CN111067889B - 2-甲基萘并[1,2-b]呋喃类化合物在制备与糖尿病肾病有关药物方面的应用 - Google Patents
2-甲基萘并[1,2-b]呋喃类化合物在制备与糖尿病肾病有关药物方面的应用 Download PDFInfo
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- CN111067889B CN111067889B CN201911119378.2A CN201911119378A CN111067889B CN 111067889 B CN111067889 B CN 111067889B CN 201911119378 A CN201911119378 A CN 201911119378A CN 111067889 B CN111067889 B CN 111067889B
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- 239000003814 drug Substances 0.000 title claims abstract description 14
- 208000007342 Diabetic Nephropathies Diseases 0.000 title abstract description 24
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- 238000002360 preparation method Methods 0.000 title abstract description 8
- -1 2-methyl naphtho [1,2-b ] furan compound Chemical class 0.000 title description 40
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- 239000004480 active ingredient Substances 0.000 claims description 6
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Abstract
本发明涉及一类2‑甲基萘并[1,2‑b]呋喃类化合物在制备与糖尿病肾病有关药物方面的应用，属于药物化学和药物治疗学领域，该类化合物对Sirt1酶具有明显的酶激活作用。本发明提供的式I所示的化合物，异构体或其药学上可接受的盐可应用在制备与糖尿病肾病有关药物方面。
Description
技术领域
本发明涉及药物化学和药物治疗学领域，具体涉及2-甲基萘并[1,2-b]呋喃类化合物在制备与糖尿病肾病有关药物方面的应用，特别是与Sirt1激活剂有关的药物方面的应用。
背景技术
糖尿病肾病(diabetic nephropathy,DN)是糖尿病主要并发症之一，是终末期肾病的主要原因，其较高的致死致残率给糖尿病患者和社会带来严重危害。寻找防治DN的新药物已成为世界范围内的研究热点。沉默信息调节因子1(silent information regulator1，S irt1)与DN的发生发展密切相关，Sirt1可通过促进高糖环境下肾脏细胞能量稳态重建、调节DN发病过程中的氧化应激状态、抵抗肾脏细胞凋亡、抑制肾脏炎症反应、改善肾脏纤维化等作用，阻止DN发生和发展，Sirt1已成为防治DN的新靶点。
Sirt1是一种依赖于烟酰胺腺嘌呤二核苷酸(NAD+)的去乙酰化酶，为Sirtuins家族7种去乙酰化酶中研究最多的一种酶。Sirt1可通过多个信号通路调节在高糖环境下受损的肾脏细胞功能，促进其恢复能量代谢稳态，并且调节损伤信号共同导致的纤维化与坏死，表现出肾保护作用。高糖诱导下的氧化应激和炎症反应是DN的中心环节和主要病理生理机制。氧化应激可通过激活多条信号通路，包括晚期糖基化、PKC通路、多元醇通路等，介导DN的发生和发展，因此改善DN的氧化应激状态至关重要。研究表明，Sirt1的激活不仅可以抑制氧化应激的产生，还可促进细胞内还原系统的激活。有文献报道Sirt1可通过p53、FOXOs和TGF-β等多个途径，调节信号转导，改善由氧化应激介导的肾脏细胞的凋亡与坏死。炎症是DN持续发展的关键因素，DN时肾组织中分泌大量的炎症因子，导致ECM沉积，肾小球损伤，蛋白尿漏出。研究表明，Sirt1可通过去乙酰化组蛋白以及NF-κB和AP-1等重要转录因子，抑制下游相关炎症因子基因表达，改善DN的炎症反应。以上结果充分表明，激活Sirt1可以拮抗高糖诱导引起的细胞损伤，从而发挥其对DN的防治作用。
目前，已有多种类型的Sirt1激动剂被报道出来，其中包括多个天然产物，如白芦藜醇及其衍生物、查尔酮类、黄酮类和二苯乙烯葡萄糖苷类等。这些天然产物Sirt1激动活性均不高。而一些小分子实体化合物如SRT2183，SRT1460和SRT1720等虽属于较强的Sirt1激动剂，在细胞或者动物水平上也可以显著减轻DN的相关症状，但多数化合物尚处于早期开发阶段，其激动活性有待于进一步提高。因此，亟需开发出更多结构新颖的高活性Sirt1激动剂。
发明内容
本发明的目的是在现有技术的基础上，提供一类2-甲基萘并[1,2-b]呋喃类化合物在制备与糖尿病肾病有关药物方面的应用，该类化合物对Sirt1酶具有明显的酶激活作用。
本发明提供的上述2-甲基萘并[1,2-b]呋喃类化合物，具有良好的Sirt1激动活性，可以用于制备与糖尿病肾病有关的药物。
本发明的另一个目的是提供一种药物组合物，它以上述提及的化合物、异构体或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的载体。
本发明的技术方案如下：
式I所示的化合物、异构体，或其药学上可接受的盐在制备与糖尿病肾病有关药物方面的应用，
其中，
R1代表C1-C10烷基、C1-C6羟基烷基、C1-C4烷基烷氧基、C1-C4氨基烷基、C1-C4卤代烷基、C1-C4醚基、苯基、取代苯基、苄基或取代苄基，所述的取代苯基或取代苄基可任意地由下述取代基单取代或多取代：羟基、硝基、羧基、氰基、氨基、卤素、C1-C4烷基、C1-C4烷氧基；
R2代表C1-C4烷基、苯基、取代苯基、喹啉、取代喹啉、萘基、取代萘基、噻吩、取代噻吩、苄基或取代苄基、联苯基、呋喃、吡咯、吡啶、噻唑、哌啶、吗啉、吲哚，所述的取代苯基、取代喹啉、取代萘基、取代噻吩或取代苄基可任意地由下述取代基单取代或多取代：羟基、硝基、羧基、氰基、氨基、卤素、C1-C4烷基、C1-C4烷氧基。
在一种优选方案中，R1代表C1-C8烷基、C1-C4羟基烷基、C1-C4烷基烷氧基、苯基、取代苯基、苄基或取代苄基，所述的取代苯基或取代苄基可任意地由下述取代基单取代或多取代：羟基、氟、溴、C1-C4烷基、C1-C4烷氧基。
在一种更优选方案中，R1代表C1-C8烷基、4-羟基丁基、3-羟丙基、2-羟乙基、2-甲氧基乙基、2-乙氧基乙基、3-甲氧基丙基、苯基、苄基、取代苯基或取代苄基，所述的取代苯基或取代苄基可任意地由下述取代基单取代或多取代：羟基、氟、溴、甲基、乙基、甲氧基、乙氧基。
在一种特别优选方案中，R1代表C1-C8烷基、4-羟基丁基、3-羟丙基、2-羟乙基、2-甲氧基乙基、苯基或苄基。
在一种优选方案中，R2代表苯基、取代苯基、喹啉、取代喹啉、萘基、取代萘基、噻吩、取代噻吩、呋喃、吡咯、吡啶、噻唑、哌啶、吗啉、吲哚，所述的取代苯基、取代喹啉、取代噻吩或取代萘基可任意地由下述取代基单取代或多取代：羟基、氨基、卤素、C1-C4烷基、C1-C4烷氧基。
在一种更优选方案中，R2代表苯基、取代苯基、萘基、喹啉、噻吩、呋喃、吡咯、吡啶、噻唑、哌啶、吗啉、吲哚，所述的取代苯基可任意地由下述取代基单取代或多取代：羟基、氨基、氟、溴、甲基、乙基、丙基、叔丁基、甲氧基、乙氧基。
在一种特别优选方案中，R2代表苯基、取代苯基、萘基、喹啉、噻吩，所述的取代苯基可任意地由下述取代基单取代或多取代：羟基、氨基、氟、溴、甲基、乙基、丙基、叔丁基、甲氧基、乙氧基。
进一步地，式I所示的化合物、异构体，或其药学上可接受的盐中，所述化合物选自下列化合物：
本发明提供的上述化合物的命名如下：
Y1化合物命名:5-(4-乙基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸异丙酯
Y2化合物命名:5-(4-(叔丁基)苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸2-甲氧基乙酯
Y3化合物命名:5-(2,4-二甲基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸2-甲氧基乙酯
Y4化合物命名:2-甲基-5-(2,4,6-三甲基苯基磺酰胺基)萘并[1,2-b]呋喃-3-羧酸2-甲氧基乙酯
Y5化合物命名:5-(4-溴苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸2-甲氧基乙酯
Y6化合物命名:5-(4-乙基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸2-甲氧基乙酯
Y7化合物命名:5-(2,5-二甲基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸2-甲氧基乙酯
Y8化合物命名：2-甲基-5-(4-甲基苯基磺酰胺基)萘并[1,2-b]呋喃-3-羧酸2-甲氧基乙酯
Y9化合物命名：2-甲基-5-(苯基磺酰胺基)萘并[1,2-b]呋喃-3-羧酸辛酯
Y10化合物命名：5-(4-甲氧基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸戊酯
Y11化合物命名：5-(4-乙氧基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸戊酯
Y12化合物命名：5-(2,4-二甲基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸戊酯
Y13化合物命名：5-(4-氟苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸戊酯
Y14化合物命名：5-(4-溴苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸戊酯
Y15化合物命名：5-(2,5-二甲基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸戊酯
Y16化合物命名：2-甲基-5-(萘-2-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸戊酯
Y17化合物命名：5-(4-氟苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸丁酯
Y18化合物命名：5-(2,5-二甲基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸丁酯
Y19化合物命名：5-(4-乙基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸丁酯
Y20化合物命名：5-(4-甲氧基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸丁酯
Y21化合物命名：2-甲基-5-(4-甲基苯基磺酰胺基)萘并[1,2-b]呋喃-3-羧酸庚酯
Y22化合物命名：5-(4-乙基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸庚酯
Y23化合物命名：5-(4-甲氧基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸庚酯
Y24化合物命名:2-甲基-5-(苯基磺酰胺基)萘并[1,2-b]呋喃-3-羧酸庚酯
Y25化合物命名：5-(4-乙氧基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸丙酯
Y26化合物命名：2-甲基-5-(4-甲基苯基磺酰胺基)萘并[1,2-b]呋喃-3-羧酸苄酯
Y27化合物命名：2-甲基-5-(萘-2-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸甲酯
Y28化合物命名：2-甲基-5-(2,4,5-三甲基苯磺酰胺基)萘并[1,2-b]呋喃-3-羧酸2-甲氧基乙酯
Y29化合物命名：2-甲基-5-(2,4,5-三甲基苯基磺酰胺基)萘并[1,2-b]呋喃-3-羧酸戊酯
Y30化合物命名：2-甲基-5-(2,4,5-三甲基苯基磺酰氨基)萘并[1,2-b]呋喃-3-羧酸丁酯
Y31化合物命名：2-甲基-5-(噻吩-2-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸丁酯
Y32化合物命名：5-(2,5-二甲氧基苯基磺酰胺基)-2-甲基萘并[1,2-b]呋喃-3-羧酸丁酯
Y33化合物命名：2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸丁酯
Y34化合物命名：2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸4-羟基丁酯
Y35化合物命名：2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸丙酯
Y36化合物命名：2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸3-羟基丙酯
Y37：2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸乙酯
Y38化合物命名：2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸2-羟基乙酯
Y39化合物命名：2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸甲酯
具体地讲，通式I所述化合物进一步优选自下列化合物：
更具体地讲，通式I所述化合物进一步更优选自下列化合物：
本发明公开了当R2代表喹啉时，通式I所示化合物的合成路线如下：
该路线的具体制备方法包括如下步骤：
将4-氨基-1-萘酚(1)与喹啉-8-磺酰氯(2)反应得N-(4-羟基萘-1-基)喹啉-8-磺酰胺(3)，化合物(3)与重铬酸钾(K2Cr2O7)在乙酸中反应生成(E)-N-(4-氧代萘-1(4H)-亚烷基)喹啉-8-磺酰胺(4)，在有机溶剂中化合物(4)与乙酰乙酸乙酯(5)反应12小时，采用的温度是65℃回流，生成2-(1-羟基-4-(喹啉-8-磺酰胺基)萘-2-基)-3-氧代丁酸乙酯(6)，化合物(6)与硫酸在乙酸条件下反应生成2-甲基-5-(喹啉-8-磺酰胺基)萘[1,2-b]呋喃-3-羧酸乙酯(7)，在有机溶剂中化合物(7)与氢氧化钠在65℃下回流12h，生成2-甲基-5-(喹啉-8-磺酰胺基)萘[1,2-b]呋喃-3-羧酸(8)，化合物(8)与醇类化合物在酸性条件下冷凝回流15小时，反应生成通式I所示目标化合物Y33-39，具体合成路线如下：
本发明提供的上述化合物、异构体或其药学上可接受的盐在制备与糖尿病肾病有关药物方面的应用。
在一种优选方案中，本发明提供了一种药物组合物，它以本发明的化合物、异构体或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的载体。进一步的，该药物组合物可以制成液体制剂或固体制剂。更进一步的，该药物组合物可以制成注射剂、口服液、颗粒剂、片剂、粉剂或胶囊剂。
除非另外说明，在说明书和权利要求中使用的以下术语具有下面讨论的含义：
“烷基”表示1-20个碳原子的饱和的脂烃基，包括直链和支链基团(本申请书中提到的数字范围，例如“1-20”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括20个碳原子)。含1-4个碳原子的烷基称为低级烷基。当低级烷基没有取代基时，称其为未取代的低级烷基。更优选的是，烷基是有1-6个碳原子的中等大小的烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。最好是，烷基为有1-4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。当是取代的烷基时，该取代基优选是一或多个，更优选1-3个，最优选1或2个取代基。
“卤代烷基”表示卤素取代的烷基，优选如上所定义的卤素取代的低级烷基，它被一个或多个相同或不同的卤原子取代，例如-CH2Cl、-CF3、-CH2CF3、-CH2CCl3等。
“卤素”表示氟、氯、溴或碘，优选为氟或氯。
“羟基”表示-OH基团。
“氰基”表示-CN基团。
“硝基”表示-NO2基团。
“羧基”表示-COOH基团。
“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“羟基烷基”表示氨基取代的烷基，优选如上所定义的羟基取代的低级烷基，它被一个或多个相同或不同的羟基取代，例如-CH2 CH2-OH、-CH2 CH2 CH2-OH等。
“氨基烷基”表示氨基取代的烷基，优选如上所定义的氨基取代的低级烷基，它被一个或多个相同或不同的氨基取代，例如-CH2NH2、-CH2 NH2、-CH2 C H2 NH2等。
“烷基烷氧基”表示烷基上的至少一个氢为烷氧基取代的基团，例如20甲氨基乙基、2-乙氧基乙基、3-甲氧基丙基等。
“醚基”表示-R-O-R’基团，其中R或R’是选自以下基团：氢、未取代的低级烷基、三卤甲基、未取代的环烷基，可选地被一或多个、优选被1、2或3个选自未取代的低级烷基、三卤甲基、未取代的低级烷氧基取代。
“杂脂环基”表示单环或稠合环基团，在环中具有5到9个环原子，其中一个或两个环原子是选自N、O或S(O)m(其中m是0至2的整数)的杂原子，其余环原子是C。这些环可以具有一条或多条双键，但这些环不具有完全共轭的π电子系统。未取代的杂脂环基的非限制性实例有吡咯烷基、哌啶子基、哌嗪子基、吗啉代基等。
“药学上可接受的盐”表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、三氟乙酸、丙酸、丙烯酸、己酸、环戊烷丙酸、羟乙酸、丙酮酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、苯甲酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、肉桂酸、十二烷基硫酸、葡糖酸、谷氨酸、天冬氨酸、硬脂酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属离子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺、奎宁等。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分，例如药学上可接受的载体，混合。药物组合物的目的是促进给药给动物的过程。
采用本发明的技术方案，优势如下:
本发明提供的一类2-甲基萘并[1,2-b]呋喃类化合物对Sirt1酶具有明显的酶激活作用，具有良好的Sirt1激动活性，可以用于制备与糖尿病肾病有关的药物。
具体实施方式
为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
实施例1
2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸丁酯(Y33)
4-氨基-1-萘酚(1g，1e.q)溶于吡啶(30.14ml，62e.q)中，冰浴冷却至0℃，缓慢滴加DCM溶解的喹啉-8-磺酰氯(1.43g，1e.q)，搅拌反应3h后，依次用1N HCl/EA、蒸馏水/EA、饱和食盐水/EA洗涤后，有机层用无水硫酸钠干燥，过滤，减压去除溶剂后得白色固体N-(4-羟基萘-1-基)喹啉-8-磺酰胺(1.58g,71.7％)。加入乙酸(8.41ml，0.33e.q)溶解K2Cr2O7(335.8mg，0.8e.q)，在20℃条件下搅拌1h，再加入N-(4-羟基萘-1-基)喹啉-8-磺酰胺(500mg，1e.q)，混合液在20℃条件下搅拌2.5h。然后用水/DCM萃取，有机层再用水洗涤两次，用无水硫酸钠干燥，过滤，减压去除溶剂后得黄色固体(E)-N-(4-氧代萘-1(4H)-亚烷基)喹啉-8-磺酰胺(493.8g,99％)。(E)-N-(4-氧代萘-1(4H)-亚烷基)喹啉-8-磺酰胺(483mg，1e.q)和乙酰乙酸乙酯(192.69μl，1.1e.q)混合，加入适量的1，4-二氧六环，在25℃下搅拌5min，然后再加入甲醇钠(14.15mg，0.15e.q)。混合物在25℃条件下连续反应30min，然后过滤并真空浓缩以除去溶剂，并用甲基环己烷少量多次加入并旋干，以除去1,4-二氧六环，将所形成的油状物溶于乙醇并浓缩旋干，得到褐色固体2-(1-羟基-4-(喹啉-8-磺酰胺基)萘-2-基)-3-氧代丁酸乙酯(364.89mg，55％)。用乙酸(2.524ml，30.84e.q)溶解2-(1-羟基-4-(喹啉-8-磺酰胺基)萘-2-基)-3-氧代丁酸乙酯(685mg，1e.q)，缓慢加入H2SO4(189.5μl，2.2e.q)，混合液在117℃下冷凝回流30min，然后倒入冰水中，用碳酸钠调节pH至中性，水溶液用二氯甲烷萃取，有机层用无水硫酸钠干燥并浓缩旋干，得到中间体褐色固体2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸乙酯(509mg，77.41％)。在2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸乙酯(500mg，1e.q)的甲醇溶液中，加入氢氧化钠(3.3ml，84e.q)溶液，将反应在65℃下反应12h。将反应液浓缩以除去甲醇(50℃)，用盐酸(2N)将残余物(可加水溶解)酸化至pH＝3，抽滤，烘干，得到黄色固体2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸(389.2mg，82.89％)。将2-甲基-5-(喹啉-8-磺酰胺基)萘[1,2-b]呋喃-3-羧酸(100mg，1e.q)溶解在乙醇(1122.56μl)中。在0.5小时内向混合物中滴加硫(15.3μl)。滴加后，冷凝回流15小时。在大气压下蒸馏除去乙醇，滴加水溶解固体。向该悬浊液中加入氢氧化钠水溶液并将pH调节至6.5，过滤析出固体，固体用水多次洗涤后烘干成白色粉末固体(45mg,43％)。
m.p.191.8-192.9℃；
ESI-MS:m/z 447.1[M+H]+.
1H-NMR(400MHz,CDCl3)δ9.24(d,J＝4.1Hz,1H),8.58(s,1H),8.48(d,J＝8.8Hz,1H),8.38(d,J＝8.4Hz,1H),8.26(d,J＝7.2Hz,1H),8.15(d,J＝8Hz,1H),8.07(d,J＝8Hz,1H),7.68(q,J＝4.1Hz,1H),7.59-7.57(m,1H),7.56-7.54(m,1H),7.53-7.48(m,1H),7.14(s,1H),3.57(s,3H),2.74(s,3H)；13C NMR(100MHz,DMSO)δ164.36,163.13,151.64,148.10,143.51,137.33,135.97,133.43,131.72,129.23,128.97,127.18,126.04,124.95,122.47,121.14,120.74,119.79,116.95,109.81，51.02，14.40。
实施例2
2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸4-羟基丁基酯(Y34)
按实施例1的类似方法，使用2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸(140mg，1e.q)、1,4-丁二醇(3442.5μl)滴加适量硫酸反应15小时得到白色粉末固体(102.4mg,62.7％)。
m.p.190.8-191.2℃
ESI-MS:m/z 505.2[M+H]+
1H-NMR(400MHz,CDCl3)δ9.24(s,1H),8.70(s,1H),8.35(d,J＝8.2Hz,1H),8.31-8.23(m,2H),8.15(d,J＝8.2Hz,1H),8.05(d,J＝9.1Hz,1H),7.67(d,J＝8.2Hz,1H),7.58(d,J＝3.7Hz,1H),7.55(s,1H),7.54-7.50(1H),7.41(t,J＝8.5Hz,1H),4.19(t,J＝5.9Hz,2H),4.09(t,J＝6.4Hz,1H),3.72(t,J＝5.9Hz,2H),2.77(s,3H),1.72-1.68(5H).13CNMR(100MHz,CDCl3):δ164.20,163.18,151.56,137.40,133.54,131.41,129.04,128.07,125.95,125.70,124.09,122.52,121.08,121.05,119.98,116.66,64.14,62.47,29.46,25.35,14.49.
实施例3
2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸丙酯(Y35)
按实施例1的类似方法，使用2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸(100mg，1e.q)、正丙醇(700.94μl)滴加适量硫酸反应15小时得到白色粉末固体(70mg,63.8％)。
m.p.237.8-238.6℃；
ESI-MS:m/z 475.2[M+H]+
1H-NMR(400MHz,CDCl3)δ9.24(s,1H),8.77(s,1H),8.47(d,J＝8.2Hz,1H),8.39(d,J＝6.4Hz,1H),8.27(d,J＝7.2Hz,1H),8.17(d,J＝8.0Hz,1H),8.07(d,J＝8.0Hz,1H),7.69(s,1H),7.57(t,J＝7.5Hz,2H),7.51(t,J＝7.3Hz,1H),7.33(s,1H),4.01(t,J＝6.9Hz,2H),2.76(s,3H),1.41(td,J＝14.4,7.3Hz,2H),0.85(t,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ164.55,163.45,151.93,148.52,143.56,138.12,136.48,133.87,132.16,129.63,129.50,129.39,127.59,126.56,126.30,125.33,122.95,121.60,121.41,120.27,117.29,110.53,66.18,22.47,14.94,10.93.
实施例4
2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸3-羟基丙酯(Y36)
按实施例1的类似方法，使用2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸(100mg，1e.q)、1,3-丙二醇(2010μl)滴加适量硫酸反应15小时得到白色粉末固体(54mg,49％)。
m.p.188.9-190.3℃；
ESI-MS:m/z 491.1[M+H]+；
1H-NMR(400MHz,CDCl3)δ9.23(q,J＝2.0Hz,1H),8.68(s,1H),8.36(d,J＝1.8Hz,1H),8.34(d,J＝1.4Hz,1H),8.28(dd,J＝7.3,1.4Hz,1H),8.14(d,J＝8.2Hz,1H),8.05(dd,J＝8.2,1.4Hz,1H),7.66(q,J＝4.3Hz,1H),7.55(td,J＝7.7,2.4Hz,2H),7.50-7.42(m,2H),4.28(t,J＝6.2Hz,2H),3.68(t,J＝6.2Hz,2H),2.75(s,3H),1.82-1.75(m,2H)；13C NMR(100MHz,CDCl3)δ164.54,163.26,151.57,147.85,143.41,137.44,135.99,133.58,131.59,129.21,129.01,128.21,127.08,125.94,125.78,124.28,122.52,121.08,120.95,119.91,116.22,109.88,60.94,58.95,14.49.
实施例5
2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸乙酯(Y37)
按实施例1的类似方法，使用2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸(100mg，1e.q)、乙醇(1570μl)滴加适量硫酸反应15小时得到白色粉末固体(44mg,42.7％)。
m.p.201.8-202.9℃；
ESI-MS:m/z 461.1[M+H]+.
1H-NMR(400MHz,CDCl3)δ9.23(d,J＝5.9Hz,1H),8.68(s,1H),8.49(d,J＝8.2Hz,1H),8.40-8.34(1H),8.28(s,1H),8.17(d,J＝7.3Hz,1H),8.07(d,J＝9.6Hz,1H),7.67(q,J＝4.1Hz,1H),7.62-7.58(m,1H),7.56(dd,J＝4.2,3.5Hz,1H),7.55-7.49(m,1H),7.29-7.26(m,1H),4.08(q,J＝7.2Hz,2H),2.79-2.72(m,3H),1.03(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ164.02,163.06,151.54,148.10,143.41,137.41,136.08,133.43,131.59,129.23,129.00,127.17,126.06,125.85,124.96,122.49,121.18,120.88,119.82,116.80,110.02,60.02,14.31.
实施例6
2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸2-羟基乙酯(Y38)
按实施例1的类似方法，使用2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸(100mg，1e.q)、乙二醇(1540μl)滴加适量硫酸反应15小时得到白色粉末固体(93mg,87.7％)。
m.p.196.5-197.8℃；
ESI-MS:m/z 477.1[M+H]+
1H-NMR(400MHz,DMSO-D6)δ10.01-9.90(1H),9.18(q,J＝2.1Hz,1H),8.55(dd,J＝8.7,1.8Hz,1H),8.24(t,J＝1.6Hz,1H),8.22(t,J＝1.6Hz,1H),8.10(dd,J＝7.3,1.4Hz,1H),8.05(d,J＝8.7Hz,1H),7.75(q,J＝4.1Hz,1H),7.61-7.50(m,2H),7.41(s,1H),7.39-7.33(m,1H),4.10(t,J＝5.3Hz,2H),3.42(t,J＝6.4Hz,2H),2.71(s,3H)；13C NMR(100MHz,DMSO)δ163.54,163.46,152.05,147.21,143.51,137.65,136.41,134.52,131.92,130.16,129.09,128.72,127.75,126.18,125.83,125.51,123.20,121.19,120.57,119.68,117.81,109.85,66.00,59.48,14.79.
实施例7
2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸甲酯(Y39)
按实施例1的类似方法，使用2-甲基-5-(喹啉-8-磺酰胺基)萘并[1,2-b]呋喃-3-羧酸(100mg，1e.q)、正丁醇(2540μl)滴加适量硫酸反应15小时得到白色粉末固体(100.9mg,89.37％)。
m.p.210.8-211.2℃；
ESI-MS:m/z 489.2[M+H]+.
1H-NMR(400MHz,CDCl3)δ9.24(s,1H),8.74(s,1H),8.45(d,J＝8.4Hz,1H),8.38(d,J＝8.1Hz,1H),8.28(d,J＝7.0Hz,1H),8.17(d,J＝8.1Hz,1H),8.07(d,J＝8.1Hz,1H),7.69(dd,J＝7.9,3.9Hz,1H),7.54(dt,J＝28.1,7.3Hz,3H),7.36(s,1H),4.08(t,J＝6.8Hz,2H),2.77(s,3H),1.53–1.41(m,2H),1.34(dd,J＝14.1,7.1Hz,2H),0.95(t,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3)δ164.23,163.05,151.64,148.14,143.38,137.69,136.20,133.57,131.70,129.30,129.13,128.91 127.23,126.16,125.94,124.90,122.63,121.25,121.14,119.95,116.88,64.12,30.80,19.34,14.64,13.96.
实验方法与结果一、Sirt1酶活实验
实验原理：采用GENMED细胞沉默调节蛋白1(SIRT1)活性荧光定量检测试剂盒，测试Y1-Y39化合物的Sirt1激动活性。该方法是一种旨在通过荧光探针氨甲基香豆素标记人工合成的乙酰化p53多肽底物，经过SIRT1脱乙酰基后，被位点特异性氨基肽酶水解，释放释放出具有强烈荧光的7-氨-4甲基香豆素，即采用荧光法来测定细胞裂解萃取样品中的酶活性。
实验步骤：
首先将准备好的待测培养细胞肾小管上皮细胞(HK-2)(1-5×107细胞)，小心抽去培养液，小心加入10毫升的磷酸盐缓冲溶液(PBS)，覆盖生长表面，小心抽去清理液，使用细胞刮脱棒轻柔刮脱细胞。加入1毫升GENMED裂解液(Reagent A)，混匀细胞。移入到预冷的15毫升锥形离心管。强力涡旋震荡10秒。置于冰槽里孵育15分钟。加入4毫升预冷的GENMED分离液(Reagent B)，混匀。放进4℃台式离心机离心10分钟，速度为1300g。小心抽去上清液。加入4毫升预冷的GENMED清理液(Reagent C)；放进4℃台式离心机离心10分钟，速度为1300g；小心抽去上清液；小心加入100微升预冷的GENMED萃取液(Reagent D)，混匀；转移到新的预冷的1.5毫升离心管；超声处理30秒；置于冰槽里孵育30分钟；放进4℃微型台式离心机离心10分钟，速度为13000RPM；小心移取上清液到新的预冷的1.5毫升离心管；移取10微升进行蛋白定量检测；即刻置于冰上。然后建立标准曲线，进行活性测定，在黑色96孔板上做好相应标记：背景空对照和待测样品；分别移取58微升GENMED缓冲液(Reagent E)到相应孔里；分别加入2微升GENMED底物液(Reagent F)；分别加入20微升GENMED补充液(ReagentI)或待测样品(200微克细胞裂解萃取液总蛋白)(注意：样品须清澈)；轻轻摇动黑色96孔板30秒；放进30℃培养箱里，孵育60分钟，避免光照；分别加入10微升GENMED终止液(ReagentG)；分别加入10微升GENMED酶解液(Reagent H)；轻轻摇动黑色96孔板30秒；在30℃培养箱里，孵育30分钟；即刻放进荧光酶标仪，在荧光分光光度仪里检测：获得相对荧光单位(Relative Fluorescence Unit；RFU)读数；最后按照以下公式计算样品活性。
公式：[根据标准曲线获得样品对应氨甲基香豆素浓度(微摩尔/升)X样品稀释倍数]÷60(反应时间；分钟]＝纳摩尔/毫升/分钟÷(样品蛋白浓度)毫克/毫升＝纳摩尔/毫克/分钟。
实验结果：如下表1所示，与DMSO组相比，本发明中的化合物Y6、Y7、Y19、Y37-Y39有明显的Sirt1酶活激动活性，可使酶活力提升至200％以上，与阳性对照药SRT2104激动活性相当。化合物Y1、Y4、Y5、Y9、Y11、Y13-Y16、Y23、Y31-Y33、Y35和Y36具有中等强度的Sirt1激动活性，活性弱于SRT2104，但明显高于白芦藜醇。本发明的2-甲基萘并[1,2-b]呋喃类化合物是一类高活性的Sirt1激活剂。
表1本发明的39个化合物在10μM的给药浓度下Sirt1酶活力值(与DMSO组对比)
a白芦藜醇是弱的Sirt1激活剂，给药浓度为50μM；
b定义DMSO浓度为10μM时的Sirt1酶活力为100％。
二、细胞活力实验
实验原理：试剂中含有WST-8，它在电子载体1-甲氧基-5-甲基吩嗪鎓硫酸二甲酯(1-Methoxy PMS)的作用下被细胞中的脱氢酶还原为具有高度水溶性的黄色甲瓒产物(Formazan dye)。生成的甲瓒物的数量与活细胞的数量成正比。因此可利用这一特性直接进行细胞增殖和毒性分析。
实验步骤：
1.铺板：取对数生长期的肾小管上皮细胞(HK-2)系接种96孔板，每孔细胞悬液100μL，细胞数为5×103/孔，空白对照组只加100μL含10％FBS完全培养基RPMI-1640，每组设置3～5个复孔。
2.不同浓度梯度小分子化合物处理的HK-2置于细胞培养箱(37℃、5％CO2)培养，24h后每孔加入5μL CCK-8溶液，继续培养3小时后酶标仪检测；
3.检测：将空白对照组调零，检测450nm波长下的吸光度(OD值)，重复2-3次，取平均值，绘制细胞活力柱状图，计算给药化合物的IC50值。
实验结果：如下表2所示，本发明中的化合物Y19、Y33-Y39对肾小管上皮细胞HK-2无明显的增殖抑制能力，细胞毒性明显低于阳性对照药SRT2104和白芦藜醇。尤其化合物Y33、Y34、Y37-Y39甚至是促进细胞增殖。
表2本发明的8个化合物对人肾小管上皮细胞HK-2的细胞活力的影响
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：其依然可能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范围。
Claims (3)
1.化合物、异构体，或其药学上可接受的盐在制备与糖尿病肾病有关药物方面的应用，所述化合物选自：
2.根据权利要求1所述的应用，其特征在于，所述药物它以权利要求1所述的化合物、异构体，或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的载体。
3.根据权利要求2所述的应用，其特征在于，所述药物制成注射剂、口服液、颗粒剂、粉剂、片剂或胶囊剂。
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| WO2012017166A2 (fr) * | 2010-07-19 | 2012-02-09 | Vaxconsulting | Traitement d'une pathologie liee a un effet excessif du tnf par un compose de benzene sulfonamide |
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