CN116874407A - 一种异吲哚啉酮衍生物、制备方法、药物组合物及应用 - Google Patents
一种异吲哚啉酮衍生物、制备方法、药物组合物及应用 Download PDFInfo
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- CN116874407A CN116874407A CN202310708669.5A CN202310708669A CN116874407A CN 116874407 A CN116874407 A CN 116874407A CN 202310708669 A CN202310708669 A CN 202310708669A CN 116874407 A CN116874407 A CN 116874407A
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- Prior art keywords
- substituted
- aryl
- alkyl
- isoindolinone
- compound
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 20
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- 229910052736 halogen Inorganic materials 0.000 claims description 5
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
本发明涉及一种异吲哚啉酮衍生物、制备方法、药物组合物及应用。该衍生物为式I化合物或式I化合物药学上可接受的盐,其中Ra为取代的或未取代的芳基、取代的或未取代的C1~C6烷基中的一种;Rb、Rc为取代的或未取代的C1~C6烷基中的一种。
Description
技术领域
本发明属于医药技术领域,尤其是涉及一种异吲哚啉酮衍生物、制备方法、药物组合物及应用。
背景技术
随着诊疗手段的不断提升,肿瘤等疾病越来越容易被发现和诊断。恶性肿瘤是影响人类健康的最危险的疾病之一;不仅从生理上,而且在心理上对病人都存在着巨大的伤害。手术切除是目前最常用的癌症治疗方法,但是其创伤性大,不适于老年人或体弱的患者。随着诊断发现的癌症疾病不断增多、科学对于癌症理解的不断加深,癌症制药领域正快速发展。尽管市场上已经存在多种治疗癌症的药物,但是或多或少都存在着缺陷,例如生物利用度不高、毒副作用大等问题。因此,发现具有抗癌活性的新型化合物先导结构,探索新的作用靶标,进而通过结构改造和优化,快速发现高活性化合物,对于新抗癌药的发现有着重要的意义。
异吲哚啉酮类化合物是一类重要的生物碱,也是重要的结构基序。其结构也包含了一个非常重要的γ-丁烯内酰胺骨架,常见于众多具有广泛生物活性的合成药物和天然产物中,也是制备多种功能化衍生物的关键中间体。异吲哚啉酮类衍生物具有广泛的生物活性,如:抗真菌、抗焦虑、抗炎、抗病毒作用等。
在前期的研究中,发明人发现了一类新型的γ-丁烯内酰胺类衍生物具有良好的抗肿瘤活性(专利授权号:ZL201911018651.2)。在此结构的基础上进行合理设计:将苯环和丁烯内酰胺进行并环,可以得到一类异吲哚啉酮结构骨架。
从种类众多的异吲哚啉酮类化合物中筛选并发现具有显著的抑制癌细胞增殖活性的化合物,将有很好的实用意义和价值,也是目前研究者亟需解决的问题。
发明内容
本发明的目的就是为了解决上述问题而提供一种异吲哚啉酮衍生物、制备方法、药物组合物及应用,本发明基于结构进行设计,得到一种结构新颖的具有抗癌活性的异吲哚啉酮衍生物。
本发明的目的通过以下技术方案实现:
本发明第一方面提供一种异吲哚啉酮衍生物,所述的衍生物为式I化合物或式I化合物药学上可接受的盐:
其中:
Ra为取代的或未取代的芳基、取代的或未取代的C1~C6烷基中的一种;
Rb、Rc为取代的或未取代的C1~C6烷基中的一种。
进一步地,所述Ra中,取代的芳基为一个或多个取代基取代的芳基,取代的C1~C6烷基为一个或多个取代基取代的C1~C6烷基;
所述Rb和Rc中,取代的C1~C6烷基为一个或多个取代基取代的C1~C6烷基,所述取代基选自卤素、氰基、硝基、三氟甲基、芳基、取代芳基、杂环芳基、取代杂环芳基、C1~C6烷基、C1~C6烷氧基中的一种。
进一步地,所述Rb和Rc中,取代芳基为一个或多个取代基取代的芳基,所述的取代芳基中的取代基选自卤素、氰基、硝基、三氟甲基、C1~C6烷基或C1~C6烷氧基;
所述Rb和Rc中,取代杂环芳基为一个或多个取代基取代的杂环芳基,其中的取代基选自C1~C6烷基;
所述Rb和Rc中,所述的芳基选自苯基或萘基中的一种;
所述Rb和Rc中,所述的杂环芳基选自呋喃基、噻吩基、吡啶基或喹啉基中的一种。
进一步地,所述异吲哚啉酮衍生物选自B1~B22中的一种:
本发明第二方面提供一种如上述的异吲哚啉酮衍生物的制备方法,包括以下步骤:
在惰性溶剂中,将邻苯二甲酰亚胺和劳森试剂反应得到化合物2,化合物2和卤代丙二酸二酯经过Eschenmoser偶联反应得到化合物3,化合物3经亲核取代反应得到异吲哚啉酮衍生物:
本发明第三方面提供一种如上述的异吲哚啉酮衍生物的应用,所述异吲哚啉酮衍生物用于制备抗肿瘤药物。
进一步地,所述的肿瘤选自:鼻咽癌;食管癌;胃癌;肝癌;乳腺癌;结肠癌;前列腺癌;肺癌;宫颈癌;白血病;口腔癌;唾液腺肿瘤;鼻腔与鼻旁窦恶性肿瘤;喉癌;耳部肿瘤;眼部肿瘤;甲状腺肿瘤;纵隔肿瘤;胸壁;胸膜肿瘤;小肠肿瘤;胆道肿瘤;胰腺与壶腹周围肿瘤;肠系膜与腹膜后肿瘤;肾脏肿瘤;肾上腺肿瘤;膀胱肿瘤;前列腺癌;睾丸肿瘤;阴茎癌;子宫内膜癌;卵巢恶性肿瘤;恶性滋养细胞肿瘤;外阴癌与阴道癌;恶性淋巴瘤;多发性骨髓瘤;软组织肿瘤;骨肿瘤;皮肤及附件肿瘤;恶性黑色素瘤或神经系统肿瘤。
本发明第四方面提供一种抗肿瘤药物组合物,该药物组合物含有上述异吲哚啉酮衍生物。
进一步地,所述药物组合物包括一种或多种所述的异吲哚啉酮衍生物,以及药学上可接受的载体介质和/或赋形剂。
进一步地,所述的异吲哚啉酮衍生物在组合物中的质量百分含量为0.001-99.99%。
本发明第五方面提供一种如上述抗肿瘤药物组合物的应用,所述的组合物用于制备抗肿瘤药物。
与现有技术相比,本发明具有以下技术优势:
1)本发明提供了一类结构新颖的异吲哚啉酮衍生物,抗肿瘤药用价值显著。
2)本发明中的化合物以及组合物具有显著抗癌细胞增殖活性(包括但不限于:肝癌细胞系HepG2和肺癌细胞系A549),多个化合物优于阿霉素的活性。
具体实施方式
本发明中合成的一类结构新颖的、具有显著抗癌活性的异吲哚啉酮衍生物。这类化合物经MTT法测试后,显示出显著的抑制肝癌细胞系HepG2和肺癌细胞系A549的增殖活性。
基团定义:
术语“烷基”是指烷烃分子中少掉一个氢原子而成的基团;术语“亚烷基”是指烷烃分子中少掉两个氢原子而成的基团。
术语“卤素”指氟、氯、溴、或碘。术语“卤代的”指被相同或不同的一个或多个上述卤原子取代的基团,例如三氟甲基、五氟乙基、七氟异丙基、或类似基团。
术语“惰性酸溶剂”指的是不与原料发生反应的各种酸性溶剂,包括各种直链、支链或环状的烷基或芳基羧酸,如甲酸、乙酸、丙酸、异丙酸、丁酸、苯甲酸、苯乙酸等。
术语“药学上可接受的盐”指本发明的式I化合物与药学上可接受的无机酸和有机酸所形成的盐,其中,优选的无机酸包括(但并不限于):盐酸、氢溴酸、磷酸、硝酸、硫酸;优选的有机酸包括(但并不限于):甲酸、乙酸、丙酸、丁二酸、1,5-萘二磺酸、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸,以及氨基酸。
药物组合物和施用方法:
本发明中所用的“组合物”指任何混合物。可以是溶液、混合液、液体、粉末、油膏、水性的、非水性的或他们的任何组合。
本发明化合物及其药学上可接受的盐或含有它的组合物可以单位剂量形式给药,给药突进可分为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括O/W、W/O型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物及其药学上可接受的盐可以制成普通制剂、也可制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物及其药学上可接受的盐制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、驻留剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;湿润剂可以是水、乙醇、异丙醇等:粘合剂可以是淀粉剂、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。为了将给药单元制成胶囊剂,可以将有效成分本发明化合物及其药学上可接受的盐与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物及其药学上可接受的盐先与稀释剂、粘合剂、崩解剂制成颗粒或微丸,在置于硬胶囊或软胶囊中。用于制备本发明化合物及其药学上可接受的盐片剂的各稀释剂、粘合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物及其药学上可接受的盐的胶囊剂。
为将本发明化合物及其药学上可接受的盐制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等,pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其他添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明提供了一种异吲哚啉酮衍生物的制备方法,包括步骤:
在惰性溶剂中(如甲苯、二甲苯、苯、DMF、乙腈、四氢呋喃等),将邻苯二甲酰亚胺和劳森试剂反应得到化合物2,化合物2和卤代丙二酸酯经过Eschenmoser偶联反应得到化合物3,化合物3经亲核取代反应得到异吲哚啉酮衍生物。
式中,Ra、Rb和Rc定义同前。
下面结合具体实施例对本发明进行详细说明,但绝不是对本发明的限制。本技术方案中如未明确说明的制备手段、材料、结构或组成配比等特征,均视为现有技术中公开的常见技术特征。
实施例1
中间体2的制备
在50mL的圆底烧瓶中加入邻苯二甲酰亚胺(5mmol,736mg),劳森试剂(2mmol,809mg)和20mL甲苯,80℃油浴下搅拌24小时,TLC点板跟踪反应过程。反应结束后,旋转蒸发除去溶剂,加入15mL饱和食盐水,用乙酸乙酯(3×15mL)萃取,合并萃取液,用无水硫酸镁干燥,旋转蒸发除去溶剂,粗产物通过柱层析(石油醚/乙酸乙酯)纯化分离后得到粉色固体3204mg,产率25%。1H NMR(400MHz,CDCl3)δ10.05(s,1H),7.79(J=7.4,1.5Hz,1H),7.66(dd,J=7.4,1.5Hz,1H),7.54(m,J=7.4,1.6Hz,1H),7.45(m,J=7.4,1.6Hz,1H);MS(GC-MS):m/z 163.1(M+).绿色固体4 358mg,产率40%。1H NMR(500MHz,CDCl3)δ10.03(s,1H),7.87(m,J=5.6,3.4Hz,2H),7.54(m,J=5.6,3.5Hz,2H);MS(GC-MS):m/z 179.0(M+).
中间体3的制备
在25mL圆底烧瓶中加入2,3-二氢-3-硫代-1H-异吲哚啉-1-酮(2mmol,326mg),溴丙二酸二甲酯(2mmol,264mg),无水碳酸钾(20mmol,2.469g)和10mL无水四氢呋喃,60℃油浴下搅拌6小时,TLC点板跟踪反应过程。反应结束后,旋转蒸发除去溶剂,加入10mL饱和食盐水,用乙酸乙酯(3×10mL)萃取,合并萃取液,用无水硫酸镁干燥,旋转蒸发除去溶剂,粗产物通过柱层析(石油醚/乙酸乙酯)纯化分离后得到黄色固体496mg,产率95%。1HNMR(400MHz,CDCl3)δ10.05(s,1H),7.90(dd,J=5.0,3.3Hz,1H),7.69–7.59(m,2H),7.55(dt,J=5.0,3.1Hz,1H),3.98(s,3H),3.86(s,3H);MS(GC-MS):m/z261.1(M+).
目标产物B1的制备
在10mL的圆底烧瓶中加入2-(2,3-二氢-3-氧代-1H-异吲哚-1-亚基)丙二酸二甲酯(0.3mmol,78mg),溴化苄(0.225mmol,39mg),无水碳酸钾(0.225mmol,31mg)和3mL无水乙腈。启动搅拌,将反应液加热至回流后,继续保持回流3小时,TLC点板跟踪反应过程。反应结束后,旋转蒸发除去溶剂,加入5mL饱和食盐水,用乙酸乙酯(3×5mL)萃取,合并萃取液,用无水硫酸镁干燥,旋转蒸发除去溶剂,粗产物通过柱层析(石油醚/乙酸乙酯)纯化分离后得到黄色固体53mg,产率67%,m.p.133.2。1H NMR(400MHz,CDCl3)δ7.94(dd,J=5.8,2.8Hz,1H),7.71–7.65(m,1H),7.64–7.57(m,2H),7.31–7.21(m,3H),7.04(d,J=7.1Hz,2H),5.26(s,2H),3.85(s,3H),3.51(s,3H).13C NMR(101MHz,CDCl3)δ168.24,165.90,164.24,144.41,135.38,135.36,133.24,131.51,128.49(2C),128.43,127.38,126.47(2C),124.45,124.14,107.02,53.14,52.63,45.09;HRMS(EI)calcd for C20H17NO5[M]+351.1107,found 351.1111.
实施例2
目标产物B2的制备
在10mL的圆底烧瓶中加入2-(2,3-二氢-3-氧代-1H-异吲哚-1-亚基)丙二酸二甲酯(0.3mmol,78mg),4-甲基溴苄(0.225mmol,42mg),无水碳酸钾(0.225mmol,31mg)和3mL无水乙腈。启动搅拌,将反应液加热至回流后,继续保持回流3小时,TLC点板跟踪反应过程。反应结束后,旋转蒸发除去溶剂,加入5mL饱和食盐水,用乙酸乙酯(3×5mL)萃取,合并萃取液,用无水硫酸镁干燥,旋转蒸发除去溶剂,粗产物通过柱层析(石油醚/乙酸乙酯)纯化分离后得到白色固体50mg,产率61%,m.p.144.2℃。1H NMR(400MHz,CDCl3)δ7.99–7.92(m,1H),7.75–7.68(m,1H),7.67–7.60(m,2H),7.54(d,J=8.1Hz,2H),7.19(d,J=8.0Hz,2H),5.30(s,2H),3.87(s,3H),3.49(s,3H).13CNMR(101MHz,CDCl3)δ168.28,165.96,164.25,144.54,136.98,135.42,133.19,132.26,131.47,129.18(2C),128.49,126.46(2C),124.41,124.10,106.90,53.13,52.65,44.84,21.11;HRMS(EI)calcd for C21H19NO5[M]+365.1263,found 365.1258.
实施例3
目标产物B3的制备
在10mL的圆底烧瓶中加入2-(2,3-二氢-3-氧代-1H-异吲哚-1-亚基)丙二酸二甲酯(0.3mmol,78mg),3-甲基溴苄(0.225mmol,42mg),无水碳酸钾(0.225mmol,31mg)和3mL无水乙腈。启动搅拌,将反应液加热至回流后,继续保持回流3小时,TLC点板跟踪反应过程。反应结束后,旋转蒸发除去溶剂,加入5mL饱和食盐水,用乙酸乙酯(3×5mL)萃取,合并萃取液,用无水硫酸镁干燥,旋转蒸发除去溶剂,粗产物通过柱层析(石油醚/乙酸乙酯)纯化分离后得到黄色固体74mg,产率90%,m.p.125.5℃。1H NMR(400MHz,CDCl3)δ7.97–7.90(m,1H),7.67(ddt,J=8.1,5.5,2.4Hz,1H),7.64–7.57(m,2H),7.15(t,J=7.6Hz,1H),7.02(d,J=7.5Hz,1H),6.85(s,1H),6.82(d,J=7.7Hz,1H),5.21(s,2H),3.85(s,3H),3.52(s,3H),2.28(s,3H).13C NMR(101MHz,CDCl3)δ168.27,165.94,164.23,144.49,138.07,135.42,135.26,133.21,131.47,128.47,128.39,128.15,127.26,124.42,124.14,123.57,106.94,53.13,52.61,45.05,21.41;HRMS(EI)calcd for C21H19NO5[M]+365.1263,found 365.1261.
实施例4
目标产物B4的制备
在10mL的圆底烧瓶中加入2-(2,3-二氢-3-氧代-1H-异吲哚-1-亚基)丙二酸二甲酯(0.3mmol,78mg),4-(三氟甲基)苄溴(0.225mmol,54mg),无水碳酸钾(0.225mmol,31mg)和3mL无水乙腈。启动搅拌,将反应液加热至回流后,继续保持回流3小时,TLC点板跟踪反应过程。反应结束后,旋转蒸发除去溶剂,加入5mL饱和食盐水,用乙酸乙酯(3×5mL)萃取,合并萃取液,用无水硫酸镁干燥,旋转蒸发除去溶剂,粗产物通过柱层析(石油醚/乙酸乙酯)纯化分离后得到黄色固体89mg,产率91%,m.p.120.8℃。1H NMR(400MHz,CDCl3)δ7.99–7.92(m,1H),7.75–7.68(m,1H),7.67–7.60(m,2H),7.54(d,J=8.1Hz,2H),7.19(d,J=8.0Hz,2H),5.30(s,2H),3.87(s,3H),3.49(s,3H).13C NMR(101MHz,CDCl3)δ168.09,165.71,164.20,144.29,139.79,135.23,133.46(2C),131.72(2C),129.69(q,J=32.5Hz),128.21,126.76,125.48(q,J=3.7Hz),124.59,124.26,123.99(q,J=272.0Hz),107.04,53.24,52.68,44.89;HRMS(EI)calcd for C21H16F3NO5[M]+419.0981,found 419.0977.
实施例5~22
参照实施例1-4所述方法,采用不同的起始原来制备如下所示的异吲哚啉酮衍生物。
1H NMR(400MHz,CDCl3)δ8.03–7.92(m,1H),7.70–7.62(m,3H),7.55(d,J=7.7Hz,1H),7.40(dd,J=14.2,6.4Hz,2H),7.30(d,J=7.9Hz,1H),5.27(s,2H),3.87(s,3H),3.57(s,3H).13C NMR(101MHz,CDCl3)δ168.11,165.66,164.09,144.30,137.42,135.23,133.59,131.84,131.22,131.02,130.30,129.43,128.05,124.53,124.35,118.46,112.65,106.92,53.29,52.81,44.62;HRMS(EI)calcd for C21H16N2O5[M]+376.1059,found 376.1061.
1H NMR(400MHz,CDCl3)δ8.12(d,J=8.1Hz,1H),8.02–7.93(m,2H),7.70–7.61(m,3H),7.48(t,J=7.9Hz,1H),7.39(d,J=7.8Hz,1H),5.34(s,2H),3.86(s,3H),3.59(s,3H).13C NMR(101MHz,CDCl3)δ168.17,165.69,164.12,148.26,144.43,138.05,135.28,133.62,132.75,131.85,129.68,128.05,124.50,124.39,122.68,121.94,106.91,53.29,52.91,44.70;HRMS(EI)calcd for C20H16N2O7[M]+396.0958,found396.0955.
1H NMR(400 MHz,CDCl3)δ8.16(d,J=8.8 Hz,2H),8.00–7.93(m,1H),7.74–7.62(m,3H),7.24(d,J=8.8 Hz,2H),5.34(s,2H),3.88(s,3H),3.53(s,3H).13C NMR(101 MHz,CDCl3)δ168.04,165.61,164.06,147.24,144.37,143.36,135.18,133.64,131.88,128.02,127.29(2C),124.58,124.34,123.76(2C),106.97,53.31,52.83,44.97;HRMS(EI)calcd for C20H16N2O7[M]+396.0958,found 396.0954.
1H NMR(400 MHz,CDCl3)δ8.00–7.90(m,1H),7.70–7.60(m,3H),7.50(d,J=7.8 Hz,1H),7.39(dd,J=14.5,6.7 Hz,2H),7.19(d,J=7.7 Hz,1H),5.31(s,2H),3.85(s,3H),3.51(s,3H).13C NMR(101 MHz,CDCl3)δ168.18,165.76,164.13,144.29,136.68,135.31,133.47,131.71,130.80(q,J=32.2Hz),129.74,129.17,128.16,124.46,124.36(q,J=4.0 Hz),124.31,123.94(q,J=272.3 Hz),123.69(q,J=3.6 Hz),107.06,53.22,52.67,44.84;HRMS(EI)calcd forC21H16F3NO5[M]+419.0981,found419.0983./>
1H NMR(400 MHz,CDCl3)δ7.96–7.89(m,1H),7.69–7.56(m,3H),6.96(d,J=8.7 Hz,2H),6.79(d,J=8.7 Hz,2H),5.18(s,2H),3.85(s,3H),3.75(s,3H),3.59(s,3H).13C NMR(101 MHz,CDCl3)δ168.30,165.99,164.23,158.84,144.51,135.43,133.20,131.47,128.47,127.86(2C),127.29,124.35,124.08,113.91(2C),106.89,55.20,53.14,52.68,44.50;HRMS(EI)calcd forC21H19NO6[M]+381.1212,found381.1210.
1H NMR(400 MHz,CDCl3)δ7.95(p,J=3.6 Hz,1H),7.73–7.63(m,3H),7.59(d,J=8.1 Hz,2H),7.18(d,J=8.1 Hz,2H),5.30(s,2H),3.88(s,3H),3.51(s,3H).13C NMR(101 MHz,CDCl3)δ168.06,165.64,164.09,144.32,141.30,135.19,133.59,132.33(2C),131.84,128.07,127.18(2C),124.59,124.34,118.57,111.37,107.01,53.31,52.78,45.09;HRMS(EI)calcd for C21H16NO5[M]+376.1059,found376.1062.
1H NMR(400 MHz,CDCl3)δ7.98(dd,J=5.3,2.4Hz,1H),7.82–7.71(m,3H),7.70–7.59(m,3H),7.50(s,1H),7.44(dd,J=6.2,3.2 Hz,2H),7.15(d,J=8.5 Hz,1H),5.42(s,2H),3.81(s,3H),3.43(s,3H).13CNMR(101 MHz,DMSO)δ163.07,160.63,159.02,139.22,130.21,128.04,127.94,127.69,127.47,126.30,123.23,123.19,122.49,122.39,121.02,120.64,120.38,119.20,119.11,118.95,101.80,47.86,47.30,40.06.;HRMS(EI)calcd forC24H19NO5[M]+401.1263,found 401.1266./>
1H NMR(400 MHz,CDCl3)δ7.88(dt,J=4.5,3.3 Hz,1H),7.68(dt,J=5.6,3.5 Hz,1H),7.62–7.55(m,2H),5.69(ddt,J=17.0,10.6,5.4 Hz,1H),5.20–5.09(m,2H),4.63(d,J=5.4 Hz,2H),3.93(s,3H),3.82(s,3H).13CNMR(101 MHz,CDCl3)δ167.87,166.12,164.50,145.05,135.33,133.13,131.96,131.46,128.57,124.32,123.95,117.66,106.26,53.20,52.90,44.00;HRMS(EI)calcd for C16H15NO5[M]+301.0950,found301.0953.
1H NMR(400 MHz,CDCl3)δ7.99–7.90(m,1H),7.67(dt,J=7.9,3.3 Hz,1H),7.63–7.55(m,2H),7.18(t,J=7.9 Hz,1H),6.75(dd,J=8.2,2.0 Hz,1H),6.62(d,J=7.6 Hz,1H),6.58(s,1H),5.23(s,2H),3.85(s,3H),3.73(s,3H),3.54(s,3H).13C NMR(101 MHz,CDCl3)δ168.18,165.90,164.22,159.74,144.42,137.01,135.37,133.23,131.49,129.55,128.39,124.42,124.13,118.81,112.61,112.48,106.99,55.18,53.12,52.65,45.01;HRMS(EI)calcd forC21H19NO6[M]+381.1212,found 381.1210.
1H NMR(400 MHz,CDCl3)δ8.16–8.09(m,1H),8.00–7.94(m,1H),7.82(dt,J=5.8,3.6 Hz,1H),7.69–7.63(m,2H),7.59–7.52(m,1H),7.44(t,J=7.7Hz,1H),7.11(d,J=7.7 Hz,1H),5.49(s,2H),3.88(s,3H),3.46(s,3H).13C NMR(151 MHz,CDCl3)δ163.46,160.76,159.43,142.95,139.84,130.36,129.03,128.84,127.50,127.12,123.50,123.32,122.80,120.37,120.31,119.52,102.28,48.50,48.06,39.31;HRMS(EI)calcd for C20H16N2O7[M]+396.0958,found 396.0961./>
1H NMR(400 MHz,CDCl3)δ8.97(dd,J=4.2,1.7 Hz,1H),8.65(d,J=7.7 Hz,1H),8.14(dd,J=8.3,1.6 Hz,1H),8.04(d,J=6.3 Hz,1H),7.77–7.71(m,1H),7.52–7.46(m,1H),7.46–7.40(m,2H),7.40–7.35(m,2H),5.24(s,2H),4.05(s,3H),3.92(s,3H).13C NMR(101 MHz,CDCl3)δ178.47,166.48,164.33,158.49,149.69,146.26,139.74,136.42,136.39,135.59,130.88,130.75,130.60,128.42,127.90,127.51,126.41,121.27,120.14,119.27,52.78,52.59,30.63;HRMS(EI)calcd for C23H18N2O5[M]+402.1216,found 402.1210.
1H NMR(400 MHz,CDCl3)δ7.97–7.91(m,1H),7.80–7.74(m,1H),7.64–7.59(m,2H),7.47(t,J=7.7 Hz,1H),7.00(d,J=7.6 Hz,1H),6.79(d,J=7.7Hz,1H),5.26(s,2H),3.86(s,3H),3.58(s,3H),2.49(s,3H).13C NMR(101 MHz,CDCl3)δ168.29,165.79,164.34,157.93,154.83,145.01,136.81,135.41,133.22,131.47,128.56,124.71,124.03,121.70,117.42,106.92,53.07,52.82,47.11,24.29;HRMS(EI)calcd forC20H18N2O5[M]+366.1216,found366.1219.
1H NMR(400 MHz,CDCl3)δ7.91(dd,J=5.8,2.4 Hz,1H),7.65(dt,J=7.5,3.2 Hz,1H),7.59(dd,J=5.6,3.2 Hz,2H),7.23(dd,J=5.0,3.0 Hz,1H),6.96(d,J=2.7 Hz,1H),6.87–6.79(m,1H),5.25(s,2H),3.87(s,3H),3.64(s,3H).13C NMR(151 MHz,CDCl3)δ163.29,161.25,159.58,139.67,131.55,130.65,128.50,126.77,123.70,121.71,121.70,121.46,119.62,119.35,117.32,102.01,60.28,48.45,48.14,48.03,36.36,28.77;HRMS(EI)calcd for C18H15NO5S[M]+357.0671,found 357.0674./>
1H NMR(400 MHz,CDCl3)δ7.99–7.91(m,1H),7.88–7.80(m,1H),7.70–7.60(m,3H),7.45(t,J=7.5 Hz,1H),7.36(t,J=7.5 Hz,1H),7.02(d,J=7.8Hz,1H),5.32(s,2H),3.90(s,3H),3.41(s,3H).13C NMR(101 MHz,CDCl3)δ168.08,165.63,164.12,145.08,135.19,134.23,133.46,132.06,131.75,128.34,127.07,126.79(q,J=31.1 Hz),126.09,126.03(q,J=3.7 Hz),125.00,124.16,121.63(q,J=274.2 Hz),106.97,53.21,52.56,43.21(q,J=3.8 Hz);HRMS(EI)calcd for C21H16F3NO5[M]+419.0981,found 419.0986.
1H NMR(400 MHz,CDCl3)δ7.98–7.90(m,1H),7.81–7.72(m,1H),7.67–7.58(m,2H),7.11(dt,J=12.9,4.7 Hz,3H),6.77(d,J=7.0Hz,1H),5.17(s,2H),3.86(s,3H),3.27(s,3H),2.32(s,3H).13C NMR(101 MHz,CDCl3)δ168.09,165.74,164.20,144.29,135.20,135.02,133.19,132.90,131.48,130.20,128.53,127.05,126.08,124.97,124.71,124.07,107.15,53.12,52.27,43.51,19.05;HRMS(EI)calcd for C21H19NO5[M]+365.1263,found 365.1260.
1H NMR(400 MHz,CDCl3)δ7.93(dd,J=5.6,2.5Hz,1H),7.68(dd,J=5.8,2.6 Hz,1H),7.65–7.56(m,2H),7.25(d,J=8.5 Hz,2H),6.99(d,J=8.5Hz,2H),5.22(s,2H),3.86(s,3H),3.55(s,3H).13C NMR(101MHz,CDCl3)δ168.14,165.80,164.17,144.33,135.31,134.04,133.36,133.18,131.62,128.68(2C),128.28,127.91(2C),124.47,124.19,106.99,53.20,52.71,44.56;HRMS(EI)calcd forC20H16 35ClNO5[M]+385.0701,found 385.0717./>
1H NMR(400MHz,CDCl3)δ8.10(dd,J=6.5,1.8Hz,1H),7.97(dd,J=6.1,2.3Hz,1H),7.72–7.64(m,2H),7.49(t,J=7.6Hz,2H),7.40(t,J=7.4Hz,1H),7.33(s,2H),3.92(s,3H),3.13(s,3H).13C NMR(151MHz,CDCl3)δ167.20,165.56,164.30,146.97,134.99,133.55,131.92,128.97(2C),128.57,128.30(2C),128.06,125.53,107.36,53.07,52.16;HRMS(EI)calcd for C19H15NO5[M]+337.0950,found 337.0947.
1H NMR(400MHz,CDCl3)δ8.08(dd,J=6.3,1.9Hz,1H),7.96–7.91(m,1H),7.69–7.61(m,2H),7.35(t,J=7.7Hz,1H),7.18(d,J=7.6Hz,1H),7.12(d,J=11.1Hz,2H),3.90(s,3H),3.12(s,3H),2.39(s,3H).13C NMR(151MHz,CDCl3)δ167.21,165.58,164.33,146.99,138.91,134.87,134.73,133.48,131.86,128.78,128.63,128.57,128.49,125.55,125.19,124.14,107.34,53.04,52.05,21.27;HRMS(EI)calcd forC20H17NO5[M]+351.1107,found 351.1104.
验证例1
本发明化合物的抗肿瘤活性测试
1.实验原理
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(Formazan)并沉积在细胞中,而死细胞无此功能。二甲基亚砜(DMSO),其作用是能够溶解细胞中甲瓒,用酶标仪测定其光吸收值就可反映活细胞数量。
2.抗肿瘤活性实验
试样:实施例化合物
细胞系:肝癌细胞系HepG2和肺癌细胞系A549
试剂:0.5%MTT溶液,RPMI 1640培养液、新生牛血清;胰酶;96孔培养板;二甲基亚砜;
仪器:超净台、培养箱、Perkin Elmer全自动多功能酶标仪
实验步骤:
1)将指数生长期的HepG2和A549细胞(2×10 5个/mL)接种到96孔板上培养过夜,然后用设定浓度的药物处理细胞。
2)药物处理24小时后,向每个孔中加入20μL MTT试剂(5mg/mL)。5%CO2,37℃孵育4小时后,吸出培养基的上清液,向每个孔中加入150μLDMSO溶解甲瓒晶体。
3)采用双波长法测定,通过酶标仪测定在492和630nm的吸光度。
3.抗肿瘤活性评价
1)细胞活力抑制率计算
细胞活力抑制率=[1-加药(OD492-OD630)/对照(OD492-OD630)]×100(%)
2)IC50值计算
试样浓度与细胞抑制率线性回归,利用软件计算试样对细胞的半数抑制浓度IC50值。
表1细胞活力抑制IC50值
由表1可以看出,对于HepG2细胞和A549细胞,22个化合物的IC50值均低于10μM;并且,对于HepG2细胞,有16个化合物表现出了优于阳性对照阿霉素的活性;对于A549细胞,有20个化合物表现出了优于阳性对照阿霉素的活性。可见,该类结构新颖的异吲哚啉酮衍生物具有优异的抗癌活性。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
1.一种异吲哚啉酮衍生物,其特征在于,所述的衍生物为式I化合物或式I化合物药学上可接受的盐:
其中:
Ra为取代的或未取代的芳基、取代的或未取代的C1~C6烷基中的一种;
Rb、Rc为取代的或未取代的C1~C6烷基中的一种。
2.根据权利要求1所述的一种异吲哚啉酮衍生物,其特征在于,所述Ra中,取代的芳基为一个或多个取代基取代的芳基,取代的C1~C6烷基为一个或多个取代基取代的C1~C6烷基;
所述Rb和Rc中,取代的C1~C6烷基为一个或多个取代基取代的C1~C6烷基,所述取代基选自卤素、氰基、硝基、三氟甲基、芳基、取代芳基、杂环芳基、取代杂环芳基、C1~C6烷基、C1~C6烷氧基中的一种。
3.根据权利要求1所述的一种异吲哚啉酮衍生物,其特征在于,所述Rb和Rc中,取代芳基为一个或多个取代基取代的芳基,所述的取代芳基中的取代基选自卤素、氰基、硝基、三氟甲基、C1~C6烷基或C1~C6烷氧基;
所述Rb和Rc中,取代杂环芳基为一个或多个取代基取代的杂环芳基,其中的取代基选自C1~C6烷基;
所述Rb和Rc中,芳基选自苯基或萘基中的一种;
所述Rb和Rc中,杂环芳基选自呋喃基、噻吩基、吡啶基或喹啉基中的一种。
4.根据权利要求1所述的一种异吲哚啉酮衍生物,其特征在于,所述异吲哚啉酮衍生物选自B1~B22中的一种:
5.一种如权利要求1至4中任意一项所述的异吲哚啉酮衍生物的制备方法,其特征在于,包括以下步骤:
在惰性溶剂中,将邻苯二甲酰亚胺和劳森试剂反应得到化合物2,化合物2和卤代丙二酸二酯经过Eschenmoser偶联反应得到化合物3,化合物3经亲核取代反应得到异吲哚啉酮衍生物:
6.一种如权利要求1至4中任意一项所述的异吲哚啉酮衍生物的应用,其特征在于,所述异吲哚啉酮衍生物用于制备抗肿瘤药物。
7.一种抗肿瘤药物组合物,其特征在于,该药物组合物含有如权利要求1至4中任意一项所述异吲哚啉酮衍生物。
8.根据权利要求7所述的抗肿瘤药物组合物,其特征在于,所述药物组合物包括一种或多种所述的异吲哚啉酮衍生物,以及药学上可接受的载体介质和/或赋形剂。
9.根据权利要求7所述的抗肿瘤药物组合物,其特征在于,所述的异吲哚啉酮衍生物在组合物中的质量百分含量为0.001-99.99%。
10.一种如权利要求7所述抗肿瘤药物组合物的应用,其特征在于,所述的组合物用于制备抗肿瘤药物。
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