CN114478464A - 一种炎症小体选择性抑制剂及其合成方法和应用 - Google Patents
一种炎症小体选择性抑制剂及其合成方法和应用 Download PDFInfo
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Abstract
本发明公开一种炎症小体选择性抑制剂及其合成方法和应用。其中炎症小体选择性抑制剂具有式I所示结构。本发明的抑制剂能够用于选择性抑制寡聚化核苷酸结合结构域样受体3炎症小体，从而治疗与NLRP3炎症小体激活相关的疾病，尤其是能够显著改善阿尔兹海默病模型小鼠的病理症状和多发性硬化症模型小鼠的临床症状。
Description
技术领域
本发明涉及生物医药领域，具体涉及一种炎症小体选择性抑制剂及其合成方法和应用。
背景技术
NOD样受体3(NOD-like receptor protein 3，NLRP3)是NLRP3炎症小体的关键受体，在炎症小体激活中发挥重要作用。NLRP3炎症小体的激活分为两步，病原相关模式分子先通过其模式识别受体激活核因子κB通路，促进炎症因子前体蛋白表达，然后再通过NLRP3复合体形成，招募胱天蛋白酶1切割这些前体蛋白，释放具有活性的炎症因子。NLRP3炎症小体激活将导致IL-1β和IL-18等促炎细胞因子表达和分泌增加，随之在多发性硬化症、炎症性肠病、阿尔兹海默病(Alzheimer’s disease,AD)、帕金森病和痛风等疾病的进展过程中发挥重要作用。
作为潜在的疾病干预靶点，至今已经开发了数种针对NLRP3炎症小体抑制剂。例如，中国专利申请CN113164763A、CN112424207A、CN111793011A等公开了各种对NLRP3炎症小体具有抑制作用的小分子制剂。不过，目前仍存在开发一种简单、高效、低成本的制备方法以及具有选择性抑制NLRP3炎症小体激活的抑制剂的需求。
背景技术中的信息仅仅在于说明本发明的总体背景，不应视为承认或以任何形式暗示这些信息构成本领域一般技术人员所公知的现有技术。
发明内容
为解决现有技术中的技术问题，本发明提供一种能够选择性抑制NLRP3炎症小体，进而治疗阿尔兹海默病、帕金森病、多发性硬化症的选择性抑制剂。具体地，本发明包括以下内容。
本发明的第一方面，提供式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药，
其中：
R1选自H、取代或未取代的C1-12烷基和苯基；
R2包括H或取代或未取代的C1-12烷基。
优选地，R1＝H，R2＝CH2CH3，或R1＝CH3，R2＝CH3，或R1＝C6H5，R2＝CH3或R1＝CH3，R2＝CH2CH3。
根据本发明所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药，优选地，所述R1和R2的基团相同或不同。
根据本发明所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药，优选地，其为(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼。
本发明的第二方面，提供根据第一方面所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药的制备方法，其包括以下步骤：
(1)使式II的化合物与水合肼在第一溶剂中反应，得到式III的第一中间体，
(2)原甲酸三乙酯或其类似物的醚键在第二溶剂中被酸催化剂活化，并与所述酸催化剂提供的氢离子结合脱去两分子的醇，并在水分子的参与下发生重排生成活性酯中间体，随后2,3,4三羟基苯甲醛中的4位，3位酚羟基中的氧原子在酸性条件下先后进攻活性酯中间体的碳正离子而脱去一分子的水生成五元缩酮类结构，得到式IV的第二中间体，
(3)使第一中间体和第二中间体在醇溶液中进行反应，得到所述化合物；
其中，所述R1和所述R2如本发明的第一方面所定义。
根据本发明所述的制备方法，优选地，所述第一溶剂包括醇溶剂，所述第二溶剂包括芳香族溶剂。
本发明的第三方面，提供一种药物组合物，其包括根据第一方面所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药以及任选的一种或多种药学上可接受的载体和/或赋形剂；
任选地，所述组合物进一步包含活性物质。
优选地，所述活性物质包括诊断剂、预防剂和/或治疗剂。
本发明的第四方面，提供根据第一方面所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药，或第三方面所述的药物组合物在制备用于治疗和/或预防与NLRP3炎症小体相关的疾病或病症的药物中的用途。
根据本发明所述的用途，优选地，与NLRP3炎症小体相关的疾病或病症包括：神经退行性疾病、神经炎症相关疾病、先天性免疫疾病和代谢炎症。
根据本发明所述的用途，优选地，与NLRP3炎症小体相关的疾病或病症包括：阿尔茨海默症疾病、帕金森、多发性硬化症、抑郁、痛风、类风湿性关节炎、炎症性肠病、肥胖、II型糖尿病和动脉粥样硬化。
本发明的第五方面，提供一种在有需要的受试者中选择性抑制NLRP3炎症小体的方法，其包括向有需要的受试者施用治疗有效量的第一方面所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药，或第三方面所述的药物组合物。
本发明公开了式1所示新化合物的合成方法，并发现式1所示化合物通过特异性抑制NLRP3炎症小体，进而发挥治疗阿尔兹海默病、帕金森病、多发性硬化症、炎症性肠病、视神经脊髓炎症和痛风的作用并显著改善相关的病理症状和临床症状。本发明的合成方法和抑制剂在用于改善其他NLRP3炎症小体介导的疾病同样具有广泛的应用前景。
附图说明
图1示例性的示出了(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼(Y1123)合成路径。
图2(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼(Y1123)选择性抑制NLRP3炎症小体激活。
图3(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼(Y1123)抑制AD模型小鼠病理进程。
图4(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼(Y1123)改善多发性硬化症模型小鼠临床症状。
具体实施方式
现详细说明本发明的多种示例性实施方式，该详细说明不应认为是对本发明的限制，而应理解为是对本发明的某些方面、特性和实施方案的更详细的描述。
应理解本发明中所述的术语仅仅是为描述特别的实施方式，并非用于限制本发明。另外，对于本发明中的数值范围，应理解为具体公开了该范围的上限和下限以及它们之间的每个中间值。在任何陈述值或陈述范围内的中间值以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本发明内。这些较小范围的上限和下限可独立地包括或排除在范围内。
除非另有说明，否则本文使用的所有技术和科学术语具有本发明所述领域的常规技术人员通常理解的相同含义。虽然本发明仅描述了优选的方法和材料，但是在本发明的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入，用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时，以本说明书的内容为准。除非另有说明，否则“％”为基于重量的百分数。
本领域技术人员可通过已知手段对本发明合成过程中得到的任何中间产物及目的化合物产物进行测定，测定方法包括但不限于高效液相色谱法(HPLC)、质谱法(MS)或气相色谱-质谱联用(GC-MS)法。并进一步通过例如1H、13C及多种二维核磁共振(NMR)技术对制备过程中任意化合物的分子结构进行表征。
用于制备的式(I)化合物以及中间体可根据各种熟知方法(例如结晶或层析法)来纯化及分离。
本发明的化合物可以以衍生自无机酸或有机酸的药学上可接受的盐的形式使用。术语“药学上可接受的盐”指在可靠的医学判断范围内，适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等，且与合理的效果/风险比相称的盐。药学上可接受的盐是本领域公知的。所述盐可通过使本发明化合物的游离碱官能度与合适的有机酸反应，在本发明化合物的最终分离和纯化过程中原位制备或者单独制备。代表性的酸加成盐包括但不限于乙酸盐、己二酸盐、海藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一烷酸盐。同样，碱性含氮基团可用以下物质季铵化：低级烷基卤化物如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物；硫酸二烷基酯如硫酸二甲酯、二乙酯、二丁酯和二戊酯；长链卤化物如癸基、十二烷基、十四烷基和十八烷基的氯化物、溴化物和碘化物；芳基烷基卤化物如苄基溴和苯乙基溴及其他。因此得到可溶于或分散于水或油的产品。可用来形成药学上可接受的酸加成盐的酸实例包括无机酸如盐酸、氢溴酸、硫酸和磷酸，以及有机酸如草酸、马来酸、琥珀酸和柠檬酸。
碱加成盐可通过使本发明化合物的含羧酸部分与合适的碱反应，在本发明化合物的最终分离和纯化过程中原位制备，所述的碱例如药学上可接受的金属阳离子的氢氧化物、碳酸盐和碳酸氢盐，或者氨或有机伯胺、仲胺或叔胺。
药学上可接受的盐还包括但不限于基于碱金属或碱土金属的阳离子如锂、钠、钾、钙、镁和铝盐等，以及无毒的季铵和胺阳离子，包括铵、四甲基铵、四乙基铵、甲基铵、二甲基铵、三甲基铵、三乙基铵、二乙基铵和乙基铵等。可用于形成碱加成盐的其他代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶、哌嗪等。
式(I)化合物的药物学上可接受的盐的制备方法不特别限定，例如可通过下述三个方法中之一或多种方法进行制备：
(i)通过使式(I)化合物与所需酸或碱反应；
(ii)使用所需酸或碱，通过源自式(I)化合物的适合前体去除酸或碱不稳定保护基或通过使适合环状前体(例如内酯或内酰胺)开环；或
(iii)通过使式(I)化合物的盐经由与合适酸或碱反应或借助于适合离子交换柱而转化为另一种盐。
本文所用术语“水合物、溶剂化物、异构体、络合物或前药”具有本领域通常理解的含义，旨在说明本发明的化合物能够以例如非晶型(无定型)、结晶、非溶剂化或溶剂化形式存在。
本文所用术语“前药”为药理学惰性的化学衍生物，可在体内转化成活性药物分子以发挥治疗作用。前药包括但不限于可氧化、还原、胺化、脱胺、羟基化、去羟基化、水解、脱水、烷基化、去烷基化、酰化、去酰化、磷酸化和/或去磷酸化以产生活性化合物的化合物。
术语“烷基”通常指碳链长度为1-12个碳原子的饱和的支链和直链烷基，优选1-10个碳原子，更优选1-8碳原子，进一步优选1-6个碳原子的烷基。代表性的烷基包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、(环己基)甲基、环丙基甲基、正戊基、正己基、正庚基、正辛基等。除非另外说明，否则术语“烷基”不包括“环烷基”。
除非另有说明，本文所用术语“取代的”指其所修饰的基团可任选地被1-5个(通常为1、2或3个)选自以下的取代基取代：C1-C4烷基、羧基、卤素、C1-C4烷氧基、氰基、硝基、氨基、羟基、醛基、C1-C6酰基、羟甲基、卤素取代的C1-C4烷基(例如三氟甲基)、C1-C10硫代烷基(例如五氟硫甲基)，C1-C10硫代烷氧基(例如五氟硫甲氧基)，卤素取代的C1-C4烷氧基(例如三氟甲氧基)、巯基和C1-C4酰基。
术语“基团”是指化合物的任何部分。
术语“抑制剂”是指抑制性分子，例如用于减少、阻断、预防、延迟活化、灭活、脱敏或下调例如基因、蛋白、配体、受体或细胞的分子。抑制剂也可定义为降低、阻断或抑制NLRP3炎症小体激活的分子。
术语“组合物”旨在包含指定量的各指定成分的产品，以及直接或间接从指定量的各指定成分的组合产生的任何产品。
除非另有说明，本文中所示的结构式中的构型、元素符号、短线、楔形实线和楔形虚线等具有本领域通常的定义。
式I化合物
本发明的式I化合物中，R1选自H、取代或未取代的C1-12烷基和苯基；R2为H或取代或未取代的C1-12烷基。优选地，R1和R2的基团相同或不同。进一步优选地，苯基为未取代的苯基。在一些实施方案中，R1＝R2＝CH2R3。在一些实施方案中，R1＝H，R2＝CH2R3。在一些实施方案中，R1＝C6H5，R2＝CH2R3。在一些实施方案中，R1＝CH2R3，R2＝H。优选地，R3为H或取代或未取代的C1-7烷基，优选为C1-6烷基，还优选为C1-4烷基。
合成方法
本发明的合成或制备方法包括步骤(1)-(3)，下面进行详细说明。
在步骤(1)中，使式II的化合物与水合肼在第一溶剂中反应，得到式III的第一中间体。优选地，所述第一溶剂为醇溶剂。还优选为低碳醇溶剂。醇溶剂的实例包括但不限于：甲醇、乙醇、正丙醇、2-丁醇、2-丙醇、2-丁醇和正丁醇。反应时间为24-72h，优选为48-72h。
在步骤(2)中，原甲酸三乙酯或其类似物的醚键在第二溶剂中被酸催化剂活化，并与酸催化剂提供的氢离子结合脱去两分子的醇，并在水分子的参与下发生重排生成活性酯中间体，随后2,3,4三羟基苯甲醛中的4位，3位酚羟基中的氧原子由于电子云密度较高在酸性条件下先后进攻活性酯中间体的碳正离子而脱去一分子的水生成五元缩酮类结构，得到式IV的第二中间体。所述第二溶剂为芳香族溶剂，芳香族溶剂的实例包括但不限于苯、甲苯和二甲苯。优选地，催化剂为对甲基苯磺酸。反应温度为100-150℃，优选为105-120℃。反应时间为15-30h，优选为16-25h。
在步骤(3)中，使第一中间体和第二中间体在醇溶液中进行反应，得到所述化合物。醇溶液优选甲醇溶液。优选地，第一中间体和第二中间体加入的重量比1-3:1，还优选为1.1-2.5:1，进一步优选为1.1-1.8:1。
在本发明的方法中，反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的，或者是可以通过文献公知的方法制得的，或者是可以通过商业购得的。反应路线中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以作适当改变的。或者，本领域技术人员也可以根据本发明所述方法合成本发明未具体列举的其它式I所示的(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼类衍生物。
本领域技术人员应理解，只要能够实现本发明的目的，在本发明制备方法步骤(1)-(3)前后，或步骤之间还可包含其他步骤或操作，例如纯化或醇溶液洗涤以提高产率的步骤，以及进一步优化和/或改善本发明所述的方法。
药物组合物
本发明提供的组合物包括本发明所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药以及任选的一种或多种药学上可接受的载体和/或赋形剂；
任选地，所述组合物进一步包含活性物质，优选地，活性物质为诊断剂、预防剂和/或治疗剂。其中治疗剂的实例包括但不限于：类法尼醇X受体(FXR)激动剂；抗脂肪变性剂；抗纤维化剂；JAK抑制剂；检查点抑制剂；降尿酸疗法；合成代谢剂和软骨再生疗法；IL-17的阻断剂；补体抑制剂；BTK抑制剂；Toll样受体抑制剂(TLR7/8抑制剂)；CAR-T治疗剂；抗高血压剂；降胆固醇剂；白三烯A4水解酶(LTAH4)抑制剂；SGLT2抑制剂；β2-激动剂；抗炎剂；非类固醇抗炎药(“NSAID”)；乙酰水杨酸药(ASA)；囊性纤维化治疗和动脉粥样硬化治疗剂。
药用辅料不特别限定，只要能够用于添加而形成有效、稳定和安全的制剂均可用于本发明的药物组合物。本发明的药物组合物，其药物制剂形式可以是任何可药用的剂型，这些剂型包括：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂。本发明的制剂，优选的是口服剂型，如：胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等。
本发明的药物组合物，其口服给药的制剂可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂包括，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于注射剂，制备的液体单位剂型含有本发明的药物组合物和无菌载体。根据载体和浓度，可以将药物组合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性，可在装入小瓶以后将这种药物组合物冰冻，并在真空下将水除去。
本发明的药物组合物，在制备成药剂时可选择性的加入适合的药物可接受的载体，所述药物可接受的载体选自：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
用途
本发明提供基于所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药，或所述的药物组合物的多种医药用途。
除非另有说明，本文所用术语“受试者”和“患者”在本文中互换地用于指可能需要本文描述的药物组合物或药物治疗和/或预防的任何动物。受试者和患者因此包括但不限于：灵长类动物(包括人类)、犬科动物、猫科动物、鼠和其它哺乳动物受试者。优选地，所述患者是人类。
在本发明中，术语“治疗”是指治疗性治疗和预防性或防治性措施，其目的是预防或减缓(减少)不期望发生的生理改变或紊乱，例如神经退行性疾病、神经炎症相关疾病、先天性免疫疾病和代谢炎症的进程。有益的或期望的临床结果包括但不限于以下无论是可检测还是不可检测的结果，包括症状的缓解、疾病程度的减小、疾病状态的稳定(即不恶化)、疾病进展的延迟或减缓、疾病状态的改善或缓和以及减轻(无论是部分还是全部)。“治疗”还意指与不接受治疗时预期的生存期限相比所延长的生存期限。需要治疗的包括那些已经患有病症或紊乱的人，以及那些容易患有病症或紊乱的人，或者那些需要预防该病症或紊乱的人。
本文所用术语“预防”包括避免疾病、病症或紊乱的发生和/或延迟疾病、病症或紊乱的发作。如通过受控临床试验测量的任何统计学显著(p≤0.05)的发生避免、发作延迟或风险降低均可被视为疾病、病症或微乱的预防。适合预防的受试者包括如通过遗传或生物化学标记物所鉴定疾病、病症或紊乱的风险加重的那些受试者。典型地，遗传或生物化学标记物适用于所考虑的疾病、病症或疾患并且可包括(例如)炎症性生物标记物，如在炎症的情况下的C反应蛋白(CRP)和单核细胞趋化蛋白1(MCP 1)；在NAFLD和NASH的情况下的总胆固醇、甘油三酯、胰岛素抗性和C肽、对NLRP3抑制有响应的IL 1β和IL 18。
本文所用术语“有效量”表示引发例如研究者或临床医师所追求的组织、系统、动物或人的生物学或药学响应的药物或药剂的量。此外，术语“治疗有效量”表示与没有接受该量的相应受试者相比，引起疾病、病症或副作用的改进治疗、治愈、预防或减轻的量，或者使疾病或病况的进展速率降低的量。该术语在其范围内还包括有效增强正常生理功能的量。通常，本文中的有效量根据各种因素而变化，所述因素例如给定的药物或化合物、药学制剂、给药途径、疾病或病症的类型、被治疗的受试者等等，但仍然可以由本领域技术人员常规地确定。本发明的化合物或其药物组合物的有效量可以由本领域技术人员通过本领域已知的常规方法容易地确定。一般说来，本发明式I化合物用于哺乳动物，特别是人的剂量可以为0.001-1000mg/kg体重/天，例如0.01-100mg/kg体重/天、0.01-10mg/kg体重/天。
术语“施用”与“给予”可互换用于在将本发明的化合物、包含其的药物组合物应用至例如受试者、细胞、组织、器官或生物流体时，其与所述受试者、细胞、组织、器官或生物流体接触。在细胞的情况下，施用包括使本发明的化合物、包含其的药物组合物与细胞(例如，体外或离体)接触以及使本发明的化合物、包含其的药物组合物与流体接触，其中所述流体与细胞接触。
本发明中，疾病、病症或紊乱可以是免疫系统、心血管系统、内分泌系统、胃肠道、肾系统、肝系统、代谢系统、呼吸系统、中枢神经系统相关的疾病、病症或紊乱，也可以是癌症或其他恶性肿瘤。
本发明中，所述疾病、病症或紊乱对NLRP3抑制有响应。术语“NLRP3抑制”是指完全或部分降低NLRP3的活性水平并且包括例如抑制活性NLRP3和/或抑制NLRP3的活化。
实施例1
本实施例为(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼(Y1123)的合成，包括以下步骤：
按照图1合成路径，依次合成中间体IM1和IM2，最后合成终产物(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼盐酸盐，具体路线及结果如下：
1.化合物IM1制备
盐酸丝氨酸甲酯与水合肼在甲醇溶剂中反应2天，有白色固体析出，得化合物IM1。1HNMR(400MHz,D2O)δ3.83(dt,J＝5.6,4.1Hz,1H),3.74–3.73(m,1H),3.71–3.70(m,1H),3.68(d,J＝0.6Hz,1H),3.67(d,J＝0.6Hz,1H),3.65(d,J＝0.6Hz,1H),3.64(d,J＝0.6Hz,1H)。
2.化合物IM2制备
将原甲酸三乙酯倒入50ml甲苯中，称取0.1倍对甲基苯磺酸一水合物作为催化剂在110℃回流30min，加入2,3,4三羟基苯甲醛(40mmol)于反应瓶中继续在惰性气体中回流19h，抽滤，将上清旋蒸拌样，过柱分离(PE:EtoAc＝30:1)得白色固体，洗涤，干燥，称重，得化合物IM2。1H NMR(600MHz,CDCl3)δ11.03–10.92(m,1H),9.73(d,J＝22.0Hz,1H),7.21–7.17(m,1H),6.99(s,1H),6.73–6.62(m,1H),3.82–3.72(m,2H),1.47–1.06(m,3H)。
3.化合物Y1123制备
投入2.1g的IM2(10mmol)与1.56g的盐酸丝氨酰肼在甲醇溶液(20ml)中缩合，室温搅拌1天，反应随时间增加由淡黄色透明溶液变为白色浑浊溶液，有白色固体析出。反应后处理：过滤，使用甲醇洗涤，过滤的母液进行重结晶，固体称重为0.9g，收率为30.4％。得化合物Y1123。1H NMR(600MHz,DMSO)δ8.53–8.04(m,1H),7.32(t,J＝19.5Hz,1H),7.23–7.00(m,1H),6.65(dd,J＝28.0,8.3Hz,1H),5.58(dd,J＝26.9,21.9Hz,1H),4.07–3.51(m,1H),3.33(s,2H),1.39–0.94(m,3H)。
实施例2
本实施例示出了(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼(Y1123)抑制NLRP3炎症小体激活，具体如下。
巨噬细胞接种至24孔细胞培养板，分为8组(组1、组2、组3、组4、组5、组6、组7、组8)，每组3个重复孔。组1为对照组，加入药物等体积生理盐水；组2为Y1123单加药组，加入Y1123至终浓度为100μM；剩余6组加入磷酸脂多糖(LPS，Sigma-Aldrich)，同时，组1、组3、组5和组7加入1μl DMSO，组2、组4、组6和组8加入终浓度分别为100μM的Y1123，细胞继续培养3.5h后，组5和组6加入ATP至终浓度为5mM，组7和组8加入尼日利亚菌素(Nig)至终浓度为5μM，再继续培养45min，收集细胞培养上清，低速离心(1000xg)去除细胞碎片后，通过酶联免疫吸附试验(ELISA)检测上清中的IL-1β和TNF-α浓度。
ELISA实验步骤(按照说明书操作，购自Biolegend公司)：
①根据待测样品数量和标准品的数量决定所需的板条数，并增加1孔作为空白对照孔。分别将标本和不同浓度标准品(100μl/孔)加入相应孔中(零孔只加标准品/样本稀释液)，用封板胶纸封住反应孔，37℃孵箱孵育90分钟(空白对照孔除外)。
②洗板4次：(1)自动洗板机：要求注入的洗涤液为350μl，注入与吸出间隔15-30秒。(2)手工洗板：甩尽孔内液体，每孔加洗涤液350μl，静置30秒后甩尽液体，在厚迭吸水纸上拍干。
③加入生物素化抗体工作液(100μl/孔)。用封板胶纸封住反应孔，37℃孵箱孵育60分钟(空白对照孔除外)。
④洗板4次。
⑤加入酶结合物工作液(100μl/孔)。用封板胶纸封住反应孔，37℃孵箱孵育30分钟(空白对照孔除外)。
⑥洗板4次。
⑦加入显色剂100μl/孔，避光，37℃孵箱孵育5-10分钟。
⑧加入终止液100μl/孔，混匀后即刻测量OD450值(5分钟内)
检测结果图2所示，其中图2A：Y1123抑制LPS+ATP及LPS+Nig诱导的NLRP3炎症小体激活；图2B：Y1123对TNF-α的表达及释放无显著影响。加入LPS和ATP，以及加入LPS和Nig均可通过激活NLRP3炎症小体，促进IL-1β释放；再加入Y1123则可以显著抑制IL-1β的释放，且对两种激活模式导致的IL-1β释放均有显著抑制作用。但是，无论在哪种刺激条件性，Y1123对TNF-α的释放均无显著影响，该结果表明Y1123仅选择性抑制NLRP3炎症小体激活，而对LPS激活的其它炎症反应无抑制作用。
实施例3
本实施例示出了(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼(Y1123)抑制AD模型小鼠淀粉样斑块沉积，具体如下。
取5×FAD小鼠36只，随机分为3组，分别为5×FAD对照组、5×FAD+Y1123(100mg/kg)和5×FAD+Y1123(50mg/kg)；野生型小鼠(C57BL/6J)12只(5×FAD小鼠为C57BL/6和SJL杂交背景，其它SPF级C57BL/6J小鼠购于斯贝福公司)。所有小鼠饲养于23℃，12h昼夜周期节律，水和粮食自由获取的动物房中。
在5×FAD小鼠90天时给药，连续60天按上述剂量灌胃给药，每天一次。之后，将上述小鼠处死取脑组织，4％多聚甲醛固定脑组织24。然后用30％蔗糖脱水处理24h，之后用冰冻切片机将鼠脑切成40μm的冠状切片，放入磷酸盐缓冲液中。然后每只小鼠挑5张切片(各鼠之间脑片在大脑中的位置一致)，用硫黄素S染色(TS)进行淀粉样蛋白斑块染色。TS是一种特异性结合Aβ斑块的染料。
TS染色步骤为：将脑片用0.002％TS(溶于50％的乙醇)避光染色8min，50％的乙醇洗2次，PBS洗3次。然后将脑片平贴至载玻片，并用抗荧光猝灭剂进行封片，然后通过激光共聚焦显微镜进行图像采集。最后用图像分析软件ImageJ进行淀粉样斑块数量统计。
结果如图3所示，图3A：Y1123抑制AD模型小鼠病理进程。A：TS染色检测淀粉样蛋白斑块；图3B：A图对应统计分析结果。给予Y1123可以显著抑制AD模型小鼠大脑皮层和海马等脑区淀粉样斑块沉积，表明Y1123可以延缓AD模型小鼠病理进程。
实施例4
本实施例示出了(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼(Y1123)改善多发性硬化症模型小鼠的临床症状，具体如下。
1.准备体重约16g雌鼠(品系C57，年龄6-8周，购自维通利华)40只，随机分为2组，每组20只。
2.EAE模型准备：一组为非模型组，另一组为模型组。模型制备方式为：小鼠皮下注射100μl乳化均匀的MOG35-55多肽与弗氏完全佐剂，其中MOG35-55多肽终浓度为2mg/ml，并于当天及第48h时各注射一次百日咳毒素(pertussis toxin，PT)(货号181，ListLab)。记录每天体重并进行临床评分，评分标准分为以下五个级别：1分，尾巴瘫痪；2分，尾巴及单后肢瘫痪；3分，尾巴及双后肢瘫痪；4分，尾巴及双后肢瘫痪，并伴有脊柱弯曲变形；5分，小鼠死亡。
3.给药：考虑到小鼠将于造模第10天开始陆陆续续发病，所以本实施例中，于造模后第5天开始给药。将非模型组和模型组分别再随机各分为两组，共4组小鼠：溶剂对照组，单纯给药组，溶剂模型组，给药模型组。给药方式为将Y1123用蒸馏水配制为10mg/ml，然后给药组及给药模型组每只每天灌胃给药100μl，溶剂对照组及溶剂模型组每只每天灌胃100μl生理盐水。继续记录每日体重与临床评分，直至造模后第30天。
结果如图4所示，溶剂对照组和单纯给药组均未发病，临床评分一直为0。溶剂模型组及给药模型组在第9天开始陆续发病，并于发病后第16天开始达到高峰。给药模型组在给予Y1123之后，临床评分显著低于溶剂模型组，并且恢复速度显著快于溶剂模型组。这些结果表明Y1123对于改善多发性硬化症模型小鼠的临床症状显著。
尽管已经参考示例性实施方案对本发明进行了描述，但应理解本发明不限于公开的示例性实施方案。在不背离本发明的范围或精神的情况下，可对示例性实施方案做多种调整或变化。本发明的范围应基于最宽的解释以涵盖所有修改和等同结构与功能。
Claims (10)
1.一种式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药，其特征在于，
其中：
R1＝H，R2＝CH2CH3，或R1＝CH3，R2＝CH3，或R1＝C6H5，R2＝CH3或R1＝CH3，R2＝CH2CH3。
2.根据权利要求1所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药，其特征在于，所述R1和R2的基团相同或不同。
3.根据权利要求2所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药，其特征在于，其为(E)-2-氨基-N-((2-乙氧基-4-羟基苯并[d][1,3]二氧杂环戊二醇基)亚甲基)-3-羟基丙酰肼。
4.根据权利要求1-3任一项所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药的制备方法，其特征在于，包括以下步骤：
(1)使式II的化合物与水合肼在第一溶剂中反应，得到式III的第一中间体，
(2)原甲酸三乙酯或其类似物的醚键在第二溶剂中被酸催化剂活化，并与所述酸催化剂提供的氢离子结合脱去两分子的醇，并在水分子的参与下发生重排生成活性酯中间体，随后2,3,4三羟基苯甲醛在酸性条件下先后进攻所述活性酯中间体的碳正离子而脱去一分子的水生成五元缩酮类结构，得到式IV的第二中间体，
(3)使所述第一中间体和所述第二中间体在醇溶液中进行反应，得到所述式I化合物。
5.根据权利要求4所述的制备方法，其特征在于，所述第一溶剂包括醇溶剂，所述第二溶剂包括芳香族溶剂。
6.一种药物组合物，其特征在于，其包括根据权利要求1-3任一项所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药以及任选的一种或多种药学上可接受的载体和/或赋形剂；
优选地，所述组合物进一步包含活性物质；
优选地，活性物质包括诊断剂、预防剂和/或治疗剂。
7.根据权利要求1-3任一项所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药在制备用于治疗和/或预防与NLRP3炎症小体相关的疾病或病症的药物中的用途。
8.根据权利要求7所述的用途，其特征在于，与NLRP3炎症小体相关的疾病或病症包括：神经退行性疾病、神经炎症相关疾病、先天性免疫疾病和代谢炎症。
9.根据权利要求8所述的用途，其特征在于，与NLRP3炎症小体相关的疾病或病症包括：阿尔茨海默症疾病、帕金森、多发性硬化症、抑郁、痛风、类风湿性关节炎、炎症性肠病、肥胖、II型糖尿病和动脉粥样硬化。
10.一种在有需要的受试者中选择性抑制NLRP3炎症小体的方法，其特征在于，包括向有需要的受试者施用治疗有效量的权利要求1-3任一项所述的式I化合物，或其药学上可接受的盐、水合物、溶剂化物、异构体、络合物或前药，或权利要求6所述的药物组合物。
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| CN111253327A (zh) * | 2018-12-03 | 2020-06-09 | 中国医学科学院基础医学研究所 | 羧胺三唑类化合物或其盐在制备治疗nlrp3炎症小体活化相关疾病的药物中的应用 |
| CN111848461A (zh) * | 2019-04-29 | 2020-10-30 | 苏州大学 | Nlrp3炎症小体抑制剂及其制备方法和应用 |
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| CN111253327A (zh) * | 2018-12-03 | 2020-06-09 | 中国医学科学院基础医学研究所 | 羧胺三唑类化合物或其盐在制备治疗nlrp3炎症小体活化相关疾病的药物中的应用 |
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