CN118146221A - 一种吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂、制法及其药物组合物和应用 - Google Patents
一种吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂、制法及其药物组合物和应用 Download PDFInfo
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- CN118146221A CN118146221A CN202410585422.3A CN202410585422A CN118146221A CN 118146221 A CN118146221 A CN 118146221A CN 202410585422 A CN202410585422 A CN 202410585422A CN 118146221 A CN118146221 A CN 118146221A
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- indolo
- isoquinolin
- chloro
- methoxy
- propyl
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Abstract
本发明涉及一种吡咯并[3,2‑b]吡啶类拓扑异构酶抑制剂、制法及其药物组合物和应用,属于医药技术领域。本发明的抑制剂为通式V所示的取代吡咯并[3,2‑b]吡啶类化合物,或其立体异构体、水合物或药学上可接受的盐;所述抑制剂具有高效优异的Top1/2双重抑制活性,且成本低、疗效佳、毒性小,在合成过程中的中间产物收率高,降低了资源浪费,进而有利于降低成本;应用于抗肿瘤药物中使用剂量小,活性显著。
Description
技术领域
本发明涉及一种吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂、制法及其药物组合物和应用,属于医药技术领域。
背景技术
拓扑异构酶是一类在 DNA 代谢中起重要作用的内切酶,其在细胞增殖、分化和存活过程中能够触发、控制和修饰大量拓扑 DNA 问题。在人体细胞中,拓扑异构酶通常根据其催化功能、反应机理、氨基酸序列和结构分为 I 型和 II 型。研究表明,拓扑异构酶在许多肿瘤细胞中存在过表达现象,而调节肿瘤细胞内拓扑异构酶活性,干扰 DNA 复制进而抑制肿瘤细胞生长,使拓扑异构酶成为当下肿瘤治疗的重要药物靶点。在目前的临床用药指南中,拓扑异构酶抑制剂已经成为多种癌症的治疗药物。例如,靶向拓扑异构酶 I(Top1)的药物,主要是喜树碱(CPT)及其衍生物,包括拓扑替康和伊立替康,用于治疗结直肠癌、肺癌和胃癌等。依托泊苷和柔红霉素作为拓扑异构酶 II(Top2)抑制剂,也被广泛用于癌症的化疗。尽管这些拓扑异构酶抑制剂疗抗肿瘤效显著,但由于其具有严重的毒副作,因此这些药物在临床中的使用往往受到限制。传统的 Top1 抑制剂具有显著的剂量限制性毒性和耐药性,Top2 靶向药物也会导致耐药性和继发性恶性肿瘤。因此,亟待开发一款临床上用于治疗肿瘤的低毒性的拓扑异构酶抑制剂。
目前已报道的关于开发新型拓扑异构酶抑制剂的临床前研究中,许多天然产物,如吴茱萸碱(evodiamine)、咔唑醌生物碱(Calothrixin A)与光叶花椒酮碱(oxynitidine)等,已被用作新型拓扑异构酶抑制剂的核心骨架。这些天然产物在结构上与已上市的喜树碱类 Top1 抑制剂的结构相似,分子内的杂多环骨架是这些药物分子发挥拓扑异构酶抑制活性的关键。而在人工设计合成的拓扑异构酶抑制剂中,许多不同的杂多环骨架也仍是药物分子发挥拓扑异构酶抑制活性的药效团。例如,茚并异喹啉作为一种人工设计合成的杂多环骨架,被发现具有很强的 Top1 抑制活性。目前,这类化合物的构效关系已被系统地报道,并且许多基于茚并异喹啉类的 Top1 抑制剂,如吲哚替康(indoteCan)与茚替康(indimiteCan)正在临床开发中。相比于传统的喜树碱(CPT)类拓扑异构酶抑制剂,这些杂多环结构具有不含内酯环的优点,因此比喜树碱类拓扑异构酶抑制剂表现得更加有效。基于这些研究现状,寻找一类新的杂多环骨架进行后续结构修饰,并最终获得一些高效候选化合物,是开发新型拓扑异构酶抑制剂的有效手段。
发明内容
本发明的目的是针对现有技术存在的缺陷,提出一种吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂、制法及其药物组合物和应用,高效抑制 Top1/2 活性,为开发拓扑异构酶抑制剂提供新的途径。
传统的拓扑异构酶抑制剂具有显著的剂量限制性毒性和耐药性,且考虑到药物注射引起的高暴露是药物产生毒副作用的重要原因,而口服给药具有患者依从性高、副作用少等优点,是一种更安全、更方便的治疗方式,因此开发一类口服有效的低毒性的拓扑异构酶抑制剂对于癌症治疗尤为必要。对于结构新颖化合物的发现,结构拼接策略是药物化学家用来设计具有原始骨架的先导化合物的有效手段,而天然活性产物作为药物发现的丰富来源,往往为新药开发提供了许多功能性片段。本发明基于这些研究基础,通过结构拼接策略将吴茱萸碱(evodiamine)中的吲哚基团与光叶花椒酮碱(oxynitidine)中的异喹啉结构进行拼接,设计出一类新型吡咯并[3,2-b]吡啶类杂多环骨架。通过对该核心杂多环骨架进行下一步的结构修饰,最终得到一系列新型吡咯并[3,2-b]吡啶类衍生物。
基于上述目的,本发明首先提供一种吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂,为以下通式 V 所示的取代吡咯并[3,2-b]吡啶类化合物或其立体异构体、水合物或药学上可接受的盐,,
其中,n 等于 0-7;
A、B 环为取代的苯环、吡啶、嘧啶等芳杂环;
R1 为氢,氯或氧原子;
X 为氮原子或羰基;
R2 为烷基、羟胺基或与 X 为氮原子时所形成的具有取代基的
五元杂环及六元杂环衍生物;
-X-R2 的结构式含有以下结构,。
进一步地,所述抑制剂为通式 Ⅰ 或 Ⅱ 所示的化合物:,
其中,n等于1或2;A、B环及R1的定义同上述。
优选的,所述通式 V 的抑制剂中,与碳相连的氢替换为氢的同位素氘。
进一步优选为,烷基由氘代烷基替代,烷氧基由氘代环氧基替代,苯环由氘代苯环替代,芳环由氘代芳环替代。
优选的,药学上可接受的盐是指把母体化合物中的碱性基团转换成盐的形式;其中,药学上可接受的盐为碱性基团,进一步优选为胺基或氨基的无机或有机酸盐类;由母体化合物中的碱性基团与 1~4 当量的酸在一个溶剂系统中反应。
优选的,本发明中化合物碱性基团可与酸成盐,所述酸成盐具体为,与无机酸,尤其氢卤酸(如氢氯酸、氢溴酸、氢碘酸)、硝酸、硫酸、磷酸、碳酸等形成的盐;低级烷基磺酸,如甲磺酸,三氟甲磺酸形成的盐;与芳基磺酸,如苯磺酸或对甲苯磺酸形成的盐;与有机酸,如乙酸、富马酸、酒石酸、草酸、柠檬酸、马来酸、苹果酸或琥珀酸形成的盐;与氨基酸,如天冬氨酸或谷氨酸形成的盐。
优选的,本发明的化合物和药学上可接受的盐还包括溶剂化物或水合物的形式。
本发明的吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂中化合物的结构式包括同分异构形式,如对映异构、非对映异构、几何异构或构象异构,具体为含有不对称中心的 R、S 构型,双键的 (Z)、(E) 异构体,(Z)、(E) 的构象异构体。所述抑制剂为以下其中之一:
(1)11-(3-(二甲基氨基)丙基)-6,11-二氢-5H-吲哚并[3,2-c]异喹啉-5-酮;
(2)11-(3-(二甲基氨基)丙基)-8-甲氧基-6,11-二氢-5H-吲哚并[3,2-c]异喹啉-5-酮;
(3)11-(3-(二甲基氨基)丙基)-8-异丙氧基-6,11-二氢-5H-吲哚并[3,2-c]异喹啉-5-酮;
(4)12-(3-(二甲基氨基)丙基)-6,12-二氢-5H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-5-酮;
(5)3-(5-氯-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺;
(6)3-(5-氯-9-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺;
(7)3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺;
(8)3-(5-氯-12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N,N-二甲基-1-丙胺;
(9)3-(8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺;
(10)3-(12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N,N-二甲基-1-丙胺;
(11)N-羟基-4-(5-氧代-5,6-二氢-12H-[1,3]二氧并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)丁酰胺;
(12)4-(5-氯-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(13)4-(5-氯-9-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(14)4-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(15)4-(5-氯-8-(二氟甲氧基)-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(16)4-(5-氯-8-乙氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(17)4-(5-氯-12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N-羟基丁酰胺;
(18)N-羟基-4-(8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丁酰胺;
(19)4-(8-(二氟甲氧基)-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(20)4-(8-乙氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(21)N-羟基-4-(8-异丙氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丁酰胺;
(22)4-(12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N-羟基丁酰胺;
(23)5-氯-8-甲氧基-11-(3-(4-甲基-1H-咪唑-1-基)丙基)-11H-吲哚并[3,2-c]异喹啉;
(24)5-氯-11-(3-(2,4-二甲基-1H-咪唑-1-基)丙基)-8-甲氧基-11H-吲哚并[3,2-c]异喹啉;
(25)(R)-1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)吡咯烷-3-醇;
(26)(R)-(1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)吡咯烷-2-基)甲醇;
(27)5-氯-8-甲氧基-11-(3-(4-甲基哌嗪-1-基)丙基)-11H-吲哚并[3,2-c]异喹啉;
(28)5-氯-11-(3-(4-异丙基哌嗪-1-基)丙基)-8-甲氧基-11H-吲哚并[3,2-c]异喹啉;
(29)(R)-1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)哌啶-3-醇;
(30)1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)哌啶-4-醇;
(31)(1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)哌啶-4-基)甲醇;
(32)1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-N,N-二甲基哌啶-4-胺;
(33)1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-4,4-二甲基哌啶-2,6-二酮;
(34)4-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)吗啉;
(35)3-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-5-氟嘧啶-2,4-(1H,3H)-二酮;
(36)3-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-1-((2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基)-5-氟嘧啶-2,4(1H,3H)-二酮;
(37)4-((3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)氨基)-1-((2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基)-5-氟嘧啶-2(1H)-酮;
(38)4-((3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)氨基)-1-((2R,3S,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基)嘧啶-2(1H)-酮;
(39)4-((3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)氨基)-1-((2R,4S,5R)-4-羟基-5-(羟甲基)四氢呋喃-2-基)嘧啶-2(1H)-酮;
(40)8-甲氧基-11-(3-(4-甲基哌嗪-1-基)丙基)-11H-吲哚并[3,2-c]异喹啉;
(41)11-(3-(4-异丙基哌嗪-1-基)丙基)-8-甲氧基-11H-吲哚并[3,2-c]异喹啉。
本发明进一步提供吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂的制法,具体是以具有不同取代基的邻硝基苯甲醛 1a-g 为原料,与甲氧胺反应后生成化合物 2a-g,接着再与高酞酸酐发生加成反应生成关键中间体 3a-g,中间体 3a-g 随后与硫化钠发生还原反应,生成母核 4a-g,母核 4a-g 接着与三氯氧磷反应,生成母核 5a-g,具体合成路线如下:。
本发明进一步提供具体抑制剂(1)-(41)的制备方法:以母核 4a-g 与 5a-g 为原料,与 N,N-二甲氨基氯丙烷反应生成产物(1)-(8);与 4-溴丁酸乙酯反应生成中间体 6g与 7a-g;中间体 6g,7a-g与羟胺反应生成产物(11)-(17);产物(7)、(8)、(14)-(17)被锌粉、乙酸还原生成产物(9)、(10)、(18)-(22);产物(21)的合成路线与产物(18)的合成路线一致;母核 5c 与 1-溴-3-氯丙烷反应生成中间体 8c,中间体 8c 与含伯胺与仲胺结构的砌块反应,生成产物(23)-(39),产物(27)、(28)被锌粉/乙酸还原生成产物(40)、(41),具体合成路线如下:反应条件如下:(a)3-氯-1-(N,N-二甲基)丙胺,氢化钠,DMF,0°C-80°C,12h;(b)4-溴丁酸乙酯,碳酸钾,DMF,80°C,12h;(c)羟胺,氢氧化钾,甲醇,50°C,4h;(d)锌粉,乙酸,水,70°C,4 h;(e)1-溴-3-氯丙烷,氢化钠,DMF,0°C-35°C,12h;(f)四丁基碘化铵,仲胺或氨基苷类似物,DMF,110°C。
本发明再进一步提供一种药物组合物,所述组合物包含至少一种药学上可接受的辅料、辅助剂或载体,以及所述的吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂。
上述吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂或药物组合物的应用包括在制备用于预防、治疗或辅助治疗拓扑异构酶过度活化引起的增殖性疾病、代谢性疾病、神经系统性疾病或结节性硬化症的药物中的应用。所述增殖性疾病包括结直肠癌、胃癌、乳腺癌、肺癌、肝癌、前列腺癌、胰腺癌、甲状腺癌、膀胱癌、肾癌、脑癌、宫颈癌、CNS的癌症、恶性胶质瘤、骨髓增生病、血液癌或淋巴癌。
上述吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂或药物组合物的应用还包括在制备用于抑制癌症细胞生长的药物中的应用。
与现有技术相比,本发明具有如下显著优点:(1)具有高效抑制 Top1/2 活性的特点,且对多种肿瘤细胞具有优异的体外抗增殖活性;(2)成本低、疗效佳、毒性小,且在合成过程中的中间产物收率高,降低了资源浪费,进而有利于降低成本;(3)具有显著的口服有效的体内抗肿瘤活性,且毒性较小,优于目前已上市的拓扑异构酶抑制剂。
附图说明
图 1 为本发明中部分实施例对 Top1 与 Top2 的活性筛选结果图。
图 2 为实施例 10 与 18 在小鼠体内的毒性研究结果,包含(A)小鼠体重变化曲线,(B)小鼠各脏器系数柱状图以及(C)小鼠各脏器组织病理切片染色图像。
图 3 为实施例 10 的体内抗肿瘤疗效的结果,图 A、B 分别为实施例 10在 H446与 HCT116 两种异种移植瘤模型中的抗肿瘤效果,其中各包含小鼠肿瘤体积变化曲线以及肿瘤组织重量柱状图。
具体实施方式
下面结合实施例和附图对本发明的技术方案作进一步说明。
试剂购买于商品供应商如安徽泽升科技有限公司、百灵威科技有限公司、阿拉丁试剂有限公司、北京偶合科技有限公司等,使用时都没有经过进一步纯化,除非其他方面表明。一般的试剂从西陇化工股份有限公司、南京化学试剂股份有限公司、国药集团化学试剂有限公司和青岛海洋化工有限公司等购买得到。实施例中除非其他方面表明,所有的温度定为摄氏度。
下面所描述的实施例中色谱柱使用硅胶柱,硅胶(200-300 目)购于青岛海洋化工有限公司。核磁共振光谱以 CDCl3 或 DMSO-d6 为溶剂(以 ppm 为单位),用 TMS(0 ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰),d(doublet,双峰),t(triplet ,三重峰),m(multiplet,多重峰),dd(doublet of doublets,双双重峰),dt(doublet of triplets,双三重峰)。偶合常数,用赫兹(Hz)表示。
下面描述的实施例为了便于表述,部分原料会以其简称进行描述,其全称与对照说明如下:DMF 为 N,N-二甲基甲酰胺;DCM 为二氯甲烷;MeOH为甲醇;PE 为石油醚;EA 为乙酸乙酯;THF 为四氢呋喃;CDC13 为氘代氯仿;DMSO-d6 为六氘代二甲亚砜;Et3N 为三乙胺;NaH 为氢化钠,TABI 为四丁基碘化铵。
实施例1
本实施例的结构式如下:
11-(3-(二甲基氨基)丙基)-6,11-二氢-5H-吲哚并[3,2-c]异喹啉-5-酮(1)的合成,合成步骤如下:将母核 4a(1.0 mmol,234.1 mg)溶于 20 mLDMF 中,随即缓慢加入 NaH(1.1 mmol,26.0 mg)搅拌 30 min,接着加入 N,N-二甲氨基氯丙烷(1.5 mmol,182.4 mg)于 80 ℃ 反应过夜。反应结束后,将反应液倒入冷水中搅拌,乙酸乙酯萃取上述水溶液三次,收集有机相,用饱和氯化钠水溶液(50 mL)洗涤有机相,经无水硫酸钠干燥后减压浓缩得到粗品,经硅胶柱层析(DCM:MeOH=5:1-2:1/v:v)纯化得白色固体,收率:82%。1H NMR (400 MHz, DMSO-d 6) δ 12.32 (s, 1H), 8.46 (dd, J = 8.0, 1.5Hz, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.89–7.84 (m,1H), 7.66 (d, J = 8.5 Hz, 1H), 7.60–7.51 (m, 1H), 7.37–7.33 (m, 1H), 7.18–7.08 (m, 1H), 4.70 (t, J = 7.1 Hz, 2H), 2.23 (t, J = 6.6 Hz, 2H), 2.13 (s,6H), 1.90 (p, J = 6.8 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 160.43, 138.18,132.73, 129.45, 129.10, 125.51, 125.07, 124.58, 121.17, 120.26, 119.13,119.05, 117.40, 115.60, 110.05, 55.76, 45.26, 42.63, 27.83. ESI-HRMS cacldfor C20H21N3O m/z [M + H]+ 320.1757, found [M + H]+ 320.1759.
实施例2
本实施例的结构式如下:
11-(3-(二甲基氨基)丙基)-8-甲氧基-6,11-二氢-5H-吲哚并[3,2-c]异喹啉-5-酮的合成:将实施例 1 中母核 4a 改为 4c,其他步骤及操作同实施例 1;得白色固体,收率:65%。1H NMR (400 MHz, DMSO-d 6) δ 12.50 (s, 1H), 8.35(d, J = 8.3 Hz, 2H), 7.83 (t, J = 7.6 Hz, 1H), 7.53 (dd, J = 15.4, 8.2 Hz,2H), 7.31 (s, 1H), 7.00 (dd, J = 9.0, 2.2 Hz, 1H), 4.63 (t, J = 6.9 Hz, 2H),3.88 (s, 3H), 3.32–3.15 (m, 2H), 2.72 (s, 6H), 2.38–2.18 (m, 2H). 13C NMR (101MHz, DMSO-d 6) δ 160.12, 153.47, 132.47, 132.35, 128.79, 128.28, 126.21,123.22, 121.34, 120.26, 118.64, 115.87, 114.22, 113.21, 101.22, 55.70, 54.26,41.95, 40.94, 24.03. ESI-HRMS cacld for C21H23N3O2 m/z [M + H]+ 350.1863, found[M + H]+ 350.1863.
实施例3
本实施例的结构式如下:
11-(3-(二甲基氨基)丙基)-8-异丙氧基-6,11-二氢-5H-吲哚并[3,2-c]异喹啉-5-酮的合成:将实施例 1 中母核 4a 改为4f,其他步骤及操作同实施例 1;得黄色固体,收率:53%。1H NMR (400 MHz, DMSO-d 6) δ 12.15 (s, 1H),8.44 (dd, J = 8.0, 1.5 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.85 (dt, J = 8.4,7.1, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.55 (dd, J = 8.2, 6.1 Hz, 2H), 6.96 (dd,J = 9.0, 2.5 Hz, 1H), 4.64 (t, J = 7.1 Hz, 2H), 4.57–4.51 (m, J = 6.1 Hz,1H), 2.27 (t, J = 6.7 Hz, 2H), 2.15 (s, 6H), 1.88 (p, J = 6.9 Hz, 2H), 1.32(d, J = 6.0 Hz, 6H). 13C NMR (101 MHz, DMSO-d 6) δ 160.23, 151.17, 133.65,132.64, 129.54, 129.07, 125.38, 124.99, 121.04, 119.96, 117.98, 116.44,115.67, 111.02, 103.04, 69.98, 55.64, 45.06, 42.67, 27.70, 22.01. ESI-HRMScacld for C23H27N3O2 m/z [M + H]+ 378.2176, found [M + H]+ 378.2177.
实施例4
本实施例的结构式如下:
12-(3-(二甲基氨基)丙基)-6,12-二氢-5H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-5-酮的合成:将实施例 1 中母核4a 改为4g,其他步骤及操作同实施例 1;得黄色固体,收率:67%。1H NMR (400 MHz, DMSO-d 6) δ12.11 (s, 1H), 8.40 (dd, J = 8.0, 1.5 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H),7.82–7.78 (m, 1H), 7.53 (s, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.28 (s, 1H), 6.03(s, 2H), 4.58 (t, J = 7.1 Hz, 2H), 2.22 (t, J = 6.6 Hz, 2H), 2.13 (s, 6H),1.85 (p, J = 6.8 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 160.38, 146.90, 142.13,134.43, 132.63, 129.57, 129.05, 124.64, 124.00, 120.72, 120.45, 116.58,108.88, 100.90, 96.96, 91.19, 55.68, 45.23, 42.88, 27.72. ESI-HRMS cacld forC21H21N3O3 m/z [M + H]+ 364.1656, found [M + H]+ 364.1665.
实施例5
本实施例的结构式如下:
3-(5-氯-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺的合成:将实施例 1 中母核 4a 改为 5a,其他步骤及操作同实施例 1;得白色固体,收率:86%。1H NMR (300 MHz, CDCl3) δ 8.30–8.20 (m, 2H), 8.14 (d, J = 8.5Hz, 1H), 7.62–7.57 (m, 1H), 7.47–7.39 (m, 1H), 7.37 (d, J = 4.4 Hz, 2H),7.24–7.19 (m, 1H), 4.39 (t, J = 7.3 Hz, 2H), 2.18 (t, J = 6.5 Hz, 2H), 2.14(s, 6H), 1.85 (p, J = 6.9 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 143.07, 139.81,132.76, 130.18, 127.78, 125.98, 125.94, 125.93, 125.72, 124.20, 121.32,121.17, 120.24, 119.64, 109.20, 56.08, 45.43, 42.96, 27.61. ESI-HRMS cacldfor C20H20ClN3 m/z [M + H]+ 338.1419, found [M + H]+ 338.1425.
实施例6
本实施例的结构式如下:
3-(5-氯-9-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺的合成:将实施例 1 中母核 4a 改为 5b,其他步骤及操作同实施例 1;得白色固体,收率:72%。1H NMR (300 MHz, DMSO-d 6) δ 8.70 (d, J = 8.6 Hz, 1H),8.49 (dd, J = 8.6, 1.3 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.04–7.98 (m, 1H),7.81 (dd, J = 8.5, 6.9 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 6.99 (dd, J = 8.6,2.1 Hz, 1H), 4.89 (t, J = 7.2 Hz, 2H), 3.94 (s, 3H), 2.28 (s, 6H), 2.13–1.99(m, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 159.42, 142.23, 141.55, 132.80, 131.20,127.35, 126.65, 125.70, 125.48, 123.09, 121.90, 120.14, 114.76, 110.59,93.69, 55.63, 45.13, 42.83, 26.99. ESI-HRMS calcd for C21H22ClN3O m/z [M + H]+368.1524, found [M + H]+ 368.1529.
实施例7
本实施例的结构式如下:
3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺的合成:将实施例 1 中母核 4a 改为 5c,其他步骤及操作同实施例 1;得黄色固体,收率:75%。1H NMR (300 MHz, CDCl3) δ 8.57–8.49 (m, 1H), 8.45(dt, J = 8.5, 0.9 Hz, 1H), 7.85–7.76 (m, 2H), 7.68–7.62 (m, 1H), 7.50 (d, J =9.0 Hz, 1H), 7.15 (dd, J = 9.0, 2.5 Hz, 1H), 4.72 (t, J = 7.2 Hz, 2H), 3.94(s, 3H), 2.31 (t, J = 6.5 Hz, 2H), 2.23 (s, 6H), 2.07 (t, J = 6.9 Hz, 2H). 13CNMR (101 MHz, CDCl3) δ 154.76, 143.06, 135.38, 133.02, 130.48, 128.38,126.81, 126.50, 126.27, 124.68, 121.97, 121.51, 117.00, 110.59, 100.77,56.34, 56.03, 45.65, 43.50, 28.03. ESI-HRMS cacld for C21H22ClN3O m/z [M + H]+368.1524, found [M + H]+ 368.1527.
实施例8
本实施例的结构式如下:
3-(5-氯-12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N,N-二甲基-1-丙胺的合成:将实施例 1 中母核 4a改为 5g,其他步骤及操作同实施例 1;得黄色固体,收率:70%。1H NMR (300 MHz, DMSO-d 6) δ 8.62(d, J = 8.6 Hz, 1H), 8.44 (d, J = 8.5 Hz, 1H), 8.09–7.88 (m, 1H), 7.84–7.68(m, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 6.13 (s, 2H), 4.78 (t, J = 7.2 Hz, 2H),2.35 (t, J = 6.6 Hz, 2H), 2.20 (s, 6H), 1.97 (p, J = 6.8 Hz, 2H). 13C NMR (101MHz, DMSO-d 6) δ 148.04, 143.22, 141.88, 136.06, 132.55, 131.05, 127.28,126.34, 125.68, 124.94, 122.84, 121.58, 114.28, 101.28, 97.26, 91.48, 55.52,45.05, 43.10, 27.03. ESI-HRMS cacld for C21H20ClN3O2 m/z [M + H]+ 382.1317,found [M + H]+ 382.1318.
实施例9
本实施例的结构式如下:
3-(8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺的合成,合成步骤如下:将产物(7)(1.0 mmol,367.1 mg)溶于 20 mL乙酸与 3 mL 水中,加入(650.4 mg, 10.0 mmol)锌粉,于 70 ℃ 中搅拌反应过夜。待反应完成后,减压蒸馏除去乙酸,剩余残渣用乙酸乙酯萃取三次,收集有机相,用饱和氯化钠水溶液(50 mL)洗涤有机相,经无水硫酸钠干燥后减压浓缩得到粗品,经硅胶柱层析(DCM:MeOH=5:1-2:1/v:v)纯化得黄色油状固体,收率:76%。1H NMR (300 MHz, CDCl3) δ 9.04(s, 1H), 8.43 (d, J = 8.7 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 2.5Hz, 1H), 7.81–7.71 (m, 1H), 7.64–7.47 (m, 2H), 7.17 (dd, J = 8.9, 2.6 Hz,1H), 4.74 (td, J = 7.2, 1.8 Hz, 2H), 3.97 (s, 3H), 2.33 (t, J = 6.6 Hz, 2H),2.23 (s, 6H), 2.09 (p, J = 6.8 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 154.61,145.16, 135.24, 134.68, 129.76, 129.51, 127.58, 127.21, 125.37, 124.66,122.74, 121.05, 116.43, 110.43, 100.85, 56.44, 56.00, 45.62, 43.45, 28.14.ESI-HRMS cacld for C21H23N3O m/z [M + H]+ 334.1914, found [M + H]+ 334.1916.
实施例 10
本实施例的结构式如下:
3-(12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N,N-二甲基-1-丙胺的合成:将实施例 9 中产物(7)改为产物(8),其他步骤及操作同实施例 9;得黄色固体,收率:71%。
1H NMR (300 MHz, DMSO-d 6) δ 9.05 (s, 1H), 8.55 (d, J= 8.6 Hz, 1H),8.26 (dd, J = 8.3, 1.4 Hz, 1H), 7.89–7.84 (m, 1H), 7.69–7.59 (m, 2H), 7.49(s, 1H), 6.11 (s, 2H), 4.79 (t, J = 7.1 Hz, 2H), 2.30 (t, J = 6.6 Hz, 2H),2.16 (s, 6H), 1.97 (p, J = 6.7 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 147.61,144.95, 142.88, 135.73, 134.49, 130.08, 129.25, 126.34, 125.13, 125.05,123.69, 120.72, 115.30, 101.11, 97.52, 91.39, 55.70, 45.19, 43.07, 27.36.ESI-HRMS cacld for C21H21N3O2 m/z [M + H]+ 348.1707, found [M + H]+ 348.1702.
实施例11
本实施例的结构式如下:
N-羟基-4-(5-氧代-5,6-二氢-12H-[1,3]二氧并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)丁酰胺的合成,合成步骤如下:将母核 4g(1.0mmol,278.1 mg)溶于 20 mL DMF 中,随即加入(830 mg,6.0 mmol)K2CO3 于 80 ℃ 中搅拌,滴加 4-溴丁酸乙酯(215 mg,1.1 mmol)反应过夜。待反应完成后,将反应体系倒入冷水,乙酸乙酯萃取上述水溶液三次,收集有机相,用饱和氯化钠水溶液(50 mL)洗涤有机相,经无水硫酸钠干燥后减压浓缩得到粗品,经硅胶柱层析(PE:EA=5:1-2:1/v:v)纯化得白色固体 6g。取 6g(1.0 mmol,392.1 mg)溶于20 mL 甲醇,随即加入(30.0 mmol,990 mg)羟胺与(10.0 mmol,560 mg)KOH,于 50 ℃ 中搅拌反应 4 h。待反应完成后,减压蒸馏除去溶剂得到粗品,经硅胶柱层析(DCM:MeOH=10:1-2:1/v:v)纯化得红色固体,收率:76%。1H NMR(300 MHz, DMSO-d 6) δ 11.88 (s, 1H), 10.51 (s, 1H), 8.78 (s, 1H), 8.32 (d, J =8.0 Hz, 2H), 7.84 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.43 (s,1H), 7.13 (s, 1H), 6.06 (s, 2H), 4.55 (t, J = 6.1 Hz, 2H), 2.28 (t, J = 7.3Hz, 2H), 2.13 (p, J = 6.5 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 168.90,154.73, 146.60, 142.32, 133.74, 130.47, 129.36, 126.30, 125.21, 124.99,123.25, 120.65, 116.82, 115.75, 100.78, 97.28, 92.67, 64.96, 29.25, 24.91.ESI-HRMS cacld for C20H17N3O5 m/z [M + H]+ 380.1241, found [M + H]+ 380.1236.
实施例12
本实施例的结构式如下:
4-(5-氯-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺的合成:将实施例 11 中母核 4g 改为 5a,其他步骤及操作同实施例 11;得黄色固体,收率:72%。1H NMR (300 MHz, DMSO-d 6) δ 10.47 (s, 1H), 8.99–8.63 (m, 2H), 8.46(d, J = 8.3 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.01 (t, J = 7.6 Hz, 1H),7.94–7.71 (m, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 4.85(t, J = 7.1 Hz, 2H), 2.23–2.09 (m, 4H). 13C NMR (75 MHz, DMSO-d 6) δ 168.59,142.34, 139.83, 132.17, 131.34, 127.33, 127.25, 126.37, 126.00, 125.69,123.85, 122.39, 120.90, 120.63, 119.21, 110.32, 44.38, 28.87, 25.28. ESI-HRMScacld for C19H16ClN3O2 m/z [M + H]+ 354.1004, found [M + H]+ 354.1009.
实施例 13
本实施例的结构式如下:
4-(5-氯-9-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺的合成:将实施例 11 中母核 4g 改为 5b,其他步骤及操作同实施例 11;得黄色固体,收率:69%。1H NMR (300 MHz, DMSO-d 6) δ 10.46 (d, J = 1.7 Hz,1H), 8.78 (d, J = 1.5 Hz, 1H), 8.75 (d, J = 8.5 Hz, 1H), 8.48 (d, J = 8.4 Hz,1H), 8.08 (d, J = 8.5 Hz, 1H), 8.00 (t, J = 7.7 Hz, 1H), 7.81 (t, J = 7.6 Hz,1H), 7.43 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 8.6, 1.9 Hz, 1H), 4.85 (t, J =7.1 Hz, 2H), 3.95 (s, 3H), 2.21–2.12 (m, 4H). 13C NMR (101 MHz, DMSO-d 6) δ168.66, 159.46, 142.24, 141.46, 132.73, 131.24, 127.28, 126.64, 125.61,125.46, 123.06, 122.03, 120.13, 114.77, 110.56, 93.80, 55.67, 44.30, 28.77,25.10. ESI-HRMS cacld for C20H18ClN3O3 m/z [M + H]+ 384.1109, found [M + H]+384.1111.
实施例 14
本实施例的结构式如下:
4-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺的合成:将实施例 11 中母核 4g 改为 5c,其他步骤及操作同实施例 11;得黄色固体,收率:69%。1H NMR (400 MHz, DMSO-d 6) δ 10.51 (s, 1H), 8.80 (s,1H), 8.72 (d, J = 8.6 Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.04–7.96 (m, 1H),7.83 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H),7.17 (dd, J = 9.0, 2.6 Hz, 1H), 4.81 (t, J = 7.4 Hz, 2H), 3.89 (s, 3H), 2.18(t, J = 7.1 Hz, 2H), 2.09 (q, J = 7.0 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6) δ168.62, 154.42, 141.78, 134.86, 131.89, 131.31, 127.34, 127.19, 126.32,125.82, 123.78, 122.34, 121.21, 116.58, 111.47, 100.29, 55.58, 44.47, 28.88,25.37. ESI-HRMS cacld for C20H18ClN3O3 m/z [M + H]+ 384.1109, found [M + H]+384.1112.
实施例 15
本实施例的结构式如下:
4-(5-氯-8-(二氟甲氧基)-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺的合成:将实施例 11 中母核 4g 改为5d,其他步骤及操作同实施例 11;得白色固体,收率:65%。1H NMR (400 MHz, DMSO-d 6) δ 10.45 (s, 1H),8.97–8.59 (m, 2H), 8.44 (d, J = 7.5 Hz, 1H), 8.16–7.67 (m, 4H), 7.59–7.10 (m,2H), 4.83 (t, J = 7.1 Hz, 2H), 2.13 (dt, J = 36.4, 7.2 Hz, 4H). 13C NMR (101MHz, DMSO-d 6) δ 168.57, 145.25, 142.58, 137.02, 131.55, 127.61, 127.39,127.04, 125.70, 124.07, 122.43, 121.07, 119.55, 118.84, 116.99, 111.84,108.46, 44.57, 28.77, 25.25. ESI-HRMS cacld for C20H16ClF2N3O3 m/z [M + H]+420.0921, found [M + H]+ 420.0922.
实施例 16
本实施例的结构式如下:
4-(5-氯-8-乙氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺的合成:将实施例 11 中母核 4g 改为 5e,其他步骤及操作同实施例 11;得红色固体,收率:78%。1H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 8.78(s, 1H), 8.71 (s, 1H), 8.44 (d, J = 6.9 Hz, 1H), 7.98 (s, 1H), 7.88–7.67 (m,2H), 7.58 (s, 1H), 7.15 (d, J = 7.7 Hz, 1H), 4.80 (t, J = 8.1 Hz, 2H), 4.23–4.03 (m, 2H), 2.30–2.00 (m, 4H), 1.40 (t, J = 6.3 Hz, 3H). 13C NMR (101 MHz,DMSO-d 6 ) δ 168.57, 153.55, 141.69, 134.77, 131.86, 131.16, 127.26, 127.05,126.25, 125.75, 123.72, 122.23, 121.18, 116.89, 111.34, 100.94, 63.47, 44.43,28.83, 25.30, 14.83. ESI-HRMS cacld for C21H20ClN3O3 m/z [M + H]+ 398.1266,found [M + H]+ 398.1275.
实施例 17
本实施例的结构式如下:
4-(5-氯-12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N-羟基丁酰胺的合成:将实施例 11 中母核 4g改为 5g,其他步骤及操作同实施例 11;得黄色固体,收率:72%。1H NMR (400 MHz, DMSO-d 6) δ 10.45(s, 1H), 8.78 (s, 1H), 8.62 (d, J = 8.5 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H),7.93 (t, J = 7.7 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.48 (d, J = 3.5 Hz, 2H),6.11 (s, 2H), 4.72 (t, J = 7.5 Hz, 2H), 2.18 (t, J = 7.1 Hz, 2H), 2.06 (t, J= 7.6 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 168.68, 148.04, 143.25, 141.93,135.89, 132.44, 131.12, 127.24, 126.34, 125.59, 124.93, 122.82, 121.74,114.32, 101.32, 97.30, 91.52, 44.61, 28.79, 25.21. ESI-HRMS cacld forC20H16ClN3O4 m/z [M + H]+ 398.0902, found [M + H]+ 398.0901.
实施例 18
本实施例的结构式如下:
N-羟基-4-(8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丁酰胺的合成:将实施例 9 中产物(7)改为产物(14),其他步骤及操作同实施例9;得黄色固体,收率:86%。1H NMR (300 MHz, DMSO-d 6) δ 10.45 (s, 1H), 9.11 (s, 1H),8.79 (s, 1H), 8.67 (d, J = 8.5 Hz, 1H), 8.31 (d, J = 8.1 Hz, 1H), 7.91 (t, J= 7.7 Hz, 1H), 7.84–7.66 (m, 3H), 7.18 (dd, J = 8.9, 2.5 Hz, 1H), 4.85 (t, J= 7.0 Hz, 2H), 3.90 (s, 3H), 2.20–2.06 (m, 4H). 13C NMR (101 MHz, DMSO-d 6) δ168.65, 154.17, 144.90, 134.70, 133.87, 130.30, 129.31, 127.19, 126.52,125.88, 123.81, 122.27, 121.42, 115.83, 111.14, 100.77, 55.58, 44.43, 29.00,25.57. ESI-HRMS cacld for C20H19N3O3 m/z [M + H]+ 350.1499, found [M + H]+350.1500./>
实施例 19
本实施例的结构式如下:
4-(8-(二氟甲氧基)-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺的合成:将实施例 9 中产物(7)改为产物(15),其他步骤及操作同实施例 9;得黄色固体,收率:78%。 1H NMR (300 MHz, DMSO-d 6) δ 10.45 (s, 1H),9.17 (s, 1H), 8.78 (d, J = 1.6 Hz, 1H), 8.72 (d, J = 8.5 Hz, 1H), 8.35 (d, J= 8.0 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.4, 6.5 Hz, 2H), 7.78(t, J = 7.5 Hz, 1H), 7.39 (dd, J = 8.9, 2.5 Hz,1H), 7.33 (t, J = 74.7 Hz,1H),5.01–4.77 (m, 2H), 2.26–2.00 (m, 4H). 13C NMR (101 MHz, DMSO-d 6) δ 168.58,145.76, 144.99, 144.95, 144.92, 136.93, 133.55, 130.59, 129.41, 127.46,127.25, 126.35, 123.75, 122.17, 121.55, 118.41, 117.07, 111.53, 108.91,44.53, 28.90, 25.47. ESI-HRMS cacld for C20H17F2N3O3 m/z [M + H]+ 386.1311, found[M + H]+ 386.1309.
实施例20
本实施例的结构式如下:
4-(8-乙氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺的合成:将实施例 9 中产物(7)改为产物(16),其他步骤及操作同实施例 9;得黄色固体,收率:82%。1H NMR (300 MHz, DMSO-d 6) δ 10.45 (s, 1H), 9.10 (s,1H), 8.79 (s, 1H), 8.67 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 7.9 Hz, 1H), 7.91(t, J = 7.5 Hz, 1H), 7.85–7.60 (m, 3H), 7.17 (dd, J = 8.9, 2.4 Hz, 1H), 4.84(t, J = 7.0 Hz, 2H), 4.17 (q, J = 6.7 Hz, 2H), 2.20–2.08 (m, 4H), 1.41 (t, J= 6.8 Hz, 4H). 13C NMR (101 MHz, DMSO-d 6) δ 168.61, 153.33, 144.84, 134.64,133.86, 130.26, 129.27, 127.16, 126.48, 125.84, 123.78, 122.25, 121.40,116.23, 111.10, 101.46, 63.51, 44.40, 28.97, 25.55, 14.91. ESI-HRMS cacld forC21H21N3O3 m/z [M + H]+ 364.1656, found [M + H]+ 364.1653./>
实施例 21
本实施例的结构式如下:
N-羟基-4-(8-异丙氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丁酰胺的合成:将实施例 11 中母核 4g 改为母核 5f,按照实施例 11 的操作步骤得到中间体 7f,随后按照实施例11 的其他操作步骤与实施例 9 中的操作步骤,最终得到产物(21)为黄色固体,收率:84%。1H NMR (300 MHz, DMSO-d 6) δ 10.46 (s, 1H),9.10 (s, 1H), 8.79 (s, 1H), 8.67 (d, J = 8.5 Hz, 1H), 8.31 (d, J = 8.1 Hz,1H), 7.91 (t, J = 7.7 Hz, 1H), 7.80–7.69 (m, 3H), 7.15 (dd, J = 8.9, 2.5 Hz,1H), 4.84 (t, J = 7.1 Hz, 2H), 4.72 (p, J = 6.0 Hz, 1H), 2.15 (dd, J = 16.0,6.7 Hz, 4H), 1.34 (d, J = 6.0 Hz, 7H). 13C NMR (101 MHz, DMSO-d 6) δ 168.63,152.03, 144.84, 134.72, 133.81, 130.26, 129.28, 127.18, 126.54, 125.84,123.76, 122.34, 121.40, 117.48, 111.12, 103.65, 70.09, 44.40, 28.99, 25.53,22.03. ESI-HRMS cacld for C22H23N3O3 m/z [M + H]+ 378.1812, found [M + H]+378.1812.
实施例 22
本实施例的结构式如下:
4-(12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N-羟基丁酰胺的合成:将实施例 9 中产物(7)改为产物(17),其他步骤及操作同实施例 9;得黄色固体,收率:76%。1H NMR (300 MHz, DMSO-d 6) δ 10.46 (s,1H), 9.08 (s, 1H), 8.78 (s, 1H), 8.63 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 8.1Hz, 1H), 7.89 (t, J = 7.9 Hz, 1H), 7.66 (d, J = 10.0 Hz, 2H), 7.56 (s, 1H),6.13 (s, 2H), 4.81 (t, J = 7.4 Hz, 2H), 2.28–1.90 (m, 4H). 13C NMR (101 MHz,DMSO-d 6) δ 168.67, 147.67, 145.05, 142.96, 135.62, 134.44, 130.25, 129.67,129.27, 126.37, 125.16, 123.66, 120.93, 115.38, 101.16, 97.61, 91.52, 44.58,28.90, 25.42. ESI-HRMS cacld for C20H17N3O4 m/z [M + H]+ 364.1292, found [M + H]+364.1288.
实施例 23
本实施例的结构式如下:
5-氯-8-甲氧基-11-(3-(4-甲基-1H-咪唑-1-基)丙基)-11H-吲哚并[3,2-c]异喹啉的合成,合成步骤如下:将母核 5c(1.0 mmol,282.0mg)溶于 20 mL DMF,随即缓慢加入 NaH(1.0 mmol,24.0 mg),于常温下搅拌 30 min,随即缓慢滴加 1-溴-3-氯丙烷(1.0 mmol,155.9 mg),常温反应过夜。待反应完成后,将反应体系倒入冷水中,乙酸乙酯萃取上述水溶液三次,收集有机相,用饱和氯化钠水溶液(50 mL)洗涤有机相,经无水硫酸钠干燥后减压浓缩得到粗品,经硅胶柱层析(PE:EA=5:1-2:1/v:v)纯化得白色固体8c。取中间体8c(0.5 mmol,179.0 mg)溶于 20 mL DMF 中,随即加入 TBAI(554.0 mg,1.0 mmol)与4-甲基咪唑(82.1 mg,1.0 mmol)于 110 ℃ 下反应 12 h。待反应完成后,将反应体系倒入冷水,乙酸乙酯萃取上述水溶液三次,收集有机相,用饱和氯化钠水溶液(50 mL)洗涤有机相,经无水硫酸钠干燥后减压浓缩得到粗品,经硅胶柱层析(DCM:MeOH=5:1-2:1/v:v)纯化得白色固体,收率:67%。1H NMR (300 MHz, CDCl3) δ 8.45 (dd, J= 8.2, 1.7 Hz, 1H), 7.80–7.56 (m, 4H), 7.41 (dd, J = 26.1, 1.3 Hz, 1H), 7.19–7.04 (m, 2H), 6.75 (dt, J = 68.5, 1.2 Hz, 1H), 4.56–4.46 (m, 2H), 3.95–3.87(m, 5H), 2.32–2.21 (m, 5H). 13C NMR (101 MHz, DMSO-d 6) δ 154.93, 143.45,139.31, 136.49, 134.65, 132.98, 130.74, 128.46, 126.47, 126.31, 126.07,124.56, 122.17, 120.61, 117.09, 115.35, 109.79, 101.03, 56.01, 44.13, 42.68,31.02, 13.92. ESI-HRMS cacld for C23H21ClN4O m/z [M + H]+ 405.1477, found [M +H]+ 405.1470.
实施例 24
本实施例的结构式如下:
5-氯-11-(3-(2,4-二甲基-1H-咪唑-1-基)丙基)-8-甲氧基-11H-吲哚并[3,2-c]异喹啉的合成:将实施例23中 4-甲基咪唑改为 2,4-二甲基咪唑,其他步骤及操作同实施例 23;得白色固体,收率:43%。1H NMR (300 MHz, CDCl3)δ 8.52 (dt, J = 8.4, 1.9 Hz, 1H), 7.86–7.57 (m, 4H), 7.37–7.05 (m, 2H), 6.67(dd, J = 35.6, 1.2 Hz, 1H), 4.62 (q, J = 8.2 Hz, 2H), 3.95 (d, J = 1.3 Hz,3H), 3.88 (dt, J = 6.7, 4.4 Hz, 2H), 2.35–2.19 (m, 8H). 13C NMR (101 MHz,CDCl3) δ 154.98, 143.87, 143.54, 136.80, 134.73, 133.06, 130.88, 128.54,126.56, 126.39, 126.20, 125.37, 124.66, 122.26, 120.63, 117.19, 115.42,109.75, 101.10, 56.05, 43.05, 42.68, 30.61, 13.72, 13.06. ESI-HRMS cacld forC24H23ClN4O m/z [M + H]+ 419.1633, found [M + H]+ 419.1636.
实施例 25
本实施例的结构式如下:
(R)-1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)吡咯烷-3-醇的合成:将实施例 23 中 4-甲基咪唑改为(R)-3-吡咯烷醇,其他步骤及操作同实施例 23;得白色固体,收率:78%。1H NMR (300 MHz, CDCl3) δ8.45 (dd, J = 8.5, 1.3 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.82–7.70 (m, 2H),7.62–7.57 (m, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.10 (dd, J = 9.0, 2.6 Hz, 1H),4.61 (t, J = 7.1 Hz, 2H), 4.36–4.31 (m, 1H), 3.92 (s, 3H), 3.01 (s, 1H), 2.85(td, J = 8.5, 5.0 Hz, 1H), 2.69 (dt, J = 10.2, 1.4 Hz, 1H), 2.56–2.41 (m,3H), 2.34–1.95 (m, 4H), 1.83–1.65 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 154.73,143.05, 135.25, 132.89, 130.50, 128.32, 126.69, 126.33, 126.27, 124.57,121.91, 121.31, 116.92, 110.48, 100.82, 71.24, 63.05, 56.02, 52.72, 52.63,43.41, 34.95, 28.72. ESI-HRMS cacld for C23H24ClN3O3 m/z [M + H]+ 410.1630,found [M + H]+ 410.1634.
实施例 26
本实施例的结构式如下:
(R)-(1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)吡咯烷-2-基)甲醇的合成:将实施例 23 中 4-甲基咪唑改为 D-脯氨醇,其他步骤及操作同实施例 23;得白色固体,收率:76%。1H NMR (300 MHz, CDCl3) δ8.50 (dd, J = 8.5, 1.3 Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 7.87–7.75 (m, 2H),7.66–7.61 (m, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.13 (dd, J = 9.0, 2.6 Hz, 1H),4.64 (t, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.85 (q, J = 5.5, 4.7 Hz, 1H), 2.62–2.44 (m, 1H), 2.34 (t, J = 6.5 Hz, 4H), 2.04 (p, J = 6.9 Hz, 2H), 1.90–1.46(m, 4H), 1.25 (d, J = 3.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 154.77, 143.09,135.26, 132.97, 130.50, 128.41, 126.71, 126.40, 126.30, 124.63, 121.98,121.30, 116.95, 110.47, 100.86, 66.61, 60.76, 56.05, 55.17, 53.99, 43.54,32.15, 27.11, 22.05. ESI-HRMS cacld for C24H26ClN3O2 m/z [M + H]+ 424.1786,found [M + H]+ 424.1786.
实施例 27
本实施例的结构式如下:
5-氯-8-甲氧基-11-(3-(4-甲基哌嗪-1-基)丙基)-11H-吲哚并[3,2-c]异喹啉的合成:将实施例 23 中 4-甲基咪唑改为N-甲基哌嗪,其他步骤及操作同实施例 23;得黄色固体,收率:87%。1H NMR (400 MHz, DMSO-d 6) δ 8.58(d, J = 8.5 Hz, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.93 (t, J = 7.7 Hz, 1H), 7.78(t, J = 7.7 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 2.5 Hz, 1H), 7.13(dd, J = 9.0, 2.5 Hz, 1H), 4.74 (t, J = 6.9 Hz, 2H), 3.88 (s, 3H), 2.49–2.15(m, 10H), 2.14 (s, 3H), 1.93 (h, J = 7.6, 6.7 Hz, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 154.28, 141.59, 134.94, 131.92, 130.91, 127.28, 126.96, 126.26, 125.85,123.71, 122.03, 121.12, 116.30, 111.45, 100.17, 55.50, 54.68, 54.24, 52.67,45.68, 42.96, 26.41. ESI-HRMS cacld for C24H27ClN4O m/z [M + H]+ 423.1946,found [M + H]+ 423.1949./>
实施例 28
本实施例的结构式如下:
5-氯-11-(3-(4-异丙基哌嗪-1-基)丙基)-8-甲氧基-11H-吲哚并[3,2-c]异喹啉的合成:将实施例 23 中 4-甲基咪唑改为 1-异丙基哌嗪,其他步骤及操作同实施例 23;得黄色固体,收率:73%。1H NMR (400 MHz, CDCl3)δ 8.53 (dd, J = 8.5, 1.3 Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H), 7.84–7.75 (m,2H), 7.67–7.63 (m, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.13 (dd, J = 8.9, 2.6 Hz,1H), 4.71 (t, J = 7.0 Hz, 2H), 3.94 (s, 3H), 2.73–2.67 (m, 1H), 2.63–2.44 (m,8H), 2.35 (t, J = 6.4 Hz, 2H), 2.11–2.04 (m, 2H), 1.08 (d, J = 6.5 Hz, 6H).13C NMR (101 MHz, CDCl3) δ 154.79, 143.11, 135.42, 133.08, 130.46, 128.46,126.85, 126.56, 126.30, 124.71, 122.01, 121.55, 116.95, 110.76, 100.77,56.06, 54.97, 54.80, 53.37, 48.75, 43.59, 27.05, 18.65. ESI-HRMS cacld forC26H31ClN4O m/z [M + H]+ 451.2259, found [M + H]+ 451.2267.
实施例 29
本实施例的结构式如下:
(R)-1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)哌啶-3-醇的合成:将实施例23中4-甲基咪唑改为(R)-3-哌啶醇,其他步骤及操作同实施例 23;得黄色固体,收率:77%。1H NMR (300 MHz, CDCl3) δ 8.46(dd, J = 8.5, 1.3 Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 7.82–7.70 (m, 2H), 7.64–7.58 (m, 1H), 7.33 (d, J = 8.9 Hz, 1H), 7.12 (dd, J = 8.9, 2.5 Hz, 1H), 4.72–4.41 (m, 2H), 3.94 (s, 3H), 3.66 (dd, J = 10.9, 3.8 Hz, 1H), 3.49 (dd, J =10.9, 3.1 Hz, 1H), 3.23–3.17 (m, 1H), 2.96–2.86 (m, 2H), 2.67–2.60 (m, 1H),2.43 (dt, J = 12.1, 5.9 Hz, 1H), 2.27–2.18 (m, 1H), 2.14–1.98 (m, 2H), 1.99–1.69 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 154.68, 142.92, 134.88, 132.73,130.36, 128.24, 126.50, 126.20, 126.13, 124.46, 121.87, 121.08, 116.85,110.07, 100.85, 65.49, 62.57, 55.97, 54.59, 52.16, 43.74, 29.06, 27.56,23.64. ESI-HRMS cacld for C24H26ClN3O2 m/z [M + H]+ 424.1786, found [M + H]+424.1792.
实施例 30
本实施例的结构式如下:
1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)哌啶-4-醇的合成:将实施例 23 中 4-甲基咪唑改为4-羟基哌啶,其他步骤及操作同实施例 23;得黄色固体,收率:78%。1H NMR (400 MHz, DMSO-d 6) δ 8.65(d, J = 8.5 Hz, 1H), 8.46 (dd, J = 8.5, 1.3 Hz, 1H), 7.97 (t, J = 8.5, 1H),7.86–7.78 (m, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.16(dd, J = 9.0, 2.6 Hz, 1H), 4.79 (t, J = 7.0 Hz, 2H), 4.55 (d, J = 4.2 Hz,1H), 3.89 (s, 3H), 3.49–3.38 (m, 1H), 2.60 (d, J = 11.0 Hz, 2H), 2.24 (t, J =6.3 Hz, 2H), 1.94 (dt, J = 16.0, 9.2 Hz, 4H), 1.70 (dd, J = 11.6, 4.8 Hz,2H), 1.45–1.36 (m, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 154.31, 141.62, 134.99,131.94, 130.95, 127.34, 127.04, 126.27, 125.88, 123.75, 122.10, 121.11,116.34, 111.50, 100.19, 55.52, 54.26, 51.19, 43.03, 34.50, 26.84. ESI-HRMScacld for C24H26ClN3O2 m/z [M + H]+ 424.1786, found [M + H]+ 424.1793.
实施例 31
本实施例的结构式如下:
(1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)哌啶-4-基)甲醇的合成:将实施例 23 中 4-甲基咪唑改为 4-羟甲基哌啶,其他步骤及操作同实施例 23;得黄色固体,收率:69%。1H NMR (300 MHz, CDCl3)δ 8.50 (dd, J = 8.6, 3.7 Hz, 1H), 8.39 (t, J = 7.1 Hz, 1H), 7.87–7.72 (m,2H), 7.63 (t, J = 7.7 Hz, 1H), 7.48 (dd, J = 9.0, 3.8 Hz, 1H), 7.13 (dd, J =8.9, 2.5 Hz, 1H), 4.66 (q, J = 6.8 Hz, 2H), 3.94 (s, 3H), 3.75–3.67 (m, 1H),2.70 (dt, J = 10.3, 4.4 Hz, 2H), 2.30 (t, J = 6.4 Hz, 2H), 2.05 (p, J = 7.8,6.5 Hz, 4H), 1.97–1.80 (m, 4H), 1.73–1.50 (m, 2H). 13C NMR (101 MHz, CDCl3) δ154.72, 143.02, 135.35, 132.95, 130.42, 128.38, 126.73, 126.44, 126.26,124.62, 121.90, 121.44, 116.87, 110.64, 100.75, 77.48, 77.16, 76.84, 68.06,56.04, 54.75, 51.35, 43.43, 34.70, 27.40. ESI-HRMS cacld for C25H28ClN3O2 m/z [M+ H]+ 438.1943, found [M + H]+ 438.1945.
实施例 32
本实施例的结构式如下:
1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-N,N-二甲基哌啶-4-胺的合成:将实施例 23 中 4-甲基咪唑改为4-二甲氨基哌啶,其他步骤及操作同实施例 23;得黄色固体,收率:75%。1H NMR (300 MHz,Chloroform-d) δ 8.54 (dd, J = 8.5, 1.3 Hz, 1H), 8.45 (d, J = 8.5 Hz, 1H),7.87–7.75 (m, 2H), 7.68–7.63 (m, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.14 (dd, J =9.0, 2.6 Hz, 1H), 4.73 (t, J = 7.0 Hz, 2H), 3.95 (s, 3H), 3.00–2.75 (m, 2H),2.29 (s, 8H), 2.20 (t, J = 7.6 Hz, 1H), 2.15–1.96 (m, 4H), 1.93–1.85 (m, 2H),1.55 (td, J = 12.0, 3.7 Hz, 2H). 13C NMR (101 MHz, Chloroform-d) δ 154.78,143.08, 135.45, 133.08, 130.44, 128.45, 126.83, 126.57, 126.28, 124.71,121.99, 121.55, 116.94, 110.77, 100.75, 62.44, 56.05, 54.88, 53.31, 43.56,41.96, 28.79, 27.43. ESI-HRMS cacld for C26H31ClN4O m/z [M + H]+ 451.2259,found [M + H]+ 451.2264.
实施例 33
本实施例的结构式如下:
1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-4,4-二甲基哌啶-2,6-二酮的合成:将实施例 23 中 4-甲基咪唑改为 3,3-二甲基谷酰胺,其他步骤及操作同实施例23;得白色固体,收率:76%。1H NMR (300 MHz,CDCl3) δ 8.53 (dd, J = 8.5, 1.3 Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 7.90–7.85(m, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.70–7.64 (m, 1H), 7.42 (d, J = 9.0 Hz,1H), 7.15 (dd, J = 9.0, 2.6 Hz, 1H), 4.79–4.49 (m, 2H), 4.05–3.96 (m, 2H),3.94 (s, 3H), 2.48 (s, 4H), 2.28–2.08 (m, 2H), 1.04 (s, 6H). 13C NMR (101 MHz,CDCl3) δ 171.89, 154.92, 143.33, 134.93, 133.07, 130.81, 128.50, 126.79,126.45, 126.38, 124.75, 122.23, 121.31, 117.17, 110.15, 101.07, 56.09, 46.41,43.74, 37.04, 29.28, 28.42, 27.78. ESI-HRMS cacld for C26H26ClN3O3 m/z [M + H]+464.1735, found [M + H]+ 464.1744.
实施例 34
本实施例的结构式如下:
4-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)吗啉的合成:将实施例 23 中 4-甲基咪唑改为吗啉,其他步骤及操作同实施例 23;得红色固体,收率:74%。1H NMR (300 MHz, CDCl3) δ 8.52 (dd, J = 8.5, 1.3Hz, 1H), 8.45–8.35 (m, 1H), 7.87–7.74 (m, 2H), 7.68–7.62 (m, 1H), 7.50 (d, J= 9.0 Hz, 1H), 7.13 (dd, J = 9.0, 2.5 Hz, 1H), 4.71 (t, J = 6.9 Hz, 2H), 3.94(s, 3H), 3.73 (t, J = 4.6 Hz, 4H), 2.49–2.21 (m, 6H), 2.07 (p, J = 6.7 Hz,2H). 13C NMR (101 MHz, CDCl3) δ 154.78, 143.15, 135.37, 133.08, 130.43,128.48, 126.75, 126.50, 126.31, 124.69, 122.00, 121.42, 116.93, 110.67,100.74, 67.13, 56.05, 55.29, 53.83, 43.34, 26.68. ESI-HRMS cacld forC23H24ClN3O2 m/z [M + H]+ 410.1630, found [M + H]+ 410.1631.
实施例 35
本实施例的结构式如下:
3-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-5-氟嘧啶-2,4-(1H,3H)-二酮的合成:将实施例 23 中 4-甲基咪唑改为 5-氟尿嘧啶,其他步骤及操作同实施例 23;得白色固体,收率:62%。1H NMR (400 MHz,DMSO-d 6) δ 11.07 (s, 1H), 8.64–8.38 (m, 2H), 7.94 (t, J = 8.5 Hz, 1H), 7.87–7.75 (m, 3H), 7.63 (d, J = 2.6 Hz, 1H), 7.18 (dd, J = 9.0, 2.5 Hz, 1H), 4.88(t, J = 7.5 Hz, 2H), 3.99–3.91 (m, 2H), 3.90 (s, 3H), 2.12 (p, J = 7.5 Hz,2H). 13C NMR (101 MHz, DMSO-d 6) δ 157.43, 157.18, 154.42, 149.77, 141.83,140.54, 138.30, 134.90, 132.08, 131.09, 127.41, 127.12, 126.24, 125.81,125.18, 124.87, 123.78, 121.97, 121.25, 116.55, 111.38, 100.37, 55.56, 42.78,37.97, 27.57. ESI-HRMS cacld for C23H18ClFN4O3 m/z [M + H]+ 453.1124, found [M +H]+ 453.1133.
实施例 36
本实施例的结构式如下:
3-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-1-((2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基)-5-氟嘧啶-2,4(1H,3H)-二酮的合成:将实施例 23 中 4-甲基咪唑改为 5-氟尿嘧啶核苷,其他步骤及操作同实施例23;得白色固体,收率:62%。1H NMR (300 MHz, DMSO-d 6) δ 8.55 (d, J= 8.5 Hz, 1H), 8.50–8.34 (m, 2H), 7.99–7.94 (m, 1H), 7.87–7.75 (m, 2H), 7.63(d, J = 2.5 Hz, 1H), 7.19 (dd, J = 9.0, 2.6 Hz, 1H), 5.80–5.66 (m, 1H), 5.42(s, 1H), 5.32 (t, J = 4.7 Hz, 1H), 5.09 (s, 1H), 4.89 (t, J = 7.4 Hz, 2H),3.97 (dd, J = 8.6, 4.4 Hz, 4H), 3.90 (s, 3H), 3.86 (q, J = 2.5 Hz, 1H), 3.72(dd, J = 12.1, 4.3 Hz, 1H), 3.58 (dt, J = 12.4, 3.4 Hz, 1H), 2.24–2.04 (m,2H). 13C NMR (101 MHz, DMSO-d 6) δ 156.56, 156.30, 154.44, 149.05, 141.87,140.57, 138.31, 134.91, 132.09, 131.18, 127.42, 127.17, 126.24, 125.81,123.79, 122.00, 121.27, 116.58, 111.40, 100.39, 89.42, 84.47, 73.98, 68.88,59.93, 55.57, 42.75, 38.79, 27.50. ESI-HRMS cacld for C28H26ClFN4O7 m/z [M + H]+585.1547, found [M + H]+ 585.1559.
实施例 37
本实施例的结构式如下:
4-((3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)氨基)-1-((2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基)-5-氟嘧啶-2(1H)-酮的合成:将实施例 23 中 4-甲基咪唑改为 5-氟胞苷,其他步骤及操作同实施例 23;得白色固体,收率:48%。1H NMR (300 MHz, DMSO-d 6) δ 8.57 (d, J =8.6 Hz, 1H), 8.48 (dd, J = 8.6, 1.3 Hz, 1H), 8.01–7.95 (m, 1H), 7.89–7.71 (m,4H), 7.63 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 9.0, 2.6 Hz, 1H), 5.84–5.68 (m,1H), 5.32 (d, J = 5.3 Hz, 1H), 5.20 (t, J = 4.9 Hz, 1H), 5.07 (d, J = 4.8 Hz,1H), 4.97–4.74 (m, 2H), 4.18–4.06 (m, 2H), 4.00–3.90 (m, 2H), 3.90 (s, 3H),3.82–3.80 (m, 1H), 3.69–3.49 (m, 2H), 2.29–2.11 (m, 2H). 13C NMR (101 MHz,DMSO-d 6) δ 154.43, 154.00, 151.23, 151.21, 150.92, 150.91, 149.23, 149.22,141.80, 134.85, 132.02, 131.22, 127.41, 127.17, 126.29, 125.81, 123.79,122.08, 121.26, 116.59, 111.31, 100.42, 88.37, 84.61, 73.29, 69.67, 60.66,55.58, 42.98, 27.02. ESI-HRMS cacld for C28H27ClFN5O6 m/z [M + H]+ 584.1707,found [M + H]+ 584.1722.
实施例 38
本实施例的结构式如下:
4-((3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)氨基)-1-((2R,3S,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基)嘧啶-2(1H)-酮的合成:将实施例 23 中4-甲基咪唑改为阿糖胞苷,其他步骤及操作同实施例23;得白色固体,收率:49%。1H NMR (300 MHz, DMSO-d 6) δ 8.53 (d, J = 8.6 Hz,1H), 8.47 (d, J = 8.5 Hz, 1H), 8.04–7.99 (m, 1H), 7.89–7.74 (m, 2H), 7.62 (d,J = 2.5 Hz, 1H), 7.58 (d, J = 9.1 Hz, 1H), 7.21 (dd, J = 9.0, 2.5 Hz, 1H),7.15 (d, J = 15.1 Hz, 2H), 6.27 (d, J = 5.1 Hz, 1H), 5.80–5.70 (m, 1H), 5.63(d, J = 4.8 Hz, 1H), 5.09 (t, J = 5.5 Hz, 1H), 4.80–4.54 (m, 2H), 4.16 (q, J= 4.5 Hz, 1H), 3.98 (dd, J = 5.2, 3.8 Hz, 1H), 3.90 (s, 3H), 3.83–3.60 (m,4H), 2.05–1.85 (m, 2H). 13C NMR (75 MHz, DMSO-d 6) δ 165.70, 155.34, 154.46,142.71, 141.82, 134.77, 131.95, 131.38, 127.42, 127.22, 126.17, 125.77,123.79, 122.00, 121.14, 116.86, 111.09, 100.32, 93.04, 84.33, 83.72, 73.32,66.88, 60.57, 55.61, 42.07, 29.69. ESI-HRMS cacld for C28H28ClN5O6 m/z [M + H]+566.1801, found [M + H]+ 566.1777.
实施例 39
本实施例的结构式如下:
4-((3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)氨基)-1-((2R,4S,5R)-4-羟基-5-(羟甲基)四氢呋喃-2-基)嘧啶-2(1H)-酮的合成:将实施例 23 中 4-甲基咪唑改为 2’-脱氧胞苷,其他步骤及操作同实施例 23;得白色固体,收率:42%。1H NMR (400 MHz, DMSO-d 6) δ 8.56 (d, J = 8.5Hz, 1H), 8.45 (dd, J = 8.5, 1.3 Hz, 1H), 7.94–7.90 (m, 2H), 7.83–7.77 (m,3H), 7.61 (d, J = 2.6 Hz, 1H), 7.16 (dd, J = 9.0, 2.6 Hz, 1H), 6.16 (dd, J =7.4, 5.9 Hz, 1H), 5.80 (d, J = 7.4 Hz, 1H), 5.22 (d, J = 4.2 Hz, 1H), 5.00(t, J = 5.2 Hz, 1H), 4.85 (t, J = 7.6 Hz, 2H), 4.22 (dq, J = 6.7, 3.2 Hz,1H), 3.89 (s, 3H), 3.78 (q, J = 3.6 Hz, 1H), 3.65–3.48 (m, 2H), 3.45–3.41 (m,1H), 2.14–2.07 (m, 3H), 1.98–1.91 (m, 1H). 13C NMR (101 MHz, DMSO-d 6) δ163.51, 155.08, 154.43, 141.81, 140.06, 134.85, 131.98, 131.21, 127.39,127.11, 126.24, 125.81, 123.79, 122.09, 121.23, 116.54, 111.39, 100.37,94.66, 87.24, 84.93, 70.48, 61.44, 55.58, 42.98, 40.37, 37.23, 29.00. ESI-HRMS cacld for C28H28ClN5O5 m/z [M + H]+ 550.1852, found [M + H]+ 550.1863.
实施例 40
本实施例的结构式如下:
8-甲氧基-11-(3-(4-甲基哌嗪-1-基)丙基)-11H-吲哚并[3,2-c]异喹啉的合成:将实施例 9 中产物(7)改为产物(27),其他步骤及操作同实施例 9;得白色固体,收率:79%。1H NMR (300 MHz, CDCl3) δ 9.05 (s, 1H),8.45 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H),7.80–7.75 (m, 1H), 7.65–7.50 (m, 2H), 7.15 (dd, J = 8.9, 2.6 Hz, 1H), 4.78(t, J = 7.0 Hz, 2H), 3.97 (s, 3H), 2.60–2.36 (m, 10H), 2.32 (s, 3H), 2.11 (q,J = 6.7 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 154.65, 145.25, 135.33, 134.79,129.82, 129.65, 127.65, 127.28, 125.45, 124.77, 122.80, 121.13, 116.43,110.63, 100.84, 56.05, 55.25, 54.92, 53.17, 46.10, 43.48, 29.82, 27.22. ESI-HRMS cacld for C24H28N4O m/z [M + H]+ 389.2336, found [M + H]+ 389.2336.
实施例 41
本实施例的结构式如下:
11-(3-(4-异丙基哌嗪-1-基)丙基)-8-甲氧基-11H-吲哚并[3,2-c]异喹啉的合成:将实施例 9 中产物(7)改为产物(28),其他步骤及操作同实施例 9;得白色固体,收率:74%。1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H),8.49 (d, J = 8.5 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 2.5 Hz, 1H),7.82–7.78 (m, 1H), 7.66–7.62 (m, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.19 (dd, J =8.9, 2.6 Hz, 1H), 4.82 (t, J = 7.0 Hz, 2H), 4.00 (s, 3H), 2.76–2.70 (m, 1H),2.68–2.44 (m, 8H), 2.41 (t, J = 6.5 Hz, 2H), 2.16 (p, J = 6.8 Hz, 2H), 1.11(d, J = 6.5 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 154.67, 145.25, 135.34,134.81, 129.78, 129.63, 127.66, 127.31, 125.44, 124.78, 122.84, 121.17,116.43, 110.65, 100.85, 56.05, 55.07, 54.82, 53.36, 48.76, 43.61, 27.19,18.65. ESI-HRMS cacld for C26H32N4O m/z [M + H]+ 417.2649, found [M + H]+417.265.
针对以上实施例进行体外抗肿瘤活性筛选:
采用 MTT 法评价化合物对肿瘤细胞的增殖抑制活性,计算各化合物对多种肿瘤细胞株的 IC50 值,其检测原理如下:活细胞线粒体中的琥珀酸脱氢酶能使外源性 MTT 还原为不溶于水的蓝紫色结晶甲瓒,并使其沉积在细胞当中,而死细胞中线粒体失活,则无此功能。二甲基亚砜(DMSO)能够溶解细胞中的甲瓒,用酶标仪在 490 nm 波长处测定其光吸收值,在一定细胞数范围内,甲瓒结晶形成的量与活细胞数成正比。根据酶标仪测得的吸光度(OD)值来判断活细胞数量,OD 值越大,则细胞活性越强,活细胞数越多,进而测算出细胞的存活率。
实验方法如下:
(1)接种细胞:用含 10% 的胎牛血清的培养基将肿瘤细胞配成单个细胞悬液,于96 孔板中每孔接种 100 μL 密度为 2×104个/mL 的肿瘤细胞悬液,并置于 37 ℃,含 5%CO2 培养箱中培养 24 h。
(2)加入待测样品溶液:待 96 孔板中细胞贴壁后,每孔加入 100 μL 样品溶液,每个样品测定 6 个浓度,每个浓度设置 3 个复孔。阴性对照组加入等体积的含 0.1%DMSO 的相同培养基。加药完成后,将 96 孔板继续置于培养箱培养 72 h。
(3)检测:每孔加入 10 μL 5 mg/mL 的 MTT 溶液,于 37 ℃ 下继续培养4 h,弃去上清液,每孔加入 100 μL DMSO,平板摇床混匀后,酶标仪检测 OD值,检测波长为 490nm。
(4)应用 ExCel 软件进行原始数据标准化处理。IC50 通过 GraphPad Prism 8 计算。肿瘤细胞生长抑制率计算公式:生长抑制率(%)=1-(给药组 OD 值-空白组OD值)/(阴性对照组OD值-空白组OD值)×100%。
表 1 实施例 1-41 的体外抗肿瘤活性(IC50,μM)
实施例 | MCF-7 | MDA-MB-231 | PC3 | HCT116 | H2228 | Huh-7 |
实施例1 | 6.84 ± 1.05 | 5.90 ± 0.54 | 4.38 ± 0.32 | 4.05 ± 0.59 | 7.03 ± 1.37 | >10 |
实施例2 | 1.41 ± 0.17 | 1.92 ± 0.58 | 1.32 ± 0.16 | 0.55 ± 0.10 | 2.03 ± 0.30 | 2.55 ± 0.29 |
实施例3 | >10 | 5.60 ± 0.39 | 4.91 ± 0.36 | 2.56 ± 0.19 | 2.56 ± 0.09 | 6.84 ± 0.67 |
实施例4 | 0.60 ± 0.06 | 0.48 ± 0.03 | 0.63 ± 0.06 | 0.22 ± 0.02 | 1.16 ± 0.08 | 1.24 ± 0.18 |
实施例5 | 2.75 ± 0.31 | 1.95 ± 0.13 | 2.67 ± 0.22 | 1.33 ± 0.20 | 1.51 ± 0.15 | 2.99 ± 0.18 |
实施例6 | 1.83 ± 0.15 | 1.36 ± 0.05 | 1.65 ± 0.15 | 0.96 ± 0.06 | 1.50 ± 0.24 | 2.49 ± 0.38 |
实施例7 | 1.64 ± 0.24 | 1.20 ± 0.13 | 1.22 ± 0.36 | 0.82 ± 0.10 | 1.28 ± 0.26 | 1.77 ± 0.27 |
实施例8 | 0.37±0.02 | 0.56±0.04 | 0.47 ± 0.04 | 0.26 ± 0.04 | 0.96 ± 0.26 | 0.94 ± 0.06 |
实施例9 | 1.45 ± 0.07 | 1.09 ± 0.11 | 1.01 ± 0.17 | 0.62 ± 0.06 | 1.05 ± 0.07 | 1.50 ± 0.34 |
实施例10 | 0.35 ± 0.04 | 0.29 ± 0.02 | 0.40 ± 0.03 | 0.21 ± 0.03 | 0.88 ± 0.14 | 0.83 ± 0.05 |
实施例11 | 6.57 ± 0.54 | 4.88 ± 0.87 | 7.14 ± 0.66 | 4.08 ± 0.76 | >10 | >10 |
实施例12 | 3.87 ± 0.35 | 2.98 ± 0.46 | 3.14 ± 0.52 | 2.87 ± 0.14 | 4.28 ± 0.11 | 5.76 ± 0.46 |
实施例13 | 4.60 ± 0.49 | 3.06 ± 0.16 | 3.70 ± 0.26 | 2.70 ± 0.37 | 4.60 ± 0.36 | >10 |
实施例14 | 1.51 ± 0.15 | 0.98 ± 0.03 | 1.66 ± 0.07 | 0.74 ± 0.02 | 2.39 ± 0.21 | 2.98 ± 0.10 |
实施例15 | 4.35 ± 0.35 | 3.69 ± 0.36 | 4.11 ± 0.54 | 2.50 ± 0.39 | 5.31 ± 0.41 | 4.13 ± 0.25 |
实施例16 | 3.73 ± 0.53 | 1.92 ± 0.17 | 2.58 ± 0.82 | 1.80 ± 0.19 | 4.66 ± 0.82 | 3.92 ± 0.31 |
实施例17 | 2.86 ± 0.16 | 1.64 ± 0.09 | 2.44 ± 0.37 | 1.87 ± 0.38 | 3.64 ± 0.38 | 4.10 ± 0.28 |
实施例18 | 0.67 ± 0.04 | 0.55 ± 0.06 | 0.97 ± 0.07 | 0.53 ± 0.12 | 2.34 ± 0.32 | 2.50 ± 0.19 |
实施例19 | 5.71 ± 0.29 | 2.38 ± 0.17 | 4.30 ± 0.31 | 4.07 ± 0.38 | 3.74 ± 0.10 | 3.37 ± 0.35 |
实施例20 | 0.97 ± 0.23 | 0.80 ± 0.03 | 1.55 ± 0.13 | 1.38 ± 0.19 | 3.06 ± 0.21 | 3.41 ± 0.46 |
实施例21 | 4.56 ± 0.24 | 1.78 ± 0.21 | 2.57 ± 0.19 | 2.14 ± 0.31 | 4.86 ± 0.46 | 4.43 ± 0.58 |
实施例22 | 2.32 ± 0.29 | 0.95 ± 0.14 | 1.55 ± 0.26 | 1.32 ± 0.85 | 3.07 ± 0.60 | 2.89 ± 0.52 |
实施例23 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例24 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例25 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例26 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例27 | 1.36 ± 0.03 | 2.24 ± 0.11 | 0.82 ± 0.17 | 1.65 ± 0.37 | 2.41 ± 0.52 | 3.31 ± 0.15 |
实施例28 | 1.76 ± 0.14 | 2.52 ± 0.19 | 1.12 ± 0.09 | 1.79 ± 0.22 | 2.36 ± 0.34 | 2.26 ± 0.14 |
实施例29 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例30 | 3.61 ± 0.12 | 5.04 ± 0.48 | 3.26 ± 0.19 | 3.68 ± 0.11 | 3.10 ± 0.41 | 4.57 ± 0.21 |
实施例31 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例32 | 2.96 ± 0.13 | 4.10 ± 0.18 | 2.70 ± 0.17 | 2.55 ± 0.41 | 2.73 ± 0.37 | 4.36 ± 0.28 |
实施例33 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例34 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例35 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例36 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例37 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例38 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例39 | >10 | >10 | >10 | >10 | >10 | >10 |
实施例40 | 1.12 ± 0.10 | 1.68 ± 0.08 | 0.74 ± 0.13 | 1.17 ± 0.15 | 1.84 ± 0.21 | 2.24 ± 0.16 |
实施例41 | 1.45 ± 0.17 | 2.04 ± 0.07 | 1.07 ± 0.15 | 1.38 ± 0.14 | 2.04 ± 0.17 | 2.18 ± 0.23 |
伊立替康 | 4.59 ± 0.70 | >10 | 3.67 ± 0.21 | 3.16 ± 0.22 | 3.43 ± 0.31 | >10 |
依托泊苷 | 1.18 ± 0.41 | 2.87 ± 0.19 | 1.59 ± 0.36 | 2.00 ± 1.12 | 2.51 ± 0.04 | 3.80 ± 0.55 |
。
表 2 实施例 10 与 18 的体外抗肿瘤活性(IC50,μM)
实施例 | H1975 | A549 | H1650 | H446 | PC9 | DU145 |
实施例10 | 0.74 ± 0.02 | 1.10 ± 0.02 | 0.88 ± 0.23 | 0.09 ± 0.03 | 0.76 ± 0.10 | 0.52 ± 0.07 |
实施例18 | 0.96 ± 0.07 | 2.51 ± 0.43 | 1.02 ± 0.06 | 0.12 ± 0.05 | 1.26 ± 0.02 | 0.86 ± 0.05 |
伊立替康 | 3.41 ± 0.39 | >10 | 6.80 ± 1.93 | 0.78 ± 0.08 | 3.84 ± 0.62 | 0.96 ± 0.07 |
依托泊苷 | 0.34 ± 0.04 | >10 | 2.65 ± 0.92 | 0.24 ± 0.07 | 2.22 ± 0.10 | 1.65 ± 0.27 |
。
从表 1、2 可以看出,本发明中大部分实施例对不同肿瘤细胞株都具有微摩尔水平的体外抗增殖活性,且多个实施例,如实施例 4、8、10、18、20 与 40 的活性均优于阳性对照药伊立替康与依托泊苷。其中,实施例 10 与 18 为两类具有不同取代基的吡咯并[3,2-b]吡啶类衍生物中的两个活性最优化合物。通过对十二种不同肿瘤细胞株进行筛选,其中 H446 与 HCT116 细胞系对实施例10 与 18最为敏感。实施例 10 对 H446 与 HCT116细胞系的 IC50 分别为 0.09 与 0.21 μM,实施例 18 对 H446 与 HCT116 细胞系的 IC50分别为 0.12 与 0.53 μM,显著优于阳性对照伊立替康与依托泊苷。由此可见,本发明的实施例可潜在用于上述肿瘤的临床治疗。
针对本发明中实施例进行拓扑异构酶活性抑制实验:
选取体外抗肿瘤活性较好的实施例进行 Top1 与 Top2 抑制活性筛选,其结果如图 1 所示。所选取的实施例中,大部分实施例,如实施例 4、8、10、11、17、18、22 的 Top1的抑制活性维持至 10 μM,且实施例 10 与 17 的 Top1 抑制活性维持至 5 μM,表现出优越的 Top1 抑制活性。在Top2抑制活性筛选实验中,大部分实施例,如实施例 4、8、10、11、17、18、22 的 Top2 的抑制活性维持至 50 μM,其中实施例10与18在0.5 μM时依旧表现出优越的Top2抑制活性,且活性优于阳性对照药依托泊苷。
针对本发明中实施例 10 和 18 进行小鼠体内毒性研究:
首先对实施例 10 和 18 进行急性毒性实验。选取 KM 小鼠 24 只,随机分成四组,分别为空白对照组、实施例 10 给药组、实施例 18 给药组以及阳性对照拓扑替康组,实施例给药组与阳性对照组给药剂量均为 1000 mg/kg。单次口服给药后,连续观察一周,记录小鼠死亡情况。实验结果表明实施例 10 与 18 对的 KM 小鼠的 LD50大于 1000 mg/kg,而拓扑替康对的 KM 小鼠的 LD50 小于 1000 mg/kg,这个结果初步说明实施例 10 与18 的安全性优于阳性对照药拓扑替康。
为了进一步探究实施例 10 与 18 在小鼠体内的毒性作用,并与已上市拓扑异构酶抑制剂拓扑替康、伊立替康以及依托泊苷进行对比,随机选取 KM 小鼠36 只分成六组,分别为空白对照组、实施例 10 给药组、实施例 18 给药组以及阳性对照拓扑替康组、伊立替康组以及依托泊苷组,见图2。实施例给药组与拓扑替康组给药组剂量均为口服 100 mg/kg,而伊立替康组与依托泊苷组均为注射给药,给药剂量为 30 mg/kg。所有小组连续给药两周,实验结果显示:口服剂量为 100 mg/kg 的实施例 10 与 18 给药组小鼠的体重维持在正常水平甚至增加,但在口服剂量为 100 mg/kg 的拓扑替康组和腹腔注射剂量为 30mg/kg 的伊立替康组或依托泊苷阳性对照组中,小鼠连续给药 3 d 后体重急剧下降 10%以上,且在第 4 天出现死亡。这些结果表明,与市售的拓扑异构酶抑制剂相比,实施例 10与 18 在体内具有更好的耐受性。
血液生化分析结果显示,实施例 10 与 18 给药组小鼠肝、肾功能正常,血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、血尿素氮(BUN)和肌酐(CRE)水平均在正常范围内。此外,实施例 10 与 18 给药组小鼠各器官均未观察到明显形态异常,给药组和空白对照组器官系数差异无统计学意义。总的来说,这些结果表明实施例 10 与 18 在体内具有良好的安全性,且优于已上市药拓扑替康、伊立替康以及依托泊苷。
针对本发明实施例 10 与 18 进行大鼠口服药代动力学实验:
称取供试品 10 mg 置于无菌小瓶中,加入 400 µL DMSO 溶解后再加入 1.2 mLPEG400 混匀,最后加入 dd H2O,并用稀盐酸将溶液 PH 调制至 3.5,最终超声、振荡混匀并定容至 4 mL,配制成 2.5 mg/mL 的供试品溶液,以此溶液作为灌胃给药制剂。
将 6 只 SD 大鼠分为两组,分别对实施例 10 和 18 给予灌胃(10 mg/kg)给药,并于给药后 15 min、30 min、45 min、1 h、2 h、4 h、6 h、8 h、24 h 自眼眶后静脉丛采集血样约 0.1 mL,离心后获得血浆。利用 LC-MS/MS 检测各时间点 SD 大鼠血浆样本中实施例10 和 18 的浓度,最终运用 WinNolin 软件计算药代动力学参数,结果如表 3。
结果表明,本发明的实施例 10 在大鼠体内具有较好的口服吸收和暴露量,能够用于口服给药。
表 3 实施例 10 与 18 的药代动力学参数
实施例 | T1/2(h) | Tmax(h) | Cmax(ng/mL) | MRT0-t (h) | MRT0-∞(h) | AUC0-t (h∙ng/mL) | AUC0-∞(h∙ng/mL) |
10 | 1.66 | 2.00 | 283.62 | 5.00 | 5.00 | 2035.14 | 2035.34 |
18 | 1.15 | 1.00 | 109.32 | 1.35 | 1.72 | 244.29 | 267.04 |
。
针对本发明中实施例 10 进行小鼠体内抗肿瘤疗效研究:
药物为实施例10。细胞株为人小细胞肺癌细胞系 NCI-H446 以及人结肠癌细胞系HCT116。受试动物为 SPF 级 Balb/c 裸小鼠;雄性;每组 5−6 只。药物剂量与阳性对照组设置如表4。
药物配制方法:
实施例10(50 mg/kg 与 100 mg/kg):称取 50 mg 或者 100 mg待测试化合物粉末溶于 1 mL DMSO,随即加入 3 mL PEG400 混匀,最后加入 dd H2O,并用稀盐酸将溶液PH 调制至 3.5,最终超声、振荡混匀并定容至 10 mL,配制成5 mg/mL 与 10 mg/mL 的供试品溶液,以此溶液作为灌胃给药制剂。
依托泊苷(4 mg/kg):称取 4 mg 待测试化合物粉末溶于 0.5 mL DMSO,随即加入1 mL PEG400 混匀,最后加入 3.5 mL 生理盐水超声、振荡混匀,配制成 0.8 mg/mL 的供试品溶液,以此溶液作为腹腔注射给药制剂。
顺铂(2.5 mg/kg):称取 2.5 mg 待测试化合物粉末溶于 0.5 mL DMSO,随即加入1 mL PEG400 混匀,最后加入 3.5 mL 生理盐水超声、振荡混匀,配制成 0.5 mg/mL 的供试品溶液,以此溶液作为腹腔注射给药制剂。
伊立替康(20 mg/kg):称取 20 mg 待测试化合物粉末溶于 0.5 mL DMSO,随即加入 1 mL PEG400 混匀,最后加入 3.5 mL 生理盐水超声、振荡混匀,配制成 4 mg/mL 的供试品溶液,以此溶液作为腹腔注射给药制剂。
表 4 药物剂量配置与阳性对照组
。
实验方法:人小细胞肺癌与人结肠癌异种移植瘤模型的建立。取对数生长期H446细胞与 HCT116 细胞分别接种于裸小鼠右前肢皮下,细胞接种量为 5×106个/只。待皮下肿瘤生长至 80 mm3 左右时,随机将人小细胞肺癌荷瘤鼠与人结肠癌荷瘤鼠分为 4 组,每组 5-6 只,分别为空白对照组,实施例 10 低剂量组、实施例 10 高剂量组以及阳性对照组。实施例 10 高剂量组与低剂量组每天灌胃给药,空白对照组给予相应的等容量溶剂对照。H446 模型阳性对照组与 HCT116模型阳性对照组按照表 4 所示进行给药。每天监测各组小鼠体重变化以及肿瘤体积大小,给药周期完成后,处死小鼠,剥取肿瘤组织与主要脏器称重固定。
实验结果如图3:受试药实施例 10 在人小细胞肺癌异种移植瘤模型中表现出良好的抗肿瘤活性,其在给药剂量为 50 mg/kg 时表现出明显的抗肿瘤活性,TGI 值为49.2%,T/C 值为 52.3%,当给药剂量提高至 100 mg/kg 时,实施例 10 则表现出更高的抗肿瘤活性,TGI 值为66.1%,T/C 值为35.2%,优于阳性对照组(TGI = 27.7% 和 T/C =68.2%)。
此外,在人结肠癌异种移植瘤模型中,实施例 10 依旧表现出良好的抗肿瘤活性,与伊立替康(TGI = 65.7%和T/C = 33.1%)治疗组相比,实施例 10 在 50 mg/kg 下显示出稍弱的抗肿瘤活性(TGI = 40.8%和T/C = 55.0%),但在 100 mg/kg 的剂量下,实施例 10则表现出比伊立替康更有效的抗肿瘤活性,其 TGI 值为 77.4%,T/C值为 18.0%。综上所述,实施例 10 具有明显的体内抗肿瘤作用。
本发明中的吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂,通过对拓扑异构酶的高效抑制作用,能够抑制多种肿瘤细胞增殖,并在小鼠体内表现出良好的安全性以及抗肿瘤活性,可作为抗肿瘤活性小分子用于抗肿瘤新药的开发。
除上述实施外,本发明还可以有其他实施方式。凡采用等同替换或等效变换形成的技术方案,均落在本发明要求的保护范围。
Claims (9)
1.一种吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂,其特征在于:所述抑制剂为通式 V所示的取代吡咯并[3,2-b]吡啶类化合物或其立体异构体、水合物或药学上可接受的盐,,
其中,n 等于 0-7;
A、B 环为取代的苯环、吡啶、嘧啶;
R1 为氢,氯或氧原子;
X 为氮原子或羰基;
R2 为烷基、羟胺基或与 X 为氮原子时所形成的具有取代基的
五元杂环及六元杂环衍生物;
-X-R2 的结构式含有以下结构,。
2. 根据权利要求1所述吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂,其特征在于:所述通式 V中,与碳相连的氢替换为氢的同位素氘。
3.根据权利要求1所述吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂,其特征在于:烷基由氘代烷基替代,烷氧基由氘代环氧基替代,苯环由氘代苯环替代,芳环由氘代芳环替代。
4.根据权利要求 1或2或3所述抑制剂,其特征在于,所述抑制剂为以下其中之一:
(1)11-(3-(二甲基氨基)丙基)-6,11-二氢-5H-吲哚并[3,2-c]异喹啉-5-酮;
(2)11-(3-(二甲基氨基)丙基)-8-甲氧基-6,11-二氢-5H-吲哚并[3,2-c]异喹啉-5-酮;
(3)11-(3-(二甲基氨基)丙基)-8-异丙氧基-6,11-二氢-5H-吲哚并[3,2-c]异喹啉-5-酮;
(4)12-(3-(二甲基氨基)丙基)-6,12-二氢-5H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-5-酮;
(5)3-(5-氯-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺;
(6)3-(5-氯-9-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺;
(7)3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺;
(8)3-(5-氯-12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N,N-二甲基-1-丙胺;
(9)3-(8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N,N-二甲基-1-丙胺;
(10)3-(12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N,N-二甲基-1-丙胺;
(11)N-羟基-4-(5-氧代-5,6-二氢-12H-[1,3]二氧并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)丁酰胺;
(12)4-(5-氯-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(13)4-(5-氯-9-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(14)4-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(15)4-(5-氯-8-(二氟甲氧基)-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(16)4-(5-氯-8-乙氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(17)4-(5-氯-12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N-羟基丁酰胺;
(18)N-羟基-4-(8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丁酰胺;
(19)4-(8-(二氟甲氧基)-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(20)4-(8-乙氧基-11H-吲哚并[3,2-c]异喹啉-11-基)-N-羟基丁酰胺;
(21)N-羟基-4-(8-异丙氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丁酰胺;
(22)4-(12H-[1,3]二氧杂环戊并[4',5':5,6]吲哚并[3,2-c]异喹啉-12-基)-N-羟基丁酰胺;
(23)5-氯-8-甲氧基-11-(3-(4-甲基-1H-咪唑-1-基)丙基)-11H-吲哚并[3,2-c]异喹啉;
(24)5-氯-11-(3-(2,4-二甲基-1H-咪唑-1-基)丙基)-8-甲氧基-11H-吲哚并[3,2-c]异喹啉;
(25)(R)-1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)吡咯烷-3-醇;
(26)(R)-(1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)吡咯烷-2-基)甲醇;
(27)5-氯-8-甲氧基-11-(3-(4-甲基哌嗪-1-基)丙基)-11H-吲哚并[3,2-c]异喹啉;
(28)5-氯-11-(3-(4-异丙基哌嗪-1-基)丙基)-8-甲氧基-11H-吲哚并[3,2-c]异喹啉;
(29)(R)-1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)哌啶-3-醇;
(30)1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)哌啶-4-醇;
(31)(1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)哌啶-4-基)甲醇;
(32)1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-N,N-二甲基哌啶-4-胺;
(33)1-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-4,4-二甲基哌啶-2,6-二酮;
(34)4-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)吗啉;
(35)3-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-5-氟嘧啶-2,4-(1H,3H)-二酮;
(36)3-(3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)-1-((2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基)-5-氟嘧啶-2,4(1H,3H)-二酮;
(37)4-((3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)氨基)-1-((2R,3R,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基)-5-氟嘧啶-2(1H)-酮;
(38)4-((3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)氨基)-1-((2R,3S,4S,5R)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-基)嘧啶-2(1H)-酮;
(39)4-((3-(5-氯-8-甲氧基-11H-吲哚并[3,2-c]异喹啉-11-基)丙基)氨基)-1-((2R,4S,5R)-4-羟基-5-(羟甲基)四氢呋喃-2-基)嘧啶-2(1H)-酮;
(40)8-甲氧基-11-(3-(4-甲基哌嗪-1-基)丙基)-11H-吲哚并[3,2-c]异喹啉;
(41)11-(3-(4-异丙基哌嗪-1-基)丙基)-8-甲氧基-11H-吲哚并[3,2-c]异喹啉。
5.根据权利要求1所述吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂的制法,其特征在于:以具有不同取代基的邻硝基苯甲醛 1a-g 为原料,与甲氧胺反应后生成化合物 2a-g,接着再与高酞酸酐发生加成反应生成关键中间体 3a-g,中间体 3a-g 随后与硫化钠发生还原反应,生成母核 4a-g,母核 4a-g 接着与三氯氧磷反应,生成母核 5a-g,具体合成路线如下:。
6.根据权利要求5所述吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂的制法,其特征在于:所述抑制剂(1)-(41)的制备以母核 4a-g 与 5a-g 为原料,与 N,N-二甲氨基氯丙烷反应生成产物(1)-(8);与 4-溴丁酸乙酯反应生成中间体 6g 与 7a-g;中间体 6g,7a-g与羟胺反应生成产物(11)-(17);产物(7)、(8)、(14)-(17)被锌粉、乙酸还原生成产物(9)、(10)、(18)-(22);产物(21)的合成路线与产物(18)的合成路线一致;母核 5c 与 1-溴-3-氯丙烷反应生成中间体 8c,中间体 8c 与含伯胺与仲胺结构的砌块反应,生成产物(23)-(39),产物(27)、(28)被锌粉/乙酸还原生成产物(40)、(41),具体合成路线如下,反应条件如下,(a)3-氯-1-(N,N-二甲基)丙胺,氢化钠,DMF,0°C-80°C,12h;(b)4-溴丁酸乙酯,碳酸钾,DMF,80°C,12h;(c)羟胺,氢氧化钾,甲醇,50°C,4h;(d)锌粉,乙酸,水,70°C,4 h;(e)1-溴-3-氯丙烷,氢化钠,DMF,0°C-35°C,12h;(f)四丁基碘化铵,仲胺或氨基苷类似物,DMF,110°C。
7.一种药物组合物,其特征在于:所述组合物包含至少一种药学上可接受的辅料、辅助剂或载体,以及权利要求 1-3 任一项所述的吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂。
8.根据权利要求 1或7所述吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂或药物组合物在制备用于预防、治疗或辅助治疗拓扑异构酶过度活化引起的增殖性疾病、代谢性疾病、神经系统性疾病或结节性硬化症的药物中的应用。
9.根据权利要求 1或7所述吡咯并[3,2-b]吡啶类拓扑异构酶抑制剂或药物组合物在制备用于抑制癌症细胞生长的药物中的应用。
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