CN113620890A - 苯并喹喔啉酮化合物及其合成方法和用途 - Google Patents
苯并喹喔啉酮化合物及其合成方法和用途 Download PDFInfo
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- CN113620890A CN113620890A CN202010615740.1A CN202010615740A CN113620890A CN 113620890 A CN113620890 A CN 113620890A CN 202010615740 A CN202010615740 A CN 202010615740A CN 113620890 A CN113620890 A CN 113620890A
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- Prior art keywords
- quinoxalin
- dihydrobenzo
- oxy
- oxo
- ethyl
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- LRSIAADTOWRQHP-UHFFFAOYSA-N 1h-benzo[h]quinoxalin-2-one Chemical class C1=CC=CC2=C(NC(=O)C=N3)C3=CC=C21 LRSIAADTOWRQHP-UHFFFAOYSA-N 0.000 title abstract description 9
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Abstract
本发明公开了一系列苯并喹喔啉酮化合物及其合成方法和应用,具体涉及式(I)的化合物及其合成方法和其在用于治疗癌症中的用途
Description
技术领域
本发明涉及药物化合物和药物技术领域,具体涉及苯并喹喔啉酮化合物及其合成方法和用途。
背景技术
喹喔啉酮类化合物是一类由芳香环苯环和吡嗪稠合而成的含氮杂环化合物,是一类具有重要应用价值的杂环化合物,具有多种生物活性,可作为抗肿瘤剂、HIV-1逆转录酶抑制剂、N-甲基-D-天(门)冬氨酸受体拮抗剂、抗(真)菌剂、抗凝血剂、降血糖剂等。除此以外,喹喔啉酮化合物的衍生物在染料、荧光材料、有机光电(OPV)细胞中的半导体、杀虫剂、除草剂和驱虫药等方面同样具有广泛的应用。因此,此类化合物在药物化学的研究中意义重大,但目前尚未见在苯并喹喔啉酮引入长链酸酯或长链酰胺官能团、及这类化合物在抗肿瘤方面应用的公开报道。因此,对苯并喹喔啉酮引入长链酸酯或长链酰胺官能团进行深入研究,有助于拓展此类化合物在药物研究领域的更广泛的应用,对开发新的治疗药物具有十分重要的意义。
目前,基于表观遗传学研究的抗肿瘤药物越来越受到研发人员的青睐和重视。表观遗变化与肿瘤的发生发展关系紧密。所谓表观遗传修饰是指不依赖于DNA序列变化而实现对基因表达造成可遗传的调控机制,其核心是染色质重塑。通过对染色质的基本单位——核小体的修饰,可将染色质调整为相对“开放”或“封闭”的结构。核小体由DNA和组蛋白组成,组蛋白的氨基酸残基能被多种生物过程修饰,如乙酰化、甲基化、磷酸化、泛素化、poly-ADP核酸糖小体化等等。通过特定的修饰,染色质“开启”或“关闭”基因的表达,从而沉默或激活肿瘤抑制基因,导致细胞增殖阻滞和凋亡诱导。
甲基化和乙酰化是表观遗传学抗肿瘤治疗策略研究的2个主要方向。甲基化是通过DNA甲基转移酶的作用,向特定的DNA序列读写框上添加甲基,从而沉默下游基团。乙酰化是通过组蛋白乙酰转移酶(histone acetyltransferases,HATs)和组蛋白去乙酰化酶(histone deacetylases,HDACs)的共同作用,向组蛋白上添加或者移除乙酰基。HATs可添加乙酰基,导致组蛋白结构“松弛”,以利于转录的启动;HDACs则是移除乙酰基,导致组蛋白结构的相对“致密”,从而抑制了相关基因的转录活性。
普遍认同的是,广义的表观遗传干扰可通过激活肿瘤基因,丢弃DNA印迹,破坏基因稳定性等作用与肿瘤基因学紧密相关联。研究发现,恶性肿瘤组织中,较正常组织中带有更多异常的表观遗传修饰。同时,随着恶性程度的加深,异常表观遗传修饰的程度也在加深。诸多文献报道,组蛋白的乙酰化状态是肿瘤的生成及演变的重要特征之一,研究发现,与正常细胞及组织相比,众多肿瘤细胞及组织中呈现出组蛋白乙酰化明显偏低的状态,而组蛋白去乙酰化没呈现出明显的过表达状态。近年来研究显示,在以试图恢复表观遗传常态肿瘤治疗研究中,组蛋白去乙酰化酶显示出作为有效药物靶点的极高潜力。研究人员开发了HDAC抑制剂,通过上调组蛋白的乙酰化程度,显示出卓越的抗肿瘤活性和肿瘤选择性,提示开发HDAC抑制剂具有良好的应用前景,同时为提供肿瘤的诊断和防治新的标记物,开发高效低毒的新先导结构、创新药物,开辟了新的思路。
HDAC酶的亚型有四类一共18种:第I类HDAC(包括HDAC1、HDAC2、HDAC3和HDAC8),第II类HDAC(包括HDAC4、HDAC5、HDAC6、HDAC7、HDAC9和HDAC10),第III类HDAC(包括SIRT1-7),第IV类HDAC(HDAC11)。HDAC抑制剂有羟肟酸类、环肽类、苯酰胺类、短链脂肪酸类、其他类。其中,羟肟酸类HDAC抑制剂的代表性化合物为SAHA(Vorinostat,商品名:Zolinza),是首个被FDA批准的HDAC抑制剂(2006年)。目前临床尚无以苯并喹喔啉酮长链酸酯或长链酰胺作为HDAC抑制剂的抗肿瘤药物,因此,开发苯并喹喔啉酮长链酸酯或长链酰胺可以拓展HDAC的范围,开辟肿瘤治疗新药物。
发明内容
根据本发明的一个方面,提供了具有式(I)结构的化合物或其药学上可接受的盐:
其中
R独立地选自氢、卤素、羟基、巯基、C1~C6烷基(烯基/炔基)、卤代C1~C6烷基(烯基/炔基)、取代的羟基C1~C6烷基(烯基/炔基)、任选取代的氨基C1~C6烷基(烯基/炔基)、取代的酰胺基C1~C6烷基(烯基/炔基)、取代的羧基C1~C6烷基(烯基/炔基)、C1~C6烷氧基、苄基或其取代衍生物、苯基或其取代基、和五元或六元杂环甲基或其取代的衍生物;
R1为羟基或C1~C6烷基;
R2为氢、C2~C6酰基或C5~C10芳基甲酰基;
各个R3独立的选自氢、卤素、羟基、羧基、巯基、C1-C6烃硫基、C1-C6烷基(烯基/炔基)、卤代C1~C6烷基(烯基/炔基)、羟基取代的C1~C6烷基(烯基/炔基)、氨基取代的C1~C6烷基(烯基/炔基)、酰胺基取代的C1~C6烷基(烯基/炔基)、羧基取代的C1~C6烷基(烯基/炔基)、C1~C6烷氧基;
m选自1、2、3或4的整数;
X为O或NH;
A为(CH2)n,n选自0、1、2、3、4、5、6或7的整数;
B为O或CH2;
和C为CH2、CH=CH或者为下式(2I)所示的基团,
其中
各个R4独立的选自氢、卤素、羟基、羧基、巯基、C1-C6烃硫基、C1-C6烷基(烯基/炔基)、卤代C1~C6烷基(烯基/炔基)、羟基取代的C1~C6烷基(烯基/炔基)、氨基取代的C1~C6烷基(烯基/炔基)、酰胺基取代的C1~C6烷基(烯基/炔基)、羧基取代的C1~C6烷基(烯基/炔基)、和C1~C6烷氧基;
s为选自1、2、3或4的整数;t为选自0、1、2或3的整数;u为选自0、1或2的整数;虚线的键可存在或不存在,若虚线存在,表示为双键,则(2I)的构型为E式或Z式,若虚线不存在,则表示虚线处的键也不存在,苯环直接与(CH2)t连接。
在本发明的一个实施方案中,其中所述各个R3均为氢。
在本发明的一个实施方案中,当R1为羟基时,X为NH,R2为氢;当R1为C1~C6烷基时,X为O,其中C1~C6烷基为甲基或乙基,R2为氢或乙酰基。
在本发明的一个实施方案中,R为异丙基、苄基、邻甲基苄基。
根据本发明的另一个方面,提供了选自以下化合物或其药学上可接受的盐:
4-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酸乙酯;
5-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯;
6-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酸乙酯;
8-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酸乙酯;
4-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酸乙酯;
5-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯;
6-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酸乙酯;
7-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)庚酸乙酯;
8-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酸乙酯;
4-((4-乙酰基-2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酸乙酯;
5-((4-乙酰基-2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯;
7-((4-乙酰基-2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)庚酸乙酯;
4-(((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)甲基)苯甲酸乙酯;
(E)-4-(((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-2-丁烯酸乙酯;
(E)-3-(4-(3-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丙氧基)苯基)丙烯酸甲酯;
(E)-4-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-2-丁烯酸乙酯;
4-(((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)甲基)苯甲酸乙酯;
5-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯;
6-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酸乙酯;
8-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酸乙酯;
4-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基丁酰胺;
8-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基辛酰胺;
N-羟基-4-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酰胺;
N-羟基-5-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酰胺;
N-羟基-6-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酰胺;
N-羟基-8-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酰胺;
N-羟基-(E)-3-(4-(4-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁氧基)苯基)丙烯酰胺(Ib-7);
N-羟基-5-((2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酰胺;
N-羟基-6-((2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酰胺;
7-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基庚酰胺;
5-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基戊酰胺;
6-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基己酰胺;
4-(((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)甲基)-N-羟基苯甲酰胺;
N-羟基-7-((2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)庚酰胺。
“药学上可接受的盐”是指对所施用的生物体不产生显著刺激并且不破坏化合物的生物活性和性质的化合物的盐。能通过使化合物与无机酸反应获得药物盐,所述无机酸例如氢卤酸(例如,氢氯酸或氢溴酸)、硫酸、硝酸和磷酸。能通过使化合物与有机酸反应获得药物盐,所述有机酸例如脂肪族或芳香族的羧酸或磺酸,例如甲酸、乙酸、琥珀酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、烟酸、甲烷磺酸、乙烷磺酸、对甲苯磺酸、水杨酸或萘磺酸。还能通过使化合物与碱反应以形成盐来获得药物盐,例如铵盐、诸如钠盐或钾盐的碱金属盐、诸如钙盐或镁盐的碱土金属盐、诸如二环己基胺、N-甲基-D-葡糖胺、三(羟基甲基)甲基胺、C1-C7烷基胺、环己基胺、三乙醇胺、乙二胺的有机碱盐和与诸如精氨酸和赖氨酸的氨基酸的盐。
本发明的化合物中存在几何构型(Z式及E式),各异构体及它们的混合物也包括在本发明中。
本发明的化合物中存在具有手性碳的化合物,各旋光异构体及它们的外消旋体中的任一种也包括在本发明中。旋光异构体由以上所得的外消旋体利用其碱性,采用具有光学活性的酸(酒石酸、二苯甲酰酒石酸、苦杏仁酸、10-樟脑磺酸等)通过公知的方法进行光纤离析而获得,或者将预先调制的具有光学活性的化合物用作原料而制得。
根据本发明的另一个方面,提供了合成式(I)化合物的方法,所述合成方法包括如下所示的步骤:
当R1为C1~C6烷基时,X为O,式(I)化合物为式(Ia)化合物,合成方法包括如下步骤(a)~(e):
或当R1为羟基时,X为NH,R2’除不包括氢外,其余定义与R2一致,式(I)化合物为式(Ib)化合物,合成方法包括如下步骤(a)~(f):
(a)使氨基萘醌与BOC-氨基酸反应,其中BOC-指叔丁氧羰基;
(b)使步骤(a)得到的产物环合;
(c)使步骤(b)得到的产物与酸酐R2’-O-R2’反应;
(d)使步骤(c)得到的产物与卤代酯(即化合物(II))反应得到目标产物Ia,其中化合物(II)中Y为Cl、Br或I;
(e)使步骤(e)得到的产物与羟胺的碱金属盐NH2OM反应后酸化得到目标产物Ib,所述M为Li、Na或K;
其中R、R1、R2、R3、A、B、C和m如上文所述;
合成化合物(Ia)和化合物(Ib)的步骤(a)~(d)是相同的;
当合成化合物(Ia)时,若R2为氢,则无步骤(c),直接经步骤(b)得到的产物与卤代酯(即化合物(II))反应得到目标产物Ia;
当合成化合物(Ia)时,若R2不是氢,则按照上述步骤(a)~步骤(d)得到化合物(Ia)。
所述合成化合物(Ia)和(Ib)的方法,其中:
步骤(a)的反应条件为在催化剂1-羟基苯并三唑和缩合剂1-(3-二甲氨基丙基)-3-乙基碳二亚盐酸盐存在的条件下,在-10~40℃下、优选-5~30℃在溶剂二氯甲烷、乙腈、四氢呋喃、N,N-二甲基甲酰胺等非质子极性溶剂中反应12~24小时,优选16~20小时;
步骤(b)的反应条件为在三氟乙酸存在下在10~35℃下进行环合反应;
步骤(c)的反应条件为在催化剂碱存在下,包括三乙胺、吡啶、N,N二异丙基乙胺、甲醇钠、甲醇钾、乙醇钠、乙醇钾、碳酸钾、碳酸钠、碳酸氢钠和碳酸氢钾等有机碱和无机碱,在40~100℃、优选60~80℃条件下反应2~5小时;
步骤(d)的反应条件为在碱存在下,包括有机碱和无机碱的存在下反应;
步骤(e)反应条件在20~30℃下、反应20分钟~2小时、优选反应30分钟~1小时后进行酸化。
根据本发明的另一个方面,提供了药物组合物,其包含本申请具有活性的化合物或其药学上可接受的盐、或者根据合成式(I)化合物的方法得到的化合物或其药学上可接受的盐、以及一种或多种药学上可接受的载体、稀释剂、赋形剂或其组合。
本发明具有活性的化合物用作药物时,可以直接使用,或者以药物组合物的形式使用。该药物组合物含有0.1-99%,优选为0.5-90%的本发明具有活性的化合物,其余为药物学上可接受的、对人和动物无毒和惰性的可药用的载体。
任选地,该药物组合物中含有的活性化合物的比例为1%、10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、或99%。
药学上可接受的载体是一种或多种固体、半固体和液体稀释剂、填料以及药物制品辅料。本申请的药物组合物以单位体重服用量的形式使用。应用本申请的药物可采用本领域惯用的剂型,例如:药膏、片剂、丸剂、栓剂乳剂、输入液和注射液等。这些剂型按照众所周知的方法,使用传统的添加剂和赋型剂制得。由此制得的药物根据需要可按局部、非肠道、口服等途径给药。
本发明具有活性的化合物的施用量可根据用药途径、患者的年龄、体重、所治疗的疾病的类型和严重程度等变化,其日剂量可以是0.01-10mg/kg体重,优选0.1-5mg/kg体重。可以一次或多次施用。
根据本发明的另一个方面,提供了本申请的化合物或其药学上可接受的盐、根据合成式(I)化合物的方法得到的化合物或其药学上可接受的盐、或者或者本发明的药物组合物在制备用于抑制HDAC的药物中的用途。
根据本发明的另一个方面,提供了本申请的化合物或其药学上可接受的盐、根据合成式(I)化合物的方法得到的化合物或其药学上可接受的盐、或者或者本发明的药物组合物在制备用于治疗癌症的药物中的用途。
本发明所述的癌症选自结肠癌、直肠癌、卵巢癌、肝癌、胃癌、膀胱癌、子宫颈癌、肺癌、肾癌、淋巴瘤、骨髓瘤、乳腺癌、前列腺癌、脑癌等恶性肿瘤。
附图说明
图1为细胞凋亡测试的空白对照图。
图2为阳性对照药SAHA(2μM)的细胞凋亡测试图。
图3为本发明化合物Ib-10(2μM)的细胞凋亡测试图。
图4为阳性对照药SAHA(4μM)的细胞凋亡测试图。
图5为本发明化合物Ib-10(4μM)的细胞凋亡测试图。
图6为阳性对照药SAHA(8μM)的细胞凋亡测试图。
图7为本发明化合物Ib-10(8μM)的细胞凋亡测试图。
具体实施方式
下面以具体实施例对本发明作进一步说明,但本发明并不局限于这些实施例。
本发明实施例中所使用的试剂如下:
1,4-萘醌、苄氧基胺盐酸盐、BOC-L-苯丙氨酸、BOC-L-缬氨酸、BOC-L-2-甲基苯丙氨酸、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑、4-溴丁酸乙酯、5-溴戊酸乙酯、6-溴己酸乙酯、7-溴己酸乙酯、8-溴己酸乙酯、4-溴丁烯酸乙酯、4-(溴甲基)苯甲酸乙酯、4-羟基肉桂酸甲酯、1,3-二溴丙烷、1,4-二溴丁烷和盐酸羟胺,阿魏酸甲酯均为分析纯,以上试剂购自伊诺凯科技股份有限公司;
无水乙腈、三乙胺、吡啶、乙酸酐、三氟乙酸、柠檬酸、碳酸氢钠、碳酸钾、氯化钠、氢氧化钠、无水硫酸钠、甲醇、二氯甲烷、无水乙醇、石油醚、乙酸乙酯和浓盐酸,均为分析纯,以上试剂均购自广东西陇化工厂;
本发明实施例所使用的仪器和设备如下:
SHB-IIIA循环水多用真空泵、旋转蒸发器(郑州长城科工贸有限公司);电子智能控温仪、85-1A型磁力搅拌器(巩义市予华仪器有限责任公司);AVANCE AV 400Hz超导核磁共振仪(瑞士,布鲁克公司);EL104电子天平(梅特勒-托利多仪器有限公司);KQ5200E型超声波清洗器(昆山市超声仪器有限公司);DHG-9140A型电热恒温鼓风干燥箱(上海一恒科学仪器有限公司);旋转蒸发仪N-1300V-W(日本,东京理化公司);Agilent6545Q-TOF LS/MS液质联用系统(美国,安捷伦科技有限公司)。
制备例1:起始物料2-氨基-1,4-萘醌的合成
称取苄氧基胺盐酸盐4.79g于500ml的圆底烧瓶中,在5℃下,加入120ml无水乙醇,再加入三乙胺3.03g,使混合物充分搅拌,再向该混合物中滴加7.12g 1,4-萘醌的50mL无水乙醇溶液。将混合物置于常温下搅拌反应2-5小时,用薄层色谱跟踪反应。反应结束后,将溶剂减压旋干,用乙酸乙酯重新溶解,硅胶柱层析得到橘红色化合物2-氨基-1,4-萘醌,收率为92%。
制备例2:卤代烷酯((E)-3-(4-(3-溴丙氧基)-3-甲氧基苯基丙烯酸甲酯、(E)-3-(4-(4-溴丁氧基)-3-甲氧基苯基丙烯酸甲酯、(E)-3-(4-(3-溴丙氧基)苯基)丙烯酸甲酯和(E)-3-(4-(4-溴丁氧基)苯基)丙烯酸甲酯)的合成
圆底烧瓶中依次加入ω-二卤代烷、无水乙腈、K2CO3和酯,摩尔比:1.5∶20~50∶2∶1,将混合物在60~70℃下搅拌2-8小时。浓缩混合物,加入水和乙酸乙酯,萃取,分离有机相,浓缩收集有机相,并通过柱色谱法进一步纯化,得到卤代烷酯为无色油。合成方法中选择的酯为4-羟基肉桂酸甲酯,阿魏酸甲酯;ω-二卤代烷为1,3-二溴丙烷,1,4-二溴丁烷。
制备例3:羟胺钾盐(NH2OK)的合成
在无水甲醇中加入过量的氢氧化钾配成饱和溶液,取14ml该溶液缓慢滴加到24ml含有4.67g盐酸羟胺的无水甲醇溶液中,控制反应液内温低于40℃,控制滴加速度小于3滴/秒,滴加完毕后使其反应过夜,将化合物减压抽滤,现配现用。
实施例1 式(Ia)的化合物(化合物Ia-1~Ia-20)的合成
(1)步骤(a)得到的中间体的合成
在0℃下搅拌向烧瓶加入BOC-氨基酸(包括BOC-L-苯丙氨酸、BOC-L-缬氨酸和BOC-L-2-甲基苯丙氨酸)、二氯甲烷、1-羟基苯并三唑、三乙胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、2-氨基-1,4萘醌的摩尔比为1.3∶5∶1.3∶1∶1.3∶1,加完所有的反应物后,在0℃下反应1个小时,再将其置于室温下反应16~20小时,期间用薄层色谱跟踪监测反应。反应完全后,将反应液先后用0.1mol/L盐酸溶液、饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤,其与溶剂体积之比为1∶2∶2∶2,用无水硫酸钠干燥,硅胶柱层析(石油醚∶乙酸乙酯=8∶1~6∶1,体积比)得到黄色固体,即为步骤(a)得到的中间体。
(2)步骤(b)得到的中间体的合成
将步骤(a)得到的黄色固体产物:二氯甲烷∶三氟乙酸摩尔比为1∶30∶8加入反应烧瓶,使混合物在室温下搅拌12-24小时,期间用薄层色谱跟踪监测反应。反应完全后,将反应液减压旋干,加入乙酸乙酯使其溶解,再加入适量的水,萃取,分离出有机层,再用乙酸乙酯萃取水层,复萃取三次,合并有机层,并用无水硫酸钠干燥,硅胶柱层析(二氯甲烷∶甲醇=15∶1,体积比)纯化,得到淡黄色产物,为取代的苯并[f]喹喔啉-3(4H)-酮,分别为2-苄基-6-羟基苯并[f]喹喔啉-3(4H)-酮、6-羟基-2-异丙基苯并[f]喹喔啉-3(4H)-酮和6-羟基-2-(2-甲基苯基)苯并[f]喹喔啉-3(4H)-酮,即为步骤(b)得到的中间体。
(3)步骤(c)得到的中间体的合成(可选,若R2为H,则无此步骤)
向烧瓶加入步骤(b)得到的取代的苯并[f]喹喔啉-3(4H)-酮、无水乙腈、三乙胺、乙酸酐,按照摩尔比1∶30∶1∶1.2加入,使其置于80℃下搅拌回流反应2-5小时,反应结束后,将反应液抽滤,滤渣用无水乙腈洗涤,滤液减压旋干,用乙酸乙酯溶解,再加入水,用乙酸乙酯萃取3次,有机相用无水硫酸钠干燥,合并滤渣和有机相,硅胶柱层析(石油醚∶乙酸乙酯=6∶1,体积比)得到浅绿色固体产物,该产物为酰化产物,为步骤(c)得到的中间体。
(4)化合物(Ia)的合成
向烧瓶加入步骤(c)得到的中间体或者步骤(b)得到的中间体,再加入碳酸钾、丙酮、卤代烷酯,加入的量按照摩尔比1∶3.6∶3∶1.2,混合物加热回流5-8小时,期间用薄层色谱跟踪监测反应。反应完全后,减压抽滤,用二氯甲烷洗涤滤渣,丢弃滤渣,收集滤液,减压旋干,硅胶柱层析(石油醚∶乙酸乙酯=30∶1,体积比)得到白色固体。该步骤中选择的卤代烷酯为4-(溴甲基)苯甲酸乙酯、4-溴丁酸乙酯、5-溴戊酸乙酯、6-溴己酸乙酯、7-溴庚酸乙酯、8-溴辛酸乙酯、4-溴丁烯酸乙酯、(E)-3-(4-(2-溴乙氧基)苯基)丙烯酸甲酯、(E)-3-(4-(3-溴丙氧基)苯基)丙烯酸甲酯、(E)-3-(4-(3-溴丙氧基)-3-甲氧基苯基)丙烯酸甲酯和(E)-3-(4-(4-溴丁氧基)苯基)丙烯酸甲酯。
式(Ia)化合物的化学名称及参数表征如下:
4-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酸乙酯(Ia-1)
路线总产率:36.2%。白色固体。1H NMR(400MHz,CDCl3)δ9.17(d,J=8.2Hz,1H),7.94(d,J=8.0Hz,1H),7.77-7.72(m,1H),7.69-7.64(m,1H),7.55(s,1H),7.37(d,J=7.3Hz,2H),7.30-7.25(m,2H),7.19(t,J=7.3Hz,1H),4.50(t,J=6.1Hz,2H),4.39(s,2H),4.15(q,J=7.1Hz,2H),2.50(s,3H),2.38(t,J=7.5Hz,2H),2.19-2.09(m,2H),1.27(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.12,169.10,156.86,147.82,146.53,138.68,137.97,133.87,131.77,129.24,129.24,128.38,128.38,127.79,127.32,126.44,126.19,124.22,121.37,116.91,65.58,60.48,39.94,30.87,24.26,21.10,14.27。HR-MS(m/z):计算为C27H26N2O5Na[M+Na]+:481.1739;实测值:481.1740。
5-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯(Ia-2)
路线总产率:37.5%。白色固体。1H NMR(400MHz,CDCl3)δ9.16(d,J=8.2Hz,1H),7.93(d,J=8.1Hz,1H),7.76-7.71(m,1H),7.67-7.62(m,1H),7.55(s,1H),7.38(d,J=7.4Hz,2H),7.26(dd,J=12.0,4.2Hz,2H),7.18(t,J=7.3Hz,1H),4.46(t,J=6.2Hz,2H),4.38(s,2H),4.15(q,J=7.1Hz,2H),2.49(s,3H),2.36(t,J=7.3Hz,2H),1.89-1.80(m,2H),1.78-1.70(m,2H),1.26(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.49,169.19,157.09,147.86,146.73,138.80,138.13,133.92,131.92,129.38,129.38,128.42,128.42,127.84,127.35,126.47,126.24,124.28,121.45,117.03,66.15,60.44,40.03,34.03,28.36,21.73,21.19,14.40。HR-MS(m/z):计算为C28H28N2O5Na[M+Na]+:495.1896;实测值:495.1890。
6-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酸乙酯(Ia-3)
路线总产率:34.3%。白色固体。1H NMR(400MHz,CDCl3)δ9.13(d,J=7.9Hz,1H),7.90(d,J=8.0Hz,1H),7.74-7.68(m,1H),7.65-7.60(m,1H),7.52(s,1H),7.34(d,J=7.3Hz,2H),7.27-7.21(m,2H),7.16(t,J=7.3Hz,1H),4.42(t,J=6.4Hz,2H),4.35(s,2H),4.11(q,J=7.1Hz,2H),2.47(s,3H),2.27(t,J=7.5Hz,2H),1.84-1.75(m,2H),1.66(dt,J=15.3,7.6Hz,2H),1.44-1.34(m,2H),1.23(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.76,169.22,157.20,147.86,146.77,138.85,138.19,133.89,131.95,129.38,129.38,128.43,128.43,127.84,127.34,126.49,126.24,124.29,121.46,117.07,66.45,60.40,40.06,34.39,28.63,25.80,24.83,21.21,14.42。HR-MS(m/z):计算为C29H30N2O5Na[M+Na]+:509.2052;实测值:509.2048。
8-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酸乙酯(Ia-4)
路线总产率:38.7%。白色固体。1H NMR(400MHz,CDCl3)δ9.15(d,J=8.0Hz,1H),7.92(d,J=8.1Hz,1H),7.76-7.71(m,1H),7.67-7.62(m,1H),7.55(s,1H),7.38(d,J=7.3Hz,2H),7.28-7.24(m,2H),7.18(t,J=7.3Hz,1H),4.44(t,J=6.5Hz,2H),4.37(s,2H),4.12(q,J=7.1Hz,2H),2.49(s,3H),2.30(t,J=7.5Hz,2H),1.83-1.75(m,2H),1.64(dd,J=14.5,7.2Hz,2H),1.41-1.31(m,6H),1.25(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.64,168.91,156.96,147.51,146.50,138.55,137.88,133.53,131.64,129.08,129.08,128.09,128.09,127.50,126.99,126.16,125.90,123.96,121.13,116.77,66.39,60.00,39.71,34.18,28.88,28.81,28.55,25.72,24.74,20.88,14.09。HR-MS(m/z):计算为C31H34N2O5Na[M+Na]+:537.2365;实测值:537.2359。
4-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酸乙酯(Ia-5)
路线总产率:32.7%。白色固体。1H NMR(400MHz,CDCl3)δ9.18(d,J=8.2Hz,1H),7.92(d,J=8.2Hz,1H),7.73(t,J=7.6Hz,1H),7.64(t,J=7.5Hz,1H),7.56(s,1H),4.55(t,J=6.2Hz,2H),4.17(q,J=7.1Hz,2H),3.61-3.49(m,1H),2.56(t,J=7.4Hz,2H),2.50(s,3H),2.27-2.19(m,2H),1.43(d,J=6.8Hz,6H),1.26(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.13,169.17,156.31,152.44,147.45,137.92,133.71,131.90,127.60,127.14,126.11,124.21,121.29,116.92,65.44,60.54,31.15,30.59,24.37,21.10,20.73,20.73,14.26。HR-MS(m/z):计算为C23H26N2O5Na[M+Na]+:433.1739;实测值:433.1732。
5-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯(Ia-6)
路线总产率:31.1%。白色固体。1H NMR(400MHz,CDCl3)δ9.18(d,J=7.9Hz,1H),7.92(d,J=7.9Hz,1H),7.75-7.70(m,1H),7.64(ddd,J=8.2,7.0,1.2Hz,1H),7.56(s,1H),4.52(t,J=6.0Hz,2H),4.15(q,J=7.1Hz,2H),3.56(hept,J=6.8Hz,1H),2.49(s,3H),2.43(t,J=7.1Hz,2H),1.97-1.83(m,4H),1.43(d,J=6.8Hz,6H),1.26(t,J=7.1Hz,3H)。13C NM[R(101MHz,CDCl3)δ173.45,169.17,156.46,152.52,147.42,137.97,133.61,131.93,127.57,127.09,126.08,124.19,121.29,116.96,65.90,60.36,33.98,30.63,28.36,21.82,21.09,20.72,20.72,14.28。HR-MS(m/z):计算为C24H28N2O5Na[M+Na]+:447.1896;实测值:447.1892。
6-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酸乙酯(Ia-7)
路线总产率:28.9%。白色固体。1H NMR(400MHz,CDCl3)δ9.18(d,J=8.2Hz,1H),7.91(d,J=8.1Hz,1H),7.74-7.69(m,1H),7.65-7.60(m,1H),7.56(s,1H),4.49(t,J=6.5Hz,2H),4.13(q,J=7.1Hz,2H),3.55(hept,J=6.8Hz,1H),2.48(s,3H),2.35(t,J=7.5Hz,2H),1.93-1.85(m,2H),1.75(dt,J=15.2,7.5Hz,2H),1.58-1.51(m,2H),1.43(d,J=6.8Hz,6H),1.25(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.62,169.16,156.53,152.51,147.41,138.01,133.55,131.93,127.55,127.06,126.06,124.17,121.29,116.97,66.19,60.28,34.31,30.66,28.58,25.86,24.75,21.07,20.70,20.70,14.29。HR-MS(m/z):计算为C25H30N2O5Na[M+Na]+:461.2052;实测值:461.2048。
7-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)庚酸乙酯(Ia-8)
路线总产率:29.7%。白色固体。1H NMR(400MHz,CDCl3)δ9.18(d,J=7.9Hz,1H),7.92(d,J=8.1Hz,1H),7.71(dd,J=11.2,4.0Hz,1H),7.63(t,J=7.6Hz,1H),7.57(s,1H),4.49(t,J=6.5Hz,2H),4.13(q,J=7.1Hz,2H),3.56(hept,J=6.8Hz,1H),2.49(s,3H),2.32(t,J=7.5Hz,2H),1.92-1.83(m,2H),1.73-1.64(m,2H),1.54(dt,J=14.5,7.1Hz,2H),1.47-1.39(m,8H),1.25(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.76,169.16,156.57,152.54,147.37,138.01,133.52,131.93,127.53,127.03,126.03,124.15,121.27,116.97,66.33,60.24,34.30,30.67,28.87,28.69,25.94,24.93,21.08,20.70,20.70,14.29。HR-MS(m/z):计算为C26H32N2O5Na[M+Na]+:475.2209;实测值:475.2204。
8-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酸乙酯(Ia-9)
路线总产率:30.6%。白色固体。1H NMR(400MHz,CDCl3)δ9.18(d,J=8.2Hz,1H),7.92(d,J=8.1Hz,1H),7.73(dd,J=11.1,4.0Hz,1H),7.66-7.61(m,1H),7.57(s,1H),4.50(t,J=6.5Hz,2H),4.13(q,J=7.1Hz,2H),3.56(hept,J=6.8Hz,1H),2.50(s,3H),2.31(t,J=7.5Hz,2H),1.91-1.83(m,2H),1.66(dt,J=14.7,7.5Hz,2H),1.57-1.48(m,2H),1.45-1.36(m,10H),1.25(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.85,169.18,156.60,152.59,147.35,138.00,133.50,131.94,127.53,127.02,126.02,124.16,121.26,116.97,66.43,60.21,34.37,30.66,29.10,29.03,28.80,26.07,24.94,21.10,20.68,20.68,14.29。HR-MS(m/z):计算为C27H34N2O5Na[M+Na]+:489.2365;实测值:489.2361。
4-((4-乙酰基-2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酸乙酯(Ia-10)
路线总产率:39.1%。白色固体。1H NMR(400MHz,CDCl3)δ9.06-9.02(m,1H),7.93(d,J=7.7Hz,1H),7.73-7.69(m,1H),7.67-7.62(m,1H),7.56(s,1H),7.23-7.17(m,2H),7.16-7.07(m,2H),4.52(t,J=6.2Hz,2H),4.38(s,2H),4.15(q,J=7.1Hz,2H),2.50(s,3H),2.48(s,3H),2.38(t,J=7.5Hz,2H),2.20-2.12(m,2H),1.27(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.10,169.12,156.89,147.78,146.30,138.48,137.02,136.36,133.82,131.79,130.27,129.85,127.80,127.28,126.60,126.16,125.79,124.15,121.33,116.90,65.62,60.48,37.21,30.87,24.26,21.10,20.06,14.27。HR-MS(m/z):计算为C28H28N2O5Na[M+Na]+:495.1896;实测值:495.1890。
5-((4-乙酰基-2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯(Ia-11)
路线总产率:34.8%。白色固体。1H NMR(400MHz,CDCl3)δ9.03(d,J=8.2Hz,1H),7.92(d,J=8.0Hz,1H),7.73-7.68(m,1H),7.66-7.61(m,1H),7.56(s,1H),7.24-7.21(m,1H),7.18(d,J=6.8Hz,1H),7.15-7.07(m,2H),4.49(t,J=6.3Hz,2H),4.38(s,2H),4.14(q,J=7.1Hz,2H),2.50(s,3H),2.48(s,3H),2.36(t,J=7.4Hz,2H),1.91-1.83(m,2H),1.78-1.70(m,2H),1.26(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.40,169.14,157.03,147.74,146.38,138.52,137.05,136.43,133.75,131.82,130.22,129.91,127.78,127.23,126.55,126.12,125.76,124.14,121.32,116.92,66.13,60.36,37.17,33.94,28.26,21.63,21.10,20.06,14.30。HR-MS(m/z):计算为C29H30N2O5Na[M+Na]+:509.2052;实测值:509.2049。
7-((4-乙酰基-2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)庚酸乙酯(Ia-12)
路线总产率:32.3%。白色固体。1H NMR(400MHz,CDCl3)δ9.04(d,J=8.1Hz,1H),7.92(d,J=8.1Hz,1H),7.71(t,J=7.1Hz,1H),7.66-7.61(m,1H),7.56(s,1H),7.24-7.21(m,1H),7.18(d,J=7.0Hz,1H),7.15-7.07(m,2H),4.46(t,J=6.5Hz,2H),4.37(s,2H),4.13(q,J=7.1Hz,2H),2.50(s,3H),2.49(s,3H),2.30(t,J=7.5Hz,2H),1.87-1.78(m,2H),1.68-1.60(m,2H),1.41-1.37(m,4H),1.26(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ173.80,169.16,157.16,147.71,146.45,138.57,137.04,136.46,133.67,131.83,130.22,129.88,127.76,127.20,126.55,126.09,125.74,124.12,121.32,116.96,66.59,60.25,37.13,34.32,28.89,28.65,25.78,24.91,21.11,20.08,14.31。HR-MS(m/z):计算为C31H34N2O5Na[M+Na]+:537.2365;实测值:537.2362。
4-(((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)甲基)苯甲酸乙酯(Ia-13)
路线总产率:37.9%。白色固体。1H NMR(400MHz,CDCl3)δ9.14(d,J=7.8Hz,1H),7.98(d,J=8.3Hz,2H),7.91(d,J=7.9Hz,1H),7.75-7.70(m,1H),7.63(ddd,J=8.2,7.0,1.3Hz,1H),7.53(s,1H),7.35-7.30(m,4H),7.25-7.21(m,2H),7.18(ddd,J=7.2,3.5,1.3Hz,1H),5.52(s,2H),4.40(s,2H),4.35(q,J=7.1Hz,2H),2.47(s,3H),1.36(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ169.21,166.51,156.53,148.04,146.56,141.74,138.67,137.96,134.32,131.87,130.15,129.82,129.82,129.41,129.41,128.54,128.54,127.97,127.66,127.66,127.57,126.63,126.41,124.38,121.51,116.94,67.63,61.14,40.14,21.22,14.48。HR-MS(m/z):计算为C31H26N2O5Na[M+Na]+:529.1739;实测值:529.1735。
(E)-4-(((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-2-丁烯酸乙酯(Ia-14)
路线总产率:28.7%。白色固体。1H NMR(400MHz,CDCl3)δ9.17(d,J=8.2Hz,1H),7.95(d,J=8.1Hz,1H),7.76(t,J=7.3Hz,1H),7.68(t,J=7.2Hz,1H),7.56(s,1H),7.40(d,J=7.4Hz,2H),7.30(t,J=7.5Hz,2H),7.22(t,J=7.3Hz,1H),7.11(dt,J=15.8,4.3Hz,1H),6.01(d,J=15.8Hz,1H),5.18(dd,J=4.2,1.9Hz,2H),4.45(s,2H),4.23(q,J=7.1Hz,2H),2.51(s,3H),1.32(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ169.50,166.49,156.33,148.41,146.72,142.28,138.86,138.16,134.76,132.14,129.67,129.67,128.90,128.90,128.31,127.94,126.99,126.76,124.72,122.49,121.83,117.22,65.00,60.99,40.22,21.52,14.69。HR-MS(m/z):计算为C27H24N2O5Na[M+Na]+:479.1583;实测值:479.1579。
(E)-3-(4-(3-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丙氧基)苯基)丙烯酸甲酯(Ia-15)
路线总产率:33.5%。白色固体。1H NMR(400MHz,CDCl3)δ9.18(d,J=8.0Hz,1H),7.93(d,J=8.0Hz,1H),7.76-7.71(m,1H),7.68-7.62(m,2H),7.55(s,1H),7.47(d,J=8.7Hz,2H),6.93(d,J=8.7Hz,2H),6.30(d,J=16.0Hz,1H),4.72(t,J=6.1Hz,2H),4.24(t,J=6.2Hz,2H),3.79(s,3H),3.61-3.48(m,1H),2.51(s,3H),2.39(p,J=6.1Hz,2H),1.42(d,J=6.8Hz,6H)。13C NMR(101MHz,CDCl3)δ169.17,167.80,160.71,156.27,152.35,147.48,144.54,137.92,133.75,131.89,129.78,129.78,127.62,127.19,126.13,124.21,121.30,116.90,115.29,114.85,114.85,64.87,63.06,51.61,30.65,28.87,21.11,20.71,20.71。HR-MS(m/z):计算为C30H30N2O6Na[M+Na]+:537.2002;实测值:527.1994。
(E)-4-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-2-丁烯酸乙酯(Ia-16)
路线总产率:28.6%。白色固体。1H NMR(400MHz,CDCl3)δ9.20(d,J=8.2Hz,1H),7.94(d,J=8.1Hz,1H),7.75(t,J=7.2Hz,1H),7.67(dd,J=11.2,4.0Hz,1H),7.57(s,1H),7.19(dt,J=15.8,4.3Hz,1H),6.20(dt,J=15.7,1.8Hz,1H),5.22(dd,J=4.3,1.9Hz,2H),4.24(q,J=7.1Hz,2H),3.62(hept,J=6.8Hz,1H),2.51(s,3H),1.46(d,J=6.8Hz,6H),1.32(t,J=7.1Hz,3H)。13C NMR(101MHz,CDCl3)δ169.24,166.23,155.48,152.35,147.74,142.30,137.85,134.26,131.95,127.82,127.47,126.39,124.41,122.11,121.45,116.93,64.67,60.76,30.72,21.23,20.90,20.90,14.40。HR-MS(m/z):计算为C23H24N2O5Na[M+Na]+:431.1583;实测值:431.1580。
4-(((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)甲基)苯甲酸乙酯(Ia-17)
路线总产率:38.1%。白色固体。1H NMR(400MHz,CDCl3)δ9.21-9.17(m,1H),8.09(d,J=8.3Hz,2H),7.94(d,J=7.9Hz,1H),7.74(ddd,J=8.2,7.0,1.2Hz,1H),7.66(ddd,J=8.2,7.0,1.3Hz,1H),7.59(t,J=4.2Hz,3H),5.63(s,2H),4.44-4.33(m,2H),3.63(hept,J=6.8Hz,1H),2.52(s,3H),1.45(d,J=6.8Hz,6H),1.40(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ169.04,166.27,155.77,152.28,147.50,141.84,137.72,133.94,131.78,130.00,129.74,129.74,127.58,127.44,127.44,127.19,126.14,124.18,121.24,116.75,67.29,60.93,30.60,21.02,20.65,20.65,14.27.HR-MS(m/z):calcd forC27H26N2O5[M+Na]+:481.1739;found:481.1742.
5-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯(Ia-18)
路线总产率:29.8%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),8.92(d,J=8.2Hz,1H),8.25(d,J=8.0Hz,1H),7.77-7.71(m,1H),7.66(t,J=7.3Hz,1H),7.33(d,J=7.3Hz,2H),7.26(t,J=6.0Hz,2H),7.17(t,J=6.1Hz,1H),7.03(d,J=4.2Hz,1H),4.39(d,J=3.7Hz,2H),4.25(s,2H),4.05(q,J=7.0Hz,2H),2.32(t,J=7.0Hz,2H),1.76(s,2H),1.64(d,J=6.2Hz,2H),1.16(t,J=7.0Hz,3H)。13C NMR(101MHz,DMSO-d6)δ172.66,156.42,155.06,142.36,140.23,138.32,130.93,129.80,128.88,128.88,128.88,128.26,128.26,127.67,126.56,126.18,125.36,123.03,122.33,103.93,65.60,59.69,33.15,27.70,21.20,14.10。HR-MS(m/z):计算为C26H27N2O4[M+H]+:431.1971;实测值:431.1968。
6-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酸乙酯(Ia-19)
路线总产率:36.0%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.93(d,J=8.1Hz,1H),8.26(d,J=8.0Hz,1H),7.76(t,J=7.4Hz,1H),7.68(t,J=7.2Hz,1H),7.34(d,J=7.3Hz,2H),7.29(t,J=7.5Hz,2H),7.20(t,J=7.1Hz,1H),7.04(s,1H),4.40(d,J=4.5Hz,2H),4.27(s,2H),4.05(q,J=7.1Hz,2H),2.28(t,J=7.2Hz,2H),1.79-1.71(m,2H),1.62-1.53(m,2H),1.41-1.32(m,2H),1.17(t,J=7.1Hz,3H)。13C NMR(101MHz,DMSO-d6)δ172.36,156.08,154.63,141.99,139.83,137.94,130.51,129.35,128.43,128.43,128.43,127.85,127.85,127.29,126.16,125.77,124.92,122.60,121.91,103.51,65.38,59.23,33.02,27.53,24.63,23.75,13.68。HR-MS(m/z):计算为C27H29N2O4[M+H]+:445.2127;实测值:445.2123。
8-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酸乙酯(Ia-20)
路线总产率:37.4%。白色固体。1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.94(d,J=8.0Hz,1H),8.26(d,J=8.0Hz,1H),7.76(t,J=7.4Hz,1H),7.68(t,J=7.5Hz,1H),7.33(d,J=7.2Hz,2H),7.28(t,J=7.5Hz,2H),7.19(t,J=7.1Hz,1H),7.06(s,1H),4.39(t,J=6.1Hz,2H),4.27(s,2H),4.04(q,J=7.1Hz,2H),2.27(t,J=7.3Hz,2H),1.77-1.68(m,2H),1.56-1.47(m,2H),1.37-1.23(m,6H),1.17(t,J=7.1Hz,3H)。13C NMR(101MHz,DMSO-d6)δ172.84,156.54,155.08,142.36,140.28,138.37,130.93,129.74,128.81,128.81,128.81,128.26,128.26,127.69,126.56,126.18,125.35,123.01,122.32,103.95,65.94,59.60,33.49,28.36,28.36,28.23,25.35,24.37,14.10。HR-MS(m/z):计算为C29H32N2O4Na[M+Na]+:495.2260;实测值:495.2256。
实施例2 式(Ib)的化合物(化合物Ib-1~Ib-14)的合成
向烧瓶加入按照实施例1的方法合成的苯并喹喔啉酮酯1g和羟胺钾的无水甲醇溶液,两者摩尔比为1∶24,将其置于超声波清洗器20~30℃超声30分钟,减压蒸发溶剂,残余物用两倍体积的饱和柠檬酸溶液酸化,再加入同等体积的乙酸乙酯,萃取3次,合并有机相,加入20ml盐水,萃取3次。有机相用无水硫酸钠干燥,浓缩后硅胶柱层析(二氯甲烷∶甲醇=10∶1)得到固体。
式(Ib)化合物的化学名称及参数表征如下:
4-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基丁酰胺(Ib-1)
产率:95.1%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),10.47(s,1H),8.90(d,J=8.0Hz,1H),8.76(s,1H),8.24(d,J=8.1Hz,1H),7.74(t,J=7.5Hz,1H),7.66(t,J=7.4Hz,1H),7.36(d,J=7.3Hz,2H),7.28(t,J=7.5Hz,2H),7.18(t,J=7.3Hz,1H),7.02(s,1H),4.39(t,J=6.3Hz,2H),4.28(s,2H),2.16(t,J=7.3Hz,2H),2.02(dd,J=13.4,6.5Hz,2H)。13C NMR(101MHz,DMSO-d6)δ168.75,156.44,155.11,142.58,140.22,138.38,130.96,129.87,129.09,129.09,128.36,128.36,127.79,126.68,126.27,125.40,123.07,122.39,103.94,65.61,29.02,29.02,24.62。
HR-MS(m/z):计算为C23H22N3O4[M+H]+:404.1610;实测值:404.1612。
8-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基辛酰胺(Ib-2)
产率:92.3%。白色固体。1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.40(s,1H),8.97(d,J=8.1Hz,1H),8.73(s,1H),8.29(d,J=8.0Hz,1H),7.80(t,J=7.4Hz,1H),7.72(t,J=7.5Hz,1H),7.34(dt,J=14.9,7.4Hz,4H),7.24(t,J=7.0Hz,1H),7.07(s,1H),4.43(t,J=5.8Hz,2H),4.31(s,2H),2.01(t,J=7.3Hz,2H),1.80-1.73(m,2H),1.58-1.49(m,2H),1.35-1.26(m,6H)。13C NMR(101MHz,DMSO-d6)δ169.16,156.58,155.08,142.46,140.29,138.38,130.96,129.77,128.85,128.85,128.85,128.34,128.34,127.76,126.62,126.27,125.36,123.06,122.37,103.95,66.01,32.30,28.58,28.53,28.32,25.47,25.11。HR-MS(m/z):计算为C27H30N3O4[M+H]+:460.2236;实测值:460.2238。
N-羟基-4-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酰胺(Ib-3)
产率:93.6%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.47(s,1H),8.96(d,J=8.1Hz,1H),8.74(s,1H),8.24(d,J=8.1Hz,1H),7.75(t,J=7.6Hz,1H),7.66(t,J=7.5Hz,1H),7.03(s,1H),4.44(t,J=6.2Hz,2H),3.48(dq,J=13.5,6.8Hz,1H),2.21(t,J=7.3Hz,2H),2.09-2.01(m,2H),1.36(d,J=6.8Hz,6H)。13C NMR(101MHz,DMSO-d6)δ169.09,156.36,155.20,148.42,140.05,131.50,130.00,128.10,126.96,125.76,123.51,122.79,104.41,65.83,30.18,29.44,25.07,21.20,21.20。
HR-MS(m/z):计算为C19H22N3O4[M+H]+:356.1610;实测值:356.1616。
N-羟基-5-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酰胺(Ib-4)
产率:90.8%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.41(s,1H),8.97(d,J=8.1Hz,1H),8.72(s,1H),8.25(d,J=8.1Hz,1H),7.76(t,J=7.5Hz,1H),7.67(t,J=7.5Hz,1H),7.04(s,1H),4.46(t,J=5.9Hz,2H),3.47(dt,J=13.6,6.8Hz,1H),2.07(t,J=7.0Hz,2H),1.81(dd,J=13.4,6.4Hz,2H),1.74(dd,J=14.2,7.0Hz,2H),1.37(d,J=6.8Hz,6H)。13C NMR(101MHz,DMSO-d6)δ168.94,155.97,154.73,147.93,139.63,131.05,129.51,127.64,126.49,125.29,123.06,122.33,103.97,65.55,31.93,29.83,27.96,21.97,20.68,20.68。
HR-MS(m/z):计算为C20H24N3O4[M+H]+:370.1767;实测值:367.1765。
N-羟基-6-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酰胺(Ib-5)
产率:92.7%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),10.38(s,1H),8.97(d,J=8.0Hz,1H),8.69(s,1H),8.24(d,J=8.0Hz,1H),7.75(t,J=7.5Hz,1H),7.67(t,J=7.5Hz,1H),7.04(s,1H),4.44(t,J=6.3Hz,2H),3.46(dt,J=13.7,6.8Hz,1H),2.00(t,J=7.3Hz,2H),1.86-1.78(m,2H),1.61(dt,J=14.9,7.3Hz,2H),1.51-1.42(m,2H),1.36(d,J=6.8Hz,6H).13C NMR(101MHz,DMSO-d6)δ169.48,156.43,155.16,148.37,140.08,131.50,129.93,128.06,126.91,125.73,123.49,122.77,104.43,66.25,32.70,30.26,28.53,25.80,25.35,21.13,21.13。
HR-MS(m/z):计算为C21H26N3O4[M+H]+:384.1923;实测值:384.1926。
N-羟基-8-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酰胺(Ib-6)
产率:93.6%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.88(s,1H),10.35(s,1H),8.96(d,J=8.2Hz,1H),8.68(s,1H),8.24(d,J=8.1Hz,1H),7.75(t,J=7.5Hz,1H),7.66(t,J=7.5Hz,1H),7.03(s,1H),4.44(s,2H),3.45(dt,J=13.5,6.8Hz,1H),1.95(t,J=7.3Hz,2H),1.80(s,2H),1.51(dt,J=15.5,7.7Hz,4H),1.32(dd,J=31.7,6.7Hz,10H)。13CNMR(101MHz,DMSO-d6)δ169.58,156.44,155.16,148.35,140.09,131.50,129.91,128.07,126.91,125.72,123.49,122.77,104.41,66.35,32.71,30.30,29.02,28.95,28.77,26.07,25.55,21.10,21.10。
HR-MS(m/z):计算为C23H30N3O4[M+H]+:412.2236:实测值:412.2238。
N-羟基-(E)-3-(4-(4-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁氧基)苯基)丙烯酰胺(Ib-7)
产率:94.7%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.68(s,1H),8.97(d,J=8.1Hz,2H),8.25(d,J=8.0Hz,1H),7.76(t,J=7.5Hz,1H),7.68(t,J=7.6Hz,1H),7.46(dd,J=32.7,12.1Hz,3H),7.05(s,1H),6.98(d,J=8.6Hz,2H),4.53(d,J=5.7Hz,2H),4.13(d,J=5.4Hz,2H),3.45(dt,J=13.5,6.7Hz,2H),1.98(s,4H),1.35(d,J=6.8Hz,6H)。13C NMR(101MHz,DMSO-d6)δ163.66,160.12,156.39,155.19,148.34,140.07,138.55,131.50,129.97,129.50,129.50,128.09,127.78,126.94,125.74,123.50,122.78,116.89,115.32,115.32,104.42,67.76,66.13,30.25,26.03,25.62,21.12,21.12。
HR-MS(m/z):计算值C28H30N3O5[M+H]+:488.2185;实测值:488.2193。
N-羟基-5-((2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酰胺(Ib-8)
产率:96.1%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),10.40(s,1H),8.80(d,J=8.1Hz,1H),8.72(s,1H),8.24(d,J=7.9Hz,1H),7.73(t,J=7.1Hz,1H),7.66(t,J=7.0Hz,1H),7.24-7.17(m,2H),7.14-7.10(m,2H),7.03(s,1H),4.43(t,J=6.2Hz,2H),4.27(s,2H),2.43(s,3H),2.04(t,J=7.2Hz,2H),1.80-1.74(m,2H),1.70-1.63(m,2H)。13C NMR(101MHz,DMSO-d6)δ168.88,156.54,155.04,142.18,140.06,136.72,136.51,130.93,130.02,129.69,129.69,127.79,126.62,126.38,125.73,125.34,122.88,122.37,103.93,65.78,36.06,31.89,27.87,21.80,19.59。HR-MS(m/z):计算为C25H26N3O4[M+H]+:432.1923;实测值:432.1925。
N-羟基-6-((2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酰胺(Ib-9)
产率:92.8%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),10.37(s,1H),8.81(d,J=7.9Hz,1H),8.69(s,1H),8.24(d,J=7.7Hz,1H),7.76-7.71(m,1H),7.70-7.64(m,1H),7.19(dd,J=5.6,2.9Hz,2H),7.15-7.08(m,2H),7.03(s,1H),4.42(t,J=6.3Hz,2H),4.27(s,2H),2.43(s,3H),1.97(t,J=7.4Hz,2H),1.82-1.73(m,2H),1.56(dt,J=15.1,7.5Hz,2H),1.36(dt,J=15.0,7.6Hz,2H)。13C NMR(101MHz,DMSO-d6)δ169.04,156.56,155.04,142.20,140.09,136.75,136.48,130.93,130.01,129.68,129.58,127.78,126.61,126.37,125.71,125.34,122.88,122.37,103.94,65.99,36.10,32.23,28.05,25.23,24.92,19.59。
HR-MS(m/z):计算为C26H28N3O4[M+H]+:446.2080;实测值:446.2083。
7-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基庚酰胺(Ib-10)
产率:93.5%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.69(s,1H),8.63(d,J=8.3Hz,1H),8.16(dd,J=8.2,2.9Hz,1H),7.70(dd,J=10.9,4.3Hz,1H),7.58-7.52(m,1H),7.40(d,J=7.2Hz,2H),7.31(t,J=7.5Hz,2H),7.21(t,J=7.3Hz,1H),6.80(d,J=4.5Hz,1H),4.17(s,4H),1.98(dd,J=9.6,4.8Hz,2H),1.88(d,J=6.2Hz,2H),1.60-1.48(m,4H),1.37(dd,J=14.6,7.6Hz,2H)。HR-MS(m/z):计算为C26H28N3O4[M+H]+:446.2080;实测值:446.2087。
5-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基戊酰胺(Ib-11)
产率:91.2%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),10.41(s,1H),8.92(d,J=7.9Hz,1H),8.74(s,1H),8.24(d,J=7.9Hz,1H),7.78-7.73(m,1H),7.70-7.65(m,1H),7.36(d,J=7.0Hz,2H),7.29(t,J=7.2Hz,2H),7.20(d,J=7.1Hz,1H),7.02(s,1H),4.41(s,2H),4.27(s,2H),2.02(d,J=6.6Hz,2H),1.76(s,2H),1.66(d,J=6.6Hz,2H)。HR-MS(m/z):计算为:C24H24N3O4[M+H]+:418.1767;实测值:418.1766。
6-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基己酰胺(Ib-12)
产率:90.4%。白色固体。1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),10.38(s,1H),8.92(d,J=7.9Hz,1H),8.70(s,1H),8.23(d,J=7.6Hz,1H),7.74(d,J=7.1Hz,1H),7.68(d,J=7.4Hz,1H),7.36-7.26(m,4H),7.20(d,J=6.2Hz,1H),7.02(s,1H),4.39(s,2H),4.27(s,2H),1.95(d,J=6.5Hz,2H),1.75(s,2H),1.53(d,J=6.7Hz,2H),1.35(s,2H)。HR-MS(m/z):计算为C25H26N3O4[M+H]+:432.1923;实测值:432.1929。
4-(((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)甲基)-N-羟基苯甲酰胺(Ib-13)
产率:90.9%。白色固体。1H NMR(400MHz,DMSO)δ11.25(s,1H),11.06(s,1H),9.08(s,1H),8.93(d,J=8.1Hz,1H),8.25(d,J=8.1Hz,1H),7.77(d,J=7.3Hz,1H),7.74(d,J=7.0Hz,2H),7.71-7.66(m,1H),7.44(d,J=8.2Hz,2H),7.33-7.27(m,4H),7.24-7.19(m,1H),7.05(s,1H),5.56(s,2H),4.34(s,2H).13C NMR(101MHz,DMSO)δ175.07,171.76,171.76,156.46,155.70,142.80,140.57,138.72,131.32,130.59,129.39,129.39,129.39,128.85,128.85,128.85,128.34,127.89,127.89127.39,126.78,125.92,123.57,122.85,104.25,72.88,43.21。HR-MS(m/z):计算为C27H22N3O4[M+H]+:452.1610;实测值:452.1614。
N-羟基-7-((2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)庚酰胺(Ib-14)
产率:93.7%。白色固体。1H NMR(600MHz,MeOD)δ8.88(d,J=7.7Hz,1H),8.26(d,J=8.2Hz,1H),7.65-7.62(m,1H),7.60-7.57(m,1H),7.15(d,J=7.2Hz,1H),7.11(d,J=7.3Hz,1H),7.08-7.06(m,1H),7.03(dd,J=9.3,4.6Hz,1H),6.99(s,1H),4.42(t,J=6.3Hz,2H),4.29(s,2H),2.44(s,3H),2.06(t,J=7.4Hz,2H),1.77(dd,J=13.6,6.5Hz,2H),1.61-1.56(m,2H),1.35-1.31(m,4H)。HR-MS(m/z):计算为C27H30N3O4[M+H]+:460.2236;found:460.2239。
实施例3:体外抗肿瘤活性试验
以临床使用的肿瘤治疗药物瑞戈非尼为阳性对照药,以相应的溶剂作阴性对照,以T24(膀胱移行细胞癌细胞),HCV-29(人体膀胱上皮细胞)为受试细胞株:MTT法对化合物进行体外抗肿瘤活性测试。
将药物和细胞共培养48小时,根据预实验细胞生长速率的结果,接种一定密度的细胞190μl于96孔培养板(约5x104-1x105个/孔)
培养24小时待细胞贴壁后,分别加入系列浓度样品10μl,每个样品设3个复孔,另设阴性对照孔4个,加入空白基质。
细胞于饱和湿度、5%二氧化碳,37℃条件下孵化48小时,每孔加入10μl MTT(5mg/L),继续培养4小时。
吸去上清液,加入二甲基亚砜150μL/孔,充分溶解后用酶标仪在测定波长为570nm和630nm处测定OD值,计算每个给药孔细胞增值抑制率,结果如下表1所示。
表1.本发明化合物对不同细胞株的抑制活性
*瑞戈非尼结构式如下:
**SAHA结构式如下:
从表中可以看出,对于膀胱移行细胞癌细胞T24,相当部分的苯并喹喔啉酮化合物显示较好的抗肿瘤活性,化合物Ia-14、Ia-16、Ib-1~Ib-6、Ib-9和Ib-10对T24细胞的抑制活性均比临床抗肿瘤药瑞戈非尼更好;Ib-3~Ib-6和Ib-10对T24癌细胞的抑制活性比临床抗肿瘤药SAHA更好。
为了验证上述化合物对人体正常细胞的细胞毒性,我们利用MTT法对人体膀胱上皮细胞HCV-29进行活性筛选,结果表明大部分苯并喹喔啉酮化合物对人体膀胱上皮正常细胞的毒性都较小。
上述体外抗肿瘤活性测试表明,本发明所述的苯并喹喔啉酮化合物,可以有望用于抗肿瘤药物的制备。
实施例4:HDAC1、HDAC6和HDAC8酶活性测试
根据试剂商(上海抚生实业有限公司)提供的说明分别进行人HDAC1、HDAC6和HDAC8酶活性测试。将HDAC抑制剂SAHA作为阳性对照。按下面步骤进行:
(1)标准品稀释:根据试剂商进行标准品稀释;
(2)加样:分别设置空白孔(空白对照孔不加样品及酶标试剂,其余操作相同)、标准孔、待测样品孔。在酶标包被板上标准品准确加样50μl,待测样品孔中先加样品稀释液40μl,然后再加待测样品10μl(样品最终稀释度为5倍)。加样将样品加于酶标板孔底部,尽量不触及孔壁,轻轻晃动混匀;
(3)温育:用封板膜封板厚置37℃温育30分钟;
(4)配液:将20倍浓缩洗涤液用蒸馏水20倍稀释后备用;
(5)洗涤:小心揭掉封板膜,弃去液体,甩干,每孔加满洗涤液,静置30秒后弃去,如此重复5次,拍干;
(6)加酶:每孔加入酶标试剂50μl,空白孔除外;
(7)温育:操作同(3);
(8)洗涤:操作同(5);
(9)显色:每孔先加入显色剂A 50μl,再加入显色剂B 50μl,轻轻震荡混匀,37℃避光显色10分钟;
(10)终止:每孔加终止液50μl,终止反应(此时蓝色立转黄色);
(11)测定:以空白孔调零,450nm波长依序测量各孔的吸光度(OD值)。
实验结果见下表2。
表2.本申请的化合物对于HDAC1、HDAC6和HDAC8的抑制活性
通过对上述苯并喹喔啉酮化合物进行HDAC亚型抑制活性评价,本发明的大多化合物对HDAC1、HDAC8、HDAC6这三个亚型的抑制活性比SAHA更好或相当,特别是化合物Ib-10对HDAC1、HDAC8、HDAC6这三个亚型具有比阳性对照药SAHA更优的抑制活性,IC50值达到低纳摩尔级别,具有广谱的HDAC抑制活性,有希望成为广谱的HDAC抑制剂,为开发抗肿瘤先导化合物提供了参考。
实施例5化合物Ib-10细胞凋亡测试
化合物Ib-10细胞凋亡测试试验过程如下:
(1)细胞的培养:取一个100ml的培养瓶,加入一定量1%双抗和10%胎牛血清的DMEM培养基,将人体膀胱癌细胞T24置于该培养基中,使其在含5%二氧化碳和95%空气的恒温培养箱,37℃条件下进行培养。
(2)消化细胞及种板:处于对数生长期的非小细胞肺癌A549细胞用3ml PBS缓冲溶液清洗干净后(一般洗2-3次),再用1ml胰蛋白酶进行消化,观察到细胞消化完全后,加入10%胎牛血清的DMEM培养基使消化终止,小心并多次吹打,得到单细胞悬浊液,用10%胎牛血清的DMEM培养基稀释至密度为20000到30000个/ml,再将稀释后的细胞悬浊液以单孔3mL种在6孔板中。
(3)加药:使步骤(2)中的细胞在含5%二氧化碳的恒温培养箱,37℃条件下进行培养至细胞贴壁生长面积约为孔面积70%左右。向6孔板单孔加入待筛化合物Ib-10(其DMSO含量低于1%),设置药物浓度为2μM、4μM和8μM,阳性对照组与待测组一样的加药浓度,同时设置空白对照组。使实验组和空白对照组细胞在5%二氧化碳的培养箱,37℃条件下培养24小时。
(4)收集细胞:将步骤(3)细胞进行收集,并将收集好的细胞置于离心机(1500r/min)离心,将上清液弃去,用3ml PBS溶液洗涤细胞,离心并弃去上清液。
(5)染色:向该管加入200μL 1×该管加胞,离心并弃去上清液细胞悬浮液,并将其转移到1.5ml离心管,再加入5μL标记FITC的Annexin V,将其置于37℃恒温培养箱孵育20分钟。再先后加入300μL 1×Binding Buffer、5 Bindi到1.5ml离心管,混合均匀,过滤,冰层避光备用。
(6)上机检测:将步骤(5)离心管上机,并在1小时内完成所有样品检测。
结果见图1~图7,图中Q2和Q3区域中的细胞量表示凋亡的细胞量,Q4区域中的细胞数目表示活细胞数目。图1中,空白对照组在24小时后,Q2和Q3区域癌细胞凋亡数目占总的细胞数目的1.1%。阳性对照组在加入SAHA后24小时,3个浓度(2μM、4μM和8μM)下,见图2、图4和图6,Q2和Q3区域癌细胞凋亡数目分别占细胞总数目的9.3%、32.0%、43.3%。而实验组在加入化合物Ib-10后24小时,3个浓度(2μM、4μM和8μM)下,见图3、图5和图7,Q2和Q3区域癌细胞凋亡数目分别占细胞总数目的13.4%、55.9%、72.3%,细胞凋亡率比空白对照组分别提高12.3%、54.8%、71.2%,比阳性对照组分别高4.1%、23.9%、29.0%。实验结果说明,化合物Ib-10能够很好地促进细胞凋亡且在测试的各浓度下比SAHA促进细胞凋亡的效果更好。
Claims (10)
1.一种通式(I)所示的化合物或其药学上可接受的盐:
其中
R独立地选自氢、卤素、羟基、巯基、C1~C6烷基(烯基/炔基)、卤代C1~C6烷基(烯基/炔基)、羟基取代的C1~C6烷基(烯基/炔基)、氨基取代的C1~C6烷基(烯基/炔基)、酰胺基取代的C1~C6烷基(烯基/炔基)、羧基取代的C1~C6烷基(烯基/炔基)、C1~C6烷氧基、苄基或其取代衍生物、苯基或其取代的衍生物、和五元或六元杂环甲基或其取代的衍生物;
R1为羟基或C1~C6烷基;
R2为氢、C2~C6酰基或C5~C10芳基甲酰基;
各个R3独立的选自氢、卤素、羟基、羧基、巯基、C1-C6烃硫基、C1-C6烷基(烯基/炔基)、卤代C1~C6烷基(烯基/炔基)、羟基取代的C1~C6烷基(烯基/炔基)、氨基取代的C1~C6烷基(烯基/炔基)、酰胺基取代的C1~C6烷基(烯基/炔基)、羧基取代的C1~C6烷基(烯基/炔基)、和C1~C6烷氧基;
m选自1、2、3或4的整数;
X为O或NH;
A为(CH2)n,n选自0、1、2、3、4、5、6或7的整数;
B为O或CH2;
和C为CH2、CH=CH或下式(2I)所示的基团,
其中
各个R4独立的选自氢、卤素、羟基、羧基、巯基、C1-C6烃硫基、C1-C6烷基(烯基/炔基)、卤代C1~C6烷基(烯基/炔基)、羟基取代的C1~C6烷基(烯基/炔基)、氨基取代的C1~C6烷基(烯基/炔基)、酰胺基取代的C1~C6烷基(烯基/炔基)、羧基取代的C1~C6烷基(烯基/炔基)、和C1~C6烷氧基;
s为选自1、2、3或4的整数;t为选自0、1、2或3的整数;u为选自0、1或2的整数;虚线的键可存在或不存在,若虚线存在,表示为双键,则(2I)的构型为E式或Z式,若虚线不存在,则表示虚线处的键也不存在,苯环直接与(CH2)t连接。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,各个R3均为氢。
3.根据权利要求1~2任一项所述的化合物或其药学上可接受的盐,其特征在于,当R1为羟基时,X为NH,R2为氢;当R1为C1~C6烷基时,X为O,其中C1~C6烷基为甲基或乙基,R2为氢或乙酰基。
4.根据权利要求1~3任一项所述的化合物或其药学上可接受的盐,其特征在于,R为异丙基、苄基、邻甲基苄基。
5.选自以下的化合物或其药学上可接受的盐:
4-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酸乙酯;
5-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯;
6-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酸乙酯;
8-((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酸乙酯;
4-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酸乙酯;
5-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯;
6-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酸乙酯;
7-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)庚酸乙酯;
8-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酸乙酯;
4-((4-乙酰基-2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酸乙酯;
5-((4-乙酰基-2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯;
7-((4-乙酰基-2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)庚酸乙酯;
4-(((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)甲基)苯甲酸乙酯;
(E)-4-(((4-乙酰基-2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-2-丁烯酸乙酯;
(E)-3-(4-(3-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丙氧基)苯基)丙烯酸甲酯;
(E)-4-((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-2-丁烯酸乙酯;
4-(((4-乙酰基-2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)甲基)苯甲酸乙酯;
5-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酸乙酯;
6-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酸乙酯;
8-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酸乙酯;
4-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基丁酰胺;
8-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基辛酰胺;
N-羟基-4-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁酰胺;
N-羟基-5-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酰胺;
N-羟基-6-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酰胺;
N-羟基-8-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)辛酰胺;
N-羟基-(E)-3-(4-(4-((2-异丙基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)丁氧基)苯基)丙烯酰胺(Ib-7);
N-羟基-5-((2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)戊酰胺;
N-羟基-6-((2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)己酰胺;
7-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基庚酰胺;
5-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基戊酰胺;
6-((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)-N-羟基己酰胺;
4-(((2-苄基-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)甲基)-N-羟基苯甲酰胺;
N-羟基-7-((2-(2-甲基苄基)-3-氧代-3,4-二氢苯并[f]喹喔啉-6-基)氧基)庚酰胺。
6.合成权利要求1~5所述化合物的方法,所述方法包括如下所示的步骤:
当R1为C1~C6烷基时,X为O,合成方法包括如下步骤(a)~(d):
或当R1为羟基时,X为NH,R2’除不包括氢外,其余定义与R2一致,合成方法包括如下步骤(a)~(e):
(a)使氨基萘醌与BOC-氨基酸反应,其中BOC指叔丁氧羰基;
(b)使步骤(a)得到的产物环合;
(c)使步骤(b)得到的产物与酸酐R2’-O-R2’反应;
(d)使步骤(c)得到的产物与卤代酯(即化合物(II))反应得到目标产物Ia,其中化合物(II)中Y为Cl、Br或I;
(e)使步骤(e)得到的产物与羟胺的碱金属盐NH2OM反应后酸化得到目标产物Ib,所述M为Li、Na或K;
其中R、R1、R2、R3、A、B、C和m如权利要求1所述;
合成化合物(Ia)和化合物(Ib)的步骤(a)~(d)是相同的;
当合成化合物(Ia)时,若R2为氢,则无步骤(c),直接经步骤(b)得到的产物与卤代酯(即化合物(II))反应得到目标产物Ia;
当合成化合物(Ia)时,若R2不是氢,则按照上述步骤(a)~步骤(d)得到化合物(Ia)。
7.药物组合物,其包含权利要求1~5任一项所述的化合物或其药学上可接受的盐、或者根据权利要求6所述方法合成得到的化合物或其药学上可接受的盐、以及一种或多种药学上可接受的载体、稀释剂、赋形剂或其组合。
8.权利要求1~5任一项所述的化合物或其药学上可接受的盐、权利要求6所述方法合成的化合物或其药学上可接受的盐或者权利要求7所述的药物组合物在制备用于抑制HDAC的药物中的用途。
9.权利要求1~5任一项所述的化合物或其药学上可接受的盐、权利要求6所述方法合成的化合物或其药学上可接受的盐或者权利要求7所述的药物组合物在治疗癌症当中的用途。
10.根据权利要求9所述的用途,其特征在于,所述癌症选自结肠癌、直肠癌、卵巢癌、肝癌、胃癌、膀胱癌、子宫颈癌、肺癌、肾癌、淋巴瘤、骨髓瘤、乳腺癌、前列腺癌、脑癌等恶性肿瘤。
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