CN117624127A - 吲哚类化合物及其制备方法和应用 - Google Patents
吲哚类化合物及其制备方法和应用 Download PDFInfo
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- CN117624127A CN117624127A CN202210963278.3A CN202210963278A CN117624127A CN 117624127 A CN117624127 A CN 117624127A CN 202210963278 A CN202210963278 A CN 202210963278A CN 117624127 A CN117624127 A CN 117624127A
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Abstract
本发明涉及一种吲哚类化合物及其制备方法和应用。所述吲哚类化合物具有式I或式II所示结构。所述吲哚类化合物能够靶向降解Myc蛋白。
Description
技术领域
本发明涉及生物医药技术领域，特别涉及吲哚类化合物及其制备方法和应用。
背景技术
Myc可以参与调控细胞内多个进程，包括蛋白质的合成、转录翻译，信号转导，核糖体生物合成、代谢以及细胞周期等，统筹了细胞增殖、分化、存活和免疫监控等多角度的生物学功能。
Myc蛋白家族包含c-Myc、N-Myc和L-Myc三种类型，其中，c-Myc蛋白最为常见，在多数肿瘤细胞中高表达。N-Myc则是在胚胎前期高表达于发育中的大脑，到胚胎时期表达量逐渐降低，成年后的正常组织中表达甚少，主要在神经胶质瘤细胞中高表达。L-Myc则高表达于新生儿发育中的肾脏、肺部、大脑等器官，同时在小细胞肺癌中也表达异常。在正常细胞中，c-Myc的表达是被严格调控的，表达量很低。而在多数肿瘤细胞中，c-Myc处于异常状态，表现为表达量激增以及蛋白稳定性增强。研究表明，至少有75％的人类肿瘤与Myc相关，包括前列腺癌、乳腺癌、结肠癌、子宫癌、白血病、淋巴瘤、肺小细胞癌和成神经细胞瘤等。
一些病毒感染宿主细胞后会引发依赖于Myc的糖酵解和谷氨酰胺代谢重编程，类似的现象也发生在肿瘤细胞中。除了肿瘤与病毒以外，Myc也与其他一些疾病相关，包括糖尿病、动脉粥样硬化和血管增生性疾病等。
鉴于Myc在疾病中的关键作用，以Myc为靶标进行药物设计具有广泛的临床应用前景，但由于Myc属于天然无序蛋白，其构象系综的高度异质性使得难以进行传统的基于结构的药物设计，鲜有高活性的配体分子被报道。目前仅有模拟c-Myc的C端序列所设计的多肽Omomyc(Omo-103)进入了临床I期研究，尚未有小分子药物进入临床研究。
发明内容
基于此，本发明提供一种吲哚类化合物及其制备方法和应用，所提供的吲哚类化合物能够靶向降解Myc蛋白。
本发明第一方面提供一种吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体。其技术方案如下：
一种吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，所述吲哚类化合物具有式I或式II所示结构：
其中，R1选自H、C1-3烷氧基、取代或未取代的具有6-10个环原子的芳香基、取代或未取代的具有5-10个环原子的杂芳香基或取代或未取代的具有5-10个环原子的杂环烷基；
R2选自H、卤素、C1-3烷基或C1-3烷氧基；
R4和R5分别独立地选自C1-3烷基或R4和R5形成R3取代的环；
R3选自H、卤素、C1-3烷基或C1-3烷氧基；
R0选自H或C1-3烷基；
L为单键、三键或-R6-C(O)-；
R6选自-R7-NH-或具有4-6个环原子的杂环烷基；
R7选自-CH2-或具有4-6个环原子的环烷基；
n选自0、1、2、3、4、5、6、7或8；
m1选自0、1、2、3、4或5；
m2选自1、2、3或4。
本发明第二方面提供上述吲哚类化合物的制备方法。其技术方案如下：
一种吲哚类化合物的制备方法，包括以下步骤：
使具有式1所示结构的化合物与具有式2所示结构的化合物反应，制备具有式3所示结构的化合物；
使具有式3所示结构的化合物与具有式4所示结构的化合物反应，制备具有式I所示结构的化合物；或
使具有式1所示结构的化合物与具有式2所示结构的化合物反应，制备具有式3所示结构的化合物；
使具有式3所示结构的化合物与具有式4所示结构的化合物反应，制备具有式I所示结构的化合物；
使具有式I所示结构的化合物与具有式5所示结构的化合物反应，生成具有式II所示结构的化合物；
本发明第三方面提供上述吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体在制备靶向降解Myc蛋白的药物中的应用。
本发明第四方面提供上述吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体在制备治疗或预防Myc蛋白失调相关疾病的药物中的应用。
本发明具有以下有益效果：
本发明采用E3连接酶CRBN的配体沙利度胺及其衍生物作为E3连接酶配体，首次提供了一种小分子化合物，实现了靶向降解天然无序蛋白Myc，且所提供的以Myc为靶标的小分子化合物的活性高。
附图说明
图1为PKUMDL-MP3处理HL-60细胞后对c-Myc蛋白含量的影响(Western Blot采用全自动定量Western系统进行检测)；
图2为PKUMDL-MP3对c-Myc蛋白的降解作用呈现时间依赖(Western Blot采用全自动定量Western系统进行检测)；
图3为PKUMDL-MI1和PKUMDL-MP3在有(无)Lenalidomide存在下，对HL-60细胞生长抑制情况；
图4为PKUMDL-MI1和PKUMDL-MP3在在有(无)Lenalidomide存在下，对c-Myc蛋白含量的影响(Western Blot采用全自动定量Western系统进行检测)
图5为PKUMDL-MP3有(无)蛋白酶体抑制剂MG132存在下，对c-Myc蛋白含量的影响(Western Blot采用全自动定量Western系统进行检测)。
具体实施方式
以下结合具体实施例对本发明作进一步详细的说明。本发明可以以许多不同的形式来实现，并不限于本文所描述的实施方式。相反地，提供这些实施方式的目的是使对本发明公开内容理解更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
术语
除非另外说明或存在矛盾之处，本文中使用的术语或短语具有以下含义：
本文中，术语“烷基”是指包含伯(正)碳原子、或仲碳原子、或叔碳原子、或季碳原子、或其组合的饱和烃失去一个氢原子生成的一价残基。包含该术语的短语，例如，“C1～C3亚烷基”是指包含1～3个碳原子的烷基，每次出现时，可以互相独立地为C1烷基、C2烷基、C3烷基。“烷基”合适的实例包括但不限于：甲基(Me、-CH3)、乙基(Et、-CH2CH3)、1-丙基(n-Pr、n-丙基、-CH2CH2CH3)、2-丙基(i-Pr、i-丙基、-CH(CH3)2)、1-丁基(n-Bu、n-丁基、-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu、i-丁基、-CH2CH(CH3)2)、2-丁基(s-Bu、s-丁基、-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu、t-丁基、-C(CH3)3)、1-戊基(n-戊基、-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3和辛基(-(CH2)7CH3)。可以理解地，术语“亚烷基”是指在“烷基”的基础上再失去一个氢原子的残基。
“环烷基”指饱和单环、双环或多环环状烃基，该基团可以与芳基或杂芳基稠合。环烷基环可以任选地被取代。在某些实施方案中，环烷基环含有一个或多个羰基，例如氧代的基团。“C3-8环烷基”是指具有3至8个碳原子的单环环烷基，环烷基的非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丁酮、环戊酮、环戊烷-1,3-二酮等。优选为C3-6环烷基，包括环丙基、环丁基、环戊基和环己基。
“杂环烷基”指包含至少一个选自氮、氧和硫的杂原子的环烷基，该基团可以与芳基或杂芳基稠合。杂环烷基环可以任选地被取代。在某些实施方案中，杂环烷基环含有一个或多个羰基或硫代羰基，例如包含氧代和硫代的基团。“3至8元杂环烷基”是指具有3至8个环原子，其中1、2或3个环原子为选自氮、氧和硫的杂原子的单环环状烃基。单环杂环烷基的非限制性实施例包括氮丙环基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、噁唑烷基、二氧戊环基、哌啶基、哌嗪基、吗啉基、二氧六环基、硫代吗啉基、硫代吗啉-1,1-二氧化物、四氢吡喃基、氮杂环丁烷-2-酮基、氧杂环丁烷-2-酮基、二氢呋喃-2(3H)-酮基、吡咯烷-2-酮基、吡咯烷-2,5-二酮基、二氢呋喃-2,5-二酮基、哌啶-2-酮基、四氢-2H-吡喃-2-酮基、哌嗪-2-酮基、吗啉-3-酮基等。
“芳基””指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，该基团可以与环烷基环、杂环烷基环、环烯基环、杂环烯基环或杂芳基稠合。“C6-10芳基”指具有6至10个碳原子的单环或双环芳基，芳基的非限制性实施例包括苯基、萘基等。
“杂芳基”指具有环碳原子和环杂原子的单环、双环或多环的4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。本发明中，杂芳基还包括其中上述杂芳基环与一个或多个环烷基环、杂环烷基环、环烯基环、杂环烯基环或芳环稠合的环系统。杂芳基环可以任选地被取代。“5至10元杂芳基”是指具有5至10个环原子，其中1、2、3或4个环原子为杂原子的单环或双环杂芳基。“5至6元杂芳基”是指具有5至6个环原子，其中1、2、3或4个环原子为杂原子的单环杂芳基，非限制性实施例包括噻吩基、呋喃基、噻唑基、异噻唑基、咪唑基、噁唑基、吡咯基、吡唑基、三唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、四唑基、异噁唑基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-恶二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、四嗪基。“8至10元杂芳基”是指具有8至10个环原子，其中1、2、3或4个环原子为杂原子的双环杂芳基，非限制性实施例包括吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基、嘌呤基、吡啶并[3,2-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[4,3-d]嘧啶基、1,8-萘啶基、1,7-萘啶基、1,6-萘啶基、1,5-萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。“杂原子”是指氮、氧或硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。
“烷氧基”指-O-烷基，其中烷基的定义如上所述。优选C1-8烷氧基，更优选C1-6烷氧基，最优选C1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。
“卤素”指氟、氯、溴或碘。
表示与其他原子的连接。
“药学上可接受的”指在合理医学判断范围内适于施用患者且与合理益处/风险比相称的那些配体、材料、组合物和/或剂型。
“药学上可接受的载体”指药学上可接受的材料、组合物或媒剂，例如液体或固体填充剂、稀释剂、赋形剂、溶剂或囊封材料。如本文所用，语言“药学上可接受的载体”包括与药物施用相容的缓冲剂、注射用无菌水、溶剂、分散介质、包衣、抗细菌剂及抗真菌剂、等渗剂及吸收延迟剂及诸如此类。在与配制物中其他成分兼容且对患者无害的意义上，每种载体必须为“药学上可接受的”。合适的实例包括但不限于：(1)糖，例如乳糖、葡萄糖及蔗糖；(2)淀粉，例如玉米淀粉、马铃薯淀粉及经取代或未经取代的β-环糊精；(3)纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素；(4)粉状黄蓍胶；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，例如可可脂及栓剂蜡；(9)油类，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；(10)二醇，例如丙二醇；(11)多元醇，例如甘油、山梨醇、甘露醇及聚乙二醇；(12)酯类，例如油酸乙酯及月桂酸乙酯；(13)琼脂；(14)缓冲剂，例如氢氧化镁及氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格氏溶液；(19)乙醇；(20)磷酸盐缓冲液；及(21)药物配制物中所采用的其他无毒兼容物质。
“盐”是指所示结构中的任一化合物与酸或碱所形成的适合用作药物的盐。包括无机盐和有机盐。其中，一类盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、碳酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。例如：盐酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、硫酸盐、硝酸盐、碳酸氢盐、碳酸盐、戊二酸盐、氢溴酸盐、醋酸盐、枸橼酸盐、乳酸盐、马来酸盐、苯甲酸盐、甲磺酸盐、草酸盐、苯磺酸盐、对甲苯磺酸盐、酒石酸盐、苹果酸盐、琥珀酸盐、抗坏血酸盐、葡萄糖酸盐、乳酸盐等。另一类盐是本发明化合物与碱形成的盐，适合形成盐的碱包括但并不限于：碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
本发明的化合物或包含其的药物的剂型和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)注射、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，具体例如，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。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。如悬浮液可包含悬浮剂，具体例如，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。
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，以及用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水或非水载体、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。
用于局部给药的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。由活性成分在无菌条件下与药学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而成。
本发明中，“第一方面”、“第二方面”、“第三方面”、“第四方面”等仅用于描述目的，不能理解为指示或暗示相对重要性或数量，也不能理解为隐含指明所指示的技术特征的重要性或数量。而且“第一”、“第二”、“第三”、“第四”等仅起到非穷举式的列举描述目的，应当理解并不构成对数量的封闭式限定。
本发明中，以开放式描述的技术特征中，包括所列举特征组成的封闭式技术方案，也包括包含所列举特征的开放式技术方案。
本发明中涉及的百分比含量，如无特别说明，对于固液混合和固相-固相混合均指质量百分比，对于液相-液相混合指体积百分比。
本发明中涉及的百分比浓度，如无特别说明，均指终浓度。所述终浓度，指添加成分在添加该成分后的体系中的占比。
本发明中的温度参数，如无特别限定，既允许为恒温处理，也允许在一定温度区间内进行处理。所述的恒温处理允许温度在仪器控制的精度范围内进行波动。
本发明中的室温一般指4℃～30℃，较佳地指20±5℃。
本发明的一个目的是提供一种吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体。
所述吲哚类化合物具有式I或式II所示结构：
其中，R1选自H、C1-3烷氧基、取代或未取代的具有6-10个环原子的芳香基、取代或未取代的具有5-10个环原子的杂芳香基或取代或未取代的具有5-10个环原子的杂环烷基；
R2选自H、卤素C1-3烷基或C1-3烷氧基；
R4和R5分别独立地选自C1-3烷基或R4和R5形成R3取代的环；
R3选自H、卤素C1-3烷基或C1-3烷氧基；
R0选自H或C1-3烷基；
L为单键、三键或-R6-C(O)-；
R6选自-R7-NH-或具有4-6个环原子的杂环烷基；
R7选自-CH2-或具有4-6个环原子的环烷基；
n选自0、1、2、3、4、5、6、7或8；
m1选自0、1、2、3、4或5；
m2选自1、2、3或4。
可选地，所述R1选自H、C1-3烷氧基或以下取代基中的一种：
其中，R8选自H、卤素或C1-3烷氧基；q选自1、2、3、4或5。
在一些优选的实施例中，所述吲哚类化合物具有式I-1所示结构：
其中，Ar1选自具有6-10个环原子的芳香基或具有5-10个环原子的环烷基。
在一些更优选的实施例中，所述吲哚类化合物具有式I-2所示结构：
在一些进一步优选的实施例中，所述吲哚类化合物具有式I-3所示结构：
所述n选自0、1或2，所述R1选自H或以下取代基中的一种：
优选地，R2选自H或溴，R3选自H或溴。
可选地，所述L为单键、三键或以下取代基中的一种：
在一些优选的实施例中，所述吲哚类化合物具有式II-1、式II-2、式II-3或式II-4所示结构：
进一步优选地，所述L为单键，m1与m2的和选自1、2、3、4、5或6。
进一步优选地，所述L为m1选自1或2；m2选自1或2。
可以理解地，本发明的吲哚类化合物包括但不限于以下结构：
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本发明的又一个目的是提供上述吲哚类化合物的制备方法。
所述制备方法包括以下步骤：
使具有式1所示结构的化合物与具有式2所示结构的化合物反应，制备具有式3所示结构的化合物；
使具有式3所示结构的化合物与具有式4所示结构的化合物反应，制备具有式I所示结构的化合物；
或
使具有式1所示结构的化合物与具有式2所示结构的化合物反应，制备具有式3所示结构的化合物；
使具有式3所示结构的化合物与具有式4所示结构的化合物反应，制备具有式I所示结构的化合物；
使具有式I所示结构的化合物与具有式5所示结构的化合物反应，生成具有式II所示结构的化合物；
本发明的又一个目的是提供上述吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体在制备靶向降解Myc蛋白的药物中的应用。
具体地，Myc蛋白包括c-Myc、N-Myc和L-Myc蛋白。
本发明的又一个目的是提供吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体在制备治疗或预防Myc蛋白失调相关疾病的药物中的应用。
优选的，所述Myc蛋白失调相关疾病为癌症、病毒感染相关疾病、心脑血管疾病、糖尿病、肥胖、脂肪性肝病、高血压、动脉粥样硬化和免疫系统疾病等。优选的，所述癌症为肝癌、肺癌、肾癌、胰腺癌、口腔癌、胃癌、食道癌、喉癌、鼻咽癌、皮肤癌、乳腺癌、结肠癌、直肠癌、宫颈癌、卵巢癌、前列腺癌、脑癌、神经癌、粒细胞性白血病、横纹肌肉瘤、成骨肉瘤、软骨肉瘤、白血病和淋巴癌等。
实施例1、PKUMDL-MI的通用合成路线
步骤1、中间体9-环氧丙基咔唑的合成
33.4g咔唑溶于300mL DMF中，加入13.1g KOH，缓慢加入28.0g环氧溴丙烷，室温反应12小时，将反应液边搅拌边倒入冰水中(1L左右)，析出大量固体，布氏漏斗过滤固体，水洗涤2次，用石油醚洗涤1次，烘干即可得到粗品9-环氧丙基咔唑，不需纯化，直接用于下一步反应。
步骤2、PKUMDL-MI的合成
9-环氧丙基咔唑4.46g溶于50mL二氧六环，加入适量H2N-R1，回流8小时,将反应液倒入冰水中(5倍溶剂体积以上即可)，布氏漏斗过滤，水洗2次，石油醚洗涤1次，石油醚/乙酸乙酯(5:1)洗涤2次，得到粗品，将粗品固体溶解于乙酸乙酯中(恰好溶解)，逐渐加入石油醚至部分产物析出，静置24小时，过滤得到产物。
以PKUMDL-MI1为例，其步骤2如下：
9-环氧丙基咔唑4.46g溶于50mL二氧六环，加入2.00g呋喃-2-甲胺，回流8小时,将反应液倒入冰水中(5倍溶剂体积以上即可)，布氏漏斗过滤，水洗2次，石油醚洗涤1次，石油醚/乙酸乙酯(5:1)洗涤2次，得到粗品，将粗品固体溶解于乙酸乙酯中(恰好溶解)，逐渐加入石油醚至部分产物析出，静置24小时，过滤得到产物5.31g，产率81％，所合成化合物的表征数据如表1所示。
采用上述PKUMDL-MI的通用合成路线，制备PKUMDL-MI2～PKUMDL-MI15，所合成化合物的结构和表征数据如表1所示：
表1
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实施例2、PKUMDL-MP的通用合成路线
将1mmol实施例1中合成的PKUMDL-MI溶于5mL DMF中，加入1mmol不同长度的羧酸衍生物，1.2mmol HATU，1.2mmol N,N-二异丙基乙基胺，室温搅拌2小时，加入50mL乙酸乙酯，50mL水，充分萃取，有机相水洗涤2次，饱和食盐水洗涤1次，无水硫酸钠干燥有机相，旋转蒸发除去溶剂，残留物柱色谱分离，得到目标产物。
其中，不同长度的羧酸衍生物参考以下路线合成：
一、5-溴-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮的合成
1L反应瓶中，22.7g 5-溴异苯并呋喃-1,3-二酮加入600mL醋酸，1.05当量醋酸钠，16.5g 3-氨基哌啶-2,6-二酮盐酸盐，120摄氏度反应14小时。反应液冷却后直接倒入600mL水中，过滤得到产物，水洗2遍，烘干，不用额外纯化，即得到纯产物32.0g，产率95％。1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.16(d,J＝1.7Hz,1H),8.10(dd,J＝7.9,1.7Hz,1H),7.87(d,J＝7.9Hz,1H),5.17(dd,J＝12.8,5.4Hz,1H),2.89(ddd,J＝17.0,13.8,5.4Hz,1H),2.69-2.52(m,2H),2.06(ddd,J＝10.6,5.5,2.8Hz,1H).
二、6-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)-5-炔基己酸苄酯的合成
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16.8g 5-溴-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮溶解于500mL DMF,加入15.3g 5-炔基己酸苄酯,100mL三乙胺，1g二氯[双(二苯基膦苯基)醚]钯(II)，500mg碘化亚铜，除去反应体系氧气，氩气保护，80摄氏度反应5小时,冷却至室温。反应液乙酸乙酯萃取3次，饱和食盐水洗涤3次，无水硫酸钠干燥有机相，减压蒸馏除去溶剂，重结晶得到产物16.72g，产率73％。1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),7.95-7.83(m,3H),7.37(d,J＝4.2Hz,5H),5.16(dd,J＝12.8,5.4Hz,1H),5.11(s,2H),2.89(ddd,J＝16.8,13.7,5.4Hz,1H),2.57(ddq,J＝11.6,7.1,4.5,3.9Hz,6H),2.06(ddd,J＝12.1,5.5,3.3Hz,1H),1.86(p,J＝7.2Hz,2H).
三、6-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)-5-炔基己酸的合成
4.58g 6-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)-5-炔基己酸苄酯溶解于50mL三氟乙酸中，回流8小时，旋转蒸发除去三氟乙酸，乙酸乙酯/乙醇混合溶剂重结晶得到产物3.13g，产率85％。
四、6-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)己酸的合成
2.29g 6-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)-5-炔基己酸苄酯溶解于50mL DMF中，加入100mg 10％的Pd/C，100mg 20％Pd(OH)2/C,0.4Mpa压力H2下反应8小时,过滤除去催化剂。旋转蒸发除去溶剂，乙酸乙酯/乙醇混合溶剂重结晶得到产物1.45g,产率78％。1H NMR(400MHz,DMSO-d6)δ11.96(s,1H),11.11(s,1H),7.83(d,J＝7.6Hz,1H),7.78(d,J＝1.4Hz,1H),7.71(dd,J＝7.7,1.5Hz,1H),5.13(dd,J＝12.9,5.3Hz,1H),2.89(ddd,J＝17.4,14.1,5.4Hz,1H),2.78(t,J＝7.6Hz,2H),2.65-2.52(m,2H),2.20(t,J＝7.3Hz,2H),2.05(ddt,J＝13.1,5.7,2.7Hz,1H),1.63(p,J＝7.6Hz,2H),1.53(p,J＝7.4Hz,2H),1.28(dt,J＝9.8,7.1Hz,2H).
五、6-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)庚酸的合成
方法同中间体二和中间体四。1H NMR(400MHz,DMSO-d6)δ11.95(s,1H),11.12(s,1H),7.82(d,J＝7.7Hz,1H),7.76(s,1H),7.69(dd,J＝7.8,1.5Hz,1H),5.13(dd,J＝12.9,5.4Hz,1H),2.89(s,2H),2.76(d,J＝7.7Hz,2H),2.63-2.54(m,1H),2.34(t,J＝7.3Hz,2H),2.05(ddd,J＝14.7,8.7,5.1Hz,1H),1.56(dq,J＝21.5,7.1Hz,4H),1.32-1.25(m,4H).
六、6-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)戊酸的合成
方法同中间体二和中间体四。1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),11.13(s,1H),7.95(s,1H),7.85(s,2H),5.27-5.05(m,1H),2.93-2.83(m,1H),2.58(td,J＝14.5,4.1Hz,1H),2.45(p,J＝6.6,5.8Hz,3H),2.11-2.02(m,1H),1.63(q,J＝7.8Hz,2H),1.51(q,J＝7.7Hz,2H).
七、中间体3-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)丙酸的合成
HP(t-Bu)3BF4 0.75g，N,N-二环丙基甲基胺3.25mL溶于100mL二氧六环中，加入Pd2(dba)31g，混合物氩气下室温搅拌1小时，加入5-溴-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮4.38g，丙烯酸苄酯4.21g，50℃下反应3小时，冷却至室温，二氯甲烷萃取，饱和氯化铵溶液洗涤，饱和食盐水洗涤，干燥，除去溶剂，重结晶得到中间体3-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)丙烯酸苄酯2.23g，产率41％。将上述3-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)丙烯酸苄酯2.09g溶于100mL DMF中，加入100mg10％的Pd/C，100mg 20％Pd(OH)2/C,0.4Mpa压力H2下反应8小时,过滤除去催化剂。旋转蒸发除去溶剂，乙酸乙酯/乙醇混合溶剂重结晶得到产物1.17g,产率71％。1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),11.12(s,1H),7.84(d,J＝7.6Hz,1H),7.82(s,1H),7.75(dd,J＝7.6,1.5Hz,1H),5.14(dd,J＝12.9,5.4Hz,1H),3.01(t,J＝7.4Hz,2H),2.94-2.82(m,1H),2.74-2.53(m,4H),2.06(dtd,J＝13.1,6.2,5.7,3.1Hz,1H).
八、5-(2-(1-甲基-2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-4-基)戊酸的合成
2.29g 5-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-4-基)-4-炔基戊酸苄酯溶解于20mL DMF中，加入0.70g K2CO3,0.72g碘甲烷，室温搅拌3小时，倒入100mL水中，过滤得到固体产物，乙酸乙酯/乙醇重结晶得到甲基化中间体。核磁鉴定结构正确。1H NMR(400MHz,DMSO-d6)δ7.89(d,J＝8.1Hz,1H),7.79(dt,J＝4.5,2.2Hz,2H),7.43-7.26(m,5H),5.23(dd,J＝13.1,5.3Hz,1H),5.16(s,2H),3.02(s,3H),3.00-2.89(m,1H),2.83-2.69(m,5H),2.57(td,J＝13.2,4.6Hz,1H),2.14-2.05(m,1H),1.24(s,1H),0.89-0.79(m,1H).13C NMR(100MHz,DMSO-d6)δ172.21,171.72,169.99,166.99,166.89,137.92,136.59,132.21,130.45,129.75,128.89,128.50,128.41,126.08,124.23,94.93,79.72,66.16,50.15,33.05,31.54,27.11,21.58,15.42.将中间体6-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)-5-炔基己酸苄酯溶解于50mL DMF中，加入100mg 10％的Pd/C，100mg20％Pd(OH)2/C,0.4Mpa压力H2下反应8小时,过滤除去催化剂。旋转蒸发除去溶剂，乙酸乙酯/乙醇混合溶剂重结晶得到产物目标中间体5-(2-(1-甲基-2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-4-基)戊酸，不进一步纯化，直接使用。
以PKUMDL-MP3为例，其合成步骤如下：
取1-(9-咔唑基)-3-(呋喃-2-甲基)氨基丙-2-醇320mg,溶于5mL DMF,加入1mmol6-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)己酸,456mg HATU,155mg N,N-二异丙基乙基胺，室温搅拌2小时，加入50mL乙酸乙酯，50mL水，充分萃取，有机相水洗涤2次，饱和食盐水洗涤1次，无水硫酸钠干燥有机相，旋转蒸发除去溶剂，残留物柱色谱分离，得到目标产物N-(3-(9-咔唑基)-2-羟基丙基)-6-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂异吲哚-5-基)-N-(呋喃-2-甲基)己酰胺424mg，产率63％，所合成化合物的表征数据如表2所示。
采用上述PKUMDL-MP的通用合成路线，参照不同长度的羧酸衍生物的合成方法，制备PKUMDL-MP1～PKUMDL-MP2、PKUMDL-MP4～PKUMDL-MP27，所合成化合物的结构和表征数据如表2所示：
表2
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实施例3、化合物的抗肿瘤活性
一、将对数生长期的HL-60(人急性早幼粒白血病细胞)接种到96孔板中，加入不同浓度的PKUMDL-MI系列化合物和PKUMDL-MP系列化合物(溶于DMSO)，DMSO终浓度为0.2％，对照组为DMSO。加药培养72小时后，每孔加入20μL的MTT(5mg/mL，现配现用)，37℃孵育4小时后吸去上清，加入DMSO，震荡5分钟，使蓝紫色结晶充分溶解。用酶标仪检测每孔在570nm波长处的吸收值，计算PKUMDL-MI系列化合物和PKUMDL-MP系列化合物的EC50值，结果见表3和表4所示。其中，表3为PKUMDL-MI系列化合物对HL60细胞生长抑制作用；表4为PKUMDL-MP系列化合物对HL60细胞生长抑制作用。
表3
表4
由表3和表4可知，本发明PKUMDL-MI系列化合物和PKUMDL-MP系列化合物对Myc依赖型肿瘤细胞生长有抑制作用。很多化合物抑制效果优异。
二、将对数生长期的HL-60(人急性早幼粒白血病细胞)、CEM(人急性淋巴细胞白血病细胞)、Daudi(人Burkkit淋巴瘤细胞)、Jurkat(人急性T淋巴细胞白血病细胞)、K562(人慢性髓系白血病细胞)、NB4(人急性早幼粒白血病细胞)、THP-1(人急性单核细胞白血病细胞)、U937(人组织细胞淋巴瘤细胞)、P493-6(人Burkkit淋巴瘤细胞)、IMR-32(人神经母细胞瘤细胞)、LNCaP(人前列腺癌细胞)、PC-3(人前列腺癌细胞)、HeLa(人宫颈癌细胞)、MDA-MB-231(人乳腺癌细胞)、MDA-MB-468(人乳腺癌细胞)和PC-12(大鼠肾上腺嗜铬细胞瘤细胞，非Myc依赖性肿瘤细胞作为参照)接种到96孔板中，参照表5，对应向相应细胞中加入不同浓度的PKUMDL-MP3(溶于DMSO)、PKUMDL-MP4(溶于DMSO)，DMSO终浓度均为0.2％，对照组为DMSO。加药培养72小时后，每孔加入20μL的MTT(5mg/mL，现配现用)，37℃孵育4小时后吸去上清，加入DMSO，震荡5分钟，使蓝紫色结晶充分溶解。用酶标仪检测每孔在570nm波长处的吸收值，计算化合物的EC50值，结果见表5所示。
表5
由表5可知，PKUMDL-MP3、PKUMDL-MP4对多种Myc依赖型肿瘤细胞生长均具有优异的抑制效果，对非MYC依赖型肿瘤细胞无毒性，可用于癌症的治疗。进一步可知，PKUMDL-MP系列化合物多种Myc依赖型肿瘤细胞生长均具有优异的抑制效果，对非MYC依赖型肿瘤细胞无毒性，可用于癌症的治疗。
实施例4、化合物对c-Myc蛋白降解效果测试
将对数生长期的HL-60细胞接种到6孔板中，每孔共有4×105个细胞，然后加入不同浓度的PKUMDL-MP3(溶于DMSO储液中)，DMSO终浓度为0.2％，对照组为DMSO。加药培养24小时后，收集相同数量的细胞。裂解细胞后的样品进行离心，弃沉淀，取上清。BCA定量后，将样品用Simple Western试剂盒内的Master Mix试剂混合并在95℃加热5分钟变性。在检测板中，依次加入变性的样品、抗体稀释液、对应的一抗、对应的二抗、辣根过氧化物酶-底物混合物和冲洗液，放入Wes仪器(Protein Simple公司)进行Simple Western检测。该仪器可在毛细管中自动实现蛋白上样、蛋白分离、蛋白固定、免疫杂交和数据采集过程。其工作原理是毛细管电泳对样品进行分离后，通过紫外光偶联将管中蛋白组分固定在毛细管壁上，然后分别吸取一抗、二抗检测组分中的蛋白，最后采用辣根过氧化物酶催化底物产生的荧光强度进行定量，将荧光强度用不同深浅的条带表示，实现荧光数值的可视化。
通过Western Blot技术考察了PKUMDL-MP3对靶蛋白c-Myc的降解作用。实验结果表明，PKUMDL-MP3可以有效地降解c-Myc蛋白，并且该作用呈现浓度依赖(图1)和时间依赖(图2)。
实施例5、本发明化合物对靶蛋白的降解机制考察
来那度胺(Lenalidomide)为CRBN结合分子，可与基于CRBN配体合成的PKUMDL-MP3竞争结合CRBN蛋白，阻滞E3连接酶的招募，进而抑制PKUMDL-MP3对靶蛋白c-Myc的降解，破坏其抗肿瘤生长的功能。
图3为PKUMDL-MI1和PKUMDL-MP3在有(无)Lenalidomide存在下，对HL-60细胞生长抑制情况，如图3所示，来那度胺的存在对PKUMDL-MI1的抗HL-60细胞生长作用没有显著影响，而对PKUMDL-MP3的活性则有大幅度的降低。表明来那度胺可以竞争结合CRBN，阻碍PKUMDL-MP3招募E3连接酶，进而阻滞其靶向降解c-Myc蛋白的功能，只能发挥较弱的c-Myc抑制活性，大大降低了其抗肿瘤生长的功能。随后，进一步考察了c-Myc蛋白的含量变化以验证化合物的作用机制。如图4所示，在来那度胺共同作用下，PKUMDL-MI1对c-Myc蛋白含量的影响差别不大，而PKUMDL-MP3则几乎丧失了对c-Myc的降解作用。
根据蛋白质靶向降解技术的作用原理，进一步考察了蛋白酶体抑制剂MG132是否可以逆转PKUMDL-MP3对c-Myc蛋白的下调作用。实验表明，在MG132抑制蛋白酶的活性后，PKUMDL-MP3完全丧失了对c-Myc的降解作用(见图5)。
这些结果说明化合物PKUMDL-MP3是通过招募特定的CRBN E3连接酶进而促进靶蛋白c-Myc被泛素-蛋白酶体通路加速降解。
以上实验结果表明，本发明化合物可以有效地降解目标蛋白c-Myc。对多种Myc依赖型肿瘤细胞生长具有优异的抑制作用，其活性较优。将本发明的化合物或其药用盐、或其立体异构体作为有效成分，添加常规药物载体，可制备用于治疗多种癌症的药物。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (14)
1.一种吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，其特征在于，所述吲哚类化合物具有式I或式II所示结构：
其中，R1选自H、C1-3烷氧基、取代或未取代的具有6-10个环原子的芳香基、取代或未取代的具有5-10个环原子的杂芳香基或取代或未取代的具有5-10个环原子的杂环烷基；
R2选自H、卤素、C1-3烷基或C1-3烷氧基；
R4和R5分别独立地选自C1-3烷基或R4和R5形成R3取代的环；
R3选自H、卤素、C1-3烷基或C1-3烷氧基；
R0选自H或C1-3烷基；
L为单键、三键或-R6-C(O)-；
R6选自-R7-NH-或具有4-6个环原子的杂环烷基；
R7选自-CH2-或具有4-6个环原子的环烷基；
n选自0、1、2、3、4、5、6、7或8；
m1选自0、1、2、3、4或5；
m2选自1、2、3或4。
2.根据权利要求1所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，其特征在于，所述R1选自H、C1-3烷氧基或以下取代基中的一种：
其中，R8选自H、卤素或C1-3烷氧基；q选自1、2、3、4或5。
3.根据权利要求1或2所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，其特征在于，所述吲哚类化合物具有式I-1所示结构：
其中，Ar1选自具有6-10个环原子的芳香基或具有5-10个环原子的环烷基。
4.根据权利要求3所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，其特征在于，所述吲哚类化合物具有式I-2所示结构：
5.根据权利要求4所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，其特征在于，所述吲哚类化合物具有式I-3所示结构：
所述n选自0、1或2，所述R1选自H或以下取代基中的一种：
6.根据权利要求1或2所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，其特征在于，所述L为单键、三键或以下取代基中的一种：
7.根据权利要求6所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，其特征在于，所述吲哚类化合物具有式II-1、式II-2、式II-3或式II-4所示结构：
8.根据权利要求7所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，其特征在于，所述L为单键，m1与m2的和选自1、2、3、4、5或6。
9.根据权利要求7所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，其特征在于，所述L为m1选自1或2；m2选自1或2。
10.根据权利要求1所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体，其特征在于，所述吲哚类化合物具有以下结构中的一种：
11.一种权利要求1-10任一项所述的吲哚类化合物的制备方法，其特征在于，包括以下步骤：
使具有式1所示结构的化合物与具有式2所示结构的化合物反应，制备具有式3所示结构的化合物；
使具有式3所示结构的化合物与具有式4所示结构的化合物反应，制备具有式I所示结构的化合物；
或
使具有式1所示结构的化合物与具有式2所示结构的化合物反应，制备具有式3所示结构的化合物；
使具有式3所示结构的化合物与具有式4所示结构的化合物反应，制备具有式I所示结构的化合物；
使具有式I所示结构的化合物与具有式5所示结构的化合物反应，生成具有式II所示结构的化合物；
12.权利要求1～9任一项所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体在制备靶向降解Myc蛋白的药物中的应用。
13.权利要求1～9任一项所述的吲哚类化合物或其盐、或其立体异构体、或其药学上可接受的载体在制备治疗或预防Myc蛋白失调相关疾病的药物中的应用。
14.根据权利要求13所述的应用，其特征在于，所述Myc蛋白失调相关疾病为癌症、病毒感染相关疾病、心脑血管疾病、糖尿病、肥胖、脂肪性肝病、高血压、动脉粥样硬化和免疫系统疾病。
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