CN108752319A - 单胺氧化酶a抑制剂吲哚菁偶联化合物及其制备方法和应用 - Google Patents
单胺氧化酶a抑制剂吲哚菁偶联化合物及其制备方法和应用 Download PDFInfo
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- CN108752319A CN108752319A CN201810287551.9A CN201810287551A CN108752319A CN 108752319 A CN108752319 A CN 108752319A CN 201810287551 A CN201810287551 A CN 201810287551A CN 108752319 A CN108752319 A CN 108752319A
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- quaternary ammonium
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Abstract
本发明属于医药技术领域,涉及一类单胺氧化酶A抑制剂吲哚菁偶联化合物及制备方法和应用,本发明使用MAO‑A抑制剂异烟肼,采用拼合原理将其与具有优良的体内荧光成像特性及肿瘤靶向功能的吲哚七甲川菁染料经酰胺键共价结合,设计得到新型的靶向肿瘤单胺氧化酶A抑制剂‑吲哚菁偶联化合物,其结构式如式(I)‑(III)所示。体外肿瘤细胞生长抑制试验证明该类化合物对前列腺肿瘤细胞具有良好的抑制效果。
Description
技术领域
本发明涉及药学领域,具体涉及单胺氧化酶A抑制剂-吲哚七甲川菁染料偶联化合物及该类化合物的制备方法和在制备抗肿瘤药物,尤其是制备治疗前列腺肿瘤药物中的应用。
背景技术
单胺氧化酶位于细胞线粒体外膜上,根据对底物的选择性和对抑制剂作用的灵敏度,被分为单胺氧化酶A(MAO-A)与单胺氧化酶B(MAO-B)两类;单胺氧化酶A(MAO-A)主要分布在儿茶酚胺能神经元中,对底物血清素(5-HT)、去甲肾上腺素(NE)和多巴胺(DA)具有高亲和性。在人类大脑中MAO-A主要代谢5-HT和NE,保护大脑中枢不受外来胺类物质的侵入,并且终止胺类中枢神经递质的作用以及调节细胞内胺的浓度。依据MAO-A在中枢神经胺类递质代谢方面的作用,MAO-A抑制剂现今主要用于治疗神经紊乱,例如抑郁和焦虑。
Wu JB等人最新研究表明,MAO-A水平上升与前列腺癌(Prostate cancer,PCa)的进程以及患者较差的预后有密切关系。MAO-A含量的增长会导致PCa的恶化;在PCa异种移植老鼠模型中发现,在高Gleason级别PCa样本中可以持续检测到基于MAO-A的致瘤通道,低水平MAO-A可以降低甚至消除PCa细胞的增殖与转移;通过基因定点诱变发现,MAO-A催化活性是增强PCa增殖与转移的主要因素。
在高Gleason级别PCa细胞中MAO-A促进PCa产生、发展以及转移的机理如下:(1)MAO-A于线粒体外膜上催化胺类的氧化脱氨并产生副产物过氧化氢(活性氧类,ROS);(2)激活VEGF-A/NRP1介导的信号通路,稳定缺氧诱导因子HIF1α,过氧化氢以及其他转化ROS产物也可以通过抑制PHD活性稳定缺氧诱导因子HIF1α;(3)释放AKT/FOXO1信号,导致细胞核TWIST1表达增强,促进上皮间质转化(epithelial-mesenchymal transition,EMT),导致细胞去极化、细胞间粘附增强以及转移、入侵的性质的增强。基于以上研究结果,MAO-A可以作为治疗人类PCa的新的潜在药物靶标。
吲哚七甲川菁染料是一种近红外荧光染料,不仅具有良好的光学特性、优越的生物相容性,而且能特异性地靶向肿瘤,在肿瘤组织特异性聚集,其靶向肿瘤的作用机制已经明确的有:(1)肿瘤组织缺氧环境下,缺氧诱导因子HIF1α使有机负离子转运多肽OATP1B3的表达增加,实验证实OATPs是吲哚七甲川菁染料在肿瘤组织的聚集的关键因素,抑制OATPs可显著地阻止吲哚七甲川菁染料在肿瘤组织的聚集;(2)肿瘤细胞比正常细胞的线粒体负膜电位高,一些亲脂性带正电荷的离域的分子会选择性地靶向肿瘤细胞的线粒体,而吲哚七甲川菁染料是一类亲脂性带有正电荷的分子,故可选择性作用于肿瘤细胞线粒体。由此得出结论:吲哚七甲川菁染料兼具特异性靶向定位和优良的体内荧光成像特性,在肿瘤前药的设计中可作为载体发挥靶向作用。
综合上述研究基础,MAO-A可作为治疗前列腺癌的新的药物靶标,吲哚七甲川菁染料同时具有优良的体内荧光成像特性及肿瘤特异性靶向作用,在肿瘤前药的设计中可作为载体发挥靶向作用。
发明内容
本发明的目的是提供单胺氧化酶A抑制剂-吲哚七甲川菁染料偶联化合物及它们的制备方法和应用,选择有商业化来源的MAO-A抑制剂异烟肼,采用拼合原理将其与具有优良的体内荧光成像特性及肿瘤靶向功能的吲哚七甲川菁染料经酰胺键共价结合,设计得到新型的靶向肿瘤单胺氧化酶A抑制剂-吲哚菁偶联化合物,该类化合物兼具肿瘤靶向与前列腺肿瘤治疗的功能。
为实现上述目的,本发明的技术方案为:
本发明提供了式(I)-(III)所示的单胺氧化酶抑制剂-吲哚七甲川菁染料偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药:
其中:
R1和R2各自独立选自氢、C1-C10烷基、C1-C10烷氧基或卤素原子;R1、R2彼此独立,可以相同也可以不同;
R3选自H、C1-C6烷基;
R4为磺酸基丁基、C1-C6烷基、C1-C10羧基烷基、C1-C10烷氧基羰基C1-C10烷基;
Y-为卤素负离子;优选为溴或者碘。
本发明优选式(I)-(III)所示的吲哚七甲川菁染料偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药:
其中,
R1和R2各自独立选自氢、C1-C6烷基、C1-C6烷氧基或卤素原子;R1、R2彼此独立,可以相同也可以不同;
R3选自H、C1-C6烷基;
R4为磺酸基丁基、C1-C6烷基、C1-C6羧基烷基、C1-C6烷氧基羰基C1-C6烷基;
Y-为卤素负离子;优选为溴或者碘。
本发明优选式(I)-(III)所示的吲哚七甲川菁染料偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药:
其中,
R1和R2各自独立选自氢、C1-C4烷基、C1-C4烷氧基或卤素原子;R1、R2彼此独立,可以相同也可以不同;
R3选自C1-C4烷基;
R4为磺酸基丁基、C1-C6烷基、C1-C6羧基烷基、C1-C4烷氧基羰基C1-C6烷基;
Y-为卤素负离子;优选为溴或者碘。
本发明优选式(I)-(III)所示的吲哚七甲川菁染料偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药:
其中,
R1和R2选自氢、甲基、甲氧基、乙基、乙氧基、丙基、丙氧基、异丙基、异丙基、丁基、丁氧基、异丁基、异丁氧基、叔丁基、叔丁氧基、卤素;
R3选自甲基、乙基;
R4为磺酸基丁基;甲基、乙基、丙基、丁基、戊基、己基;羧基甲基、羧基乙基、羧基丙基、羧基丁基、羧基戊基;甲氧基羰基甲基、乙氧基羰基甲基、甲氧基羰基乙基、乙氧基羰基乙基、甲氧基羰基丙基、乙氧基羰基丙基、甲氧基羰基丁基、乙氧基羰基丁基、甲氧基羰基戊基、乙氧基羰基戊基;
Y-为卤素负离子;优选为溴或者碘。
本发明所述的“药用可接受的盐”主要是指带有电荷的有机或无机基团,并且可以与其它药用试剂一起给药,比如在盐中作为配对阳离子和配对阴离子。比如阳离子盐,阴离子盐,两性离子盐。所述的阳离子有钠离子、钾离子、镁离子、钙离子、锌离子、季铵盐,但并不局限于此;阴离子有氯离子、醋酸根离子、甲基苯磺酸离子、柠檬酸盐、碳酸盐和碳酸氢盐,同样阴离子盐也不局限于此。
本发明所述的单胺氧化酶抑制剂-吲哚七甲川菁染料偶联化合物的合成,具体步骤如下:
具有结构通式(I)的单胺氧化酶A抑制剂-吲哚七甲川菁染料偶联化合物,可以通过Scheme 1所列出的通法合成:
其中,R1、R2、R3、R4、Y-如权利要求所述,n=1-5。
具体实施方案如下:
(1)连有取代基R1的2,3-二甲基-3-取代吲哚与含有1~6碳原子的卤代羧酸反应制得季铵盐1,反应溶剂选自甲苯、二甲苯、二氯苯、乙醇、甲醇、乙腈,反应时间4~40小时,反应温度60~148℃,取代吲哚与卤代羧酸的摩尔比1:1~1:4。
(2)连有取代基的R2的2,3-二甲基-3-取代吲哚与丁基磺酸内酯或者X-R4反应制得季铵盐2,X-R4选自含有1~6碳原子的卤代烷烃、含有1~6碳原子的卤代羧酸、含有1~6碳原子的卤代羧酸酯,反应溶剂选自甲苯、二甲苯、二氯苯、乙醇、甲醇、乙腈,反应时间4~40小时,反应温度60~148℃,取代吲哚与烃化剂的摩尔比1:1~1:4。
(3)将步骤(1)制得的季铵盐1、步骤(2)制得的季铵盐2,与2-氯代己烯二醛3在适当的溶剂及催化体系下反应制得吲哚七甲川菁化合物4;该反应适当的溶剂及催化体系是包括但不局限于醋酐/醋酸钠、醋酐/三乙胺等适合该反应进行的配伍体系;季铵盐1、季铵盐2、化合物3的摩尔配比是1:1:1,参与反应的季铵盐1和季铵盐2可以是相同的,也可以是不同的;当季铵盐1与季铵盐2相同时,反应得到对称的吲哚七甲川菁化合物4;当季铵盐1与季铵盐2不同时,反应得到不对称的吲哚七甲川菁化合物4。
(4)吲哚七甲川菁4与异烟肼在适宜的缩合剂存在下发生缩合反应得到具有结构通式(I)化合物;适宜的缩合剂是技术范围内已知的各类缩合剂,包括但并不局限于活性酯类、碳二亚胺类、鎓盐类、有机鏻类、酰氯类等。
具有结构通式(II)的单胺氧化酶A抑制剂-吲哚七甲川菁染料偶联化合物,可以通过Scheme 2所列出的通法合成:
其中,R1、R2、R3、R4、Y-如权利要求所述,n=1-5。
具体实施方案如下:
(1)连有取代基R1的2,3-二甲基-3-取代吲哚与含有1~6碳原子的卤代羧酸反应制得季铵盐1,反应溶剂选自甲苯、二甲苯、二氯苯、乙醇、甲醇、乙腈,反应时间4~40小时,反应温度60~148℃,取代吲哚与卤代羧酸的摩尔比1:1~1:4。
(2)连有取代基的R2的2,3-二甲基-3-取代吲哚与丁基磺酸内酯或者Y-R4反应制得季铵盐2,Y-R4选自含有1~6碳原子的卤代烷烃、含有1~6碳原子的卤代羧酸、含有1~6碳原子的卤代羧酸酯,反应溶剂选自甲苯、二甲苯、二氯苯、乙醇、甲醇、乙腈,反应时间4~40小时,反应温度60~148℃,取代吲哚与烃化剂的摩尔比1:1~1:4。
(3)季铵盐1、季铵盐2、与戊二烯醛缩苯胺盐酸盐6在适当的溶剂及催化体系下反应制得吲哚七甲川菁化合物7;该反应适当的溶剂及催化体系是包括但不局限于醋酐/醋酸钠、醋酐/三乙胺等适合该反应进行的配伍体系;季铵盐1、季铵盐2及化合物6的摩尔配比是1:1:1,参与反应的季铵盐1和季铵盐2可以是相同的,也可以是不同的;当季铵盐1与季铵盐2相同时,反应得到对称的吲哚七甲川菁化合物7;当季铵盐1与季铵盐2不同时,反应得到不对称的吲哚七甲川菁化合物7。
(4)吲哚七甲川菁7与异烟肼在适宜的缩合剂存在下发生缩合反应得到具有结构通式II化合物;适宜的缩合剂是技术范围内已知的各类缩合剂,包括但并不局限于活性酯类、碳二亚胺类、鎓盐类、有机鏻类、酰氯类等。
具有结构通式(III)的单胺氧化酶A抑制剂-吲哚七甲川菁染料偶联化合物,可以通过Scheme 3所列出的通法合成:
具体实施方案如下:
(1)1,1,2-三甲基苯并[e]吲哚8与丁基磺酸内酯反应制得季铵盐9;1,1,2-三甲基苯并[e]吲哚8与6-卤代己酸发生烃反应制得季铵盐10;以上反应溶剂选自甲苯、二甲苯、二氯苯、乙醇、甲醇、乙腈,反应时间4~40小时,反应温度60~148℃,1,1,2-三甲基苯并[e]吲哚8与烃化剂的摩尔比1:1~1:4。
(2)将步骤(1)制得的季铵盐9、季铵盐10,与戊二烯醛缩苯胺盐酸盐6在适当的溶剂及催化体系下反应制得吲哚七甲川菁化合物11;季铵盐9、季铵盐10及化合物6的摩尔配比是1:1:1,该反应适当的溶剂及催化体系是包括但不局限于醋酐/醋酸钠、醋酐/三乙胺等适合该反应进行的配伍体系。
(3)吲哚七甲川菁11与异烟肼在适宜的缩合剂存在下发生缩合反应得到具有结构通式(III)化合物;适宜的缩合剂是技术范围内已知的各类缩合剂,包括但并不局限于活性酯类、碳二亚胺类、鎓盐类、有机鏻类、酰氯类等。
本发明还提供了一种药物组合物,包含所述的吲哚七甲川菁染料偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药和药学上可接受的载体。
本发明的另一目的是提供上述单胺氧化酶A抑制剂-吲哚七甲川菁染料偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药和药物组合物在制备抗肿瘤药物中的应用。
本发明所述的单胺氧化酶A抑制剂-吲哚七甲川菁染料偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药和药物组合物能够有效抑制肿瘤细胞的生长;尤其是抑制前列腺肿瘤细胞的生长。
具体实施方式
以下通过实施例的具体实施方式再对本发明内容作进一步详细说明,所述是对本发明的解释而不是限定。在不脱离本发明的精神和原则之内所做的任何修改应包括在本发明的保护范围内。
实施例1
2-[2-[3-[2-[1-(5-羧戊基)-1,3-二氢-3,3,5-三甲基-2H-吲哚-2-甲叉基]乙叉基]-2-氯-1-环己烯-1-基]乙叉基]-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3,5-三甲基-3H-吲哚溴鎓盐(G-1)的合成:
(1)1-(羧基己基)-2,3,3-三甲基-5-甲基-3H-吲哚鎓盐溴化物(1-1)的合成:
室温下,将2,3,3,5-四甲基-3H-吲哚(5g,28.9mmol)溶于140mL乙腈中,加入6-溴代己酸(22.43g,116mmol),氮气保护下反应液升温至回流反应40h。反应毕,减压干燥后得到棕黄色粘稠液体,加400mL乙酸乙酯搅拌,抽滤,得淡棕色固体1-1。
(2)2-[2-[3-[2-[1-(5-羧戊基)-1,3-二氢-3,3,5-三甲基-2H-吲哚-2-甲叉基]基]-2-氯-1-环己烯-1-基]乙叉基]-1-(5-羧戊基)-3,3,5-三甲基-3H-吲哚溴鎓盐(化合物4-1)的合成:
中间体1-1(500mg,2.9mmol)与(E)-2-氯-3-(羟基亚甲基)环已基-1-烯甲醛3(2.13g,5.8mmol)溶于60mL乙酸酐中,并加入乙酸钠(0.24g,2.9mmol),在氮气保护下,升温至70℃搅拌40min。反应结束后,冷却至室温,加入300mL水,搅拌后放置3h,抽滤后得深紫色固体化合物4-1 1.6g,收率为69.9%。
(3)化合物G-1的合成:
0℃以下将中间体4-1(400mg,0.515mmol)溶于80mL无水二氯甲烷中,搅拌中加入PyBOP(268mg,0.515mmol),搅拌15min后移至室温环境,加入异烟肼(59mg,0.429mmol),升温至25℃反应约15h。反应结束后,过滤,旋干后得粗品,经柱层析纯化后得绿色固体化合物G-1 150mg。MS(ESI)m/z:830.6[M+H]+;1H NMR(400MHz,CDCl3)δ8.64(s,2H),8.31(d,J=14.1Hz,1H),8.16(d,J=13.6Hz,1H),7.93(s,2H),7.17–7.09(m,4H),6.93(d,J=7.9Hz,1H),6.31(d,J=14.3Hz,1H),5.92(d,J=13.8Hz,1H),4.23–4.15(br,2H),3.96–3.90(br,2H),2.67–2.63(br,2H),2.52–2.47(br,2H),2.46–2.42(br,2H),2.36(d,J=7.4Hz,6H),2.34(s,2H),1.87–1.83(br,2H),1.78–1.73(br,4H),1.69(s,2H),1.65(s,6H),1.64(s,6H),1.48(d,J=6.7Hz,2H),1.38–1.33(m,4H)。
实施例2
2-[2-[3-[2-[5-甲氧基-1-(5-羧戊基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基]乙叉基]-2-氯-1-环己烯-1-基]乙叉基]-5-甲氧基-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3-二甲基-3H-吲哚鎓盐溴化物(G-2)的合成:
采用实施例1相同的制备方法,以2,3,3-三甲基-5-甲氧基-3H-吲哚为原料经3步反应制得化合物G-2。MS(ESI)m/z:862[M+H]+;1H NMR(400MHz,CDCl3)δ8.63–8.56(br,2H),8.21(d,J=14.2Hz,1H),8.17–8.10(m,2H),7.89–7.81(br,2H),7.11(d,J=8.5Hz,1H),6.89(s,1H),6.87(s,1H),6.84(s,2H),6.14(d,J=13.7Hz,1H),5.92(d,J=12.6Hz,1H),4.09–4.01(br,2H),3.94–3.87(br,2H),3.82(s,3H),3.80(d,J=3.7Hz,3H),2.58–2.54(br,2H),2.50–2.45(br,2H),2.43–2.34(br,2H),2.23(d,J=27.3Hz,4H),1.83–1.78(br,2H),1.77–1.70(br,6H),1.65(s,6H),1.63(s,6H),1.56(d,J=10.1Hz,4H)。
实施例3
2-[2-[3-[2-[5-溴-1-(5-羧戊基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基]乙叉基]-2-氯-1-环己烯-1-基]乙烯基]-5-溴-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3-二甲基-3H-吲哚鎓盐溴化物(G-3)的合成路线如下:
采用实施例1相同的制备方法,以2,3,3-三甲基-5-溴-3H-吲哚为原料经3步反应制得化合物G-3。MS(ESI)m/z:960[M+H]+;1H NMR(400MHz,CD3OD)δ8.71(d,J=5.6Hz,2H),8.42(t,J=7.0Hz,2H),8.39(s,1H),7.81(dd,J=4.6,1.5Hz,2H),7.71(d,J=1.5Hz,2H),7.69–7.65(m,1H),7.58–7.57(m,1H),7.56(dd,J=3.2,1.7Hz,1H),7.55(d,J=1.9Hz,1H),7.28(d,J=1.9Hz,1H),7.27(d,J=2.9Hz,1H),6.31(d,J=14.0Hz,1H),6.30(d,J=4.5Hz,1H),6.28(d,J=6.8Hz,1H),2.75–2.71(br,2H),2.69(t,J=5.9Hz,2H),2.36(t,J=7.1Hz,2H),2.20(t,J=5.7Hz,2H),1.92–1.89(m,4H),1.79(dt,J=14.7,7.1Hz,2H),1.73(d,J=2.8Hz,12H),1.71~1.65(m,4H),1.58(dt,J=15.4,7.7Hz,2H),1.50~1.44(m,4H)。
实施例4
2-(7-(5-甲氧基-1-(5-羧戊基)-1,3-二氢-3-乙基-3-甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-甲氧基-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3-乙基-3-三甲基-3H-吲哚鎓盐溴化物(G-4)的合成:
采用实施例1相同的制备方法,以2,3-二甲基-3-乙基-5-甲氧基-3H-吲哚为原料经3步反应制得化合物G-4。MS(ESI)m/z:891.5[M+H]+。1H NMR(400MHz,CDCl3)δ8.61–8.57(s,1H),8.21(d,J=13.2Hz,1H),8.13(d,J=13.1Hz,1H),7.77–7.70(br,2H),7.68–7.62(br,1H),7.57–7.50(br,1H),7.18–7.10(br,1H),7.07(d,J=8.5Hz,1H),6.97(d,J=8.4Hz,2H),6.91–6.87(m,1H),6.85(d,J=8.0Hz,1H),6.16(d,J=13.4Hz,2H),5.98(d,J=13.7Hz,1H),4.06–3.97(br,2H),3.95–3.88(br,2H),3.83(d,J=6.0Hz,6H),2.56–2.50(br,2H),2.50–2.44(br,2H),2.38–2.32(br,2H),2.30–2.21(br,4H),2.13–2.07(m,2H),2.00–1.94(br,4H),1.73–1.69(m,4H),1.64(d,J=5.7Hz,6H),1.53~1.48(br,2H),1.44~1.39(br,2H),1.26(d,J=7.7Hz,2H),1.21(d,J=7.0Hz,6H)。
实施例5
2-[2-[3-[2-[1-(5-羧戊基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基]乙叉基]-2-氯-1-环己烯-1-基]乙烯基]-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3-二甲基-3H-吲哚鎓盐溴化物(G-5)的合成:
采用实施例1相同的制备方法,以3,3-二甲基-3H-吲哚为原料经3步反应制得化合物G-5。MS(ESI)m/z:802.5[M+H]+。1H NMR(400MHz,CDCl3)δ8.63–8.57(br,2H),8.27(d,J=14.0Hz,1H),8.17(d,J=13.6Hz,1H),7.87–7.80(br,2H),7.77–7.70(br,1H),7.64–7.57(br,1H),7.38–7.34(m,1H),7.31(d,J=7.2Hz,2H),7.18(d,J=7.4Hz,1H),7.14(d,J=8.6Hz,2H),7.06–7.01(m,2H),6.27(d,J=13.7Hz,1H),5.97(d,J=13.0Hz,1H),4.12–4.06(br,2H),3.95–3.89(br,2H),2.55–2.50(br,2H),2.47–2.41(br,2H),2.40–2.33(br,2H),2.32–2.25(m,2H),1.89–1.79(br,2H),1.78–1.71(br,4H),1.67(d,J=9.6Hz,12H),1.63(s,2H),1.60(d,J=4.4Hz,2H),1.56(d,J=5.6Hz,2H),1.44–1.40(m,2H)。
实施例6
2-(7-(1-(5-羧戊基)-1,3-二氢-3,3,5-三甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3,5-三甲基-3H-吲哚鎓盐溴化物(G-6)的合成:
(1)2-(7-(1-(5-羧戊基)-1,3-二氢-3,3,5-三甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(5-羧戊基)-3,3,5-三甲基-3H-吲哚鎓盐溴化物(7-1)的合成:
将戊二烯醛缩二苯胺盐酸盐6(500mg,1.76mmol)与化合物1-1(1.29g,3.52mmol)溶于40mL乙酸酐中,搅拌下加入2mL三乙胺,在氮气保护下,升温至50℃反应40min。反应结束后,冷却至室温,加入300mL水搅拌后放置3h,以300mL乙酸乙酯萃取,有机层加入无水硫酸钠干燥过夜,减压蒸干溶剂,残留物柱层析纯化后得深蓝绿色固体7-1 0.45g。
(2)化合物G-6的合成:
在0℃以下,将中间体7-1(369mg,0.515mmol)溶于80mL无水二氯甲烷中,搅拌中加入PyBOP(268mg,0.515mmol),搅拌15min后移至室温环境,加入异烟肼(59mg,0.429mmol),室温反应约15h。反应结束后,过滤,减压蒸干溶剂后,残留物经柱层析纯化后,得绿色固体化合物G-6150mg。MS(ESI)m/z:756.4[M+H]+;1H NMR(400MHz,CD3OD)δ8.73(d,J=4.9Hz,2H),7.87(dd,J=12.9,5.9Hz,2H),7.83(d,J=5.6Hz,2H),7.57–7.49(br,1H),7.28(s,2H),7.20(d,J=2.8Hz,1H),7.18(d,J=2.8Hz,1H),7.14(t,J=8.0Hz,2H),6.51(t,J=12.5Hz,1H),6.43(t,J=12.6Hz,1H),6.25(d,J=13.5Hz,1H),6.19(d,J=13.3Hz,1H),4.05(dt,J=14.7,7.5Hz,4H),2.39(d,J=2.9Hz,6H),2.36(t,J=7.2Hz,2H),2.25–2.18(br,2H),1.88–1.82(m,2H),1.81–1.76(m,4H),1.68(s,2H),1.66(s,6H),1.65(s,6H),1.57(dt,J=14.9,7.6Hz,2H),1.51–1.43(m,2H)。
实施例7
2-(7-(5-甲氧基-1-(5-羧戊基)-1,3-二氢-3,5-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-甲氧基-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,5-二甲基-3H-吲哚鎓盐溴化物(G-7)的合成:
采用实施例6相同的制备方法,以3,3-二甲基-5-甲氧基-3H-吲哚为原料经3步反应制得化合物G-7。MS(ESI)m/z:788[M+H]+;1H NMR(400MHz,CDCl3)δ8.70(d,J=4.9Hz,2H),8.63–8.57(br,2H),7.89–7.80(br,2H),7.72(d,J=11.3Hz,1H),7.66(d,J=3.9Hz,2H),7.52–7.39(m,1H),7.15–7.10(m,1H),6.98(d,J=8.5Hz,1H),6.90(d,J=8.3Hz,1H),6.86(s,2H),6.53–6.42(br,1H),6.25(d,J=12.7Hz,1H),5.93(d,J=13.3Hz,1H),3.96–3.86(br,2H),3.82(s,3H),3.82(s,3H),3.48(q,J=7.0Hz,2H),2.31(d,J=35.7Hz,2H),1.79–1.61(br,6H),1.58(s,3H),1.57(s,3H),1.56–1.53(m,2H),1.52–1.48(br,2H),1.44–1.39(br,2H),1.21(t,J=7.0Hz,2H)。
实施例8
2-(7-(5-甲氧基-1-(5-羧戊基)-1,3-二氢-5-乙基-3-甲基-2H-吲哚-2-甲基)-1,3,5-庚三烯-1-基)-1-(6-(2-异烟酰肼基)-6-氧代己基)-5-甲氧基-3-乙基-3-甲基-3H-吲哚鎓盐溴化物(G-8)的合成:
采用实施例6相同的制备方法,以5-甲氧基-3-乙基-2-甲基-3H-吲哚为原料经3步反应制得化合物G-8。MS(ESI)m/z:816.6[M+H]+;1H NMR(400MHz,CD3OD)δ8.73(s,1H),7.84(d,J=4.1Hz,2H),7.80(d,J=12.7Hz,2H),7.51–7.43(br,1H),7.19(t,J=8.8Hz,2H),7.03(t,J=2.3Hz,2H),6.97–6.95(m,1H),6.95–6.94(m,1H),6.49(t,J=12.0Hz,1H),6.42(t,J=12.3Hz,1H),6.27(d,J=13.6Hz,1H),6.21(d,J=13.7Hz,1H),4.05(dd,J=15.0,7.7Hz,4H),3.84(s,3H),3.83(s,3H),2.36(t,J=7.3Hz,2H),2.32(dd,J=12.7,6.7Hz,2H),2.26–2.13(br,4H),1.85–1.81(m,2H),1.81–1.77(m,4H),1.70–1.67(br,2H),1.66(s,3H),1.65(s,3H),1.61–1.56(br,2H),1.52-1.44(br,2H)。
实施例9
2-(7-(5-甲氧基-1(4-磺酰氧丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3,5-三甲基-3H-吲哚内铵盐(G-9)的合成:
(1)5-甲氧基-1-(4-磺酰氧丁基)-2,3,3-三甲基-3H-吲哚内铵盐(2-1)的合成:
将5-甲氧基-2,3,3-三甲基-3H-吲哚(2g,10.6mmol)与1,4-丁基磺酸内酯(4.3g,31.7mmol)溶于40mL甲苯中,升温至120℃回流反应50h。反应结束后,过滤得灰白色固体,经柱层析纯化后得淡黄色固体2-1 1.9g。
(2)2-(7-(5-甲氧基-1-(4-磺酰氧基丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(5-羧戊基)-3,3,5-三甲基-3H-吲哚内铵盐(7-4)的合成:
将化合物2-1(1.5g,4.6mmol)与2-戊烯二醛二缩苯胺盐酸盐6(1.31g,4.6mmol)溶入35mL乙酸酐中,升温至50℃反应50min后加入化合物1-1(1.69g,4.6mmol)与2mL三乙胺,继续反应40min。反应结束后,冷却至室温,加1500mL乙醚,并用盐酸调pH至5,过滤得粗品,粗品经柱层析纯化后,得深紫色固体化合物7-4 800mg。
(3)化合物G-9的合成:
在0℃以下,将中间体7-4(200mg,0.297mmol)溶于40mL无水二氯甲烷中,搅拌中加入DIPEA(49μL,0.297mmol),继续加入PyBOP(154mg,0.297mmol),搅拌15min后移至室温环境,加入异烟肼(49mg,0.356mmol),室温反应约15h。反应结束后,过滤得粗品,粗品经柱层析纯化后得绿色固体化合物G-9 100mg。MS(ESI)m/z:816.3[M+Na]+;1H NMR(400MHz,CDCl3)δ8.63(s,1H),8.58–8.55(br,2H),7.79–7.76(br,2H),7.69(s,1H),7.46–7.34(m,2H),7.11–7.06(br,2H),7.02(d,J=7.1Hz,1H),6.99(s,1H),6.86(d,J=6.1Hz,1H),6.74(s,2H),6.39–6.32(br,2H),6.24–6.17(br,1H),6.03–5.93(br,1H),4.04–3.97(br,2H),3.85–3.77(br,2H),3.46(s,3H),3.04–2.99(m,2H),2.41–2.35(br,2H),2.28(s,3H),2.07–2.02(br,2H),1.88–1.83(br,2H),1.71–1.65(m,4H),1.45(s,12H),1.33(d,J=6.6Hz,2H)。
实施例10
2-(7-(5-甲氧基-1-(4-磺酰氧丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-甲氧基-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3-二甲基-3H-吲哚内铵盐(G-10)的合成:
采用实施例9相同的制备方法,中间体2-1、化合物6与中间体1-2,缩合反应得到中间体7-5,并与异烟肼缩合得到化合物G-10。MS(ESI)m/z:832.3[M+Na]+;1H NMR(400MHz,CDCl3)δ8.46–8.35(br,2H),7.72–7.62(br,2H),7.47(d,J=25.0Hz,2H),7.00–6.90(br,2H),6.94(s,1H),6.82–6.76(br,2H),6.80(s,1H),6.72(d,J=17.0Hz,2H),6.62(s,2H),6.60–6.55(br,1H),6.32–6.22(br,2H),6.05–5.98(br,1H),5.97–5.89(br,1H),3.83–3.75(br,2H),3.71(s,3H),3.52(s,3H),2.92–2.82(br,2H),2.33–2.19(br,2H),1.93–1.82(br,2H),1.57–1.43(m,6H),1.39(s,6H),1.34(s,6H),1.29–1.25(m,4H)。
实施例11
2-(7-(5-甲氧基-1-(4-磺酰氧丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-溴-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3-二甲基-3H-吲哚内铵盐(G-11)的合成:
采用实施例9相同的制备方法,中间体2-1、化合物6与中间体1-3通过缩合反应得到中间体7-6,并与异烟肼缩合得到化合物G-11。MS(ESI)m/z:880[M+Na]+;1H NMR(400MHz,CDCl3)δ8.41–8.34(br,2H),7.66–7.60(br,2H),7.57–7.54(br,1H),7.53–7.50(br,2H),7.47–7.44(br,2H),7.40–7.33(m,1H),7.22–7.19(br,1H),6.99–6.97(br,1H),6.68–6.65(br,1H),6.63(d,J=8.2Hz,1H),6.57(d,J=5.9Hz,1H),6.23(dd,J=24.2,12.2Hz,2H),6.16(d,J=9.4Hz,1H),5.76–5.69(br,1H),3.81–3.69(br,2H),3.56(s,3H),2.87–2.77(br,2H),2.24–2.14(br,2H),1.87–1.73(br,2H),1.49–1.43(br,2H),1.35(s,4H),1.34(s,6H),1.34(s,6H),1.25(t,2H),1.22–1.17(m,2H)。
实施例12
2-(7-(5-甲氧基-1-(4-磺酰氧丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3-二甲基-3H-吲哚内铵盐(G-12)的合成:
采用实施例9相同的制备方法,中间体2-1、化合物6与中间体1-5通过缩合反应得到中间体7-7,并与异烟肼缩合得到化合物G-12。MS(ESI)m/z:802[M+Na]+;1H NMR(400MHz,CD3OD)δ8.68(d,J=4.5Hz,2H),7.95–7.89(m,1H),7.86(d,J=5.2Hz,2H),7.78(t,J=13.1Hz,1H),7.70–7.64(m,1H),7.57–7.46(m,1H),7.39(d,J=7.4Hz,1H),7.33(dd,J=12.3,8.1Hz,2H),7.27–7.23(m,1H),7.14(dd,J=15.6,8.1Hz,4H),6.99(dd,J=8.7,2.4Hz,1H),6.54–6.45(m,2H),6.40(d,J=14.1Hz,1H),6.12(d,J=12.8Hz,1H),4.21–4.15(m,2H),4.02–3.98(m,2H),3.85(s,3H),2.89(t,J=7.0Hz,2H),2.35(t,J=7.0Hz,2H),2.01–1.94(m,2H),1.96–1.93(m,2H),1.83–1.78(m,3H),1.70(d,J=5.8Hz,4H),1.69(s,6H),1.66(s,6H),1.58–1.55(br,2H)。
实施例13
2-(7-(5-甲氧基-1-(4-磺酰氧丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3-二甲基-1H-4,5-苯并[e]吲哚内铵盐(G-13)的合成:
采用实施例9相同的制备方法,中间体2-1、化合物6与中间体10通过缩合反应得到中间体7-8,并与异烟肼缩合得到化合物G-13。MS(ESI)m/z:853[M+Na]+;1H NMR(400MHz,CD3OD)δ8.69(d,J=5.9Hz,2H),8.17(d,J=8.5Hz,1H),7.93(d,J=8.8Hz,1H),7.92(d,J=8.5Hz,1H),7.87(d,J=13.5Hz,1H),7.81(d,J=6.1Hz,2H),7.58(t,J=7.2Hz,2H),7.51(d,J=8.8Hz,1H),7.41(t,J=7.6Hz,1H),7.30(d,J=8.7Hz,1H),7.10(d,J=2.4Hz,1H),6.96(dd,J=8.7,2.4Hz,1H),6.48(dt,J=24.1,12.2Hz,2H),6.33(d,J=13.9Hz,1H),6.20(d,J=13.4Hz,1H),4.16–4.12(br,2H),3.84(s,2H),3.35(s,1H),2.90(t,J=7.0Hz,1H),2.36(t,J=7.2Hz,1H),1.95(s,4H),1.88(dd,J=15.2,6.7Hz,1H),1.81(dt,J=14.8,7.3Hz,1H),1.67(s,3H),1.64–1.58(m,1H),1.31–1.27(br,1H)。
实施例14
2-(7-(5-甲氧基-1-丁基-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(4-(2-异烟酰肼基)-4-氧代丁基)-1,3-二氢-3,3,5-三甲基-3H-吲哚鎓盐溴化物(G-14)的合成:
(1)5-甲氧基-1-丁基-2,3,3-三甲基-3H-吲哚溴鎓盐(2-2)的合成:
将5-甲氧基-2,3,3-三甲基-3H-吲哚(2g,10.6mmol)与1-溴丁烷(4.3g,31.7mmol)溶于60mL乙腈中,升温至75℃回流反应50h。反应结束后,过滤,得棕色油状液体2.1g,收率61.0%,经柱层析纯化后,得淡黄色固体2-2 1.5g。
(2)1-(3-羧丙基)-2,3,3,5-四甲基-3H-吲哚鎓溴盐(2-4)
同步骤(2)制备方法相同,以2,3,3,5-四甲基吲哚与4-溴丁酸乙酯为原料反应得到中间体2-3,再经盐酸水解得到中间体2-4。
(3)化合物G-14的合成
采用实施例9相同的制备方法,中间体2-2、化合物6与中间体2-4经缩合反应得到中间体7-9,再与异烟肼缩合得到化合物G-14。MS(ESI)m/z:686.4[M-Br]+;1H NMR(600MHz,CDCl3)δ8.61(d,J=4.8Hz,2H),7.84(d,J=5.0Hz,2H),7.67–7.61(m,2H),7.60–7.53(m,1H),7.34–7.28(br,1H),7.13(s,2H),7.10(d,J=8.0Hz,1H),7.06(s,1H),6.91(d,J=8.5Hz,1H),6.88(s,1H),6.83(d,J=8.5Hz,1H),6.62–6.54(br,1H),6.35(dd,J=34.6,12.5Hz,2H),5.89(d,J=12.9Hz,2H),4.19–4.14(br,2H),3.91–3.84(m,2H),3.82(s,3H),3.14(td,J=6.5,3.7Hz,2H),2.70–2.64(br,2H),2.34(s,3H),2.10–2.04(m,2H),1.75–1.69(m,2H),1.60(s,6H),1.57(s,6H),0.97(t,J=7.3Hz,3H)。
实施例15
2-(7-(5-甲氧基-1-丁基-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(4-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3,5-三甲基-3H-吲哚鎓盐溴化物(G-15)的合成:
采用实施例9相同的制备方法,中间体2-2、化合物6与中间体1-1经缩合反应得到中间体7-10,再与异烟肼缩合得到化合物G-15。MS(ESI)m/z:714.5[M-Br]+;1H NMR(400MHz,CDCl3)δ8.62(s,2H),7.67(s,4H),7.43–7.36(br,1H),7.11(d,J=8.0Hz,1H),7.08(s,1H),6.95(t,J=7.4Hz,2H),6.89(d,J=2.0Hz,1H),6.86(dd,J=8.6,2.3Hz,1H),6.55–6.48(m,1H),6.40(t,J=11.9Hz,1H),6.06(d,J=13.3Hz,1H),5.98(d,J=13.2Hz,1H),3.90(s,4H),3.83(s,3H),2.34(s,3H),1.63(s,6H),1.60(s,6H),1.54–1.50(m,2H),1.43(dq,J=14.8,7.4Hz,2H),1.32(d,J=6.6Hz,2H),0.96(t,J=7.3Hz,3H)。
实施例16
2-(7-(5-甲氧基-1-丁基-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-溴-1-(4-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3-二甲基-3H-吲哚鎓盐溴化物(G-16)的合成:
采用实施例9相同的制备方法,中间体2-2、化合物6与中间体1-3经缩合反应得到中间体7-11,再与异烟肼缩合得到化合物G-16。MS(ESI)m/z:778.3[M-Br]+;1H NMR(600MHz,CDCl3)δ8.60(s,2H),7.75(t,J=12.9Hz,1H),7.70–7.65(br,2H),7.57(t,J=12.7Hz,1H),7.41(t,J=12.1Hz,1H),7.36(d,J=8.0Hz,1H),7.29(s,1H),7.07(d,J=8.7Hz,1H),6.92(s,1H),6.90(d,J=10.6Hz,1H),6.85(d,J=8.2Hz,1H),6.46(dd,J=21.9,11.3Hz,2H),6.17(d,J=13.9Hz,1H),5.90(d,J=12.3Hz,1H),4.03–3.98(br,2H),3.84(s,3H),3.80–3.76(br,2H),2.36–2.29(br,2H),1.78–1.75(m,2H),1.72–1.67(br,4H),1.64(s,6H),1.57(s,6H),1.50–1.46(br,2H),1.45–1.42(m,2H),0.96(t,J=7.1Hz,3H)。
实施例17
2-(7-(5-甲氧基-1-(4-磺酰氧丁基)-1,3-二氢-3-乙基-3-甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-甲氧基-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3-乙基-3-三甲基-3H-吲哚内铵盐(G-17)的合成:
采用实施例9相同的制备方法,中间体2-5、化合物6与中间体1-4经缩合反应得到中间体7-12,再与异烟肼缩合得到化合物G-17。MS(ESI)m/z:860.5[M+Na]+;1H NMR(400MHz,CDCl3)δ8.60(s,2H),7.81(s,2H),7.49–7.35(br,2H),7.27(s,1H),7.15–7.07(br,1H),7.06–7.00(br,1H),7.00–6.93(br,1H),6.84–6.77(m,2H),6.75(s,1H),6.70(s,1H),6.54–6.47(br,1H),6.46–6.38(br,1H),6.28–6.21(br,1H),6.20–6.13(br,1H),4.08–3.84(m,4H),3.77(s,3H),3.70(s,3H),3.03–2.97(br,2H),2.44–2.38(br,2H),2.08–2.00(br,4H),1.98–1.92(br,2H),1.85–1.77(br,2H),1.75–1.66(br,4H),1.57–1.52(br,2H),1.52–1.43(m,6H),0.34(s,3H),0.30(s,3H)。
实施例18
2-(7-(1-(4-乙氧基-4-氧代丁基)-1,3-二氢-3,3,5-三甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3,5-三甲基-3H-吲哚鎓盐溴化物(G-18)的合成:
采用实施例9相同的制备方法,中间体2-3、化合物6与中间体1-1经缩合反应得到中间体7-12,再与异烟肼缩合得到化合物G-18。MS(ESI)m/z:756.6[M-Br]+;1H NMR(400MHz,CDCl3)δ8.69(d,J=5.6Hz,2H),7.70(d,J=5.8Hz,3H),7.67–7.60(br,1H),7.41–7.32(br,1H),7.16(d,J=8.1Hz,1H),7.13(d,J=6.2Hz,1H),7.10(s,2H),7.00(t,J=8.8Hz,1H),6.63–6.56(m,1H),6.42(t,J=12.5Hz,1H),6.23(d,J=13.4Hz,1H),6.01(d,J=13.2Hz,1H),4.17(q,J=7.1Hz,2H),3.98(dt,J=15.3,7.7Hz,4H),2.49(t,J=6.6Hz,2H),2.10–2.02(m,2H),1.84–1.75(m,4H),1.67(s,2H),1.63(d,J=3.4Hz,12H),1.59–1.53(m,2H),1.27(t,J=7.1Hz,3H)。
实施例19
2-(7-(3,3-二甲基-1-(4-磺酰氧丁基)-4,5-苯并[e]吲哚-2-甲叉基)庚-1,3,5-三烯-1-基)-1-(5-羧戊基)-1,3-二氢-3,3-二甲基-1H-4,5-苯并[e]吲哚内铵盐(G-19)的合成:
(1)中间体9与中间体10的合成:
采用实施例9步骤(1)相同的制备方法,制得中间体9;采用实施例1步骤(1)相同的制备方法,制得中间体10。
(2)化合物G-19的合成:
采用实施例9相同的制备方法,中间体9、化合物6与中间体10经缩合反应得到中间体7-14,再与异烟肼缩合得到化合物G-19。MS(ESI)m/z:872.5[M+H]+;1H NMR(400MHz,CDCl3)δ8.65(d,J=5.0Hz,1H),8.55(s,4H),7.99–7.91(m,2H),7.84–7.79(br,4H),7.74(s,2H),7.68(d,J=5.0Hz,1H),7.60–7.56(br,1H),7.53–7.46(m,2H),7.42–7.37(br,1H),7.35(d,J=7.5Hz,2H),7.31–7.29(m,1H),7.22–7.10(br,1H),6.61–6.52(br,1H),6.50–6.43(br,1H),6.37–6.28(br,1H),6.26–6.17(br,1H),4.17–4.07(br,2H),4.07–3.95(br,2H),3.08–3.00(br,2H),2.47–2.31(br,2H),2.07(s,4H),1.98–1.89(br,2H),1.78(s,6H),1.75(s,6H),1.58–1.50(m,2H)。
MTT法是一种在体外检测药物细胞毒性大小的实验方法,MTT的化学名为3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,商品名叫噻唑蓝。本专利采用MTT法测定细胞毒性,对上述单胺氧化酶A抑制剂-吲哚七甲川菁染料偶联化合物--进行抗前列腺癌细胞活性测定,所用前列腺癌细胞为PC3细胞。
具体操作如下:将需要传代的细胞制备成一定细胞密度的细胞悬液,PC3的细胞密度是8.0×104cells/mL,轻轻吹打以混合均匀。取一块在96孔板,在每个孔中快速加入100μL的细胞悬液,然后于培养箱中培养24h使其贴壁。次日,观察细胞贴壁情况,细胞状态良好便可加药。取培养基配置不同浓度的药物溶液,每孔加100μL含药细胞培养液,每个浓度设置3个复孔;空白对照组,每孔加100μL新鲜培养液。之后在培养箱中再培养48h。48h之后,将96孔板中的旧培养液吸走,每孔再加入100μL新鲜细胞培养液。然后,每孔加15μL浓度为5mg/mL的MTT溶液,放到37℃恒温箱中孵育4h,倒掉培养液,每孔加100μL DMSO,振荡10min左右使甲瓒溶解。用酶标仪测定570nm波长下的吸光度值。根据细胞生长抑制率(CellInhibition Rate)来评价药物的抗肿瘤活性的大小。Cell Inhibition Rate(%)=(1–A1/A0)×100%,其中,A1:加药孔的吸光度;A0:空白对照孔的吸光度。然后通过SPSS软件来计算药物的半数致死浓度(IC50)。
对本发明中单胺氧化酶A抑制剂-吲哚七甲川菁染料偶联化合物进行体外抗肿瘤活性测定,并以异烟肼作为阳性对照,结果如Table 1所示。
Table 1单胺氧化酶A抑制剂-吲哚七甲川菁染料偶联化合物体外抗肿瘤活性
从Table 1中可以看出,式(I)、式(II)、式(III)化合物均表现出不同程度的体外抗前列腺肿瘤活性,其中G-1、G-2、G-5活性最好,IC50值均<2μg/ml。
Claims (10)
1.具有通式(I)-(III)所示的单胺氧化酶A抑制剂吲哚菁偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药:
其中:
R1和R2各自独立选自氢、C1-C10烷基、C1-C10烷氧基或卤素原子,优选为氢、C1-C6烷基、C1-C6烷氧基或卤素原子;R1、R2彼此独立,可以相同也可以不同;
R3选自H、C1-C6烷基;优选为C1-C4烷基;
R4为磺酸基丁基、C1-C6烷基、C1-C10羧基烷基、C1-C10烷氧基羰基C1-C10烷基;优选为:磺酸基丁基、C1-C6烷基、C1-C6羧基烷基、C1-C6烷氧基羰基C1-C6烷基;
Y-为卤素负离子;优选为溴或者碘。
2.权利要求1所述的通式(I)-(III)所示的单胺氧化酶A抑制剂吲哚菁偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药,选自:
2-[2-[3-[2-[1-(5-羧戊基)-1,3-二氢-3,3,5-三甲基-2H-吲哚-2-甲叉基]乙叉基]-2-氯-1-环己烯-1-基]乙叉基]-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3,5-三甲基-3H-吲哚鎓盐溴化物;
2-[2-[3-[2-[5-甲氧基-1-(5-羧戊基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基]乙叉基]-2-氯-1-环己烯-1-基]乙叉基]-5-甲氧基-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3-二甲基-3H-吲哚鎓盐溴化物;
2-[2-[3-[2-[5-溴-1-(5-羧戊基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基]乙叉基]-2-氯-1-环己烯-1-基]乙烯基]-5-溴-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3-二甲基-3H-吲哚鎓盐溴化物;
2-(7-(5-甲氧基-1-(5-羧戊基)-1,3-二氢-3-乙基-3-甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-甲氧基-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3-乙基-3-三甲基-3H-吲哚鎓盐溴化物;
2-[2-[3-[2-[1-(5-羧戊基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基]乙叉基]-2-氯-1-环己烯-1-基]乙烯基]-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3-二甲基-3H-吲哚鎓盐溴化物;
2-(7-(1-(5-羧戊基)-1,3-二氢-3,3,5-三甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3,5-三甲基-3H-吲哚鎓盐溴化物;
2-(7-(5-甲氧基-1-(5-羧戊基)-1,3-二氢-3,5-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-甲氧基-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,5-二甲基-3H-吲哚鎓盐溴化物;
2-(7-(5-甲氧基-1-(5-羧戊基)-1,3-二氢-5-乙基-3-甲基-2H-吲哚-2-甲基)-1,3,5-庚三烯-1-基)-1-(6-(2-异烟酰肼基)-6-氧代己基)-5-甲氧基-3-乙基-3-甲基-3H-吲哚鎓盐溴化物;
2-(7-(5-甲氧基-1(4-磺酰氧丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3,5-三甲基-3H-吲哚内铵盐;
2-(7-(5-甲氧基-1-(4-磺酰氧丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-甲氧基-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3-二甲基-3H-吲哚内铵盐;
2-(7-(5-甲氧基-1-(4-磺酰氧丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-溴-1-(6-(2-异烟酰肼基)-6-氧代己基)-3,3-二甲基-3H-吲哚内铵盐;
2-(7-(5-甲氧基-1-(4-磺酰氧丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3-二甲基-3H-吲哚内铵盐;
2-(7-(5-甲氧基-1-(4-磺酰氧丁基)-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3-二甲基-1H-4,5-苯并[e]吲哚内铵盐;
2-(7-(5-甲氧基-1-丁基-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(4-(2-异烟酰肼基)-4-氧代丁基)-1,3-二氢-3,3,5-三甲基-3H-吲哚鎓盐溴化物;
2-(7-(5-甲氧基-1-丁基-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-1-(4-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3,5-三甲基-3H-吲哚鎓盐溴化物;
2-(7-(5-甲氧基-1-丁基-1,3-二氢-3,3-二甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-溴-1-(4-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3-二甲基-3H-吲哚鎓盐溴化物;
2-(7-(5-甲氧基-1-(4-磺酰氧丁基)-1,3-二氢-3-乙基-3-甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-5-甲氧基-1-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3-乙基-3-三甲基-3H-吲哚内铵盐;
2-(7-(1-(4-乙氧基-4-氧代丁基)-1,3-二氢-3,3,5-三甲基-2H-吲哚-2-甲叉基)-1,3,5-庚三烯-1-基)-(6-(2-异烟酰肼基)-6-氧代己基)-1,3-二氢-3,3,5-三甲基-3H-吲哚鎓盐溴化物;
2-(7-(3,3-二甲基-1-(4-磺酰氧丁基)-4,5-苯并[e]吲哚-2-甲叉基)庚-1,3,5-三烯-1-基)-1-(5-羧戊基)-1,3-二氢-3,3-二甲基-1H-4,5-苯并[e]吲哚内铵盐。
3.权利要求1所述的通式(I)-(III)所示的单胺氧化酶A抑制剂吲哚菁偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药的制备方法,其特征在于,通式(I)的制备包括以下步骤:
(1)连有取代基R1的2,3-二甲基-3-取代吲哚与含有1~6碳原子的卤代羧酸反应制得季铵盐1,取代吲哚与卤代羧酸的摩尔比1:1~1:4;
(2)连有取代基的R2的2,3-二甲基-3-取代吲哚与丁基磺酸内酯或者X-R4反应制得季铵盐2,X-R4是含有1~6碳原子的卤代烷烃、或者是含有1~6碳原子的卤代羧酸、或者是含有1~6碳原子的卤代羧酸酯,取代吲哚与烃化剂的摩尔比1:1~1:4;
(3)将步骤(1)制得的季铵盐1、步骤(2)制得的季铵盐2,与2-氯代己烯二醛3反应制得吲哚七甲川菁化合物4;
(4)吲哚七甲川菁4与异烟肼发生缩合反应得到具有结构通式(I)化合物;
通式(II)的制备包括以下步骤:
(1)通式(I)制备中的步骤(1)制得的季铵盐1、步骤(2)制得的季铵盐2,与戊二烯醛缩苯胺盐酸盐6反应制得吲哚七甲川菁化合物7;
(2)吲哚七甲川菁7与异烟肼发生缩合反应得到具有结构通式(II)化合物;
通式(III)的制备包括以下步骤:
(1)1,1,2-三甲基苯并[e]吲哚8与丁基磺酸内酯反应制得季铵盐9;1,1,2-三甲基苯并[e]吲哚8与6-卤代己酸发生烃反应制得季铵盐10,1,1,2-三甲基苯并[e]吲哚8与烃化剂的摩尔比1:1~1:4;
(2)将步骤(1)制得的季铵盐9、季铵盐10,与戊二烯醛缩苯胺盐酸盐6反应制得吲哚七甲川菁化合物11;
(3)吲哚七甲川菁11与异烟肼发生缩合反应得到具有结构通式化合物III;
4.如权利要求3所述的制备方法,其特征在于,通式(I)-(III)的制备中,步骤(1)的反应溶剂选自甲苯、二甲苯、二氯苯、乙醇、甲醇、乙腈,反应时间4~40小时,反应温度60~148℃。
5.如权利要求3所述的制备方法,其特征在于,
通式(I)的制备中,步骤(3)中制备吲哚七甲川菁化合物4的反应的溶剂及催化体系是包括但不局限于醋酐/醋酸钠、醋酐/三乙胺等适合该反应进行的配伍体系;季铵盐1、季铵盐2、化合物3的摩尔配比是1:1:1,参与反应的季铵盐1和季铵盐2可以是相同的,也可以是不同的;当季铵盐1与季铵盐2相同时,反应得到对称的吲哚七甲川菁化合物4;当季铵盐1与季铵盐2不同时,反应得到不对称的吲哚七甲川菁化合物4;
通式(II)的制备中,步骤(1)中制备吲哚七甲川菁化合物7的反应的溶剂及催化体系是包括但不局限于醋酐/醋酸钠、醋酐/三乙胺等适合该反应进行的配伍体系;季铵盐1、季铵盐2及化合物6的摩尔配比是1:1:1,参与反应的季铵盐1和季铵盐2可以是相同的,也可以是不同的;当季铵盐1与季铵盐2相同时,反应得到对称的吲哚七甲川菁化合物7;当季铵盐1与季铵盐2不同时,反应得到不对称的吲哚七甲川菁化合物7;
通式(III)的制备中,步骤(2)中制备吲哚七甲川菁化合物11的季铵盐9、季铵盐10及化合物6的摩尔配比是1:1:1,该反应的溶剂及催化体系是包括但不局限于醋酐/醋酸钠、醋酐/三乙胺等适合该反应进行的配伍体系。
6.如权利要求3所述的制备方法,其特征在于,所述的缩合反应中,缩合剂为活性酯类、碳二亚胺类、鎓盐类、有机鏻类或酰氯类。
7.一种药用组合物,包含权利要求1或2所述的通式(I)-(III)所示的单胺氧化酶A抑制剂吲哚菁偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药和药学上可接受的载体。
8.权利要求1或2所述的通式(I)-(III)所示的单胺氧化酶A抑制剂吲哚菁偶联化合物及其药学上可接受的盐、溶剂化物、异构体或前药的制备抗肿瘤药物中的应用。
9.权利要求7所述的药用组合物在制备抗肿瘤药物中的应用。
10.如权利要求8或9所述的应用,其特征在于,所述的肿瘤为前列腺癌。
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CN111072635A (zh) * | 2019-11-07 | 2020-04-28 | 沈阳药科大学 | 异烟肼-吲哚七甲川菁偶联化合物及其制备方法和应用 |
CN111072635B (zh) * | 2019-11-07 | 2021-06-11 | 沈阳药科大学 | 异烟肼-吲哚七甲川菁偶联化合物及其制备方法和应用 |
CN113683602A (zh) * | 2021-09-08 | 2021-11-23 | 中国人民解放军陆军军医大学 | 一种用于缺氧肿瘤多模态治疗的七甲川花菁小分子和制备方法及应用 |
CN114437153A (zh) * | 2022-01-25 | 2022-05-06 | 沈阳药科大学 | 一种阿霉素-单胺氧化酶抑制剂前药化合物及其制备方法和应用 |
CN114437153B (zh) * | 2022-01-25 | 2023-10-27 | 沈阳药科大学 | 一种阿霉素-单胺氧化酶抑制剂前药化合物及其制备方法和应用 |
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