-[5-(2，3-二氯苯基)-呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
31)2-氯-5-[5-(4-氧代-2-硫代噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸丙酯，
32)4-{5-[5-(3，4-二氯苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丁酸，
33)2-{5-[5-(4-硝基苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-琥珀酸，
34)5-[5-(4-氯苯基)呋喃-2-基亚甲基]-3-(呋喃-2-基甲基)-2-硫代噻唑烷-4-酮，
35)5-[5-(2，4-二氯苯基)呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基苯基)-噻唑烷-4-酮，
36)3-(呋喃-2-基甲基)-5-[5-(4-硝基苯基)呋喃-2-基亚甲基]-2-硫代噻唑烷-4-酮，
37)3-{5-[5-(3-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丙酸，
38)3-{5-[5-(4-氯苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}-丙酸，
39)4-{5-[3-(2，4-二甲基苯基)-4-氧代-2-硫代噻唑烷-5-亚基甲基]-呋喃-2-基}苯甲酸，
40){5-[5-(3-硝基苯基)呋喃-2-基亚甲基]-4-氧代-2-硫代噻唑烷-3-基}乙酸，以及
41)5-[5-(4-溴苯基)-呋喃-2-基亚甲基]-3-(3-氧代丁基)-2-硫代噻唑烷-4-酮。
4.权利要求1所述的药物组合物，其中所述骨关节炎是由ZIP8表达提高引起的骨关节炎。
5.权利要求1所述的药物组合物，其中所述化合物减轻滑膜炎。
6.用于预防或改善骨关节炎的食品组合物，所述食品组合物包含根据权利要求1所述的由式1表示的化合物。
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| KR10-2018-0086505 | 2018-07-25 | ||
| PCT/KR2019/009213 WO2020022789A1 (ko) | 2018-07-25 | 2019-07-25 | 로다닌 유도체를 유효성분으로 포함하는 골관절염 예방, 개선 또는 치료용 약학적 조성물 |
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| US (1) | US20210228548A1 (zh) |
| EP (1) | EP3827827A4 (zh) |
| JP (1) | JP2021532144A (zh) |
| KR (1) | KR102224999B1 (zh) |
| CN (1) | CN112752576A (zh) |
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| KR101893988B1 (ko) * | 2018-05-16 | 2018-08-31 | (주)에빅스젠 | 로다닌 유도체를 함유하는 aids 예방 또는 치료용 약학 조성물 |
| KR102620902B1 (ko) * | 2020-04-24 | 2024-01-04 | 가천대학교 산학협력단 | 신규 알파-시누클레인 방사성 리간드 및 이를 포함하는 신경퇴행성 질환 진단용 조성물 |
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| US20020052396A1 (en) * | 2001-04-23 | 2002-05-02 | Bailey Thomas R. | Compounds, compositions and methods for treating or preventing viral infections and associated diseases |
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| WO2008063671A2 (en) * | 2006-11-20 | 2008-05-29 | Alantos Pharmaceuticals Holding, Inc. | Heterobicyclic metalloprotease inhibitors |
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| KR20150115106A (ko) * | 2014-04-02 | 2015-10-14 | 광주과학기술원 | Zinc-ZIP8-MTF1 억제제를 유효성분으로 포함하는 관절질환 예방 또는 치료용 약제학적 조성물 |
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- 2019-07-25 KR KR1020190089963A patent/KR102224999B1/ko active IP Right Grant
- 2019-07-25 EP EP19840735.5A patent/EP3827827A4/en not_active Withdrawn
- 2019-07-25 JP JP2021504305A patent/JP2021532144A/ja active Pending
- 2019-07-25 CA CA3107621A patent/CA3107621A1/en not_active Abandoned
- 2019-07-25 WO PCT/KR2019/009213 patent/WO2020022789A1/ko unknown
- 2019-07-25 CN CN201980062769.7A patent/CN112752576A/zh active Pending
- 2019-07-25 US US17/262,051 patent/US20210228548A1/en not_active Abandoned
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| US20040002526A1 (en) * | 2002-04-03 | 2004-01-01 | Cell Therapeutics, Inc. | Phospholipase D inhibitors and uses thereof |
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Also Published As
| Publication number | Publication date |
|---|---|
| EP3827827A1 (en) | 2021-06-02 |
| EP3827827A4 (en) | 2022-05-04 |
| WO2020022789A1 (ko) | 2020-01-30 |
| KR102224999B1 (ko) | 2021-03-10 |
| JP2021532144A (ja) | 2021-11-25 |
| CA3107621A1 (en) | 2020-01-30 |
| US20210228548A1 (en) | 2021-07-29 |
| KR20200011900A (ko) | 2020-02-04 |
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