CN113004356A - 新型京尼平衍生物，及其制备方法和应用 - Google Patents
新型京尼平衍生物，及其制备方法和应用 Download PDFInfo
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- CN113004356A CN113004356A CN202110246027.9A CN202110246027A CN113004356A CN 113004356 A CN113004356 A CN 113004356A CN 202110246027 A CN202110246027 A CN 202110246027A CN 113004356 A CN113004356 A CN 113004356A
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Abstract
本发明提供了新型京尼平类衍生物及其制备方法，包括京尼平苷类衍生物和京尼平类衍生物。属于医药药物化学领域，所述京尼平苷类衍生物的结构如式(I)所示：
Description
技术领域
本发明涉及的是一种医药化工技术领域的化合物及其制备，具体为一种新型京尼平衍生物的制备方法和应用。
背景技术
脑瘤是指生长于颅内的肿瘤，分为原发性和继发性颅内肿瘤。原发性肿瘤是肿瘤来自脑、脑膜、脑垂体、颅神经、脑血管和胚胎残余组织者。而继发性颅内肿瘤则是由身体其他部位的恶性肿瘤转移至颅内。其中最常见的脑瘤是胶质瘤，如星状细胞瘤、少突胶质细胞瘤、室管膜瘤、髓母细胞瘤。恶性脑瘤由于与正常脑组织分界不清，手术难以全切，而且有些深部肿瘤不适合外科手术治疗，难度较大，致残、致死率极高，被称为“癌后”。与其他肿瘤类型不同，由于血脑屏障，恶性脑瘤目前还没有有效的靶向化疗方式，寻找靶向药物和生物酶抑制剂是目前治疗恶性脑瘤的较好方式。
神经退行性疾病是由神经元或髓鞘的丧失所致，随着时间的推移而恶化，出现功能障碍。可分为急性和慢性神经退行性疾病。前者包括脑缺血、脑损伤、癫痫，后者包括阿尔兹海默病、帕金森病、亨廷顿舞蹈症及肌萎缩性侧索硬化等。目前没有根治神经退行性疾病的药物，无法阻止病情发展，随着患者逐年增加，开发针对神经退行性疾病的药物具有重要意义。
很多文献证明Scp1在成骨细胞分化、神经元分化、癌细胞迁移、侵袭以及胚胎中枢神经系统发育起着重要作用。Scp1是神经元再生的良好靶标，可补偿由于阿尔茨海默氏症引起的脑细胞损失。Scp1与其他被认为“无成药性”的磷酸酶不同，其具有独特的活性位点，与其天然底物磷酸化CTD肽结合的结构揭示了与其他磷酸酶相比较宽的底物结合区域，因此，Scp1有望成为潜在的药物靶点。
综上所述，本领域尚缺乏新的Scp1抑制剂。
发明内容
本发明的目的是提供一种新型Scp1抑制剂。
本发明的第一方面，提供了一种如下式I所示的京尼平衍生物：
其中：
各个R1各自独立地选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基、取代或未取代的苄基；
R2选自下组：氢、卤素、硝基、氰基、羟基、氨基、酯基、甲酰基、酰胺基、磺酰胺基、甲酰胺基、砜基、亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基和5-14元杂芳基；
R3和R4各自独立地选自下组：氢、卤素、硝基、氰基、羟基、氨基、酯基、甲酰基、酰胺基、磺酰胺基、甲酰胺基、砜基、亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基和5-14元杂芳基；
R5选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基；或如下式II所示的基团：
各个R6各自独立地选自下组：氢、甲基，取代或未取代的苄基；
其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C4烷基、C1-C4卤代烷基、COOH、C2-C10酯基。
在另一优选例中，所述的京尼平类衍生物具有如下式所示的结构：
其中，所述的R2选自下组：氢、卤素、硝基、氰基、羟基、氨基、C2-C6酯基、甲酰基、C2-C6酰胺基、磺酰胺基、甲酰胺基、C1-C6砜基、C1-C6亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基、和5-14元杂芳基；
R3和R4各自独立地选自下组：氢、卤素、硝基、氰基、羟基、氨基、C2-C6酯基、甲酰基、C2-C6酰胺基、磺酰胺基、甲酰胺基、C1-C6砜基、C1-C6亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基、和5-14元杂芳基。
在另一优选例中，各个R1各自独立地选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基、取代或未取代的苄基；
R2选自下组：氢、卤素、硝基、氰基、羟基、氨基、C2-C6酯基、甲酰基、C2-C6酰胺基、磺酰胺基、甲酰胺基、C1-C6砜基、C1-C6亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基、和5-14元杂芳基(优选为I)；
R3和R4各自独立地选自下组：氢、卤素、硝基、氰基、羟基、氨基、C2-C6酯基、甲酰基、C2-C6酰胺基、磺酰胺基、甲酰胺基、C1-C6砜基、C1-C6亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基、和5-14元杂芳基；
R5选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基，或如下式II所示的基团：
在另一优选例中，各个R1各自独立地选自下组：H、甲基、苄基、4-甲基苄基、4-氯苄基；
R2选自下组：氢、碘；
R3选自下组：氟、氯、溴、硝基、甲基；
R4选自下组：氢、氟、氯、溴、硝基、甲基；
R5选自下组：氢、甲基，苄基，或如下式II所示的基团：
在另一优选例中，所述的京尼平衍生物选自下组：
本发明的第二方面，提供了一种如本发明第一方面所述的京尼平衍生物的制备方法，所述的方法包括步骤：
用式Ia化合物和式Ib化合物反应，得到式I化合物；
其中，各个基团的定义如本发明第一方面中所示。
在另一优选例中，所述的R5为式II所示的基团，且所述的方法包括步骤：
且所述的方法包括如下步骤：
(a)在N,N-二甲基甲酰胺中，在碱存在下，用京尼平苷与R1-Br反应过夜，得到化合物Ⅲ：
(b)在甲醇中，用式III化合物与碱反应，得到化合物Ⅳ；
(c)在N,N-二甲基甲酰胺中，用式IV化合物与取代或未取代的苯丙氨酸和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、4-二甲氨基吡啶、N,N-二异丙基乙胺共同反应，得到化合物Ⅴ。
(d)用式V化合物进行取代基修饰，制备式I化合物。
在另一优选例中，所述的R5选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基；且所述的方法包括如下步骤(i)至(v)：
(i)将京尼平加入乙醇，在酸存在下进行回流反应，得到化合物ⅰ：
(ii)在二氯甲烷中，用化合物ⅰ与三乙胺、苯磺酰氯、4-二甲氨基吡啶进行反应，得到化合物ⅱ：
(iii)在甲醇中，用化合物ⅱ与氢氧化钠溶液进行反应，得到化合物ⅲ：
(iv)在N,N-二甲基甲酰胺中，用化合物ⅲ与对氯苯丙氨甲酯盐酸盐，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，4-二甲氨基吡啶和N,N-二异丙基乙胺进行反应，得化合物ⅳ：
(v)在甲醇中，用化合物ⅳ与碱反应，得化合物ⅴ
或所述的方法包括如下步骤(1)至(5)：
(1)在苯甲醇中，用京尼平与酸回流反应，得化合物ⅵ：
(2)在N,N-二甲基甲酰胺中，用化合物ⅵ与NaH反应，然后加入对三氟甲基苄溴继续反应，得化合物ⅶ：
(3)在甲醇中，用化合物ⅶ与碱反应，得化合物ⅷ：
(4)在N,N-二甲基甲酰胺中，用化合物ⅷ与对氯苯丙氨甲酯盐酸盐、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、4-二甲氨基吡啶和N,N-二异丙基乙胺反应，得化合物ⅸ：
(5)在甲醇中，用化合物ⅸ与碱反应，得化合物ⅹ：
本发明的第三方面，提供了一种如本发明第一方面所述的京尼平衍生物在制备用于抑制蛋白酶Scp1和/或PTP1B活性的药物组合物中的用途；较佳地，所述的药物组合物用于预防或治疗选自下组的疾病：脑瘤、神经退行性疾病。
本发明的第四方面，提供了一种药物组合物，其特征在于，所述的药物组合物包括：如本发明第一方面所述的化合物，以及药学上可接受的载体。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明提供新型京尼平类衍生物的制备方法和应用。本发明基于Scp1结构特点，设计新型京尼平类衍生物，其结构中存在一端疏水端，且存在羧酸基作为亲水端，分别与Scp1比较大的疏水口袋以及活性中心镁离子和周围的亲水口袋结合。分子中裸露的羧基可以和Scp1口袋中的Ser211，Asp206，Lys190或Asp96形成分子间氢键，侧链的苄基可以与活性口袋中的Phe106，Tyr188，Tyr158中任一或多个残基发生π-π相互作用，提高小分子和蛋白结合的稳定性。经Scp1抑制活性评价发现本发明所制备的新型化合物有良好的Scp1抑制活性，可以用于制备治疗和预防脑瘤和神经退行性疾病的药物。
京尼平(京尼平苷)类化合物
本发明涉及的一种京尼平苷类化合物，其结构式为：
其中：
各个R1各自独立地选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基、取代或未取代的苄基；
R2选自下组：氢、卤素、硝基、氰基、羟基、氨基、酯基、甲酰基、酰胺基、磺酰胺基、甲酰胺基、砜基、亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基和5-14元杂芳基；
R3选自下组：氢、卤素、硝基、氰基、羟基、氨基、酯基、甲酰基、酰胺基、磺酰胺基、甲酰胺基、砜基、亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基和5-14元杂芳基；
本发明涉及的一种京尼平类化合物，其结构式为：
其中：
R1选自下组：氢、卤素、硝基、氰基、羟基、氨基、酯基、甲酰基、酰胺基、磺酰胺基、甲酰胺基、砜基、亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基和5-14元杂芳基；
R3，R4和R5各自独立地选自下组：氢、卤素、硝基、氰基、羟基、氨基、酯基、甲酰基、酰胺基、磺酰胺基、甲酰胺基、砜基、亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基和5-14元杂芳基。
京尼平(京尼平苷)类化合物的制备
本发明还涉及一种制备上述京尼平苷类衍生物的方法，包括如下步骤：
(a)取1摩尔当量的京尼平苷溶于N,N-二甲基甲酰胺中，在冰浴中加入6摩尔当量60％氢化钠，反应1h后，与6摩尔当量的苄溴过夜反应，得化合物Ⅲ。
(b)取1摩尔当量的化合物Ⅲ溶于甲醇中，加入2摩尔当量的1M氢氧化钠溶液，回流过夜，得化合物Ⅳ。
(c)取1摩尔当量的化合物Ⅳ溶于N,N-二甲基甲酰胺中，加入1.2摩尔当量的对氯苯丙氨酸，1.2摩尔当量的1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，1.5摩尔当量的4-二甲氨基吡啶，3摩尔当量的N,N-二异丙基乙胺，于室温过夜，得化合物Ⅴ。
本发明还涉及两种制备上述京尼平类衍生物的方法，第一种包括如下步骤：
(a)取1摩尔当量的京尼平溶于乙醇，加入两滴浓盐酸，回流反应10h，得到化合物ⅰ。
(b)取1摩尔当量的化合物ⅰ溶于二氯甲烷中，加入2摩尔当量的三乙胺，1.5摩尔当量的苯磺酰氯，一定量的4-二甲氨基吡啶，于室温过夜，得化合物ⅱ。
(c)取1摩尔当量的化合物ⅱ溶于甲醇中，加入2摩尔当量的2M氢氧化钠溶液，于室温反应3h，得化合物ⅲ。
(d)取1摩尔当量的对氯苯丙氨酸溶于甲醇中，加入1.2摩尔当量的二氯亚砜，回流过夜，得对氯苯丙胺甲酯盐酸盐。
(e)取1摩尔当量的化合物ⅲ溶于N,N-二甲基甲酰胺中，加入1.2摩尔当量的对氯苯丙氨甲酯盐酸盐，1.2摩尔当量的1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，1.5摩尔当量的4-二甲氨基吡啶，3摩尔当量的N,N-二异丙基乙胺，于室温过夜，得化合物ⅳ。
(f)取1摩尔当量的化合物ⅳ溶于甲醇中，加入2摩尔当量的2M氢氧化钠溶液，于室温过夜，得化合物ⅴ。
第二种包括如下步骤：
(a)取1摩尔当量的京尼平溶于苯甲醇，加入两滴浓盐酸，回流反应5h，得化合物ⅵ。
(b)取1摩尔当量的化合物ⅵ溶于N,N-二甲基甲酰胺中，在冰浴中，加入1.2摩尔当量的60％NaH，反应1h后，加入1.2摩尔当量的对三氟甲基苄溴，于室温过夜，得化合物ⅶ。
(c)取1摩尔当量的化合物ⅶ溶于甲醇中，加入2摩尔当量的2M氢氧化钠溶液，于室温反应5h，得化合物ⅷ。
(d)取1摩尔当量的对氯苯丙氨酸溶于甲醇中，加入1.2摩尔当量的二氯亚砜回流过夜，得对氯苯丙胺甲酯盐酸盐。
(e)取1摩尔当量的化合物ⅷ溶于N,N-二甲基甲酰胺中，加入1.2摩尔当量的对氯苯丙氨甲酯盐酸盐，1.2摩尔当量的1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，1.5摩尔当量的4-二甲氨基吡啶，3摩尔当量的N,N-二异丙基乙胺，于室温过夜，得化合物ⅸ。
(f)取1摩尔当量的化合物ⅸ溶于甲醇中，加入2摩尔当量的2M氢氧化钠溶液，于室温过夜，得化合物ⅹ。
药物组合物和施用方法
由于本发明化合物具有优异的对Scp1的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由Scp1介导的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：糖尿病、肥胖症等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-500mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明另外涉及以上所述的新型京尼平类衍生物在制备用于抗脑瘤和抗神经退行性疾病方面的应用。
作为优选方案，所述的新型京尼平类衍生物通过抑制Scp1来抗脑瘤和抗神经退行性疾病。
与现有技术相比，本发明具有如下有益效果：
本发明涉及的新型京尼平类衍生物，是以Scp1酶为靶点，其疏水端和亲水端是根据Scp1磷酸酶比较大的疏水口袋以及活性中心镁离子和周围的亲水残基而设计的。通过初步抑制Scp1试验确认本发明所制备的新型化合物有良好的Scp1抑制活性，后续可以用于制备治疗和预防脑瘤和神经退行性疾病的药物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1化合物Ⅲ的合成
将京尼平苷(1g,2.58mmol)溶于DMF(10mL)中，冰水浴下缓慢加入60％氢化钠(0.618g,15.46mmol)，反应1h之后，缓慢加入苄溴(15.46mmol)，常温反应过夜。反应结束后，将反应液加到冰水(60mL)中，用乙酸乙酯(90mL)萃取三次，合并有机相，依次用1M盐酸溶液(30mL)、饱和食盐水(60mL)洗涤三次，无水硫酸钠干燥，减压浓缩，硅胶色谱柱分离纯化，得到淡黄色油状液体，收率为70％。1H NMR(400MHz,Chloroform-d)δ7.54(s,1H),7.38(d,J＝4.2Hz,1H),7.33(q,J＝5.3,4.6Hz,22H),7.22(d,J＝7.2Hz,2H),5.87(s,1H),5.36(d,J＝5.8Hz,1H),5.29(s,1H),4.95(t,J＝10.7Hz,2H),4.87(d,J＝9.2Hz,2H),4.70–4.50(m,7H),4.22(d,J＝13.7Hz,2H),3.75(d,J＝11.1Hz,1H),3.69(s,3H),3.64(d,J＝9.0Hz,1H),3.54–3.45(m,2H),3.33(q,J＝7.4Hz,1H),3.01(t,J＝6.6Hz,1H),2.92(dd,J＝16.6,7.7Hz,1H),2.24(d,J＝16.9Hz,2H).
实施例2
参照实施例1，得到淡黄色油状液体，收率为61％。1H NMR(400MHz,Chloroform-d)δ7.60(s,1H),7.35–7.10(m,20H),5.91(s,1H),5.42(s,1H),4.96(s,1H),4.90(dd,J＝12.2,3.0Hz,2H),4.85(s,1H),4.75–4.47(m,8H),4.27(s,2H),3.74(s,3H),3.71–3.62(m,2H),3.52(s,2H),3.41–3.34(m,1H),3.05(s,1H),2.95(s,1H),2.41(s,15H),2.31(s,1H),2.26(s,1H).
实施例3
参照实施例1，得到淡黄色油状液体，收率为65％。1H NMR(400MHz,Chloroform-d)δ7.48(s,1H),7.30(d,J＝8.3Hz,3H),7.26–7.16(m,13H),7.14(d,J＝8.1Hz,2H),7.06(d,J＝8.0Hz,2H),5.84(s,1H),5.32(d,J＝5.8Hz,1H),5.27(s,1H),4.81(d,J＝8.6Hz,2H),4.75–4.66(m,2H),4.61(s,2H),4.57–4.47(m,3H),4.43(s,2H),4.24–4.14(m,2H),3.65(s,3H),3.58(q,J＝8.9,8.2Hz,2H),3.48–3.42(m,1H),3.38(t,J＝8.1Hz,1H),3.28(q,J＝7.4Hz,1H),3.01–2.82(m,3H),2.20(dd,J＝17.0,5.1Hz,1H).
实施例4化合物Ⅳ的合成
将化合物Ⅲ(1.73mmol)溶于THF(10mL)中，加入2M氢氧化钠水溶液(3.46mmol)，回流过夜，反应结束后，减压浓缩，加入1M盐酸溶液调节pH至1-2，以乙酸乙酯(30mL)萃取三次，饱和食盐水(20mL)洗涤三次，无水硫酸钠干燥，减压浓缩，硅胶色谱柱分离纯化，得到黄色油状液体式，收率为99％。1H NMR(400MHz,Chloroform-d)δ7.63(s,1H),7.41–7.18(m,25H),5.87(s,1H),5.32(d,J＝6.3Hz,1H),4.94(t,J＝11.4Hz,2H),4.89–4.84(m,2H),4.71–4.47(m,7H),4.27–4.19(m,2H),4.14(q,J＝7.1Hz,1H),3.73(d,J＝11.0Hz,1H),3.62(d,J＝8.8Hz,1H),3.53–3.44(m,2H),3.29(q,J＝7.5Hz,1H),2.96(d,J＝5.9Hz,2H),2.90(s,1H),2.06(s,1H).
实施例5
参照实施例4，得到黄棕色油状液体，收率为96％。1H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.32(d,J＝7.6Hz,2H),7.22(t,J＝11.1Hz,8H),7.15–7.11(m,8H),7.06(d,J＝9.0Hz,2H),5.86(s,1H),5.78(s,1H),5.33–5.28(m,1H),4.91(dt,J＝10.9,5.4Hz,2H),4.80(d,J＝14.2Hz,4H),4.50(d,J＝18.1Hz,4H),4.21(s,1H),4.15(dd,J＝14.2,7.2Hz,2H),3.71(d,J＝10.0Hz,2H),3.64(d,J＝9.5Hz,2H),3.38(s,2H),3.00–2.93(m,2H),2.34(s,15H),2.07(s,1H).
实施例6
参照实施例4，得到黄色油状液体，收率为99％。1H NMR(400MHz,Chloroform-d)δ7.59(s,1H),7.30–6.98(m,20H),5.84(s,1H),5.34(d,J＝5.8Hz,1H),5.29(s,1H),4.80(dd,J＝11.6,7.4Hz,3H),4.73–4.64(m,2H),4.55–4.37(m,6H),4.15(d,J＝14.1Hz,2H),3.64–3.62(m,1H),3.57(t,J＝7.6Hz,2H),3.43(d,J＝9.1Hz,1H),3.37(t,J＝8.1Hz,1H),3.26(q,J＝7.4Hz,1H),2.99–2.84(m,2H),2.27–2.19(m,1H).
实施例7化合物Ⅴ的合成
将化合物Ⅳ(0.197mmol)溶于DMF(4mL)中，加入EDCI(45mg,0.236mmol)，HOBT(32mg,0.236mmol)，DIPEA(0.591mmol)，常温反应2h后，加入有机胺(0.217mmol)和DMAP(0.36mg,0.296mmol)，常温搅拌过夜。反应结束后，将溶液倒入装有冰水(30mL)中，用乙酸乙酯(20mL)萃取三次，合并有机相，有机相依次用1M柠檬酸水溶液(20mL)、1M稀盐酸水溶液(20mL)及饱和食盐水(10mL)洗涤三次，最后用无水硫酸钠干燥，减压浓缩，硅胶色谱柱分离纯化，得到淡黄色油状液体，收率为29％。1H NMR(400MHz,Chloroform-d)δ8.00(s,1H),7.33–7.16(m,28H),7.06(d,J＝8.0Hz,2H),6.10(d,J＝6.4Hz,1H),5.79(s,1H),5.11(d,J＝7.2Hz,1H),4.95–4.88(m,2H),4.84(s,1H),4.81(d,J＝5.8Hz,2H),4.64(d,J＝11.0Hz,1H),4.56(d,J＝11.4Hz,1H),4.52–4.44(m,4H),4.20(s,1H),4.12(q,J＝7.1Hz,2H),3.70(d,J＝10.5Hz,1H),3.67–3.61(m,2H),3.58(d,J＝8.9Hz,1H),3.41(d,J＝8.5Hz,1H),3.19(d,J＝8.0Hz,1H),3.12(dd,J＝13.9,5.1Hz,1H),2.87–2.82(m,1H),2.60–2.53(m,1H),2.04(s,2H)；13C NMR(101MHz,Chloroform-d)δ173.33,167.03,148.30,140.40,138.55,138.29,138.16,138.09,138.02,134.71,132.91,130.85,129.14,128.96,128.63,128.56,128.47,128.37,128.34,128.32,128.28,127.95,127.87,127.79,127.76,127.69,127.65,127.60,127.55,113.77,99.48,96.75,84.45,81.69,77.60,75.67,75.18,75.00,74.75,73.41,72.41,68.71,68.10,60.41,46.37,38.26,36.72,34.64.
实施例8
参照实施例7，得到淡黄色油状液体，收率为29％。1H NMR(400MHz,Chloroform-d)δ7.37–7.21(m,25H),7.09(t,J＝6.9Hz,3H),6.94(t,J＝8.3Hz,2H),6.16(s,1H),5.80(s,1H),5.10(d,J＝7.4Hz,1H),4.95(d,J＝10.2Hz,2H),4.84(t,J＝8.3Hz,3H),4.67(d,J＝11.2Hz,1H),4.62–4.46(m,6H),4.22(s,2H),3.71–3.61(m,3H),3.52–3.43(m,2H),3.24(q,J＝11.2,7.5Hz,2H),3.11(dt,J＝14.6,7.3Hz,2H),2.55(dd,J＝15.9,8.7Hz,1H),2.06(d,J＝5.4Hz,1H)；13C NMR(101MHz,Chloroform-d)δ167.41,163.22,160.78,148.70,140.55,138.56,138.26,138.16,138.05,131.80,130.94,130.86,128.92,128.90,128.79,128.74,128.63,128.57,128.40,128.36,128.31,127.97,127.89,127.82,127.80,127.73,127.65,127.60,127.56,115.52,115.31,113.58,99.55,97.02,84.46,81.68,77.63,75.69,75.16,75.02,74.75,73.42,72.52,68.76,68.18,53.49,46.25,38.26,36.28,34.75.
实施例9
参照实施例7，得到淡黄色油状液体，收率为23％。1H NMR(400MHz,Chloroform-d)δ7.60–7.25(m,27H),7.02–6.83(m,3H),5.81(dd,J＝17.6,8.7Hz,1H),5.54(d,J＝13.7Hz,1H),5.19–5.12(m,1H),4.96–4.49(m,12H),4.27–4.14(m,2H),3.65(dq,J＝17.8,10.0,9.3Hz,4H),3.45(q,J＝7.3Hz,3H),3.00–2.83(m,3H),2.15–2.00(m,1H)；13C NMR(101MHz,Chloroform-d)δ174.29,167.37,149.17,140.39,138.58,138.29,138.18,138.13,138.09,135.24,131.62,131.05,128.93,128.35,128.31,128.15,127.93,127.86,127.78,127.75,127.71,127.68,127.60,127.56,127.53,121.56,121.02,120.96,120.86,112.82,99.56,96.51,84.44,81.66,77.83,77.62,75.65,75.18,74.98,74.72,73.41,72.52,68.72,68.21,53.61,46.23,38.33,29.68.
实施例10
参照实施例7，得到黄色油状液体，收率为45％。1H NMR(400MHz,Chloroform-d)δ8.02–7.00(m,28H),6.39–6.22(m,1H),5.86(s,1H),5.71–5.52(m,1H),5.28(s,1H),5.08(dd,J＝32.8,8.9Hz,1H),4.96–4.45(m,11H),4.26–4.11(m,2H),3.77–3.66(m,2H),3.57–3.31(m,3H),3.16(dd,J＝45.3,9.4Hz,2H),2.87(d,J＝8.9Hz,1H),2.72–2.60(m,1H),2.07(s,2H)；13C NMR(101MHz,Chloroform-d)δ171.35,170.84,152.89,140.47,140.17,140.08,138.58,138.21,138.16,138.10,138.05,137.99,132.53,129.27,128.70,128.59,128.42,128.40,128.35,128.18,128.16,128.01,127.93,127.84,127.79,127.71,127.65,127.60,113.23,99.42,99.24,84.41,83.24,82.92,81.68,77.66,75.69,75.02,74.75,73.41,72.56,68.78,68.25,60.51,46.32,38.95,34.91,29.71.
实施例11
参照实施例7，得到黄色油状液体，收率为24％。1H NMR(400MHz,Chloroform-d)δ8.06(dd,J＝13.4,8.3Hz,2H),7.51–7.12(m,28H),6.21(dd,J＝17.6,6.8Hz,1H),5.79(s,1H),5.29(s,1H),5.15(dd,J＝19.5,7.0Hz,1H),4.91(t,J＝10.4Hz,2H),4.83(d,J＝10.8Hz,2H),4.80–4.74(m,1H),4.64(dd,J＝10.9,3.1Hz,1H),4.59–4.54(m,1H),4.50(d,J＝10.6Hz,4H),4.20(s,2H),3.65(ddd,J＝25.3,13.7,6.3Hz,3H),3.50–3.42(m,2H),3.33(dt,J＝19.4,5.8Hz,1H),3.20(dp,J＝15.7,7.7Hz,2H),2.63–2.53(m,1H),2.07(q,J＝13.9,13.3Hz,2H)；13C NMR(101MHz,Chloroform-d)δ173.31,167.71,147.08,144.02,143.92,140.46,140.33,138.48,138.15,138.05,137.96,130.25,128.39,128.36,128.34,128.29,128.23,128.09,127.97,127.90,127.88,127.80,127.75,127.72,127.69,127.63,127.57,123.57,113.34,99.47,96.80,84.40,82.26,81.66,77.58,75.69,75.12,75.03,74.76,73.42,72.53,68.72,53.39,46.46,38.33,34.54,29.68.
实施例12
参照实施例7，得到淡黄色油状液体，收率为20％。1H NMR(400MHz,Chloroform-d)δ7.31–7.21(m,25H),7.20–7.18(m,1H),7.08–7.01(m,4H),5.93(s,1H),5.75(s,1H),5.08(d,J＝6.9Hz,1H),4.92(d,J＝11.3Hz,2H),4.84–4.79(m,3H),4.63(d,J＝11.0Hz,1H),4.57–4.44(m,6H),4.18(s,2H),3.69–3.62(m,3H),3.45–3.39(m,2H),3.15(s,1H),3.10(d,J＝8.7Hz,1H),2.82(t,J＝7.7Hz,1H),2.48(dd,J＝16.8,9.2Hz,2H),2.29(s,3H),2.06(d,J＝10.3Hz,1H)；13C NMR(101MHz,Chloroform-d)δ174.41,167.73,148.47,140.29,138.53,138.27,138.12,138.09,138.01,136.79,132.70,129.37,129.28,129.18,128.95,128.94,128.37,128.32,128.30,128.29,127.94,127.88,127.86,127.85,127.79,127.76,127.69,127.58,127.54,113.71,99.46,96.73,84.45,81.67,81.65,77.59,75.67,75.17,75.00,74.76,73.39,72.45,68.11,57.26,46.34,36.49,34.56,29.67,21.03.
实施例13
参照实施例7，得到淡黄色油状液体，收率为23％。1H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.28(s,1H),7.26–7.02(m,22H),6.94(t,J＝8.9Hz,2H),5.79(s,1H),4.88(t,J＝11.1Hz,2H),4.78(dt,J＝13.8,9.2Hz,4H),4.61(d,J＝10.7Hz,1H),4.47(dt,J＝15.6,9.3Hz,4H),4.19(s,2H),3.70–3.60(m,3H),3.58–3.52(m,1H),3.42–3.37(m,1H),3.34–3.16(m,3H),2.63–2.45(m,2H),2.42–2.27(m,15H),2.01(d,J＝14.9Hz,1H)；13C NMR(101MHz,Chloroform-d)δ171.28,167.07,160.73,148.33,140.54,137.46,137.40,137.29,137.28,137.20,135.62,135.28,135.20,135.12,135.04,131.05,130.97,129.03,129.00,128.98,128.46,128.14,128.06,128.01,127.96,127.92,127.88,127.77,115.36,115.15,113.77,99.55,96.85,84.91,84.33,81.56,75.58,75.22,74.88,74.63,73.30,72.35,68.50,67.96,53.30,46.34,38.29,36.74,34.70,21.16.
实施例14
参照实施例7，得到淡黄色油状液体，收率为17％。1H NMR(400MHz,Chloroform-d)δ7.17(dd,J＝19.2,6.7Hz,12H),7.09(t,J＝8.2Hz,12H),5.78(s,1H),4.88(d,J＝12.1Hz,2H),4.80–4.74(m,4H),4.60(d,J＝10.9Hz,1H),4.45(d,J＝4.6Hz,4H),4.18(s,2H),3.66–3.60(m,3H),3.53(d,J＝9.1Hz,1H),3.46–3.37(m,3H),3.23(s,1H),3.18(s,1H),2.89(s,1H),2.52(t,J＝11.8Hz,2H),2.33(d,J＝7.7Hz,15H)；13C NMR(101MHz,Chloroform-d)δ171.53,167.51,148.58,140.60,137.44,137.37,137.28,137.26,137.18,135.62,135.21,135.19,135.08,135.03,134.87,132.92,130.72,130.62,129.02,128.98,128.79,128.66,128.46,128.12,128.05,128.00,127.94,127.87,127.75,113.63,99.56,96.95,84.32,81.50,81.37,77.47,75.56,75.20,74.86,74.58,73.28,72.40,68.48,67.98,53.40,46.28,38.24,36.51,34.71,21.14.
实施例15
参照实施例7，得到淡黄色油状液体，收率为22％。1H NMR(400MHz,Chloroform-d)δ7.97(s,3H),7.39–6.93(m,23H),6.18(s,1H),5.77(s,1H),5.12(dd,J＝
19.7,6.9Hz,1H),4.89–4.80(m,3H),4.80–4.69(m,4H),4.61–4.37(m,6H),4.16(s,1H),3.69–3.33(m,7H),3.31–3.06(m,4H),2.48–2.08(m,15H)；13C NMR(101MHz,Chloroform-d)δ173.23,162.87,148.07,140.47,137.41,137.32,137.21,137.15,137.13,135.61,135.51,135.25,135.21,135.14,135.06,131.39,131.30,131.22,131.05,128.99,128.96,128.87,128.55,128.42,128.10,128.01,127.97,127.92,127.85,127.74,120.84,113.89,99.50,96.68,84.32,81.54,81.51,75.53,75.23,75.19,74.84,74.58,73.27,72.28,68.44,53.05,46.39,38.29,36.60,34.63,21.13.
实施例16
参照实施例7，得到黄色油状液体，收率为23％。1H NMR(400MHz,Chloroform-d)δ7.99(s,3H),7.45(s,1H),7.27–6.99(m,20H),6.25(d,J＝6.2Hz,1H),5.82(s,1H),5.26(d,J＝1.8Hz,1H),5.13(d,J＝7.2Hz,1H),4.80(ddt,J＝40.7,15.6,9.7Hz,8H),4.57(d,J＝10.8Hz,1H),4.45(d,J＝16.9Hz,4H),4.17(s,1H),3.69–3.56(m,4H),3.52(t,J＝9.3Hz,1H),3.46–3.34(m,3H),2.71–2.62(m,1H),2.31(d,J＝13.8Hz,15H),2.19–2.02(m,2H)；13CNMR(101MHz,Chloroform-d)δ166.78,162.92,152.80,140.42,140.25,140.10,137.41,137.33,137.19,137.14,135.64,135.61,135.28,135.23,135.12,135.07,132.66,129.03,129.00,128.96,128.83,128.38,128.10,128.02,127.99,127.92,127.88,127.77,113.46,99.42,96.70,84.30,82.61,81.61,81.33,75.53,75.23,75.13,74.83,74.57,73.28,72.28,68.49,53.32,46.47,38.87,36.66,34.66,21.14.
实施例17
参照实施例7，得到黄色油状液体，收率为25％。1H NMR(400MHz,Chloroform-d)δ8.07–8.01(m,2H),7.36–6.98(m,23H),5.76(s,1H),5.50(dd,J＝25.2,3.1Hz,1H),5.25(s,1H),5.00–4.62(m,10H),4.56(d,J＝10.8Hz,1H),4.41(s,1H),4.15–4.04(m,2H),3.69–3.50(m,5H),3.31–3.19(m,3H),2.70(d,J＝29.1Hz,1H),2.28(q,J＝6.4,4.4Hz,15H),2.03(d,J＝24.2Hz,2H)；13C NMR(101MHz,Chloroform-d)δ171.13,162.81,148.1,146.93,144.38,140.53,137.38,137.30,137.17,137.12,135.62,135.23,135.14,135.06,135.00,130.53,130.47,130.37,128.96,128.62,128.4,128.34,128.07,127.98,127.94,127.83,127.72,123.37,123.24,113.82,98.25,94.24,84.30,81.55,81.33,75.50,75.17,74.81,74.72,74.54,73.25,72.25,68.56,53.02,48.34,38.39,36.55,34.53,21.10.
实施例18
参照实施例7，得到淡黄色油状液体，收率为24％。1H NMR(400MHz,Chloroform-d)δ7.78–7.74(m,2H),7.73–7.69(m,2H),7.42–7.33(m,5H),7.23–6.96(m,16H),5.68(d,J＝32.9Hz,1H),5.51–5.42(m,1H),5.25(s,1H),4.97–4.81(m,3H),4.80–4.63(m,4H),4.42(ddd,J＝22.3,10.9,7.0Hz,4H),4.09(q,J＝7.1Hz,3H),3.69–3.53(m,3H),3.28–3.18(m,2H),3.14–3.02(m,2H),2.73(dd,J＝31.4,17.1Hz,2H),2.55–2.45(m,1H),2.26(ddd,J＝22.9,17.7,12.0Hz,15H),2.04(d,J＝10.3Hz,1H),2.01(s,3H)；13C NMR(101MHz,Chloroform-d)δ171.20,163.15,140.10,139.25,137.40,137.33,137.19,137.12,136.23,135.63,135.24,135.21,135.04,134.96,132.96,129.32,129.11,128.99,128.96,128.96,128.92,128.75,128.45,128.09,128.01,127.86,126.56,126.47,116.84,111.26,98.41,84.88,81.53,81.35,77.62,75.50,75.14,74.80,74.75,73.28,72.28,68.59,53.42,48.52,36.74,31.65,29.64,21.10,20.97.
实施例19
参照实施例7，得到淡黄色油状液体，收率为22％。1H NMR(400MHz,Chloroform-d)δ7.26–7.15(m,17H),7.07–7.00(m,4H),6.88(dd,J＝17.7,9.0Hz,4H),6.63(s,1H),5.74(s,1H),5.64(d,J＝20.1Hz,1H),5.50(d,J＝21.7Hz,1H),5.03(s,1H),4.93(d,J＝11.5Hz,1H),4.79(d,J＝10.7Hz,3H),4.69(d,J＝11.1Hz,3H),4.48–4.39(m,4H),4.12(t,J＝14.3Hz,2H),3.57(d,J＝19.0Hz,3H),3.40(t,J＝9.1Hz,2H),3.10(d,J＝18.1Hz,2H),2.93(d,J＝19.6Hz,1H),2.88(s,1H),2.76(s,1H),2.21–2.12(m,1H)；13C NMR(101MHz,Chloroform-d)δ172.07,163.13,160.65,147.37,140.16,136.79,136.65,136.48,136.38,136.34,133.62,133.58,133.49,133.46,133.40,133.34,130.93,130.84,130.78,130.70,130.62,129.84,129.50,128.98,128.93,128.88,128.82,128.78,128.75,128.64,128.61,128.52,128.50,115.54,115.34,99.30,97.97,96.73,84.72,84.20,81.35,77.32,74.97,74.67,74.04,73.66,72.55,71.56,68.11,54.28,46.29,38.15,36.54,34.51.
实施例20
参照实施例7，得到淡黄色油状液体，收率为26％。1H NMR(400MHz,Chloroform-d)δ7.53(d,J＝8.5Hz,1H),7.24–6.95(m,25H),5.77(s,1H),5.68(s,1H),5.59–5.48(m,1H),4.94(d,J＝11.3Hz,1H),4.83–4.76(m,3H),4.69(t,J＝7.7Hz,3H),4.49(dd,J＝24.7,13.7Hz,4H),4.17–4.05(m,3H),3.58(d,J＝18.7Hz,3H),3.42(d,J＝8.3Hz,1H),3.33(t,J＝8.2Hz,1H),3.17(d,J＝23.3Hz,2H),2.94–2.90(m,1H),2.82(s,1H),2.52(s,1H),2.22–2.13(m,1H)；13C NMR(101MHz,Chloroform-d)δ175.49,167.10,148.09,147.13,136.77,136.62,136.46,136.34,136.31,136.25,133.63,133.58,133.51,133.48,133.40,133.35,133.30,133.07,132.92,130.69,129.89,129.53,129.02,128.97,128.92,128.83,128.78,128.72,128.65,128.54,128.52,128.47,119.05,115.91,99.28,84.69,84.18,81.30,74.93,74.70,74.07,74.01,73.70,72.54,71.53,68.06,54.00,46.37,38.17,36.64,34.52.
实施例21
参照实施例7，得到淡黄色油状液体，收率为27％。1H NMR(400MHz,Chloroform-d)δ7.50(dd,J＝21.7,8.0Hz,1H),7.24–7.08(m,24H),6.02(s,1H),5.76(s,1H),5.09(d,J＝25.1Hz,1H),4.69(d,J＝11.1Hz,3H),4.53–4.34(m,8H),4.10(d,J＝26.5Hz,3H),3.59(s,3H),3.40(s,1H),3.23(d,J＝17.6Hz,1H),3.13(d,J＝18.7Hz,2H),2.88(s,2H),2.48(s,1H),2.03(d,J＝10.1Hz,1H)；13C NMR(101MHz,Chloroform-d)δ171.31,166.90,148.04,139.89,136.77,136.62,136.45,136.40,136.35,136.31,133.62,133.56,133.46,133.39,133.33,131.67,131.58,131.56,131.49,131.10,131.06,131.01,129.59,129.50,129.00,128.95,128.92,128.83,128.78,128.51,121.08,111.71,99.25,84.30,84.17,81.37,77.34,74.94,74.68,74.06,73.72,72.55,71.49,68.03,60.45,46.55,38.31,36.77,34.37.
实施例22
参照实施例7，得到黄色油状液体，收率为26％。1H NMR(400MHz,Chloroform-d)δ7.71(q,J＝4.1Hz,1H),7.59–6.85(m,21H),6.74(s,1H),6.06(s,1H),5.83(s,1H),5.13(s,1H),4.92(s,1H),4.79(t,J＝9.0Hz,2H),4.72–4.61(m,2H),4.45(dt,J＝34.8,14.5Hz,4H),4.30(q,J＝5.0,3.9Hz,2H),4.24–4.03(m,3H),3.61(d,J＝18.5Hz,3H),3.43(s,1H),3.34(d,J＝9.6Hz,1H),3.12(d,J＝43.0Hz,2H),2.83(d,J＝18.3Hz,2H),2.23(s,1H),2.01(s,1H)；13C NMR(101MHz,Chloroform-d)δ167.76,152.83,140.09,139.98,139.86,136.75,136.70,136.43,136.32,136.24,136.09,133.64,133.55,133.49,133.46,133.40,133.35,132.25,130.93,129.52,128.99,128.87,128.83,128.79,128.57,128.54,128.52,128.49,109.25,102.72,100.72,82.58,82.38,81.23,74.89,74.09,73.72,72.92,72.57,72.51,71.51,68.16,65.61,38.69,31.92,30.55,30.33.
实施例23
参照实施例7，得到黄色油状液体，收率为37％。1H NMR(400MHz,Chloroform-d)δ8.07(s,1H),8.06–8.01(m,2H),7.46–7.38(m,2H),7.25–7.13(m,21H),5.77(d,J＝6.2Hz,1H),5.57–5.48(m,1H),5.19–5.10(m,1H),4.79(q,J＝6.0Hz,3H),4.55–4.36(m,8H),4.11(td,J＝12.7,11.9,4.7Hz,3H),3.61(s,2H),3.37–3.31(m,2H),3.26(d,J＝6.0Hz,1H),3.21–3.14(m,2H),2.97(d,J＝3.3Hz,1H),2.86(dd,J＝12.6,6.3Hz,1H),2.58(dd,J＝21.9,11.9Hz,1H),2.24–2.17(m,1H)；13C NMR(101MHz,Chloroform-d)δ167.80,146.95,144.56,144.07,140.11,136.79,136.75,136.60,136.51,136.34,136.27,133.62,133.56,133.46,133.42,133.38,133.33,133.28,132.24,130.94,129.58,129.48,128.99,128.92,128.83,128.78,128.52,123.58,116.38,107.78,97.87,84.13,81.35,81.33,74.89,74.69,74.04,72.56,72.53,71.57,71.46,65.62,65.32,47.90,39.00,30.54,29.69.
实施例24
参照实施例7，得到淡黄色油状液体，收率为35％。1H NMR(400MHz,Chloroform-d)δ8.00(s,1H),7.62(ddd,J＝75.2,5.7,3.2Hz,1H),7.25–6.90(m,24H),5.70(d,J＝34.0Hz,1H),5.42(d,J＝68.6Hz,1H),5.09–4.88(m,1H),4.83–4.59(m,6H),4.54–4.27(m,6H),4.10(d,J＝26.6Hz,2H),3.69–3.48(m,4H),3.35(d,J＝24.7Hz,2H),3.17(s,1H),2.49(s,1H),2.26(s,3H),2.22(s,3H)；13C NMR(101MHz,Chloroform-d)δ171.77,162.77,149.17,141.94,136.80,136.71,136.50,136.45,136.41,136.33,133.60,133.55,133.45,133.36,133.27,133.22,130.91,129.61,129.29,129.20,129.07,128.97,128.89,128.82,128.77,128.64,128.56,128.52,128.48,128.45,116.96,109.99,100.62,84.65,81.32,80.82,74.94,74.68,74.07,74.00,72.51,71.43,68.13,65.57,54.70,36.61,31.53,29.70,21.05.
实施例25化合物ⅰ的合成
将京尼平(2.5g,11mmol)溶于乙醇(15mL)中，滴加两滴浓盐酸，加热回流10h。反应结束后，减压浓缩，加1M氢氧化钠水溶液调pH至中性，用乙酸乙酯(30mL)萃取三次，合并有机相，用饱和食盐水(20mL)洗涤三次，无水硫酸钠干燥，减压浓缩，硅胶色谱柱分离纯化，得到淡黄色固体，收率为90％。1H NMR(400MHz,Chloroform-d)δ7.48(d,J＝25.8Hz,1H),5.79(d,J＝33.1Hz,1H),4.54(d,J＝8.4Hz,1H),4.26(s,2H),4.05(dt,J＝16.1,7.1Hz,1H),3.72(d,J＝5.0Hz,3H),3.63(dt,J＝16.7,7.4Hz,1H),3.20(q,J＝8.3Hz,1H),2.88(dd,J＝17.5,8.3Hz,1H),2.59(t,J＝8.2Hz,1H),2.07(dd,J＝15.0,10.3Hz,1H),1.65(s,1H),1.27(t,J＝7.1Hz,3H).
实施例26化合物ⅱ的合成
将化合物ⅰ(2.5g,9.83mmol)，三乙胺(19.66mmol)溶于二氯甲烷(15mL)中，冰水浴缓慢滴加苯磺酰氯(2.06g,10.81mmol)，滴加完毕后加入DMAP(50mg)，滴加完毕之后常温反应28h。反应结束后，加入1M氢氧化钠溶液(10mL)，用二氯甲烷(30mL)萃取三次，合并有机相。有机相用1M盐酸溶液调节pH至中性，萃取的有机相用饱和食盐水(20mL)洗涤三次，无水硫酸钠干燥。减压浓缩后，硅胶色谱柱分离纯化，得无色油状液体，收率为73％。1H NMR(400MHz,Chloroform-d)δ7.43(d,J＝27.5Hz,1H),5.92(s,1H),4.52(d,J＝8.1Hz,1H),4.20(s,2H),3.96(dq,J＝9.5,7.1Hz,1H),3.68(s,3H),3.57(dq,J＝9.6,7.1Hz,1H),3.18(q,J＝8.1,7.7Hz,1H),2.86(dd,J＝17.6,9.1Hz,1H),2.68(t,J＝8.0Hz,1H),2.05(dd,J＝16.9,8.7Hz,1H),1.22(t,J＝7.1Hz,3H).
实施例27化合物ⅲ的合成
将化合物ⅱ(0.8g,2.94mmol)溶于甲醇(5mL)中，滴加2M氢氧化钠水溶液(3mL)，室温反应3h，反应结束后，减压浓缩，加入1M盐酸溶液调节pH至1-2，加入乙酸乙酯(20mL)萃取三次，再用饱和食盐水(10mL)萃取三次，无水硫酸钠干燥，减压浓缩，硅胶色谱柱分离纯化，得白色固体，收率98％。1H NMR(400MHz,Chloroform-d)δ7.56(dd,J＝28.0,1.4Hz,1H),5.83(dd,J＝3.2,1.7Hz,1H),4.61(d,J＝7.7Hz,1H),4.06(t,J＝2.1Hz,2H),3.97(dq,J＝9.6,7.1Hz,1H),3.59(dq,J＝9.6,7.1Hz,1H),3.34(s,3H),3.16(qd,J＝8.2,1.3Hz,1H),2.92–2.82(m,1H),2.64–2.56(m,1H),2.09(ddt,J＝16.6,8.0,2.2Hz,1H),1.24(t,J＝7.1Hz,3H).
实施例28化合物ⅳ的合成
将化合物ⅲ(0.62mmol)溶于DMF(4mL)中，加入EDCI(0.744mmol)，HOBT(0.744mmol)和DIPEA(324μL,1.86mmol)室温反应2h之后，加入对氯苯丙胺甲酯盐酸盐(0.682mmol)，DMAP(0.93mmol)常温搅拌过夜。反应结束后，将溶液加到冰水(30mL)中，用乙酸乙酯(20mL)萃取三次，合并有机相。有机相依次用1M柠檬酸水溶液(20mL)、1M稀盐酸水溶液(20mL)及饱和食盐水(20mL)洗涤两次，无水硫酸钠干燥，减压蒸馏，硅胶色谱柱分离纯化，得淡黄色半固体，收率28％。1H NMR(400MHz,Chloroform-d)δ7.27(s,1H),7.24(d,J＝8.3Hz,2H),7.01(d,J＝8.3Hz,2H),5.77(s,1H),4.92(dt,J＝11.4,5.5Hz,1H),4.52(d,J＝7.9Hz,1H),4.04(s,2H),3.98–3.93(m,1H),3.74(s,3H),3.61–3.53(m,1H),3.35(d,J＝8.4Hz,3H),3.21(dd,J＝13.9,5.7Hz,1H),3.11(dd,J＝14.4,7.0Hz,2H),3.05(dd,J＝13.6,5.7Hz,1H),2.64–2.58(m,1H),1.97(dd,J＝16.2,8.7Hz,1H),1.24(t,J＝5.2Hz,3H)；13C NMR(101MHz,Chloroform-d)δ174.11,167.65,149.71,140.65,134.39,134.26,133.06,130.78,128.77,128.67,128.58,112.48,101.27,70.62,65.48,58.28,58.14,53.12,46.08,38.41,36.42,35.16,15.08.
实施例29
参照实施例28，得淡黄色半固体，收率为57％。1H NMR(400MHz,Methanol-d4)δ7.22(dd,J＝8.5,5.5Hz,2H),7.15(s,1H),7.00(t,J＝8.8Hz,2H),5.75(s,1H),4.70(dd,J＝9.8,5.3Hz,1H),4.61(d,J＝7.4Hz,1H),4.11–3.98(m,2H),3.91(dq,J＝9.6,7.1Hz,1H),3.71(s,3H),3.58(dq,J＝9.6,7.1Hz,1H),3.30(s,3H),3.20(dt,J＝15.8,7.3Hz,2H),2.99(dd,J＝14.0,9.9Hz,1H),2.62–2.53(m,2H),1.87(dd,J＝16.4,7.9Hz,1H),1.21(t,J＝7.1Hz,3H)；13C NMR(101MHz,Methanol-d4)δ172.30,168.70,163.06,148.00,140.44,133.09,130.56,130.48,128.90,114.82,114.60,113.61,100.71,70.17,64.79,56.95,53.90,51.37,46.03,37.91,35.73,34.65,14.10.
实施例30
参照实施例28，得淡黄色半固体，收率为26％。1H NMR(400MHz,Methanol-d4)δ7.44(t,J＝8.2Hz,2H),7.22–7.10(m,3H),5.78(s,1H),4.78–4.70(m,1H),4.65(dd,J＝7.3,4.9Hz,1H),4.07(q,J＝13.6,12.9Hz,2H),3.98–3.89(m,1H),3.73(d,J＝3.5Hz,3H),3.65–3.56(m,1H),3.33(s,3H),3.26–3.16(m,2H),3.00(ddd,J＝14.1,9.6,6.3Hz,1H),2.60(h,J＝8.4Hz,2H),1.88(dd,J＝14.2,7.7Hz,1H),1.23(t,J＝7.1Hz,3H)；13C NMR(101MHz,Methanol-d4)δ172.18,168.73,148.02,140.41,136.51,131.15,131.07,130.88,130.77,128.92,120.21,113.60,100.68,70.16,64.79,56.94,53.60,51.40,46.05,37.90,35.93,34.63,14.10.
实施例31
参照实施例28，得黄色半固体，收率为38％。1H NMR(400MHz,Chloroform-d)δ7.54–7.44(m,1H),7.39(d,J＝4.8Hz,2H),5.84(d,J＝11.7Hz,1H),4.91–4.86(m,1H),4.56(d,J＝7.9Hz,1H),4.16–4.04(m,2H),4.00–3.93(m,1H),3.75(d,J＝12.7Hz,3H),3.64–3.53(m,1H),3.45(s,1H),3.38–3.28(m,3H),3.11(dd,J＝14.0,5.8Hz,1H),2.97(dt,J＝9.6,4.9Hz,1H),2.67–2.61(m,1H),2.13(dd,J＝15.0,9.9Hz,1H),2.03(s,1H),1.24(t,J＝2.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ173.51,167.57,152.86,150.42,140.52,140.18,139.97,132.10,129.01,112.09,101.34,82.59,82.54,70.68,65.54,60.51,58.37,53.25,46.20,39.09,35.22,31.41,15.12.
实施例32
参照实施例28，得黄色半固体，收率为43％。1H NMR(400MHz,Chloroform-d)δ8.12(d,J＝8.6Hz,2H),7.28(s,1H),7.27–7.23(m,2H),5.76(d,J＝6.9Hz,1H),4.98(q,J＝5.8Hz,1H),4.57–4.49(m,1H),4.04(s,2H),3.95(dt,J＝15.0,7.0Hz,1H),3.74(d,J＝2.8Hz,3H),3.61–3.51(m,1H),3.35–3.32(m,3H),3.21(dt,J＝13.8,5.3Hz,1H),2.94(s,1H),2.86(s,1H),2.74(dd,J＝16.8,9.6Hz,1H),2.64–2.57(m,1H),2.02(s,1H),1.23(t,J＝1.0Hz,3H)；13C NMR(101MHz,Chloroform-d)δ171.74,166.68,149.01,147.12,143.99,140.96,130.22,130.17,128.37,123.63,123.59,112.84,101.26,70.62,65.43,58.36,58.31,52.84,46.14,38.57,37.63,35.26,15.07.
实施例33
参照实施例28，得淡黄色半固体，收率为54％。1H NMR(400MHz,Chloroform-d)δ7.23(s,1H),7.05(d,J＝7.7Hz,2H),6.94(d,J＝7.7Hz,2H),5.72(s,1H),4.88(d,J＝6.7Hz,1H),4.48(d,J＝7.9Hz,1H),4.02(s,2H),3.97–3.88(m,1H),3.71(s,3H),3.54(p,J＝7.1Hz,1H),3.31(s,3H),3.17–3.10(m,1H),3.09–3.04(m,1H),2.92(s,1H),2.84(s,1H),2.56(t,J＝8.1Hz,1H),2.27(s,3H),2.01(d,J＝5.4Hz,1H),1.21(t,J＝5.7Hz,3H)；13C NMR(101MHz,DMSO-d6)δ167.62,162.03,143.83,142.55,136.02,131.94,127.95,126.41,124.48,124.36,123.71,108.44,96.44,65.92,60.59,53.52,48.31,47.58,41.43,33.68,32.43,30.53,28.72,16.27.
实施例34化合物ⅴ的合成
将化合物ⅳ(0.3mmol)溶于甲醇(4mL)中，滴加2M氢氧化钠水溶液(0.6mmol)，室温过夜反应，反应结束后，减压浓缩，加入1M盐酸溶液调节pH至1-2，加入乙酸乙酯(20mL)萃取三次，再用饱和食盐水(10mL)萃取三次，无水硫酸钠干燥，减压浓缩，硅胶色谱柱分离纯化，得淡黄色油状液体，收率83％。1H NMR(400MHz,Chloroform-d)δ8.40(s,1H),7.31(s,1H),7.24(d,J＝8.0Hz,2H),7.08(d,J＝7.9Hz,2H),5.76(s,1H),4.90(d,J＝6.0Hz,1H),4.53(d,J＝7.8Hz,1H),4.06(s,2H),3.97(dd,J＝15.4,8.5Hz,1H),3.62–3.55(m,1H),3.35(s,3H),3.14(d,J＝5.5Hz,1H),3.11–3.05(m,1H),2.95–2.78(m,1H),2.60(t,J＝7.6Hz,1H),2.48(dd,J＝15.4,8.6Hz,1H),1.93(dd,J＝15.2,9.7Hz,1H),1.24(s,3H)；13C NMR(101MHz,Chloroform-d)δ174.11,167.65,149.71,140.65,134.39,133.06,130.78,128.77,128.67,128.58,123.98,112.48,101.27,70.62,65.48,58.28,53.12,46.08,38.41,36.42,35.16,15.08.
实施例35
参照实施例34，得淡黄色油状液体，收率为49％。1H NMR(400MHz,Chloroform-d)δ9.13(s,1H),7.31(s,1H),7.15–7.07(m,2H),6.96(t,J＝8.4Hz,2H),5.75(s,1H),4.94–4.85(m,1H),4.52(d,J＝7.9Hz,1H),4.05(s,2H),3.96(dq,J＝14.3,7.2Hz,1H),3.56(dt,J＝14.3,7.1Hz,1H),3.30(s,3H),3.27(d,J＝5.2Hz,1H),3.10(dq,J＝21.5,8.2,6.8Hz,2H),2.60(t,J＝7.5Hz,1H),2.48(dd,J＝15.3,8.5Hz,1H),1.93(dd,J＝14.8,8.9Hz,1H),1.24(t,J＝6.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ174.11,167.66,160.80,149.70,140.69,131.56,130.96,130.88,128.67,115.51,115.29,112.47,101.26,70.62,65.46,58.27,53.29,46.09,38.39,36.24,35.17,15.07.
实施例36
参照实施例34，得淡黄色油状液体，收率91％。1H NMR(400MHz,Chloroform-d)δ8.54(s,1H),7.41–7.37(m,2H),7.32(d,J＝6.5Hz,1H),7.02(dd,J＝8.2,5.8Hz,2H),5.77(s,1H),4.91(q,J＝5.3Hz,1H),4.54(dd,J＝7.8,6.5Hz,1H),4.06(s,2H),4.01–3.92(m,1H),3.62–3.53(m,1H),3.36(d,J＝3.6Hz,3H),3.23(dd,J＝17.9,5.5Hz,1H),3.17–3.07(m,2H),2.66–2.58(m,1H),2.49(dd,J＝16.5,7.8Hz,1H),1.93(dd,J＝16.1,8.5Hz,1H),1.24(d,J＝1.5Hz,3H)；13C NMR(101MHz,Chloroform-d)δ174.35,167.61,149.65,140.66,134.90,131.63,131.15,131.12,128.73,128.67,121.18,112.52,101.28,70.62,65.48,58.28,53.04,46.10,38.42,36.49,35.17,15.09.
实施例37
参照实施例34，得黄色油状液体，收率84％。1H NMR(400MHz,Chloroform-d)δ7.52(s,1H),7.47(s,2H),5.81(s,1H),4.88(d,J＝6.3Hz,1H),4.56(d,J＝8.0Hz,1H),4.08(s,2H),4.01–3.96(m,1H),3.62–3.56(m,1H),3.37(s,3H),3.15(dd,J＝14.1,5.0Hz,1H),3.10(d,J＝8.0Hz,1H),3.02(dd,J＝13.8,4.9Hz,1H),2.94(dd,J＝13.7,6.5Hz,1H),2.63(d,J＝7.2Hz,1H),2.04(s,1H),1.25(d,J＝2.4Hz,3H)；13C NMR(101MHz,Chloroform-d)δ173.51,167.57,152.86,150.42,140.52,140.18,139.97,132.10,129.01,112.09,101.34,82.59,82.54,70.68,65.54,60.51,58.37,46.20,39.09,35.21,31.41,15.12.
实施例38
参照实施例34，得黄色油状液体，收率60％。1H NMR(400MHz,Chloroform-d)δ8.15–8.09(m,2H),7.34(q,J＝7.5,6.3Hz,3H),5.76(d,J＝4.6Hz,1H),4.94(d,J＝5.7Hz,1H),4.54(t,J＝7.4Hz,1H),4.06(s,2H),3.97(dt,J＝15.4,7.1Hz,1H),3.63–3.54(m,1H),3.43(dd,J＝14.2,5.6Hz,1H),3.35(s,3H),3.25(dt,J＝13.7,6.6Hz,1H),3.14–2.99(m,1H),2.75–2.47(m,2H),2.09–1.89(m,1H),1.25(d,J＝5.8Hz,3H)；13C NMR(101MHz,Chloroform-d)δ176.60,167.74,149.91,147.12,144.02,140.81,130.37,130.34,128.72,123.63,123.59,112.30,101.31,70.61,65.55,58.37,58.33,46.03,38.51,37.31,35.17,15.08.
实施例39
参照实施例34，得淡黄色油状液体，收率65％。1H NMR(400MHz,Chloroform-d)δ7.27(s,1H),7.10(d,J＝7.8Hz,2H),7.05(d,J＝7.6Hz,2H),5.73(s,1H),4.86(q,J＝6.3Hz,1H),4.52(d,J＝7.9Hz,1H),4.05(s,2H),4.01–3.91(m,1H),3.62–3.52(m,1H),3.35(s,3H),3.26(dd,J＝14.0,5.0Hz,1H),3.09(dq,J＝22.4,8.1,7.3Hz,2H),2.60(t,J＝7.6Hz,1H),2.41(dd,J＝16.9,8.5Hz,1H),2.31(s,3H),1.90(dd,J＝17.4,7.2Hz,1H),1.23(d,J＝7.1Hz,3H)；13C NMR(101MHz,Chloroform-d)δ174.60,167.87,149.45,140.67,136.87,132.58,129.39,129.21,128.56,123.05,122.81,112.66,101.19,70.65,65.43,58.33,53.39,46.18,38.26,36.49,35.14,21.04,15.07.
实施例40化合物ⅵ的合成
将京尼平(2.5g,11mmol)溶于苄醇(15mL)中，滴加两滴浓盐酸，加热回流5h。反应结束后，减压浓缩，加1M氢氧化钠水溶液调pH至中性，用乙酸乙酯(30mL)萃取三次，合并有机相，有机相用饱和食盐水(20mL)洗涤三次，无水硫酸钠干燥，减压浓缩，硅胶色谱柱分离纯化，得黄色半固体，收率88％。1H NMR(400MHz,Chloroform-d)δ7.50(d,J＝32.1Hz,1H),7.37–7.23(m,5H),5.79(s,1H),5.27–4.94(m,1H),4.74(dd,J＝51.6,10.0Hz,1H),4.57(dd,J＝36.6,11.8Hz,1H),4.24–4.10(m,2H),3.72(s,3H),3.17(dq,J＝25.6,8.2Hz,1H),2.82(ddd,J＝36.2,16.2,8.0Hz,1H),2.66(t,J＝8.0Hz,1H),2.30(dd,J＝15.0,5.8Hz,1H),2.05(dd,J＝16.7,8.5Hz,1H).
实施例41
参照实施例40，得白色固体，收率98％。1H NMR(400MHz,Chloroform-d)δ7.43(d,J＝27.2Hz,1H),5.75(d,J＝15.7Hz,1H),4.44(d,J＝7.8Hz,1H),4.18(s,2H),3.67(s,3H),3.52(s,3H),3.36(s,1H),3.12(s,1H),2.81(dd,J＝16.2,8.2Hz,1H),2.55(t,J＝7.5Hz,1H),2.02(dd,J＝15.4,8.7Hz,1H).
实施例42化合物ⅶ的合成
将化合物ⅵ(4mmol)溶于DMF(6mL)中，冰水浴下缓慢加入60％氢化钠(8mmol)，反应1h之后，缓慢加入苄溴(8mmol)，常温反应过夜。反应结束后，将反应液加入到冰水(40mL)中，用乙酸乙酯(30mL)萃取三次，合并有机相，有机相依次用1M盐酸溶液(20mL)及饱和食盐水(20mL)洗涤三次，无水硫酸钠干燥，减压浓缩，硅胶色谱柱分离纯化，得淡黄色油状液体，收率42％。1H NMR(400MHz,Chloroform-d)δ7.60–7.54(m,3H),7.41(d,J＝8.0Hz,2H),7.37–7.27(m,5H),5.91(d,J＝21.1Hz,1H),5.30–5.26(m,1H),4.96(d,J＝11.6Hz,1H),4.81–4.74(m,1H),4.50(d,J＝11.9Hz,2H),4.19(d,J＝15.8Hz,2H),3.74(s,3H),3.26(q,J＝7.8Hz,1H),2.91(dd,J＝17.3,8.7Hz,1H),2.79(t,J＝7.6Hz,1H),2.17–2.11(m,1H).
实施例43
参照实施例42，得白色固体，收率55％。1H NMR(400MHz,Chloroform-d)δ7.60(d,J＝8.1Hz,2H),7.52(s,1H),7.49–7.43(m,2H),5.90(d,J＝11.8Hz,1H),4.63–4.55(m,2H),4.53(d,J＝7.5Hz,1H),4.16(d,J＝6.9Hz,2H),3.73(d,J＝1.4Hz,3H),3.40(d,J＝90.2Hz,3H),3.20(q,J＝8.0Hz,1H),2.96–2.89(m,1H),2.68(t,J＝7.6Hz,1H),2.11(ddt,J＝16.7,7.9,2.1Hz,1H).
实施例44化合物ⅷ的合成
将化合物ⅶ(0.3mmol)溶于甲醇(4mL)中，滴加2M氢氧化钠水溶液(0.6mmol)，室温反应5h，反应结束后，减压浓缩，加入1M盐酸溶液调节pH至1-2，加入乙酸乙酯(20mL)萃取三次，再用饱和食盐水(10mL)洗涤三次，无水硫酸钠干燥，减压浓缩，硅胶色谱柱分离纯化，得淡黄色油状液体，收率96％。1H NMR(400MHz,Chloroform-d)δ7.65(s,1H),7.59–7.53(m,3H),7.40(d,J＝8.0Hz,1H),7.31(q,J＝4.7Hz,4H),7.22–7.17(m,1H),5.88(s,1H),5.30(d,J＝3.5Hz,1H),4.95(d,J＝11.6Hz,1H),4.80(d,J＝7.4Hz,1H),4.61(d,J＝11.6Hz,1H),4.48(d,J＝3.2Hz,1H),4.14(d,J＝7.1Hz,2H),3.23(q,J＝8.2Hz,1H),2.95–2.85(m,1H),2.78(t,J＝7.5Hz,1H),2.14(ddt,J＝16.6,7.1,1.9Hz,1H).
实施例45
参照实施例44，得白色固体，收率98％。1H NMR(400MHz,Chloroform-d)δ7.65–7.59(m,3H),7.51–7.43(m,2H),5.92–5.88(m,1H),4.64–4.54(m,3H),4.17(d,J＝7.6Hz,2H),3.41(d,J＝88.7Hz,3H),3.20(q,J＝7.8Hz,1H),2.96–2.91(m,1H),2.71(t,J＝7.6Hz,1H),2.15(ddd,J＝9.3,5.2,2.3Hz,1H).
实施例46
参照实施例7，得淡黄色油状液体，收率24％。1H NMR(400MHz,Chloroform-d)δ7.60(d,J＝7.8Hz,2H),7.45(d,J＝5.6Hz,2H),7.30(s,1H),7.15–7.10(m,2H),6.96(t,J＝8.5Hz,2H),6.08–6.02(m,1H),5.80(d,J＝6.9Hz,1H),4.90(p,J＝6.4Hz,1H),4.55(d,J＝5.0Hz,2H),4.13(d,J＝9.5Hz,2H),3.29(d,J＝20.8Hz,3H),3.12(dd,J＝16.1,7.1Hz,2H),2.66(t,J＝7.9Hz,1H),2.49(dd,J＝15.8,8.6Hz,1H),2.25–2.11(m,1H),1.94(dd,J＝17.4,7.2Hz,1H)；13C NMR(101MHz,Chloroform-d)δ167.48,163.24,160.80,149.25,142.28,140.32,131.76,131.62,130.94,130.86,129.60,129.17,127.55,127.41,125.34,125.30,115.53,115.32,112.76,102.18,71.56,68.44,56.85,56.42,46.18,38.37,36.27,34.93.
实施例47
参照实施例7，得淡黄色油状液体，收率31％。1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝7.9Hz,2H),7.40(d,J＝6.5Hz,2H),7.26–7.16(m,3H),7.06(dd,J＝14.8,8.4Hz,2H),5.79–5.65(m,1H),4.88(tt,J＝10.0,5.7Hz,1H),4.78(dd,J＝7.4,3.1Hz,1H),4.51(dd,J＝11.7,5.9Hz,2H),4.13–4.00(m,2H),3.35(d,J＝19.9Hz,3H),3.29–3.19(m,2H),3.08(dd,J＝13.2,6.6Hz,1H),2.93–2.84(m,1H),2.45(td,J＝16.9,16.2,8.1Hz,1H),2.16(dd,J＝11.2,8.2Hz,1H)；13C NMR(101MHz,Chloroform-d)δ171.83,167.50,149.31,142.27,140.29,138.63,134.19,133.01,131.80,130.75,128.70,128.62,127.65,127.56,127.49,127.42,125.30,125.26,112.75,102.20,71.55,68.42,56.85,55.60,46.18,38.40,36.46,34.92.
实施例48
参照实施例7，得淡黄色油状液体，收率20％。1H NMR(400MHz,Chloroform-d)δ7.60(d,J＝6.3Hz,2H),7.45(d,J＝7.8Hz,2H),7.36(d,J＝2.7Hz,1H),7.06(dt,J＝14.3,8.2Hz,2H),7.00–6.90(m,2H),6.18–6.09(m,1H),5.82(s,1H),4.84(dd,J＝9.5,3.6Hz,2H),4.54(s,1H),4.18–4.08(m,2H),3.43–3.30(m,3H),3.02(q,J＝7.3Hz,2H),2.94(d,J＝6.3Hz,1H),2.84(s,1H),2.76–2.63(m,1H),2.25–2.15(m,1H)；13C NMR(101MHz,Chloroform-d)δ170.90,165.87,145.26,142.36,140.37,135.28,131.52,131.22,131.17,131.05,130.87,129.14,127.62,127.53,127.40,125.30,125.26,120.97,102.16,71.59,68.50,60.40,55.60,45.45,36.43,31.90,29.67.
实施例49
参照实施例7，得黄色油状液体，收率14％。1H NMR(400MHz,Chloroform-d)δ7.60(d,J＝7.9Hz,2H),7.51–7.42(m,4H),5.91–5.70(m,1H),4.87(d,J＝3.1Hz,1H),4.80–4.47(m,3H),4.18–4.04(m,2H),3.49(s,1H),3.47–3.37(m,3H),3.27(d,J＝6.6Hz,1H),3.20–3.08(m,1H),3.06–2.89(m,2H),2.74–2.58(m,1H),2.23(dd,J＝11.1,8.4Hz,1H)；13C NMR(101MHz,Chloroform-d)δ177.03,165.26,152.82,149.83,142.28,140.26,140.13,139.94,138.65,132.15,129.38,127.69,127.57,127.47,127.44,125.31,102.19,99.21,82.38,82.28,71.55,68.43,56.88,56.20,46.31,38.97,36.46,34.96.
实施例50
参照实施例7，得棕色油状液体，收率17％。1H NMR(400MHz,Chloroform-d)δ8.11(dd,J＝8.1,2.8Hz,2H),7.59(d,J＝6.7Hz,2H),7.44(d,J＝7.6Hz,2H),7.34(dq,J＝18.1,9.4,9.0Hz,3H),6.25(dd,J＝15.8,7.5Hz,1H),5.80(d,J＝7.1Hz,1H),4.82(dd,J＝19.2,4.1Hz,1H),4.60–4.50(m,2H),4.15–4.08(m,2H),3.48(d,J＝2.9Hz,1H),3.43–3.37(m,3H),3.25(d,J＝1.3Hz,1H),2.91(dd,J＝17.3,7.2Hz,1H),2.83(s,1H),2.75–2.63(m,1H),2.25–2.17(m,1H)；13C NMR(101MHz,Chloroform-d)δ176.56,172.04,149.51,147.12,144.13,142.24,140.44,138.84,138.55,131.57,130.31,129.95,129.62,129.04,127.64,125.30,123.61,122.75,112.61,102.17,71.50,68.40,60.51,56.87,49.03,38.54,36.67,34.87.
实施例51
参照实施例7，得淡黄色油状液体，收率38％。1H NMR(400MHz,Chloroform-d)δ8.84(s,1H),7.60(d,J＝7.9Hz,2H),7.45(d,J＝7.7Hz,2H),7.26(d,J＝12.1Hz,1H),7.07(q,J＝7.2Hz,4H),5.80(d,J＝7.4Hz,1H),4.91(s,1H),4.59–4.51(m,2H),4.46(d,J＝7.6Hz,1H),4.13(d,J＝9.6Hz,2H),3.39(d,J＝27.2Hz,3H),3.25(d,J＝8.2Hz,2H),3.11(d,J＝8.3Hz,1H),2.96(dd,J＝20.4,11.8Hz,1H),2.65(t,J＝7.5Hz,1H),2.49(dd,J＝16.1,8.1Hz,1H),2.29(d,J＝4.7Hz,3H)；13C NMR(101MHz,Chloroform-d)δ175.64,167.38,149.08,147.55,142.33,140.19,138.34,136.76,132.68,131.87,129.29,129.25,127.65,127.56,127.42,125.32,125.29,125.25,122.79,112.98,102.19,71.50,68.46,56.80,56.18,46.20,38.31,36.68,34.96,21.02.
实施例52化合物ⅸ的合成
将化合物ⅷ(0.62mmol)溶于DMF(4mL)中，加入EDCI(0.744mmol)，HOBT(0.744mmol)和DIPEA(324μL,1.86mmol)室温反应2h之后，加入对氯苯丙胺甲酯盐酸盐(0.682mmol)和DMAP(0.93mmol)，常温搅拌过夜。反应结束后，将溶液加到冰水(30mL)中，用乙酸乙酯(20mL)萃取三次，合并有机相。有机相依次用1M柠檬酸水溶液(20mL)、1M稀盐酸水溶液(20mL)及饱和食盐水(20mL)洗涤两次，无水硫酸钠干燥，减压蒸馏，硅胶色谱柱分离纯化，得白色半固体，收率42％。1H NMR(400MHz,Chloroform-d)δ7.53(d,J＝5.0Hz,2H),7.37(s,1H),7.35(d,J＝1.9Hz,1H),7.30(dd,J＝11.3,4.0Hz,6H),7.23(d,J＝2.3Hz,2H),7.01(dd,J＝8.3,3.3Hz,2H),6.23(d,J＝7.8Hz,1H),5.06(d,J＝4.1Hz,1H),4.90(dd,J＝12.8,5.3Hz,2H),4.70–4.66(m,1H),4.44(d,J＝6.3Hz,2H),4.00(s,2H),3.38(d,J＝9.7Hz,3H),3.12(dd,J＝13.1,5.3Hz,2H),3.02–2.98(m,1H),2.94(s,1H),2.77–2.71(m,1H),2.18(dd,J＝11.1,8.3Hz,1H)；13C NMR(101MHz,Chloroform-d)δ171.16,166.57,148.37,147.05,140.41,138.86,134.48,133.01,130.62,128.80,128.64,128.61,128.44,128.40,128.24,128.00,127.87,127.79,127.48,127.42,127.27,125.23,124.42,123.92,119.07,97.97,71.43,71.14,69.91,55.87,50.41,49.25,37.05,36.45,35.20.
实施例53
参照实施例52，得白色半固体，收率68％。1H NMR(400MHz,Chloroform-d)δ7.54(s,2H),7.37(s,1H),7.35(s,1H),7.31(d,J＝4.1Hz,4H),7.29(s,2H),7.05–7.02(m,2H),6.95(d,J＝2.5Hz,2H),6.24(d,J＝7.9Hz,1H),5.05(d,J＝4.2Hz,1H),4.92(d,J＝5.7Hz,1H),4.90–4.88(m,1H),4.67(d,J＝7.5Hz,1H),4.43(s,2H),4.00(d,J＝5.0Hz,2H),3.39(s,3H),3.11(dd,J＝9.9,5.4Hz,2H),3.00(d,J＝2.6Hz,1H),2.94(s,1H),2.73(t,J＝7.8Hz,1H),2.19(dd,J＝11.1,8.3Hz,1H)；13C NMR(101MHz,Chloroform-d)δ171.16,163.21,160.77,148.40,142.35,140.42,138.85,137.35,130.80,130.72,129.03,128.83,128.39,128.23,128.00,127.87,127.79,127.48,127.42,127.26,125.24,115.43,115.22,100.16,97.27,71.42,71.13,69.92,55.87,50.40,49.25,38.47,36.90,35.20.
实施例54
参照实施例52，得淡黄色半固体，收率51％。1H NMR(400MHz,Chloroform-d)δ7.55(h,J＝9.9,8.7Hz,4H),7.45(d,J＝12.2Hz,1H),7.38(d,J＝7.9Hz,2H),7.28(td,J＝14.6,12.5,6.9Hz,6H),7.18(d,J＝7.0Hz,1H),5.88(d,J＝21.2Hz,1H),4.92(d,J＝11.6Hz,1H),4.75(d,J＝7.5Hz,1H),4.58(d,J＝11.5Hz,1H),4.47(d,J＝11.5Hz,3H),4.14(s,2H),3.72(s,3H),3.22(q,J＝7.9Hz,1H),3.09(q,J＝8.5Hz,1H),2.98–2.83(m,2H),2.75(t,J＝7.6Hz,1H),2.09(dd,J＝17.3,6.8Hz,1H)；13C NMR(101MHz,Chloroform-d)δ167.92,167.77,152.03,142.47,139.94,138.09,137.41,136.75,132.54,130.00,129.80,128.44,128.23,127.99,127.97,127.52,127.44,127.27,127.13,125.50,125.25,125.21,100.41,97.49,71.50,71.18,69.95,51.18,51.12,46.21,38.85,35.26,33.69.
实施例55
参照实施例52，得黄色半固体，收率52％。1H NMR(400MHz,Chloroform-d)δ7.55–7.53(m,2H),7.45(s,2H),7.38(d,J＝4.9Hz,4H),7.31(d,J＝2.0Hz,2H),7.31–7.30(m,1H),7.28(s,1H),6.30(d,J＝7.7Hz,1H),5.09(d,J＝4.0Hz,1H),4.86(s,1H),4.80(s,1H),4.55(d,J＝5.9Hz,1H),4.43(s,2H),4.01(d,J＝4.4Hz,2H),3.48(s,3H),3.15–3.08(m,2H),3.03–3.01(m,1H),2.93(s,1H),2.80–2.74(m,1H),2.22(d,J＝3.0Hz,1H)；13C NMR(101MHz,Chloroform-d)δ171.70,171.28,152.79,142.34,140.41,140.04,139.87,138.87,137.35,131.98,129.15,128.40,128.03,127.90,127.79,127.51,127.44,127.30,125.27,125.24,125.20,100.16,97.22,82.27,71.41,69.84,68.59,56.20,50.41,49.23,39.00,36.47,35.71.
实施例56
参照实施例52，得黄色半固体，收率36％。1H NMR(400MHz,Chloroform-d)δ8.11(s,2H),7.53(s,2H),7.36(s,2H),7.28(d,J＝5.5Hz,6H),7.18(d,J＝9.8Hz,2H),6.29(d,J＝7.8Hz,1H),5.08(d,J＝3.9Hz,1H),4.92–4.88(m,2H),4.68(d,J＝7.5Hz,1H),4.56–4.51(m,2H),3.99(d,J＝7.0Hz,2H),3.73(s,3H),3.17–3.12(m,2H),3.00–2.97(m,1H),2.94(s,1H),2.77–2.72(m,1H),2.21–2.16(m,1H)；13C NMR(101MHz,Chloroform-d)δ171.70,166.67,148.61,147.15,143.96,142.37,140.51,139.01,130.25,130.12,128.94,128.45,128.39,128.26,127.99,127.88,127.81,127.61,127.48,127.42,127.27,127.17,125.21,123.60,100.20,97.98,71.59,71.18,69.98,56.03,52.90,49.29,38.55,36.92,35.17.
实施例57
参照实施例52，得淡黄色半固体，收率38％。1H NMR(400MHz,Chloroform-d)δ7.54(s,2H),7.37(s,1H),7.35(s,1H),7.33–7.30(m,4H),7.28(s,2H),7.07(s,2H),6.96(d,J＝7.8Hz,2H),6.21(d,J＝7.8Hz,1H),5.04(d,J＝4.4Hz,1H),4.92(t,J＝3.4Hz,1H),4.89(t,J＝3.7Hz,1H),4.69–4.65(m,1H),4.44(d,J＝6.4Hz,2H),4.00(d,J＝4.3Hz,2H),3.36(d,J＝14.7Hz,3H),3.12–3.08(m,2H),3.02–2.98(m,1H),2.95(s,1H),2.73(t,J＝8.0Hz,1H),2.30(s,3H),2.19(dd,J＝11.2,8.2Hz,1H)；13C NMR(101MHz,Chloroform-d)δ171.06,166.54,148.17,142.41,140.35,138.75,138.53,136.74,132.54,129.25,129.21,129.17,129.14,128.91,128.43,128.39,128.22,128.00,127.88,127.48,127.43,127.28,125.26,125.22,100.15,97.26,71.57,69.93,68.64,55.85,50.37,49.38,37.28,36.28,35.24,21.01.
实施例58化合物ⅹ的合成
将化合物ⅸ(0.3mmol)溶于甲醇(4mL)中，滴加2M氢氧化钠水溶液(0.6mmol)，室温过夜反应，反应结束后，减压浓缩，加入1M盐酸溶液调节pH至1-2，加入乙酸乙酯(20mL)萃取三次，再用饱和食盐水(10mL)洗涤三次，无水硫酸钠干燥，减压浓缩，硅胶色谱柱分离纯化，得淡黄色油状液体，收率64％。1H NMR(400MHz,Chloroform-d)δ7.53(d,J＝6.2Hz,2H),7.35(d,J＝7.9Hz,2H),7.30(d,J＝5.3Hz,6H),7.22(s,2H),7.09(d,J＝7.9Hz,2H),6.28(d,J＝7.1Hz,1H),5.04(d,J＝3.9Hz,1H),4.87(d,J＝7.5Hz,2H),4.69–4.64(m,1H),4.44(d,J＝9.4Hz,2H),3.99(s,2H),3.09(d,J＝9.2Hz,2H),2.97(d,J＝6.4Hz,1H),2.92(d,J＝7.2Hz,1H),2.76–2.71(m,1H),2.21–2.15(m,1H)；13C NMR(101MHz,Chloroform-d)δ174.14,167.58,149.39,142.24,140.30,138.72,131.51,130.91,130.74,129.13,128.82,128.70,128.61,128.46,128.42,128.27,128.01,127.89,127.63,127.52,127.45,127.30,125.27,125.24,100.21,97.84,71.83,69.94,68.20,55.92,46.24,38.71,36.41,35.02.
实施例59
参照实施例58，得淡黄色油状液体，收率22％。1H NMR(400MHz,Chloroform-d)δ7.53(s,2H),7.35(d,J＝3.9Hz,2H),7.30(s,4H),7.29(s,2H),7.10(s,2H),6.95(s,2H),6.33(d,J＝7.6Hz,1H),5.04(d,J＝4.1Hz,1H),4.87(d,J＝5.5Hz,2H),4.67(d,J＝7.4Hz,1H),4.42(s,2H),3.99(s,2H),3.06(d,J＝10.9Hz,2H),2.97(d,J＝10.0Hz,1H),2.92(s,1H),2.72(t,J＝8.0Hz,1H),2.23–2.18(m,1H)；13C NMR(101MHz,Chloroform-d)δ
171.82,167.67,160.79,149.38,142.25,140.35,138.81,136.60,131.50,130.89,130.81,128.81,128.45,128.41,128.25,127.99,127.86,127.49,127.43,127.26,125.27,125.23,115.49,115.28,100.17,97.84,71.79,71.65,71.19,46.28,38.73,36.41,35.00.
实施例60
参照实施例58，得淡黄色油状液体，收率28％。1H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.53(d,J＝7.8Hz,4H),7.38(d,J＝7.8Hz,2H),7.31–7.27(m,6H),7.18(s,1H),5.86(s,1H),5.28(d,J＝3.3Hz,1H),4.93(d,J＝11.6Hz,1H),4.78(d,J＝7.5Hz,1H),4.59(d,J＝11.5Hz,1H),4.49(s,2H),4.07(d,J＝6.7Hz,2H),3.14–3.04(m,2H),3.01(d,J＝9.2Hz,1H),2.95(s,1H),2.79–2.74(m,1H),2.14(d,J＝8.3Hz,1H)；13C NMR(101MHz,Chloroform-d)δ172.75,167.66,154.11,152.73,142.39,139.80,136.63,132.69,130.88,130.15,128.81,128.46,128.26,128.05,127.99,127.87,127.58,127.45,127.28,127.17,125.27,125.23,110.39,100.62,71.52,70.11,68.60,55.51,46.09,38.71,34.91,33.42.
实施例61
参照实施例58，得黄色油状液体，收率49％。1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝6.9Hz,2H),7.48(d,J＝4.4Hz,2H),7.33–7.28(m,6H),7.20(d,J＝7.3Hz,1H),7.13(dd,J＝8.8,2.2Hz,1H),5.97(d,J＝6.4Hz,1H),5.84(s,1H),4.95–4.83(m,2H),4.73(d,J＝7.4Hz,1H),4.49(d,J＝4.8Hz,2H),4.12(d,J＝10.4Hz,2H),3.23–3.11(m,2H),3.05(d,J＝4.8Hz,1H),2.99(d,J＝8.7Hz,1H),2.80(d,J＝8.0Hz,1H),2.26–2.21(m,1H)；13C NMR(101MHz,Chloroform-d)δ172.77,161.97,152.84,149.93,141.88,141.49,140.31,140.06,136.58,131.97,129.16,128.81,128.47,128.26,128.05,127.45,127.33,127.29,125.29,125.25,124.42,123.94,100.11,95.97,82.33,71.62,71.20,68.52,53.34,46.37,38.83,34.84,31.40.
实施例62
参照实施例58，得黄色油状液体，收率54％。1H NMR(400MHz,Chloroform-d)δ8.09(s,2H),7.53(s,2H),7.34(s,2H),7.31–7.27(m,6H),7.24(s,1H),7.18–7.11(m,1H),6.16(s,1H),5.07(d,J＝3.6Hz,1H),4.89(d,J＝11.4Hz,2H),4.68(d,J＝7.7Hz,1H),4.52(dd,J＝21.5,10.1Hz,2H),3.99(d,J＝5.5Hz,2H),3.19–3.05(m,2H),2.94(s,1H),2.91(s,1H),2.78–2.72(m,1H),2.25–2.18(m,1H)；13C NMR(101MHz,Chloroform-d)δ172.00,167.75,147.13,143.82,143.63,142.19,140.37,138.92,130.91,130.35,130.30,130.20,128.81,128.77,128.47,128.25,127.96,127.87,127.52,127.45,127.29,127.16,125.24,123.63,100.26,97.26,71.51,69.96,68.50,55.91,49.05,38.71,36.67,31.38.
实施例63
参照实施例58，得淡黄色油状液体，收率66％。1H NMR(400MHz,Chloroform-d)δ7.53(s,2H),7.36(d,J＝2.6Hz,2H),7.32–7.31(m,2H),7.30(s,2H),7.27(d,J＝2.3Hz,2H),7.18–7.14(m,2H),7.04(s,2H),6.31(d,J＝7.6Hz,1H),5.03(d,J＝4.4Hz,1H),4.88(t,J＝4.2Hz,2H),4.65(s,1H),4.42(s,2H),3.99(d,J＝3.9Hz,2H),3.11–3.07(m,2H),2.98(d,J＝8.6Hz,1H),2.93(s,1H),2.72(t,J＝7.6Hz,1H),2.28(s,3H),2.22–2.17(m,1H)；13C NMR(101MHz,Chloroform-d)δ174.65,171.72,149.17,142.29,140.22,138.64,136.66,132.44,130.89,129.36,129.26,129.20,129.11,128.45,128.40,128.24,128.01,127.88,127.81,127.50,127.44,127.30,125.27,125.23,100.15,97.96,71.61,71.16,69.94,55.86,46.28,38.25,36.57,35.04,21.02.
实施例64
Scp1，PTP1B，SHP2，TCPTP酶抑制活性测试
构建质粒并在大肠杆菌中表达获得Scp1酶。以对硝基苯磷酸(pNPP)为底物，于波长405nm考察磷酸酶(PTPs)酶解后的产物对硝基苯酚(pNP)，计算化合物对磷酸酶(PTPs)的抑制率，同时考察化合物对同源蛋白PTP1B,TCPTP及SHP2的选择性，以钒酸钠作为阳性对照。
Scp1抑制剂活性筛选过程为：首先将化合物溶于二甲基亚砜中，配成6个浓度梯度(100μM,50μM,25μM,12.5μM,6.25μM,1μM)。在96孔板中每孔加入90μL含有酶(8μg/mL Scp1)和缓冲液(50mM Tris-醋酸，10mM MgCl2，pH 5.5)的混合物，然后向每孔中加入1μL配好的化合物溶液，室温放置15分钟，向每孔中加入10μL底物(pNPP,6mM)，将96孔板置于37℃恒温箱中孵化10分钟后，向每孔中加入10μL的2N的氢氧化钠溶液淬灭反应，于酶标仪405nm处测定OD值，计算酶的抑制率和化合物的IC50值。
类似方法可检测化合物对PTP1B,SHP2,TCPTP的抑制活性，并计算其IC50值，结果如表1、2、3所示。
表1新型京尼平类衍生物的Scp1及PTP1B蛋白抑制活性结果
a值是一式三份的平均值，重复三次；
b Na3VO4作为PTP1B阳性对照
*Scp1没有阳性对照
表2新型京尼平类衍生物的Scp1及PTP1B蛋白抑制活性结果
a值是一式三份的平均值，重复三次；
b Na3VO4作为PTP1B阳性对照
*由于化合物3-(1-6)，4-(1-6)，5-(1-3)，5-(5-6)并没有显示Scp1活性，因此并没有测其对PTP1B的抑制率。
选取Scp1抑制活性较好的化合物，考察其对同源蛋白PTP1B、TCPTP、SHP2的选择性，结果见表3。
表3新型京尼平类衍生物的PTP1B、TCPTP、SHP2蛋白抑制活性结果
a值表示一式三份，重复三次；
b金线莲苷作为阳性对照
*Scp1没有阳性对照
表1、2、3说明：
1、该生物活性测定实验中所有阳性、阴性和药物测定实验条件均一致。
2、生物活性酶实验结果表明，大部分化合物对Scp1酶具有显著的抑制作用。如化合物3-1d,3-1e,3-2d,3-3c,3-3d,3-3e,15h对Scp1酶抑制活性IC50小于15μM。构效关系表明，化合物的疏水性越强，其对PTP1B的选择性越高。当将京尼平苷的糖基去掉，由京尼平苷变为京尼平时，降低分子的疏水性，目标化合物对PTP1B和Scp1的活性同步下降，而增加分子的疏水性，则化合物对Scp1的活性相应提高。京尼平和京尼平苷衍生物亲水端的羧酸对活性是必需的，当其被甲基化成甲酯时，化合物的活性丧失。且取代苄基的苯环上含碘原子和羟基时，活性较高。由于Scp1的两个疏水口袋与同源磷酸蛋白PTP1B的差异，目标分子的疏水侧链长度适中，无论太长还是太短，均会失去选择性或者活性，如化合物3-3e具有较好的选择性，对Scp1的抑制活性比TCPTP抑制活性高3倍以上，比SHP2抑制活性高8倍以上。化合物3-2d对Scp1的抑制活性比SHP2抑制活性高5倍以上。化合物3-3c对Scp1的抑制活性比SHP2抑制活性高6倍以上。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种如下式I所示的京尼平衍生物：
其中：
各个R1各自独立地选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基、取代或未取代的苄基；
R2选自下组：氢、卤素、硝基、氰基、羟基、氨基、酯基、甲酰基、酰胺基、磺酰胺基、甲酰胺基、砜基、亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基和5-14元杂芳基；
R3和R4各自独立地选自下组：氢、卤素、硝基、氰基、羟基、氨基、酯基、甲酰基、酰胺基、磺酰胺基、甲酰胺基、砜基、亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基和5-14元杂芳基；
R5选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基；或如下式II所示的基团：
各个R6各自独立地选自下组：氢、甲基，取代或未取代的苄基；
其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C4烷基、C1-C4卤代烷基、COOH、C2-C10酯基。
2.如权利要求1所述的京尼平类衍生物，其特征在于，所述的京尼平类衍生物具有如下式所示的结构：
其中，所述的R2选自下组：氢、卤素、硝基、氰基、羟基、氨基、C2-C6酯基、甲酰基、C2-C6酰胺基、磺酰胺基、甲酰胺基、C1-C6砜基、C1-C6亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基、和5-14元杂芳基；
R3和R4各自独立地选自下组：氢、卤素、硝基、氰基、羟基、氨基、C2-C6酯基、甲酰基、C2-C6酰胺基、磺酰胺基、甲酰胺基、C1-C6砜基、C1-C6亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基、和5-14元杂芳基。
3.如权利要求1所述的京尼平类衍生物，其特征在于，各个R1各自独立地选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基、取代或未取代的苄基；
R2选自下组：氢、卤素、硝基、氰基、羟基、氨基、C2-C6酯基、甲酰基、C2-C6酰胺基、磺酰胺基、甲酰胺基、C1-C6砜基、C1-C6亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基、和5-14元杂芳基(优选为I)；
R3和R4各自独立地选自下组：氢、卤素、硝基、氰基、羟基、氨基、C2-C6酯基、甲酰基、C2-C6酰胺基、磺酰胺基、甲酰胺基、C1-C6砜基、C1-C6亚砜基、C1-C5烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、C3-C10环烷氧基、3-10元杂环基、C6-C14芳基、和5-14元杂芳基；
R5选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基，或如下式II所示的基团：
4.如权利要求1所述的京尼平类衍生物，其特征在于，各个R1各自独立地选自下组：H、甲基、苄基、4-甲基苄基、4-氯苄基；
R2选自下组：氢、碘；
R3选自下组：氟、氯、溴、硝基、甲基；
R4选自下组：氢、氟、氯、溴、硝基、甲基；
R5选自下组：氢、甲基，苄基，或如下式II所示的基团：
5.如权利要求1所述的京尼平衍生物，其特征在于，所述的京尼平衍生物选自下组：
6.如权利要求1所述的京尼平衍生物的制备方法，其特征在于，所述的方法包括步骤：
用式Ia化合物和式Ib化合物反应，得到式I化合物；
其中，各个基团的定义如权利要求1中所示。
7.如权利要求1所述的京尼平衍生物的制备方法，其特征在于，所述的R5为式II所示的基团，且所述的方法包括步骤：
且所述的方法包括如下步骤：
(a)在N,N-二甲基甲酰胺中，在碱存在下，用京尼平苷与R1-Br反应过夜，得到化合物Ⅲ：
(b)在甲醇中，用式III化合物与碱反应，得到化合物Ⅳ；
(c)在N,N-二甲基甲酰胺中，用式IV化合物与取代或未取代的苯丙氨酸和1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、4-二甲氨基吡啶、N,N-二异丙基乙胺共同反应，得到化合物Ⅴ；
(d)用式V化合物进行取代基修饰，制备式I化合物。
8.如权利要求6所述的方法，其特征在于，所述的R5选自下组：氢、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、3-10元杂环基、C6-C14芳基、5-14元杂芳基；且所述的方法包括如下步骤(i)至(v)：
(i)将京尼平加入乙醇，在酸存在下进行回流反应，得到化合物ⅰ：
(ii)在二氯甲烷中，用化合物ⅰ与三乙胺、苯磺酰氯、4-二甲氨基吡啶进行反应，得到化合物ⅱ：
(iii)在甲醇中，用化合物ⅱ与氢氧化钠溶液进行反应，得到化合物ⅲ：
(iv)在N,N-二甲基甲酰胺中，用化合物ⅲ与对氯苯丙氨甲酯盐酸盐，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，4-二甲氨基吡啶和N,N-二异丙基乙胺进行反应，得化合物ⅳ：
(v)在甲醇中，用化合物ⅳ与碱反应，得化合物ⅴ
或所述的方法包括如下步骤(1)至(5)：
(1)在苯甲醇中，用京尼平与酸回流反应，得化合物ⅵ：
(2)在N,N-二甲基甲酰胺中，用化合物ⅵ与NaH反应，然后加入对三氟甲基苄溴继续反应，得化合物ⅶ：
(3)在甲醇中，用化合物ⅶ与碱反应，得化合物ⅷ：
(4)在N,N-二甲基甲酰胺中，用化合物ⅷ与对氯苯丙氨甲酯盐酸盐、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、4-二甲氨基吡啶和N,N-二异丙基乙胺反应，得化合物ⅸ：
(5)在甲醇中，用化合物ⅸ与碱反应，得化合物ⅹ：
9.如权利要求1所述的京尼平衍生物在制备用于抑制蛋白酶Scp1和/或PTP1B活性的药物组合物中的用途；较佳地，所述的药物组合物用于预防或治疗选自下组的疾病：脑瘤、神经退行性疾病。
10.一种药物组合物，其特征在于，所述的药物组合物包括：如权利要求1所述的药物组合物，以及药学上可接受的载体。
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| WO2024168437A1 (en) * | 2023-02-16 | 2024-08-22 | Inkbox Ink Incorporated | Genipin derivatives, topical composition comprising same, use as semi-permanent colorants |
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