CN114163446B - 一种喹啉酮骨架的pde4抑制剂及其制备方法与应用 - Google Patents
一种喹啉酮骨架的pde4抑制剂及其制备方法与应用 Download PDFInfo
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- CN114163446B CN114163446B CN202111543984.4A CN202111543984A CN114163446B CN 114163446 B CN114163446 B CN 114163446B CN 202111543984 A CN202111543984 A CN 202111543984A CN 114163446 B CN114163446 B CN 114163446B
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Abstract
本发明公开了一种喹啉酮骨架的PDE4抑制剂及其制备方法与应用。该PDE4抑制剂是如通式Ⅰ和通式II所示的Toddacoumalone衍生物、其立体异构体、稳定的同位素衍生物或其药学上可接受的盐。该抑制剂对PDE4有较强的抑制效果，部分化合物达到纳摩尔水平的活性级别，远远大于阳性对照Rolipram，并且在体内实验中能够显著抑制小鼠银屑病的形成，其具有开发成新型PDE4抑制剂药物的巨大潜力。
Description
技术领域
本发明属于药物合成领域，特别涉及一种喹啉酮骨架的PDE4抑制剂及其制备方法与应用。
背景技术
磷酸二酯酶(PDEs)是一个超级酶家族，根据它们对底物的特异性和酶动力学性质等可分为11家族(PDE1-PDE11)，每个家族由若干基因编码，可使用不同的启动子对mRNA进行剪接修饰，总共有超过50中不同的同工酶。磷酸二酯酶催化cAMP和cGMP水解开环，是细胞内降解cAMP和cGMP的唯一方式。
PDE4家族分为4个亚型(PDE4A、PDE4B、PDE4C、PDE4D)，它们广泛分布于脑内和免疫活性细胞如中性粒细胞、T淋巴细胞、巨噬细胞和嗜酸性细胞中。PDE4在降解炎症细胞，肺部和神经系统疾病中发挥着重要的作用，因此这使得PDE4成为药物研发非常重要的靶目标。近年来，PDE4型抑制剂Roflumilast，Apremilast，Crisaborole分别被FDA批准用于治疗慢性阻塞性肺病，银屑病性关节炎和特应性皮炎。然而，这些抑制剂在取得治疗效果的同时，不可避免副作用如严重的恶心、呕吐和胃肠道反应等(Front.Pharmacol.2018,9,1048)极大的限制了它们的应用，因此，开发新型高效安全的PDE4抑制剂具有重大意义。
天然产物Toddacoumalone是1991年首次从芸香科植物飞龙掌血(Toddaliaasiatica(L.)Lam.(Rutaceae))中分离得到的天然分子(Tetrahedron Lett.1991,32,6907-6910)，具有很好的抗磷酸二酯酶4活性(IC50＝0.14μM，J.Nat.Prod.2014,77,955-962)。Toddacoumalone在自然界中的含量较少且提取困难，前期，我们实现了该天然产物的全合成，解决了该重要活性分子的来源问题(Org.Lett.2020,22,584-588)，并在此基础上发明了一种简洁，实用的方法来制备Toddacoumalone类化合物或药学上可接受的盐的方法(CN110407844B)。然而Toddacoumalone类化合物存在溶解度低，生物利用度差等问题。在此基础上，我们对Toddacoumalone进行药物化学设计，成功发现了多个具有优异活性的新型PDE4抑制剂，本发明对开发活性好，选择性高的PDE4抑制剂具有重要意义且具有较大的临床需求和市场价值。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足，提供一种喹啉酮骨架的PDE4抑制剂。
本发明的另一目的在于提供上述喹啉酮骨架的PDE4抑制剂的制备方法。
本发明的再一目的在于提供上述喹啉酮骨架的PDE4抑制剂的应用。
本发明的目的通过下述技术方案实现：一种喹啉酮骨架的PDE4抑制剂，是如通式Ⅰ和通式II所示的Toddacoumalone衍生物、其立体异构体、稳定的同位素衍生物或其药学上可接受的盐；
其中：
X、X1、X2、X3各自独立的选择CH或N；
R选自氢、卤素、羟基、巯基、氰基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基；所述的羟基、巯基、氰基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基，任选的可以进一步被卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基取代；
R1选自氢、卤素、羟基、巯基、氰基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基；所述的羟基、巯基、氰基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基，任选的可以进一步被卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基取代；
R2选自卤素、羟基、氨基、巯基、氰基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基；所述的羟基、氨基、巯基、氰基、羧基、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基，任选的可以进一步被卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基取代；
R3选自CH2或肟(N-OH)。
在本发明的实施例中，R选自氢、卤素、C1-6烷基、C1-6卤代烷基；所述的氢、卤素C1-6烷基、C1-6卤代烷基，任选的可以进一步被卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基取代。
在本发明进一步优选的实施例中，R选自甲基、乙基、三氟甲基。
在本发明的实施例中，R1选自氢、C1-6烷基、C1-6环烷基；所述的氢、C1-6烷基、C1-6环烷基，任选的可以进一步被卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基取代。
在本发明进一步优选的实施例中，R1选自甲基、乙基。
在本发明的实施例中，R2选自羟基、氨基、羧基；所述的羟基、氨基、羧基，任选的可以进一步被卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基或杂芳基取代。
在本发明进一步优选的实施例中，R2选自羟基。
在本发明的实施例中，R3选自CH2或肟(N-OH)。
在本发明进一步优选的实施例中，R3选自肟(N-OH)。
在本发明最优选的实施例中，包括以下具体化合物：
在本发明优选的化合物中，进一步优选以下手性化合物：
本发明还提供上述喹啉酮骨架的PDE4抑制剂的制备方法，该制备方法的反应流程如下：
上述制备方法的具体步骤为：
化合物VI的非对映异构体的制备
(a)将化合物I和伯胺(R1-NH2)混合，回流反应，冷却，浓缩，得到化合物II；
(b)化合物II在乙酸酐中回流反应，冷却，分离，得到化合物III；
(c)化合物III在叔丁醇钾中回流反应，冷却后，加入水，分层，将得到的水层的pH值调至中性，析出固体，过滤，干燥，得到化合物IV；
(d)化合物IV与异戊烯醛，在吡啶中回流反应，得到化合物V；
(e)化合物V与异戊烯醛，在酸性添加剂存在下，经二级胺催化反应，得到化合物VI的非对映异构体，即所述的喹啉酮骨架的PDE4抑制剂。
上述制备方法，还包括如下步骤：
(f)化合物VI在0℃下经戴斯马丁氧化剂氧化，过滤，浓缩，分离，得到化合物VII；
(g)化合物VII与盐酸羟胺，在碱性条件下反应，将得到的产物浓缩，分离，得到化合物VIII。
步骤(a)中所述的化合物I优选为2-氯烟酸甲酯、3-氯异烟酸乙酯、4-氯烟酸乙酯、3-氯-2-吡啶羧酸甲酯、4-氯嘧啶-5-甲酸甲酯、2-氯-6-甲基烟酸乙酯、2-氯-6-乙基吡啶-3-甲酸乙酯或2-氯-6-三氟甲基吡啶-3-甲酸乙酯。
步骤(a)中所述的伯胺优选为甲胺、乙胺、异丙胺、环丙胺、正丙胺、正丁胺或苯胺。
步骤(a)中所述的化合物I和所述的伯胺优选按摩尔比小于1配比，伯胺的用量多于化合物I是为了确保化合物I充分反应；所述的化合物I和所述的伯胺优选按摩尔比1：1.1～5配比。
步骤(a)中所述的回流反应的体系中的溶剂优选为乙醇。
步骤(a)中所述的回流反应的时间优选为2～24小时；更优选为12小时。
步骤(a)中所述的浓缩优选为减压浓缩。
步骤(b)中所述的化合物II和所述的乙酸酐优选按摩尔比小于1配比，乙酸酐的用量多于化合物II是为了确保化合物II充分反应；所述的化合物II和所述的乙酸酐优选按摩尔比1：1.1～11配比。
步骤(b)中所述的回流反应的时间优选为12～24小时；更优选为24小时。
步骤(b)中所述的分离优选为通过柱层析分离。
所述的柱层析所用的洗脱溶剂优选为石油醚和乙酸乙酯中的至少一种；更优选为石油醚和乙酸乙酯按体积比1～100：1得到的溶剂。
步骤(c)中所述的化合物III和所述的叔丁醇钾优选按摩尔比小于1配比，叔丁醇钾的用量多于化合物III是为了确保化合物III充分反应；所述的化合物III和所述的叔丁醇钾优选按摩尔比1：1.1～4配比。
步骤(c)中所述的回流反应的体系中的溶剂优选为二甲苯。
步骤(c)中所述的回流反应的时间优选为12～24小时；更优选为24小时。
步骤(c)中所述的pH值的调节剂优选为乙酸。
步骤(c)中所述的pH值为7。
步骤(d)中所述的化合物IV与所述的异戊烯醛优选按摩尔比小于1配比；更优选按摩尔比1：1.1～2配比。
步骤(d)中所述的回流反应的体系还含有催化剂。
所述的催化剂优选为无水硫酸镁。
所述的无水硫酸镁的用量优选为相当于化合物IV摩尔量的3～5倍；更优选为4倍。
步骤(d)中所述的回流反应的时间优选为1～6小时；更优选为4小时。
步骤(e)中所述的化合物V与异戊烯醛优选按摩尔比小于1配比；更优选按摩尔比1：1.1～2配比。
步骤(e)中所述的酸性添加剂优选为苯甲酸。
步骤(e)中所述的酸性添加剂的添加量优选按化合物V：酸性添加剂＝摩尔比10：1～3配比；更优选按化合物V：酸性添加剂＝摩尔比10：2配比。
步骤(e)中所述的二级胺优选为脯氨酸。
步骤(e)中所述的二级胺的添加量优选按化合物V：二级胺＝摩尔比10：1～3配比；更优选按化合物V：二级胺＝摩尔比10：2配比。
步骤(e)中所述的催化反应的体系中的溶剂优选为四氢呋喃。
步骤(e)中所述的催化反应的条件优选为室温反应12～72小时；更优选为室温反应48小时。
所述的室温为20～35℃；更优选为24～26℃。
步骤(f)中所述的化合物VI和所述的戴斯马丁氧化剂优选按摩尔比1：1～2配比；更优选按摩尔比1：1.5配比。
步骤(f)中所述的化合物VI在0℃下经戴斯马丁氧化剂氧化的具体步骤优选如下：将化合物VI溶解于有机溶剂中，在0℃下加入戴斯马丁氧化剂，反应。
所述的有机溶剂优选为二氯甲烷。
所述的反应的条件优选为室温条件下反应2～4小时；更优选为室温条件下反应3小时。
所述的室温为20～35℃；更优选为24～26℃。
步骤(f)中所述的浓缩优选为减压浓缩。
步骤(f)中所述的分离为通过柱层析分离。
步骤(g)中所述的化合物VII与所述的盐酸羟胺优选按摩尔比小于1配比；更优选按摩尔比1：2配比。
步骤(g)中所述的碱优选为碳酸钾。
步骤(g)中所述的碱的用量优选为相当于化合物VII摩尔量的1～3倍；更优选为相当于化合物VII摩尔量的2倍。
步骤(g)中所述的反应的体系中的溶剂优选为甲醇和水混合得到的溶剂；更优选为甲醇和水按体积比1：1混合得到的溶剂。
步骤(g)中所述的反应的条件优选为室温反应3～5小时；更优选为室温反应4小时。
所述的室温为20～35℃；更优选为24～26℃。
本发明还提供了一种优选方案，还涉及一种药用组合物，其包括治疗有效剂量的所述的通式Ⅰ和通式II化合物及其立体异构体、稳定的同位素衍生物或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明进一步涉及通式Ⅰ和通式II所示的化合物及其立体异构体、稳定的同位素衍生物或其药学上可接受的盐，或所述的药物组合物于预防和治疗磷酸二酯酶4相关疾病的药物中的用途。
所述的与磷酸二酯酶4相关的疾病为：涉及炎症的疾病，例如哮喘、慢性阻塞性肺病、肺纤维化和肺动脉高压等；变应性疾病状态，例如特应性皮炎、荨麻疹、变应性鼻炎、变应性结膜炎、春季结膜炎、嗜酸细胞肉芽肿、银屑病、炎性关节炎、类风湿性关节炎、脓毒性休克、炎症性肠病(包括溃疡性结肠炎和克罗恩病)、心肌和脑再灌注损伤、慢性肾小球性肾炎、内毒素性休克、囊性纤维化、动脉再狭窄、动脉粥样硬化、角化病、类风湿性脊椎炎、骨关节炎、发热、糖尿病、尘肺、中毒和过敏性接触性湿疹、特应性湿疹、脂溢性湿疹、单纯性苔癣、晒伤、肛门生殖器区域瘙痒、斑秃、肥大性瘢痕、盘状红斑狼疮、系统性红斑狼疮、滤泡性和广泛性脓皮病、内源性或外源性痤疮、红斑痤疮、Beghet’s病，过敏性紫癜肾炎、炎性肠病、白血病、多发性硬化、胃肠疾病、自身免疫病等；神经系统疾病，例如阿尔茨海默病，多发性硬化、肌萎缩性侧索硬化症、多发性系统萎缩、精神分裂症、帕金森病、亨廷顿氏病、皮克病、抑郁、中风、以及脊髓损伤、血管性痴呆等。
在一些实施例中，本发明的化合物及其立体异构体、稳定的同位素衍生物或其药学上可接受的盐，或所述的药物组合物在制备治疗磷酸二酯酶4相关疾病的药物中的应用；优选治疗银屑病、特应性皮炎、哮喘、肺纤维化及肺动脉高压等疾病或病症。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最优选1至3个碳原子的烷基。烷基的代表性例子包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基、正戊基、正己基、正庚基、辛基、壬基、癸基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、4,4-二甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、2,2,4-三甲基戊基、十一烷基、十二烷基，及它们的各种异构体等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
术语“环烷基”指饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基。环烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
术语“烷氧基”指烷基与氧直接连接的基团，即具有-O-烷基结构的基团，如-OCH3、-OCH2CH3、-OCH2CH2CH3、-O-CH2CH(CH3)2、-OCH2CH2CH2CH3、-O-CH(CH3)2等。
术语“杂环基”为饱和或部分不饱和的单环或多环环状取代基，其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳，例如：吗啉基、哌啶基、四氢吡咯基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基、四氢噻吩基等，及其N-氧化物，杂环取代基的连接可通过碳原子或通过杂原子实现。杂环基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
术语“杂芳基”指含有1个或多个选自O、N或S的杂原子的芳香环，本发明范围内的杂芳基包括但不限于：喹啉基、吡唑基、吡咯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、三氮唑基、咪唑基、噁唑基、异噁唑基、哒嗪基；“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。杂芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。
本文中所用“卤素”或“卤”意指氯、氟、溴和碘。
本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
本发明所述“异构体”是指本发明的通式Ⅰ和通式II化合物可以有不对称中心和外消旋体、外消旋混合物和单个非对映异构体，所有这些异构体，包括立体异构体、几何异构体均包含在本发明中。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本发明相对于现有技术具有如下的优点及效果：
本发明中所提供的分子对磷酸二酯酶4有较强的抑制效果，部分化合物达到纳摩尔水平的活性级别，远远大于阳性对照Rolipram，本发明中部分化合物在治疗由咪喹莫特诱导的小鼠银屑病模型中具有显著效果。
附图说明
图1是化合物12-a在IMQ诱导的小鼠银屑病模型中的治疗作用结果图，其中：(A)是7天治疗作用后的代表性结果图；(B)是小鼠体重变化图；(C)是根据PASI，每天监测从0到12的累积分数结果图；(D)、(E)和(F)是根据PASI，每日监测红斑、鳞屑和厚度评分结果图，范围从0到4。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代甲醇(CD3OD)和氘代氯仿(CDCl3)，内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1260Infinity Series质谱仪，洗脱条件：90％(v/v)甲醇-水。高压制备液相使用Hanbon Sci.&Tech高压液相色谱仪(Dubhe C18 250×20mm色谱柱)，洗脱条件10-90％(v/v)乙腈-水(流速：10mL/min，洗脱时间：45min)。
薄层层析硅胶板使用烟台黄海HSGF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中起始原料均为市售，或者可以按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氩气气氛下进行，氩气气氛是指反应体系连接一个约1L容积的氩气气球。溶剂为干燥溶剂，反应温度单位为℃。
本发明中涉及的BALB/c小鼠购买自广东药康生物科技有限公司(许可证：SCXK(粤)2020-0054)，小鼠按照国家、地方和学校生物安全法规使用和管理(动物实验伦理：SYSU-IACUC-2021-001343)
实施例1
本实施例中未给出具体实验步骤的化合物制备方法和条件均同制备化合物1的非对映异构体1-a和1-b，区别仅在于采用了不同的反应底物，以制备得到相同类型的产物。
化合物1的非对映异构体1-a和1-b的制备，其结构式如下：
(a).中间体II-1的制备:2-氯烟酸乙酯(1.85g，10mmol，1.0eq)和甲胺(50mmol，5.0eq)在乙醇(50mL)中回流12小时，冷却，减压浓缩，剩余物通过柱层析分离(石油醚PE:乙酸乙酯EA体积比＝100:1)即得到无色油状化合物II-1(1.71g，收率为95％)。
(b).中间体III-1的制备:化合物II-1(1.8g，10mmol，1.0eq)在乙酸酐(10mL)中回流24小时，冷却，减压浓缩，剩余物通过柱层析分离(PE：EA体积比＝1：1)即得到淡黄色油状化合物III-1(2.1g，收率为95％)。
(c).中间体IV-1的制备:化合物III-1(2.22g，10mmol，1eq)和叔丁醇钾(4.48g，40mmol，4.0eq)在二甲苯(50mL)中回流24小时，冷却，加入水(50mL)，分水水层，水层用乙酸调节pH＝7，析出固体，过滤，干燥得到白色固体化合物IV-1(1.5g，收率为85％)。
(d).中间体V-1的制备:化合物IV-1(1.76g，10mmol，1.0eq)、异戊烯醛(1.68g，20mmol，2.0eq)和无水硫酸镁(4.8g，40mmol,4.0eq)在吡啶(50mL)中回流4小时，冷却，减压浓缩，剩余物通过柱层析分离(PE:EA体积比＝2:1)即得到淡黄色固体中间体V(2.3g，收率为95％)。
(e).化合物1的非对映异构体1-a和1-b的制备：中间体V(1.21g，5mmol，1.0eq)、异戊烯醛(0.84g，10mmol，2.0eq)、苯甲酸(0.12g，1mmol，0.2eq)和脯氨酸(0.12g，1mmol，0.2eq)，在四氢呋喃(5mL)中室温条件下反应48小时，减压浓缩，剩余物通过柱层析分离(PE:EA体积比:二氯甲烷DCM＝6:1:6)，即得到1的非对映异构体1-a(0.46g,收率为28％)和1-b(0.48g,收率为29％)。
非对映异构体1-a的表征数据：白色固体，1H NMR(400MHz,CDCl3)δ8.58–8.55(m,1H),8.15–8.11(m,1H),7.13(dd,J＝8.0,4.8Hz,1H),5.06–4.98(m,1H),3.94(t,J＝6.8Hz,2H),3.78(s,3H),3.76–3.69(m,1H),2.10–2.04(m,2H),1.99–1.96(m,1H),1.85–1.79(m,4H),1.76(s,3H),1.38(s,3H).13C NMR(125MHz,CDCl3)δ163.26,153.89,149.54,149.09,131.88,131.14,126.62,117.25,112.00,110.41,78.79,58.70,43.38,39.09,28.85,28.12,25.87,23.01,17.98.HRMS(ESI,m/z):C19H25N2O3,calcd.for[M+H]+:329.1860,found:329.1862。
非对映异构体1-b的表征数据：白色固体，1H NMR(400MHz,CDCl3)δ8.57–8.53(m,1H),8.18–8.14(m,1H),7.15–7.10(m,1H),5.09–5.02(m,1H),3.87–3.80(m,2H),3.79–3.70(m,4H),2.15–2.00(m,2H),1.95–1.86(m,1H),1.81–1.75(m,4H),1.74(s,3H),1.49(s,3H).13C NMR(100MHz,CDCl3)δ163.48,153.99,149.61,149.16,131.95,131.25,127.06,117.38,112.09,110.51,78.65,58.75,40.69,39.61,28.97,28.22,26.10,25.95,18.10。
实施例2-5
实施例2-5的制备参照实施例1的路线合成，所用的反应原料基本与实施例1相同，区别仅在于步骤(a)分别用3-氯异烟酸乙酯(1.85g，10mmol，1.0eq)(实施例2)、4-氯烟酸乙酯(1.85g，10mmol，1.0eq)(实施例3)、3-氯-2-吡啶羧酸甲酯(1.85g，10mmol，1.0eq)(实施例4)以及4-氯嘧啶-5-甲酸甲酯(1.0g，5.8mmol，1.0eq)(实施例5)分别和甲胺(50mmol，5.0eq)在乙醇(50mL)中回流12小时，冷却，减压浓缩，剩余物通过柱层析分离(PE:EA体积比＝100:1)即得到无色油状物。
非对映异构体2-a的表征数据：白色固体，收率：31％，1H NMR(400MHz，CDCl3)δ8.76(s,1H),8.43(d,J＝5.2Hz,1H),7.69(d,J＝5.2Hz,1H),4.99(d,J＝8.4Hz,1H),3.95(t,J＝6.8Hz,2H),3.77–3.67(m,4H),2.08(dd,J＝12.8,6.6Hz,2H),2.02–1.98(m,1H),1.86–1.78(m,4H),1.75(s,3H),1.39(s,3H).13C NMR(100MHz,CDCl3)δ161.86,153.74,142.02,136.46,134.29,132.37,126.22,121.98,115.54,114.08,78.99,58.66,43.50,39.13,29.29,28.89,25.96,23.13,18.09。
非对映异构体2-b的表征数据：白色固体，收率：29％，1H NMR(400MHz,CDCl3)δ8.73(s,1H),8.40(d,J＝5.2Hz,1H),7.71(d,J＝5.2Hz,1H),5.03(d,J＝8.4Hz,1H),3.88-3.80(m,2H),3.76–3.71(m,1H),3.69(s,3H),2.17-2.11(m,1H),2.08–2.00(m,1H),1.96-1.89(m,1H),1.83–1.76(m,4H),1.74(s,3H),1.50(s,3H).13C NMR(100MHz,CDCl3)δ161.90,153.67,141.86,136.30,134.19,132.31,126.43,121.94,115.56,114.08,78.75,58.50,40.54,39.48,29.24,28.84,26.04,25.91,18.08。
非对映异构体3-a的表征数据：白色固体，收率：26％，1H NMR(400MHz，CDCl3)δ9.04(s,1H),8.56(d,J＝5.8Hz,1H),7.13(d,J＝5.9Hz,1H),4.99(d,J＝8.4Hz,1H),3.96(t,J＝6.8Hz,2H),3.69(dd,J＝16.3,8.6Hz,1H),3.61(s,3H),2.09(dd,J＝14.3,7.2Hz,2H),2.01(dd,J＝14.1,7.0Hz,1H),1.85–1.78(m,4H),1.75(s,3H),1.40(s,3H).13C NMR(100MHz,CDCl3)δ
162.62,154.99,149.41,145.69,143.87,132.15,126.49,112.68,110.74,107.97,78.88,58.41,43.59,39.15,28.98,25.93,23.10,18.05。
非对映异构体3-b的表征数据：白色固体，收率：28％，1H NMR(400MHz,CDCl3)δ9.05(s,1H),8.55(d,J＝5.6Hz,1H),7.12(d,J＝6.0Hz,1H),5.03(d,J＝8.4Hz,1H),3.89-3.80(m,2H),3.75-3.68(m,1H),3.60(s,3H),2.17–2.02(m,2H),1.97-1.89(m,1H),1.85–1.76(m,4H),1.74(s,3H),1.51(s,3H).13C NMR(101MHz,CDCl3)δ162.71,154.93,149.39,145.68,143.87,132.20,126.79,112.61,110.82,107.98,78.75,58.52,40.71,39.55,29.00,26.08,25.92,18.08。
非对映异构体4-a的表征数据：白色固体，收率：37％，1H NMR(400MHz,CDCl3)δ8.54(d,J＝4.4Hz,1H),7.63(d,J＝8.5Hz,1H),7.45(dd,J＝8.5,4.5Hz,1H),5.03(d,J＝8.5Hz,1H),4.11(ddd,J＝12.0,8.8,3.3Hz,1H),3.91–3.82(m,1H),3.76(dd,J＝16.0,8.6Hz,1H),3.65(s,3H),2.21–2.15(m,1H),2.04–1.99(m,1H),1.97–1.91(m,1H),1.83(q,J＝9.2Hz,4H),1.76(s,3H),1.46(s,3H).13C NMR(100MHz,CDCl3)δ161.84,154.78,143.89,135.39,133.51,131.97,126.56,124.58,121.34,113.23,79.78,59.11,42.81,39.82,29.22,28.97,25.98,22.68,18.09。
非对映异构体4-b的表征数据：白色固体，收率：39％，1H NMR(400MHz,CDCl3)δ8.55(d,J＝4.2Hz,1H),7.64(d,J＝8.5Hz,1H),7.46(dd,J＝8.5,4.4Hz,1H),5.10(d,J＝8.3Hz,1H),4.10–4.00(m,1H),3.78(ddd,J＝16.9,13.2,6.1Hz,2H),3.65(s,3H),2.17–2.07(m,2H),1.91–1.79(m,5H),1.75(s,3H),1.59(s,3H).13C NMR(100MHz,CDCl3)δ162.00,154.84,143.84,135.49,133.57,132.38,126.82,124.55,121.45,113.89,79.82,59.00,40.55,40.16,29.31,29.00,25.97,25.83,18.13。
非对映异构体5-a的表征数据：白色固体，收率：21％，1H NMR(400MHz,CDCl3)δ9.03(s,2H),4.98(d,J＝8.6Hz,1H),3.94(t,J＝6.7Hz,2H),3.75–3.64(m,4H),2.14–1.96(m,3H),1.86–1.78(m,4H),1.76(s,3H),1.40(s,3H).13C NMR(100MHz,CDCl3)δ163.19,157.96,153.67,153.51,152.01,132.68,125.94,111.66,109.96,79.44,58.55,43.49,39.09,28.92,27.87,25.95,23.18,18.10。
非对映异构体5-b的表征数据：白色固体，收率：19％，1H NMR(400MHz,CDCl3)δ9.05(s,1H),9.02(s,1H),5.02(d,J＝8.5Hz,1H),3.92–3.78(m,2H),3.74–3.67(m,4H),2.14(dd,J＝14.2,7.0Hz,1H),2.04(dt,J＝13.5,6.7Hz,1H),1.94(dd,J＝14.0,7.0Hz,1H),1.81–1.77(m,4H),1.75(s,3H),1.51(s,3H).13C NMR(101MHz,CDCl3)δ163.30,157.95,153.64,153.52,152.02,132.69,126.24,111.74,109.93,79.30,58.63,40.64,39.49,28.96,27.88,26.08,25.94,18.12。
实施例6-11
实施例6-11的制备参照实施例1的路线合成，所用的反应原料基本与实施例1相同，区别仅在于步骤(a)用乙胺(50mmol，5.0eq)(实施例6)、异丙胺(50mmol，5.0eq)(实施例7)、环丙胺(50mmol，5.0eq)(实施例8)、正丙胺(50mmol，5.0eq)(实施例9)、正丁胺(50mmol，5.0eq)(实施例10)以及苯胺(50mmol，5.0eq)(实施例11)分别和2-氯烟酸乙酯(1.85g，10mmol，1.0eq)在乙醇(50mL)中回流12小时，冷却，减压浓缩，剩余物通过柱层析分离(PE:EA体积比＝100:1)即得到无色油状物。
非对映异构体6-a的表征数据：白色固体，收率：39％，1H NMR(400MHz,CDCl3)δ8.58–8.54(m,1H),8.15–8.10(m,1H),7.14–7.09(m,1H),5.03(d,J＝8.4Hz,1H),4.63–4.42(m,2H),3.94(t,J＝6.8Hz,2H),3.77–3.69(m,1H),2.11–2.03(m,2H),2.01–1.95(m,1H),1.84–1.77(m,4H),1.75(s,3H),1.39(s,3H),1.30(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.74,153.88,149.73,148.61,131.72,131.24,126.89,117.23,112.05,110.56,78.80,58.76,43.52,39.21,36.27,28.94,25.94,23.22,18.06,13.64。
非对映异构体6-b的表征数据：白色固体，收率：36％，1H NMR(400MHz,CDCl3)δ8.58–8.54(m,1H),8.18–8.13(m,1H),7.15–7.10(m,1H),5.06(d,J＝8.0Hz,1H),4.60–4.42(m,2H),3.89–3.80(m,2H),3.79–3.71(m,1H),2.16–2.00(m,2H),1.96–1.87(m,1H),1.83–1.76(m,4H),1.74(s,3H),1.49(s,3H),1.30(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3)δ162.86,153.84,149.74,148.60,131.78,131.25,127.20,117.28,112.02,110.58,78.58,58.82,40.69,39.62,36.30,28.92,26.11,25.94,18.10,13.63。
非对映异构体7-a的表征数据：白色固体，收率：33％，1H NMR(400MHz,CDCl3)δ8.53–8.48(m,1H),8.12–8.06(m,1H),7.10–7.04(m,1H),5.91(s,1H),5.06–4.99(m,1H),3.90(t,J＝6.4Hz,2H),3.73–3.64(m,1H),2.07–1.92(m,3H),1.82–1.75(m,4H),1.73(s,3H),1.62(d,J＝6.8Hz,3H),1.58(d,J＝6.8Hz,3H),1.37(s,3H).13C NMR(101MHz,CDCl3)δ163.38,153.58,149.14,148.85,131.50,131.09,127.26,117.02,112.20,78.61,58.76,45.61,43.33,39.19,28.94,25.91,23.41,20.30,19.73,18.05。
非对映异构体7-b的表征数据：白色固体，收率：32％，1H NMR(400MHz,CDCl3)δ8.54–8.21(m,1H),8.14(d,J＝7.6Hz,1H),7.12–7.07(m,1H),5.93(s,1H),5.08(d,J＝7.2Hz,1H),3.88–3.77(m,2H),3.75–3.69(m,1H),2.16–2.00(m,1H),1.98–1.87(m,2H),1.78(s,3H),1.74(s,3H),1.66–1.56(m,6H),1.47(s,3H).13C NMR(101MHz,CDCl3)δ163.47,153.53,149.13,148.83,131.49,131.09,127.60,117.04,112.17,78.42,58.78,45.61,40.95,39.55,28.94,26.06,25.91,20.27,19.76,18.11。
非对映异构体8-a的表征数据：白色固体，收率：42％，1H NMR(400MHz,CDCl3)δ8.62–8.57(m,1H),8.13–8.07(m,1H),7.16–7.10(m,1H),5.01(d,J＝8.0Hz,1H),3.92(t,J＝6.8Hz,2H),3.73–3.65(m,1H),3.02–2.91(m,1H),2.13–1.94(m,3H),1.83–1.75(m,4H),1.73(s,3H),1.38(s,3H),1.34–1.25(m,2H),0.93–0.74(m,2H).13C NMR(101MHz,CDCl3)δ164.30,153.94,150.55,149.24,131.72,131.06,126.93,117.44,112.42,110.80,78.82,58.76,43.45,39.14,28.86,25.93,25.44,23.28,18.12,10.31,9.91。
非对映异构体8-b的表征数据：白色固体，收率：41％，1H NMR(400MHz,CDCl3)δ8.61–5.58(m,1H),8.15–8.11(m,1H),7.16–7.11(m,1H),5.05(d,J＝8.0Hz,1H),3.87–3.80(m,2H),3.75–3.67(m,1H),3.01–2.92(m,1H),2.15–2.01(m,2H),1.96–1.88(m,1H),1.79–1.73(m,4H),1.72(s,3H),1.48(s,3H),1.34–1.26(m,2H),0.93–0.77(m,2H).13C NMR(101MHz,CDCl3)δ164.41,153.92,150.52,149.23,131.70,131.08,127.26,117.49,112.40,110.80,78.61,58.82,40.70,39.57,28.84,26.09,25.92,25.44,18.16,10.26,9.95。
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非对映异构体9-a的表征数据：白色固体，收率：41％，1H NMR(400MHz,CDCl3)δ8.57–8.53(m,1H),8.14–8.10(m,1H),7.13–7.08(m,1H),5.03(d,J＝8.4Hz,1H),4.53–4.30(m,2H),3.93(t,J＝6.8Hz,2H),3.76–3.38(m,1H),2.13–1.90(m,4H),1.80(s,3H),1.78–1.37(m,5H),1.39(s,3H),0.98(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.93,153.84,149.70,148.86,131.64,131.15,127.03,117.21,111.93,110.55,78.78,58.79,43.48,42.72,39.20,28.93,25.94,23.26,21.56,18.05,11.57。
非对映异构体9-b的表征数据：白色固体，收率：39％，1H NMR(400MHz,CDCl3)δ8.56–8.53(m,1H),8.17–8.13(m,1H),7.14–7.08(m,1H),5.07(d,J＝8.0Hz,1H),4.48–4.31(m,2H),3.86–3.78(m,2H),3.78–3.70(m,1H),2.15–2.00(m,2H),1.95–1.88(m,1H),1.80(s,3H),1.77–1.67(m,5H),1.48(s,3H),0.98(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ163.04,153.80,149.70,148.82,131.68,131.16,127.34,117.25,111.91,110.55,78.56,58.83,42.76,40.76,39.59,28.91,26.09,25.93,21.55,18.09,11.60。
非对映异构体10-a的表征数据：白色固体，收率：19％，1H NMR(400MHz,CDCl3)δ8.55(d,J＝4.4Hz,1H),8.14(d,J＝7.6Hz,1H),7.13–7.08(m,1H),5.04(d,J＝8.0Hz,1H),4.56–4.34(m,2H),3.93(t,J＝6.8Hz,2H),3.76–3.68(m,1H),2.62(s,1H),2.13–1.95(m,3H),1.83–1.77(m,4H),1.75(s,3H),1.72–1.64(m,2H),1.47–1.41(m,2H),1.39(s,3H),0.95(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.87,153.87,149.58,148.58,131.42,131.11,126.93,117.11,111.84,110.29,78.54,58.36,43.39,40.99,39.03,30.34,28.76,25.82,23.10,20.39,17.93,13.98。
非对映异构体10-b的表征数据：白色固体，收率：21％，1H NMR(400MHz,CDCl3)δ8.57–8.53(m,1H),8.17–8.13(m,1H),7.13–7.08(m,1H),5.07(d,J＝8.0Hz,1H),4.49–4.39(m,2H),3.87–3.79(m,2H),3.78–3.70(m,1H),2.16–1.88(m,3H),1.79(s,3H),1.77–1.71(m,4H),1.70–1.64(m,2H),1.48(s,3H),1.46–1.38(m,2H),0.94(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ163.06,153.84,149.69,148.74,131.64,131.16,127.36,117.23,111.91,110.52,78.53,58.70,41.14,40.79,39.51,30.45,28.88,26.07,25.90,20.51,18.07,14.06。
非对映异构体11-a的表征数据：白色固体，收率：21％，1H NMR(500MHz,CDCl3)δ8.41(d,J＝4.5Hz,1H),8.18(d,J＝7.5Hz,1H),7.58–7.50(m,2H),7.43(t,J＝7.5Hz,1H),7.31–7.22(m,2H),7.14–7.09(m,1H),5.06(d,J＝8.0Hz,1H),3.92(t,J＝6.5Hz,2H),3.74(q,J＝8.0Hz,1H),2.14–1.97(m,3H),1.87–1.80(m,1H),1.74(s,3H),1.70(s,3H),1.43(s,3H).13CNMR(126MHz,CDCl3)δ163.24,154.69,150.10,149.99,137.41,131.82,131.32,129.33,128.31,126.58,117.75,111.92,110.62,79.12,58.71,43.45,39.19,28.92,25.97,23.38,17.98。
非对映异构体11-b的表征数据：白色固体，收率：20％，1H NMR(400MHz,CDCl3)δ8.42–8.39(m,1H),8.22–8.18(m,1H),7.57–7.47(m,2H),7.45–7.40(m,1H),7.31–7.23(m,2H),7.14–7.09(m,1H),5.10(d,J＝8.4Hz,1H),3.87(t,J＝6.8Hz,2H),3.80–3.72(m,1H),2.18–2.04(m,2H),2.00–1.93(m,1H),1.84–1.76(m,1H),1.74(s,3H),1.72–1.65(m,4H),1.53(s,3H).13C NMR(101MHz,CDCl3)δ163.34,154.59,150.16,150.00,137.48,131.88,131.29,129.37,128.31,126.96,117.78,111.92,110.72,78.97,58.87,40.98,39.66,28.97,26.18,25.98,18.04。
实施例12-14
实施例12-14的制备参照实施例1的路线合成，所用的反应原料基本与实施例1相同，区别仅在于步骤(a)用乙胺(50mmol，5.0eq)分别和2-氯-6-甲基烟酸乙酯(1.99g，10mmol,1.0eq)(实施例12)、2-氯-6-乙基吡啶-3-甲酸乙酯(CAS：2121849-39-4，2.13g，10mmol，1.0eq)(实施例13)、2-氯-6-三氟甲基吡啶-3-甲酸乙酯(CAS：1214346-14-1，2.53g，10mmol,1.0eq)(实施例14)在乙醇(50mL)中回流12小时，冷却，减压浓缩，剩余物通过柱层析分离(PE:EA体积比＝100:1)即得到无色油状物。
非对映异构体12-a的表征数据：白色固体，收率：19％，1H NMR(400MHz,CDCl3)δ7.99(d,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),5.03(d,J＝8.4Hz,1H),4.63–4.53(m,1H),4.50–4.42(m,1H),3.93(t,J＝6.8Hz,2H),3.75–3.67(m,1H),2.60(s,3H),2.10–2.01(m,2H),2.00–1.92(m,1H),1.82–1.77(m,4H),1.75(s,3H),1.37(s,3H),1.29(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.99,159.56,154.22,148.03,131.46,131.29,127.14,117.03,109.40,109.27,78.60,58.70,43.45,39.20,36.05,28.81,25.91,25.07,23.13,18.01,13.64。
非对映异构体12-b的表征数据：白色固体，收率：23％，1H NMR(400MHz,CDCl3)δ8.02(d,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),5.06(d,J＝8.4Hz,1H),4.62–4.40(m,2H),3.86–3.78(m,2H),3.77–3.69(m,1H),2.60(s,3H),2.14–1.98(m,2H),2.02,1.95–1.85(m,1H),1.79(s,3H),1.77–1.70(m,4H),1.47(s,3H),1.29(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ163.09,159.52,154.19,148.03,131.49,131.30,127.48,117.06,109.43,109.25,78.37,58.74,40.64,39.61,36.06,28.82,26.08,25.90,25.08,18.05,13.63。
非对映异构体13-a的表征数据：白色固体，收率：35％，1H NMR(400MHz,CDCl3)δ8.00(d,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),5.03(d,J＝8.4Hz,1H),4.65–4.44(m,2H),3.93(t,J＝6.4Hz,2H),3.76–3.67(m,1H),2.87(q,J＝7.6Hz,2H),2.08–2.00(m,2H),1.99–1.93(m,1H),1.83–1.76(m,4H),1.75(s,3H),1.37(s,3H),1.35–1.26(m,6H).13C NMR(101MHz,CDCl3)δ164.47,163.00,154.16,148.14,131.51,131.33,127.21,116.03,109.50,109.44,78.68,58.88,43.45,39.26,36.11,31.70,28.87,25.97,23.16,18.06,13.69,13.54。
非对映异构体13-b的表征数据：白色固体，收率：28％，1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.0Hz,1H),6.98(d,J＝8.0Hz,1H),5.09–5.03(m,1H),4.65–4.42(m,2H),3.86–3.80(m,2H),3.78–3.70(m,1H),2.87(q,J＝7.6Hz,2H),2.15–2.00(m,2H),1.93–1.87(m,1H),1.79(s,3H),1.77–1.70(m,4H),1.47(s,3H),1.35(t,J＝7.6Hz,3H),1.29(t,J＝7.2Hz,3H).13CNMR(101MHz,CDCl3)δ164.32,163.03,154.09,147.99,131.40,131.24,127.42,115.96,109.37,109.34,78.27,58.69,40.53,39.56,36.01,31.57,28.74,26.00,25.82,17.96,13.55,13.40。
非对映异构体14-a的表征数据：白色固体，收率：16％，1H NMR(400MHz,CDCl3)δ8.28(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),5.02–4.97(m,1H),4.62–4.43(m,2H),3.94(t,J＝6.8Hz,2H),3.78–3.69(m,1H),2.13–2.04(m,2H),2.03–1.97(m,1H),1.85–1.78(m,4H),1.75(s,3H),1.40(s,3H),1.30(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.59,153.20,148.21,147.37(q,J＝70Hz),132.83,132.34,126.23,121.39(d,J＝273Hz),114.34,113.29(q,J＝5Hz),112.47,79.22,58.71,43.44,39.06,36.66,29.05,25.94,23.23,18.09,13.45。
非对映异构体14-b的表征数据：白色固体，收率：19％，1H NMR(400MHz,CDCl3)δ8.30(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),5.03(d,J＝8.4Hz,1H),4.61–4.42(m,2H),3.88–3.80(m,2H),3.79–3.72(m,1H),2.17–2.10(m,1H),2.08–2.00(m,1H),1.97–1.88(m,1H),1.82–1.76(m,4H),1.74(s,3H),1.50(s,3H),1.31(d,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.71,153.19,148.20,147.35(q,J＝70Hz),132.83,132.33,126.51,121.39(d,J＝273Hz),114.32,113.32(q,J＝5Hz),112.52,79.05,58.74,40.57,39.47,36.68,29.06,26.12,25.92,18.11,13.43。
实施例15-22
实施例15-22中未给出具体实验步骤的化合物制备方法和条件均同制备化合物15。需要说明的是，由非对映异构体1-a可合成相应的非对映异构体15-a，由非对映异构体1-b可合成相应的非对映异构体15-b；以此类推，非对映异构体2-a可合成相应的非对映异构体16-a，由非对映异构体2-b可合成相应的非对映异构体16-b……非对映异构体8-a可合成相应的非对映异构体22-a，由非对映异构体8-b可合成相应的非对映异构体22-b。以非对映异构体15-a的制备进行说明。
(f).中间体VII的制备:化合物1-a(328mg，1mmol，1.0eq)溶于二氯甲烷(10mL)，在0℃下，加入戴斯马丁氧化剂(636mg，1.5mmol，1.5eq)，转入室温下反应3小时，过滤，减压浓缩，剩余物通过柱层析分离(PE:EA体积比＝20:1)即得到淡黄色油状化合物VII(325mg，收率为99％)。
(g).化合物15的制备:化合物VII(326mg，1mmol，1.0eq)、盐酸羟胺(138mg，2mmol，2.0eq)和碳酸钾(276mg，2mmol，2.0eq)在甲醇(2mL)和水(2mL)的混合溶剂中反应4小时，减压浓缩，剩余物通过柱层析分离(PE:EA体积比＝20:1)即得到白色固体15-a(340mg，收率为99％)。
非对映异构体15-a的表征数据：白色固体，收率：99％，1H NMR(400MHz,DMSO)δ11.02(s,1H),8.62–8.58(m,1H),8.23–8.18(m,1H),7.30–7.25(m,1H),6.96(t,J＝5.2Hz,1H),4.92(d,J＝8.4Hz,1H),3.60(s,3H),3.59–3.53(m,1H),2.74(d,J＝5.2Hz,2H),2.06–2.00(m,1H),1.75–1.69(m,4H),1.65(s,3H),1.33(s,3H).13C NMR(101MHz,DMSO)δ161.89,153.23,149.86,148.51,145.46,131.34,130.25,127.27,117.64,111.11,109.72,77.63,38.07,35.71,28.35,27.70,25.61,22.66,17.90。
非对映异构体16-a的表征数据：白色固体，收率：99％，1H NMR(400MHz,CDCl3)δ8.59–8.55(m,1H),8.20–8.15(m,1H),7.60(t,J＝6.4Hz,0.5H),7.15–7.10(m,1H),6.98(t,J＝5.6Hz,0.5H),5.06–4.99(m,1H),4.64–4.45(m,2H),3.80–3.71(m,1H),2.95–2.82(m,1H),2.72–2.58(m,1H),2.06–1.96(m,1H),1.85–1.76(m,4H),1.75(s,3H),1.41(s,1.5H),1.38(s,1.5H),1.31(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.79,153.85,153.78,149.81,148.45,147.44,147.06,132.17,132.15,131.44,131.41,126.50,126.47,117.31,111.96,111.92,110.45,110.40,77.93,77.54,40.92,38.91,36.34,36.15,28.84,28.81,25.88,23.48,23.35,18.06,13.57。
非对映异构体17-a的表征数据：白色固体，收率：97％，1H NMR(400MHz,CDCl3)δ8.55–8.52(m,1H),8.18–8.11(m,1H),7.57(t,J＝6.4Hz,0.5H),7.13–7.08(m,1H),6.96(t,J＝5.2Hz,0.5H),6.03–5.85(m,1H),5.05(d,J＝8.4Hz,1H),3.77–3.68(m,1H),2.93–2.79(m,1H),2.71–2.56(m,1H),2.05–1.95(m,1H),1.87–1.75(m,4H),1.74(s,3H),1.64(d,J＝6.8Hz,3H),1.60(d,J＝6.8Hz,3H),1.39(d,J＝12.8Hz,3H).13C NMR(126MHz,CDCl3)δ163.39,153.50,153.45,149.13,148.97,147.92,147.52,131.98,131.95,131.25,131.23,127.00,126.97,117.09,112.12,112.08,77.74,45.71,40.76,38.97,36.01,29.82,28.91,28.89,25.92,23.81,23.69,20.28,19.75,18.13。
非对映异构体18-a的表征数据：白色固体，收率：95％，1H NMR(400MHz,CDCl3)δ8.65–8.57(m,1H),8.18–8.12(m,1H),7.58(t,J＝6.4Hz,1H),7.17–7.12(m,1H),6.95(t,J＝5.2Hz,1H),5.05–1.96(m,1H),3.76–3.66(m,1H),3.03–2.96(m,1H),2.93–2.80(m,1H),2.70–2.56(m,1H),2.05–1.95(m,1H),1.85–1.75(m,4H),1.73(s,3H),1.42–1.28(m,5H),0.94–0.75(m,2H).13C NMR(101MHz,CDCl3)δ164.34,153.91,153.85,150.37,149.29,147.40,147.03,132.17,131.35,126.53,126.51,117.53,112.37,112.33,110.69,110.65,77.99,77.61,40.87,38.85,36.10,28.77,28.74,25.88,25.46,23.54,23.42,18.13,10.33,9.94。
非对映异构体19-a的表征数据：白色固体，收率：99％，1H NMR(400MHz,CDCl3)δ8.59–8.55(m,1H),8.22–8.12(m,1H),7.59(t,J＝6.4Hz,0.5H),7.18–7.07(m,1H),6.97(t,J＝5.6Hz,0.5H),5.10–4.93(m,1H),4.56–4.35(m,2H),3.83–3.68(m,1H),2.95–2.79(m,1H),2.72–2.57(m,1H),2.06–1.96(m,1H),1.85–1.76(m,4H),1.74(s,3H),1.73–1.63(m,2H),1.48–1.32(m,5H),0.95(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.95,153.79,153.73,149.78,148.64,147.44,147.05,132.08,132.06,131.34,131.31,126.64,126.62,117.26,111.84,111.81,110.42,110.38,77.88,77.48,41.17,40.85,38.89,36.09,30.39,28.81,28.78,25.88,23.54,23.42,20.44,18.06,14.05。
非对映异构体20-a的表征数据：白色固体，收率：98％，1H NMR(400MHz,CDCl3)δ8.04–8.00(m,1H),7.58(t,J＝6.4Hz,0.5H),7.01–6.93(m,1.5H),5.03(d,J＝8.0Hz,1H),4.64–4.43(m,1H),3.77–3.68(m,1H),2.92–2.79(m,1H),2.70–2.56(m,4H),2.04–1.94(m,1H),1.84–1.76(m,4H),1.74(s,3H),1.39(s,1.5H),1.36(s,1.5H),1.29(t,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.98,159.68,154.11,154.05,148.11,131.92,131.90,131.45,131.43,126.93,117.08,109.40,109.36,109.23,109.20,77.70,40.94,39.05,36.12,28.84,28.81,25.93,25.12,23.57,23.46,18.10,13.67。
非对映异构体21-a的表征数据：白色固体，收率：89％，1H NMR(400MHz,CDCl3)δ8.06–8.01(m,1H),7.59(t,J＝6.4Hz,0.5H),7.20–6.95(m,1.5H),5.02(d,J＝8.4Hz,1H),4.66–4.44(m,2H),3.78–3.70(m,1H),2.91–2.83(m,3H),2.67–2.60(m,1H),2.04–1.95(m,1H),1.84–1.75(m,4H),1.74(s,3H),1.41–1.27(m,9H).13C NMR(101MHz,CDCl3)δ164.59,163.01,154.13,154.06,148.16,131.93,131.91,131.50,131.48,127.02,126.98,116.08,109.42,109.38,77.66,40.91,39.09,36.17,31.73,29.84,29.80,28.87,28.84,25.96,23.59,23.50,18.12,13.69,13.52。
非对映异构体22-a的表征数据：白色固体，收率：69％，1H NMR(400MHz,CDCl3)δ8.32–8.27(m,1H),7.58(t,J＝6.4Hz,0.5H),7.48(d,J＝8.0Hz,1H),7.00–6.93(m,0.5H),5.00(d,J＝8.0Hz,1H),4.61–4.43(m,2H),3.80–3.71(m,1H),2.96–2.80(m,1H),2.73–2.60(m,1H),2.07–1.98(m,1H),1.87–1.77(m,4H),1.75(s,3H),1.43(s,1.5H),1.39(s,1.5H),1.31(t,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3)δ162.56,153.08,153.01,148.20,147.67,147.31,132.95,132.77,125.94,122.74,120.01,114.22,114.18,113.36,112.44,78.37,78.03,40.83,38.86,36.73,36.11,29.84,29.00,25.93,23.58,23.46,18.14,13.44。
生物学测试评价
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。
测试例1
磷酸二酯酶4(PDE4)抑制活性测试方法：
(1)磷酸二酯酶4抑制活性以PDE4D2催化域的抑制活性进行评价，以cAMP为底物，以Rolipram为阳性对照。
A、将含有20mM Tris/HCl缓冲液(pH 7.5)、10mM MgCl2、1mM DTT和10-30nM特异性荧光底物3H-cAMP(20,000-30,000c.p.m./assay，GE Healthcare)的分析缓冲液和待测化合物在室温(25℃)下孵育15分钟。
B、加入0.2M ZnSO4终止反应。用0.2M Ba(OH)2使反应产物3H-AMP沉淀析出，未反应的3H-cAMP留在上清液中。
C、用液体闪烁计数仪(PerkinElmer 2910liquid scintillation counter)测定上清液的放射性。
D、对于IC50的测定，至少使用8种不同的待测化合物浓度。
E、每次测量至少重复三次。采用非线性回归方法计算IC50值。
磷酸二酯酶4抑制活性测试方法可参考：
a.J.Nat.Prod.2014,77,955-962
b.Eur.J.Med.Chem.2016,114,134-140.
c.Biochem.Pharmacol.2017,130,51-59.
(2)结果分析，结果如下表1所示：
表1化合物的PDE4抑制活性评价表
测试例2
化合物在小鼠银屑病模型中的作用
(1)以化合物12-a为例研究其在咪喹莫特(IMQ)诱导的小鼠银屑病模型中的治疗作用，所用小鼠为6-8周龄雌性BALB/c小鼠，购买自广东药康生物科技有限公司(许可证：SCXK(粤)2020-0054)，小鼠按照国家、地方和学校生物安全法规使用和管理(动物实验伦理：SYSU-IACUC-2021-001343)。
A：小鼠随机分为4组，正常(Normal)组，模型(Model)组，4％-化合物12-a软膏剂组，2％-化合物12-a软膏剂组)，每组6只；小鼠背部皮肤(2cm×3cm)剃毛，用剃毛膏清除绒毛，饲养24小时后备用；
B：Normal组背部皮肤涂抹62.5毫克空白软膏基质(空白软膏基质由1.8g硬脂醇，2.0g白凡士林，1.3mL液体石蜡，0.2g月桂醇硫酸钠，1.0g甘油和15.0g蒸馏水通过乳化法制备)；Model组背部皮肤涂抹62.5毫克IMQ乳膏，6小时后涂抹62.5毫克空白软膏基质；4％-化合物12-a软膏剂组背部皮肤涂抹62.5毫克IMQ乳膏，6小时后涂抹62.5毫克4％-化合物12-a软膏剂；2％-化合物12-a软膏剂组背部皮肤涂抹62.5毫克IMQ乳膏，6小时后涂抹62.5毫克2％-化合物12-a软膏剂。每日一次，重复7天；
C：第二天开始每天记录小鼠体重，并根据PASI评分表给与每只小鼠打分，连续记录7天，打分标准如下：
表2 PASI评分表
表1和图1的结果表明，本发明中所提供的分子对磷酸二酯酶4有较强的抑制效果，部分化合物达到纳摩尔水平的活性级别，远远大于阳性对照Rolipram。此外，在IMQ诱导的小鼠银屑病模型中，化合物12-a能够显著抑制银屑病的发生，并且呈现剂量依赖性，同时小鼠体重维持在正常水平，预示该分子具有良好的安全性和耐受性，以上结果预示此类分子具有开发成新型磷酸二酯酶4抑制剂药物的巨大潜力。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (7)
1.一种喹啉酮骨架的PDE4抑制剂，其特征在于：是如通式A和通式B所示的Toddacoumalone衍生物、其立体异构体或其药学上可接受的盐；
其中：
X、X1、X2、X3各自独立的选择CH或N；
所述的R选自甲基、乙基、三氟甲基；
所述的R1选自甲基、乙基；
所述的R2选自羟基；
R3选自CH2或N-OH。
2.一种喹啉酮骨架的PDE4抑制剂，其特征在于：所述的喹啉酮骨架的PDE4抑制剂是如下结构的化合物中任一种的立体异构体或其药学上可接受的盐：
3.权利要求1所述的喹啉酮骨架的PDE4抑制剂的制备方法，其特征在于包括如下步骤：
(a)将化合物I和伯胺混合，回流反应，冷却，浓缩，得到化合物II；
(b)化合物II在乙酸酐中回流反应，冷却，分离，得到化合物III；
(c)化合物III在叔丁醇钾中回流反应，冷却后，加入水，分层，将得到的水层的pH值调至中性，析出固体，过滤，干燥，得到化合物IV；
(d)化合物IV与异戊烯醛，在吡啶中回流反应，得到化合物V；
(e)化合物V与异戊烯醛，在酸性添加剂存在下，经二级胺催化反应，得到化合物VI的非对映异构体，即所述的喹啉酮骨架的PDE4抑制剂；
(f)化合物VI在0℃下经戴斯马丁氧化剂氧化，过滤，浓缩，分离，得到化合物VII；
(g)化合物VII与盐酸羟胺，在碱性条件下反应，将得到的产物浓缩，分离，得到化合物VIII；
其中，化合物I、化合物II、化合物III、化合物IV、化合物V、化合物VI、化合物VII、化合物VIII的结构如下：
4.根据权利要求3所述的喹啉酮骨架的PDE4抑制剂的制备方法，其特征在于：
步骤(a)中所述的化合物I和所述的伯胺按摩尔比小于1配比；
步骤(a)中所述的回流反应的体系中的溶剂为乙醇；
步骤(a)中所述的回流反应的时间为2～24小时；
步骤(b)中所述的化合物II和所述的乙酸酐按摩尔比小于1配比；
步骤(b)中所述的回流反应的时间为12～24小时；
步骤(c)中所述的化合物III和所述的叔丁醇钾按摩尔比小于1配比；
步骤(c)中所述的回流反应的体系中的溶剂为二甲苯；
步骤(c)中所述的回流反应的时间为12～24小时；
步骤(c)中所述的pH值的调节剂为乙酸；
步骤(d)中所述的化合物IV与所述的异戊烯醛按摩尔比小于1配比；
步骤(d)中所述的回流反应的体系还含有无水硫酸镁；
步骤(d)中所述的回流反应的时间为1～6小时；
步骤(e)中所述的化合物V与异戊烯醛按摩尔比小于1配比；
步骤(e)中所述的酸性添加剂为苯甲酸；
步骤(e)中所述的酸性添加剂的添加量按化合物V：酸性添加剂＝摩尔比10：1～3配比；
步骤(e)中所述的二级胺为脯氨酸；
步骤(e)中所述的二级胺的添加量按化合物V：二级胺＝摩尔比10：1～3配比；
步骤(e)中所述的催化反应的体系中的溶剂为四氢呋喃；
步骤(e)中所述的催化反应的条件为室温反应12～72小时。
5.根据权利要求3所述的喹啉酮骨架的PDE4抑制剂的制备方法，其特征在于：
步骤(f)中所述的化合物VI和所述的戴斯马丁氧化剂按摩尔比1：1～2配比；
步骤(f)中所述的化合物VI在0℃下经戴斯马丁氧化剂氧化的具体步骤如下：将化合物VI溶解于有机溶剂中，在0℃下加入戴斯马丁氧化剂，反应；
步骤(g)中所述的化合物VII与所述的盐酸羟胺按摩尔比小于1配比；
步骤(g)中所述的碱为碳酸钾；
步骤(g)中所述的碱的用量相当于化合物VII摩尔量的1～3倍；
步骤(g)中所述的反应的体系中的溶剂为甲醇和水混合得到的溶剂；
步骤(g)中所述的反应的条件为室温反应3～5小时。
6.权利要求1或2所述的喹啉酮骨架的PDE4抑制剂在制备用于预防和治疗磷酸二酯酶4相关疾病的药物中的应用。
7.一种药用组合物，其特征在于：包括权利要求1或2所述的喹啉酮骨架的PDE4抑制剂，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
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