CN104402831B - 含酰脲结构单元的-5-氰基嘧啶衍生物及其制备方法和用途 - Google Patents
含酰脲结构单元的-5-氰基嘧啶衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明属于药物化学领域,公开了一类具有抗肿瘤活性的含酰脲结构单元的‑5‑氰基嘧啶衍生物、其制备方法及在药物研发中的用途。本发明以三组分一锅法构筑嘧啶母核,运用药物化学拼合原理将具有抗肿瘤的活性片段酰脲结构引入到母核,得到本系列化合物的基本骨架,又经氯代及胺化等反应制备了一系列含酰脲结构单元的‑5‑氰基嘧啶衍生物。本发明化合物通式如Ⅰ所示。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类含酰脲结构单元的-5-氰基嘧啶衍生物、它们的制备方法及其作为一类抗肿瘤药物先导化合物的应用。
背景技术
癌症是危害人类健康的一类重要疾病,世界范围内因癌症而死亡的人数呈现逐年增加的态势,攻克恶性肿瘤是现代医学的一个难题,也是当今医药工业的一个重要挑战,深入研究高效低毒且与现有抗肿瘤物没有耐药性的新型抗肿瘤药物已成为非常重要且急迫的课题。
嘧啶类化合物是一类具有非常广泛生物活性的杂环化合物,例如抗病毒、
抗菌、抗炎以及抗肿瘤等。Hoff等在2014年报道了一类新型噻吩并嘧啶衍生物(Fig.1),其可以作为一种潜在的抗肿瘤成分(Eur.J.Med.Chem.,2014,76,118-124)。另外,脲结构单元作为活性基团,广泛存在于天然和人工合成具有药理活性的化合物中,并广泛应用于抗肿瘤药物的研发。BAY 43-9006(Fig.2),一种新型RAF激酶和血管内皮生长因子受体(VEGFR)抑制剂,具有广谱的抗肿瘤活性,例如结肠癌、乳腺癌和非小细胞肺癌体外移植模型中都有明显的抑制作用(Cancer Res.,2004,64,7099-7109)。
利用活性片段整合原理,将脲结构单元引入到嘧啶母核,合成一类新型含酰脲结构单元的-5-氰基嘧啶衍生物,并对其生物活性进行初步评价,目前未见 相关报道。对拓宽嘧啶类化合物的研究领域及进一步研究新型抗肿瘤药物,开发自主知识产权药物具有重要意义。
发明内容
本发明目的在于提供一类具有抗肿瘤活性的含酰脲结构单元的-5-氰基嘧啶衍生物。
本发明的另一个目的在于提供一种简单高效,绿色环保的合成含酰脲结构单元的-5-氰基嘧啶衍生物的方法。
本发明的再一个目的在于提供所述化合物的体外抗肿瘤活性。
本发明所述一类含酰脲结构单元的-5-氰基嘧啶衍生物具有如下通式:
通式Ⅰ中X为C或N;
R1为不同位置单取代的氟、氯、溴、甲基、甲氧基、三氟甲基、硝基或异丙基中的任意一种;
R2为氢、不同位置单取代的氯、甲基、异丙基或R2为3,4,5-三甲氧基、3,4-二氟中的任意一种。
优选:X为C;
R1为不同位置单取代的氟、氯、甲基、甲氧基、三氟甲基、硝基或异丙基其中之一;
R2为为氢或3,4,5-三甲氧基。
优选:X为N;
R1为不同位置单取代的氯、溴、甲基、甲氧基、三氟甲基或硝基其中之一;
R2为不同位置单取代的氯、甲基、异丙基或R2为3,4,5-三甲氧基、3,4-二氟 其中之一。
优选如下化合物之一:
X=C时,I-1 R1=m-CF3,R2=m,p,m-triOCH3;
I-2 R1=o-OCH3,R2=m,p,m-triOCH3;
I-3 R1=p-Cl,R2=m,p,m-triOCH3;
I-4 R1=m-Cl,R2=m,p,m-triOCH3;
I-5 R1=m-NO2,R2=m,p,m-triOCH3;
I-6 R1=p-CH3,R2=m,p,m-triOCH3;
I-7 R1=p-F,R2=m,p,m-triOCH3;
I-8 R1=p-CH(CH3)2,R2=m,p,m-triOCH3;
X=N时,I-9 R1=p-CH3,R2=H;
I-10 R1=p-CH3,R2=p-CH(CH3)2;
I-11 R1=p-OCH3,R2=p-CH(CH3)2;
I-12 R1=m-CH3,R2=p-CH(CH3)2;
I-13 R1=m-CF3,R2=p-CH(CH3)2;
I-14 R1=m-CF3,R2=p-CH3;
I-15 R1=m-CF3,R2=p-Cl;
I-16 R1=m-CF3,R2=m,p-diF;
I-17 R1=m-CF3,R2=m,p,m-triOCH3;
I-18 R1=p-Br,R2=m,p,m-triOCH3;
I-19 R1=o-Cl,R2=m,p,m-triOCH3;
I-20 R1=p-Cl,R2=m,p,m-triOCH3;
I-21 R1=m-Cl,R2=m,p,m-triOCH3;
I-22 R1=m-NO2,R2=m,p,m-triOCH3;
I-23 R1=p-CH3,R2=m,p,m-triOCH3;
I-24 R1=p-CF3,R2=m,p,m-triOCH3;
I-25 R1=o-OCH3,R2=m,p,m-triOCH3;
I-26 R1=o-Cl,R2=m,p-diF;
I-27 R1=p-CH3,R2=m,p-diF;
I-28 R1=m-Cl,R2=m,p-diF;
I-29 R1=o-OCH3,R2=m,p-diF;
I-30 R1=p-Cl,R2=m,p-diF;
I-31 R1=p-Cl,R2=p-Cl;
I-32 R1=p-CF3,R2=p-Cl。
本发明所述含酰脲结构单元的-5-氰基嘧啶衍生物主要通过下列步骤制得:
(1)通式II的制备方法:
溶剂中,将氰基乙酸乙酯在碱性条件下和硫脲、多种取代芳香醛反应得到化合物II,所用的碱是氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、磷酸钠、十二水磷酸钠、磷酸钾、碳酸氢钾、碳酸氢钠、三乙胺中的一种;所用的溶剂为丙酮、N,N-二甲基甲酰胺、乙腈、乙醇、甲醇、异丙醇、1,2-二氯乙烷、二氯甲烷、氯仿、四氢呋喃、二氧六环、蒸馏水中之一或其中任意两种或三种的混合物;反应通常在0-90℃之间进行。所得产物经抽滤、重结晶得到纯品。重结晶所用的溶剂为乙醇、甲醇、乙腈、丙酮、乙酸乙酯、四氢呋喃、二氯甲烷、氯仿中的一种或其中两种的混合物。
所述的多种取代芳香醛为:苯甲醛、不同位置异丙基、氯、甲基单取代的苯甲醛,或3,4-二氟苯甲醛、3,4,5-三甲氧基苯甲醛。
(2)通式III的制备方法:
将氯乙酰胺分散于溶剂中,室温搅拌情况下向其中滴加入草酰氯,将整个体系转入油浴中回流反应,冷却至室温后,向体系中滴加入邻氨基吡啶或苯胺,搅拌,有固体析出,抽滤,得到固体,经柱层析得到纯品化合物III的固体。所用的溶剂为丙酮、N,N-二甲基甲酰胺、乙腈、乙醇、甲醇、异丙醇、1,2-二氯乙烷、二氯甲烷、氯仿、四氢呋喃、二氧六环、蒸馏水中之一或其中任意两种或三种的混合物;反应通常在0-90℃之间进行。
(3)通式IV的制备方法:
溶剂中,通式II与通式III反应,用薄层色谱监测反应进程,直至反应完成;然后直接向反应体系中滴加三氯氧磷,反应完成后,将其倒入冰水中,搅拌,有固体析出,抽滤,得到固体,经柱层析得到纯品化合物IV的固体。所用的溶剂为丙酮、N,N-二甲基甲酰胺、乙腈、乙醇、甲醇、异丙醇、1,2-二氯乙烷、二氯甲烷、氯仿、四氢呋喃、二氧六环、蒸馏水中之一或其中任意两种或三种的混合物;反应通常在0-90℃之间进行。
(4)通式I的制备方法:
溶剂中,通式IV中对应的化合物与取代苯胺反应,待反应完成后,冷凝,析出固体,抽滤即得到通式I中对应的化合物。所用的溶剂为丙酮、N,N-二甲基甲酰胺、乙腈、乙醇、甲醇、异丙醇、1,2-二氯乙烷、二氯甲烷、氯仿、四氢呋喃、二氧六环、蒸馏水中之一或其中任意两种或三种的混合物;反应通常在0-90℃之间进行。所得产物经适当的方法如柱层析或者重结晶等提纯可以得到纯产品。结晶所用溶剂为乙醇、甲醇、乙腈、丙酮、乙酸乙酯、四氢呋喃、二氯甲烷、氯仿中的一种或其中两种的混合物。
所述的取代苯胺类化合物为氟、氯、溴、甲基、甲氧基、三氟甲基、硝基或异丙基不同位置单取代的苯胺:优选:对甲基苯胺,对甲氧基苯胺,邻甲氧 基苯胺、间甲基苯胺,间三氟甲基苯胺,对三氟甲基苯胺、邻氯苯胺,对氯苯胺,间氯苯胺,对溴苯胺、对氟苯胺、间硝基苯胺,对异丙基苯胺。
本发明以三组分一锅法构筑嘧啶母核,运用药物化学拼合原理将具有抗肿瘤的活性片段酰脲结构引入到母核,得到本系列化合物的基本骨架,又经氯代及胺化等反应制备了一系列含酰脲结构单元的-5-氰基嘧啶衍生物。与现有的技术相比,本发明首次利用拼合原理将嘧啶母核与脲结构单元结合,简单高效,绿色环保的合成了含脲结构单元的4-取代-5-氰基-6-氨基嘧啶衍生物。体外抗肿瘤活性评价结果表明,本发明所提供的含脲结构单元的4-取代-5-氰基-6-氨基嘧啶衍生物对EC109,MCF-7,MGC-803和B16-F10四种肿瘤细胞具有一定的抑制作用,其中多个化合物的体外抗肿瘤活性明显优于或者与5-氟脲嘧啶相当,可作为进一步开发的候选或者先导化合物,应用于制备抗肿瘤药物。
具体实施方式
为了对本发明进行更好的说明,特举实施例如下:
实施例1通式(II)所示,R2=H的衍生物(II-1)的制备
将氰基乙酸乙酯(2.262g,20mmol)与氢氧化钠(1.200g,30mmol)加入乙醇溶液中,回流条件下,反应一段时间,再将硫脲(2.284g,30mmol)和苯甲醛(5.886g,30mmol)加入反应体系中,搅拌反应,TLC跟踪检测。反应结束后,抽滤,重结晶得到纯品。
实施例2通式(III)所示,X=C的衍生物(III-1)的制备
将氯乙酰胺(0.935g,10mmol)分散于溶剂中,在搅拌状态下滴加入草酰氯(1.904g,15mmol),将整个体系转入油浴中加热回流4h,冷却至室温后,滴加苯胺?(1.397g,15mmol),搅拌,有固体析出,抽滤,得到固体,分离纯化后得到III-1。产率80%。
实施例3通式(IV)所示,R2=H,X=C的衍生物(IV-1)的制备
将III-1(6.379g,30mmol)逐滴加入II-1(7.149g,20mmol)的1,4-二氧六环溶液中,加热搅拌反应。用TLC监测反应进程,直至反应完成;未经分离,直接向反应体系中滴加三氯氧磷(4.600g,30mmol),反应完成后,将其倒入冰水中,搅拌,有固体析出,抽滤,得到固体,经柱层析得到纯品化合物IV-1的固体。Yield 64.5%.Yellow solid.Mp:157–158℃.1HNMR(400MHz,DMSO-d6,δ,ppm)δ 11.33(s,1H,NH,D2O exchangeable),10.71(s,1H,NH,D2Oexchangeable),8.37–8.21(m,1H,ArH),8.04–7.78(m,4H,ArH),7.68–7.59(m,1H,ArH),7.56–7.37(m,2H,ArH),7.16(ddd,J=7.3,5.0,0.9Hz,1H,ArH),4.34(s,2H,CH2).13C NMR(100MHz,DMSO-d6,δ,ppm):δ173.87,170.53,168.87,163.10,151.04,150.66,148.25,139.49,134.62,132.82,129.57,129.21,129.07,128.90,120.25,115.19,113.73,102.65,36.54.
实施例4通式(I)所示,R1=m-CF3,R2=m,p,m-triOCH3,X=C的衍生物(I-1)的制备
将IV-1(514mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间三氟苯胺(322mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-1,用乙醇重结晶得到I-1的纯品。Yield 84.5%.Yellowsolid.Mp:192–193℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.86(s,1H,NH,D2Oexchangeable),10.23(s,1H,NH,D2O exchangeable),10.12(s,1H,NH,D2O exchangeable),8.10–7.83(m,2H,ArH),7.75–7.39(m,4H,ArH),7.32(t,J=7.6Hz,2H,ArH),7.22(s,2H,ArH),7.09(t,J=7.2Hz,1H,ArH),4.16(s,2H,CH2),3.83(s,6H,OCH3),3.75(s,3H,OCH3).13CNMR(100MHz,DMSO-d6,δ,ppm)δ172.63,170.58,168.22,160.62,153.17,150.84,140.72,140.63,138.94,137.88,131.01,130.02,129.39,127.62,125.86,124.21,123.15,121.61,120.32,120.28,120.13,116.39,107.00,106.92,86.10,60.65,56.50,56.46,35.71.HRMS(ESI)calcd for C30H26F3N6O5S[M+H]+:639.1637,found:639.1636.
实施例5通式(I)所示,R1=o-OCH3,R2=m,p,m-triOCH3,X=C的衍生物(I-2)的制备
将IV-1(514mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入邻甲氧基苯胺(246mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-2,用乙醇重结晶得到I-2的纯品。Yield 81.2%.Yellowsolid.Mp:231–232℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.01(s,1H,NH,D2Oexchangeable),10.58(s,1H,NH,D2O exchangeable),9.78(s,1H,NH,D2O exchangeable),8.30(s,1H,ArH),7.89(d,J=42.5Hz,2H,ArH),7.58–6.84(m,7H,ArH),4.13(s,2H,CH2),3.79(d,J=33.4Hz,9H,OCH3),2.26(s,3H,OCH3).13C NMR(100MHz,DMSO-d6,δ,ppm)δ172.61,170.58, 168.04,160.69,153.13,151.48,150.66,148.66,140.37,139.06,135.25,134.80,131.22,129.33,124.29,120.09,116.62,113.41,106.86,85.28,60.65,56.47,36.06,21.07.HRMS(ESI)calcd for C30H29N6O6S[M+H]+:601.1869,found:601.1866.
实施例6通式(I)所示,R1=p-Cl,R2=m,p,m-triOCH3,X=C衍生物(I-3)的制备
将IV-1(514mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对氯苯胺(255mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-3,用乙醇重结晶得到I-3的纯品。Yield 76.5%.Yellowsolid.Mp:205-206℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.86(s,1H,D2O exchangeable),10.23(s,1H,D2O exchangeable),9.94(s,1H,D2O exchangeable),7.56(d,J=8.8Hz,2H,ArH),7.51(d,J=7.9Hz,2H,ArH),7.42(t,J=7.8Hz,2H,ArH),7.33(dd,J=13.3,5.7Hz,2H,ArH),7.21(s,2H,ArH),7.09(t,J=7.3Hz,1H,ArH),4.15(s,2H,S-CH2),3.84(s,6H,O-CH3),3.75(s,3H,O-CH3). 13C NMR(100MHz,DMSO-d6,δ,ppm)δ172.73,170.45,168.13,160.57,153.15,150.87,140.58,137.93,136.96,131.07,129.40,129.22,128.83,125.62,124.20,120.90,120.15,116.52,106.89,85.75,60.65,56.47,35.87.HRMS(ESI)calcd forC29H25ClN6NaO5S[M+Na]+:627.1193,found:627.1193.
实施例7通式(I)所示,R1=m-Cl,R2=m,p,m-triOCH3,X=C的衍生物(I-4)的制备
将IV-1(514mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间氯苯胺(255mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-4,用乙醇重结晶得到I-4的纯品。Yield 86.0%.Yellowsolid.Mp:184-185℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.86(s,1H,D2O exchangeable),10.25(s,1H,D2O exchangeable),9.98(s,1H,D2O exchangeable),7.66(s,1H,ArH),7.56(d,J=8.1Hz,1H,ArH),7.50(d,J=7.9Hz,2H,ArH),7.39(t,J=8.1Hz,1H,ArH),7.32(t,J=7.8Hz,2H,ArH),7.23(d,J=8.1Hz,3H,ArH),7.09(t,J=7.3Hz,1H,ArH),4.16(s,2H,S-CH2),3.84(s,6H,O-CH3),3.75(s,3H,O-CH3).13C NMR(100MHz,DMSO-d6,δ,ppm)δ172.66,170.58,168.19,160.58,153.16,150.88,140.62,139.59,137.91,133.18,131.03,130.46,129.40,129.22,125.12,124.20,123.55,122.46,120.90,120.14,116.45,106.91,85.99,60.64,56.45,35.73.HRMS(ESI)calcd for C29H25ClN6NaO5S[M+Na]+:627.1193,found:627.1193.
实施例8通式(I)所示,R1=m-NO2,R2=m,p,m-triOCH3,X=C的衍生物(I-5)的制备
将IV-1(514mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间硝基苯胺(276mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-5,用乙醇重结晶得到I-5的纯品。Yield 79.2%.Yellowsolid.Mp:132-134℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.80(s,1H,D2O exchangeable),10.26(s,1H,D2O exchangeable),10.18(s,1H,D2O exchangeable),8.51(s,1H,ArH),8.02(dd,J=15.7,5.7Hz,2H,ArH),7.64(t,J=8.2Hz,1H,ArH),7.47(d,J=7.9Hz,2H,ArH),7.32(t,J=7.8Hz,2H,ArH),7.22(d,J=6.7Hz,2H,ArH),7.08(t,J=7.3Hz,1H,ArH),4.16(s,2H,S-CH2),3.84(s,6H,O-CH3),3.75(s,3H,O-CH3).13C NMR(100MHz,DMSO-d6,δ,ppm)δ172.71,170.44,168.24,160.66,153.17,150.79,148.18,140.66,139.37,137.88,130.96,130.17,129.99,129.38,124.18,120.09,119.75,118.28,116.36,106.92,86.23,60.65,56.47,35.88.HRMS(ESI)calcd for C29H26N7O7S[M+H]+:616.1614,found:616.1611.
实施例9通式(I)所示,R1=p-CH3,R2=m,p,m-triOCH3,X=C的衍生物(I-6)的制备
将IV-1(514mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对甲基苯胺(214mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-6,用乙醇重结晶得到I-6的纯品。Yield 78.9%.Yellowsolid.Mp:131–132℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.83(s,1H,D2O exchangeable),10.24(s,1H,D2O exchangeable),9.78(s,1H,D2O exchangeable),7.51(d,J=7.4Hz,2H,ArH),7.35(dd,J=16.0,7.5Hz,4H,ArH),7.21(s,2H,ArH),7.13(dd,J=19.8,7.3Hz,3H,ArH),4.11(s,2H,S-CH2),3.84(s,6H,O-CH3),3.75(s,3H,O-CH3),2.27(s,3H,Ar-CH3).13CNMR(100MHz,DMSO-d6,δ,ppm)δ172.66,170.43,168.02,160.68,153.14,150.90,140.48,137.99,135.27,134.81,131.22,129.42,129.36,124.27,124.17,120.07,116.65,106.85,85.25,60.64,56.46,35.83,21.09.HRMS(ESI)calcd for C30H28N6NaO5S[M+Na]+:607.1740,found:607.1741.
实施例10通式(I)所示,R1=p-F,R2=m,p,m-triOCH3,X=C的衍生物(I-7)的制备
将IV-1(514mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对氟苯胺(222mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-7,用乙醇重结晶得到I-7的纯品。Yield 75.0%.Yellowsolid.Mp:208–209℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.84(s,1H,D2O exchangeable),10.23(s,1H,D2O exchangeable),9.88(s,1H,D2O exchangeable),7.67–7.43(m,4H,ArH),7.34(dd,J=19.7,12.0Hz,2H,ArH),7.25–7.13(m,4H,ArH),7.09(t,J=7.3Hz,1H),4.11(s,2H,S-CH2),3.84(s,6H,O-CH3),3.75(s,3H,O-CH3).13C NMR(100MHz,DMSO-d6,δ,ppm)δ172.68,170.43,168.04,160.80,153.15,150.88,140.53,137.93,134.14,131.14,129.41,126.50,126.42,124.20,120.15,116.57,115.72,115.50,106.86,85.32,60.64,56.46,35.82.HRMS(ESI)calcd for C29H25FN6NaO5S[M+Na]+:611.1489,found:611.1488.
实施例11通式(I)所示,R1=p-CH(CH3)2,R2=m,p,m-triOCH3,X=C的衍生物(I-8)的制备
将IV-1(514mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对异丙基苯胺(270mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-8,用乙醇重结晶得到I-8的纯品。Yield 84.5%.Yellowsolid.Mp:151–152℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.87(s,1H,D2O exchangeable),10.28(s,1H,D2O exchangeable),9.76(s,1H,D2O exchangeable),7.52(d,J=7.9Hz,2H,ArH),7.44(d,J=8.4Hz,2H,ArH),7.34(dd,J=15.8,8.1Hz,2H,ArH),7.27–7.17(m,4H,ArH),7.09(t,J=7.4Hz,1H,ArH),4.14(s,2H,S-CH2),3.84(s,6H,O-CH3),3.75(s,3H,O-CH3),3.01–2.70(m,1H,-CH(CH3)2),1.19(d,J=6.9Hz,6H,-CH(CH3)2).13C NMR(100MHz,DMSO-d6,δ,ppm)δ172.70,170.54,168.06,160.51,153.14,150.91,145.62,140.50,137.97,135.62,131.21,129.41,126.67,124.18,123.92,120.07,116.64,106.87,85.39,60.63,56.46,35.82,33.42,24.29.HRMS(ESI)calcd for C32H33N6O5S[M+H]+:613.2233,found:613.2231.
实施例12通式(I)所示,R1=p-CH3,R2=H,X=N的衍生物(I-9)的制备
采取实施例1同样的方法制备II-2,R2=H;采取实施例2同样的方法,用 氨基吡啶替代苯胺,制备III-2,X=N;采取实施例3同样的方法制备IV-2。
将IV-2(425mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对甲基苯胺(214mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-9,用乙醇重结晶得到I-9的纯品。Yield 70.5%.Yellowsolid.Mp:206–207℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.03(s,1H,NH,D2Oexchangeable),10.63(s,1H,NH,D2O exchangeable),9.81(s,1H,NH,D2O exchangeable),8.30(d,J=4.1Hz,1H,ArH),8.09–7.77(m,4H,ArH),7.54(dt,J=32.2,7.3Hz,3H,ArH),7.36(d,J=8.3Hz,2H,ArH),7.14(dd,J=10.5,4.9Hz,3H,ArH),4.10(s,2H,CH2),2.25(s,3H,CH3). 13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.85,170.73,168.42,160.65,151.38,150.70,148.70,139.07,136.21,135.24,134.80,131.68,129.33,129.13,128.94,124.28,120.11,116.35,113.44,85.43,36.01,21.06.HRMS(ESI)calcd for C26H22N7O2S[M+H]+:496.1556,found:496.1553.
实施例13通式(I)所示,R1=p-CH3,R2=p-CH(CH3)2,X=N的衍生物(I-10)的制备
采取实施例1同样的方法制备II-3,R2=p-CH(CH3)2;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-3。
将IV-3(467mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对甲基苯胺(214mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-10,用乙醇重结晶得到I-10的纯品。Yield 78.5%.Yellowsolid.Mp:216–217℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.04(s,1H,NH,D2Oexchangeable),10.63(s,1H,NH,D2O exchangeable),9.77(s,1H,NH,D2O exchangeable),8.30(s,1H,ArH),8.00(s,1H,ArH),7.93–7.68(m,3H,ArH),7.36(s,4H,ArH),7.13(d,J=6.1Hz,3H,ArH),4.10(s,2H,CH2),2.94(s,1H,CH),2.26(s,3H,CH3),1.21(d,J=6.0Hz,6H,CH3). 13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.77,170.77,168.18,160.72,152.43,151.42,150.72,148.70,139.03,135.29,134.74,133.78,129.33,129.26,126.91,124.24,120.09,116.52,114.64,113.41,85.03,36.02,33.86,24.04,21.06.HRMS(ESI)calcd forC29H28N7O2S[M+H]+:538.2025,found:538.2023.
实施例14通式(I)所示,R1=p-OCH3,R2=p-CH(CH3)2,X=N的衍生物(I-11)的制备
采取实施例1同样的方法制备II-3,R2=p-CH(CH3)2;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-3。
将IV-3(467mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对甲氧基苯胺(246mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-11,用乙醇重结晶得到I-11的纯品。Yield 86.7%.Yellowsolid.Mp:175–176℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.05(s,1H,NH,D2Oexchangeable),10.66(s,1H,NH,D2O exchangeable),9.72(s,1H,NH,D2O exchangeable),8.30(d,J=4.2Hz,1H,ArH),7.99(d,J=7.2Hz,1H,ArH),7.91–7.68(m,2H,ArH),7.36(dd,J=10.3,8.8Hz,4H,ArH),6.89(d,J=8.9Hz,1H,ArH),6.65(dd,J=34.8,8.7Hz,2H,ArH),4.07(s,2H,CH2),3.73(s,3H,OCH3),2.94(dt,J=13.7,6.8Hz,1H,CH),1.20(d,J=6.9Hz,6H,CH3).13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.73,170.84,168.11,160.78,157.17,152.41,151.36,150.72,148.70,139.05,133.79,130.56,129.23,126.90,125.98,120.14,116.48,114.98,114.02,113.46,84.74,55.54,35.95,33.85,24.03.HRMS(ESI)calcd forC29H28N7O3S[M+H]+:554.1974,found:554.1972.
实施例15通式(I)所示,R1=m-CH3,R2=p-CH(CH3)2,X=N的衍生物(I-12)的制备
采取实施例1同样的方法制备II-3,R2=p-CH(CH3)2;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-3。
将IV-3(467mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间甲基苯胺(214mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-12,用乙醇重结晶得到I-12的纯品。Yield 81.0%.Yellowsolid.Mp:156–157℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.06(s,1H,NH,D2Oexchangeable),10.63(s,1H,NH,D2O exchangeable),9.78(s,1H,NH,D2O exchangeable),8.30(d,J=4.7Hz,1H,ArH),7.99(d,J=7.1Hz,1H,ArH),7.90–7.70(m,3H,ArH),7.49–7.09(m,6H,ArH),6.97(d,J=7.5Hz,1H,ArH),4.10(s,2H,CH2),2.94(dt,J=13.7,6.9Hz,1H,CH),2.27(s,3H,CH3),1.21(d,J=6.9Hz,6H,CH3).13C NMR(100MHz,DMSO-d6,δ, ppm):δ172.69,170.90,168.24,160.72,152.47,151.37,150.69,148.69,139.04,138.23,137.83,133.75,129.27,128.68,126.91,126.26,124.75,121.43,120.11,116.46,113.44,85.23,35.89,33.85,24.03,21.44.HRMS(ESI)calcd for C29H28N7O2S[M+H]+:538.2025,found:538.2022.
实施例16通式(I)所示,R1=m-CF3,R2=p-CH(CH3)2,X=N的衍生物(I-13)的制备
采取实施例1同样的方法制备II-3,R2=p-CH(CH3)2;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-3。
将IV-3(467mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间三氟甲基苯胺(322mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-13,用乙醇重结晶得到I-13的纯品。Yield 88.6%.Yellowsolid.Mp:194–195℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.08(s,1H,NH,D2Oexchangeable),10.63(s,1H,NH,D2O exchangeable),10.10(s,1H,NH,D2O exchangeable),8.29(d,J=4.0Hz,1H,ArH),8.06–7.89(m,3H,ArH),7.89–7.77(m,2H,ArH),7.60(t,J=7.8Hz,1H,ArH),7.54–7.40(m,1H,ArH),7.35(d,J=8.3Hz,2H,ArH),7.14(dd,J=6.9,5.3Hz,1H,ArH),4.14(s,2H,CH2),2.94(dt,J=13.7,6.9Hz,1H,CH),1.21(d,J=6.9Hz,6H,CH3).13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.74,170.91,168.36,160.69,152.61,151.35,150.67,148.67,138.99,138.96,133.63,129.98,129.31,127.66,126.95,125.84,123.13,121.54,120.33,120.10,116.26,113.45,85.89,35.91,33.85,24.01.HRMS(ESI)calcd forC29H25F3N7O2S[M+H]+:592.1743,found:592.1741.
实施例17通式(I)所示,R1=m-CF3,R2=p-CH3,X=N的衍生物(I-14)的制备
采取实施例1同样的方法制备II-4,R2=p-CH3;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-4。
将IV-4(439mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间三氟甲基苯胺(322mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-14,用乙醇重结晶得到I-14的纯品。Yield 72.3%.Yellowsolid.Mp:181–182℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.09(s,1H,NH,D2Oexchangeable),10.62(s,1H,NH,D2Oexchangeable),10.12(s,1H,NH,D2O exchangeable),8.28(d,J=4.4Hz,1H,ArH), 7.95(dd,J=18.1,8.7Hz,3H,ArH),7.82(dd,J=20.8,8.0Hz,3H,ArH),7.60(t,J=7.8Hz,1H,ArH),7.49(d,J=7.7Hz,1H,ArH),7.30(d,J=8.0Hz,2H,ArH),7.19–7.04(m,1H,ArH),4.14(s,2H,CH2),2.37(s,3H,Ar-CH3).13C NMR(100MHz,DMSO-d6,δ,ppm)δ172.72,170.90,168.39,151.30,150.65,148.65,142.03,139.00,138.94,133.21,129.96,129.56,129.17,127.67,126.15,125.84,123.13,121.53,120.33,120.10,116.25,113.47,85.87.HRMS(ESI)calcd for C27H21F3N7O2S[M+H]+:564.1430,found:564.1428.
实施例18通式(I)所示,R1=m-CF3,R2=p-Cl,X=N的衍生物(I-15)的制备
采取实施例1同样的方法制备II-5,R2=p-Cl;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-5。
将IV-5(459mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间三氟甲基苯胺(322mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-15,用乙醇重结晶得到I-15的纯品。Yield 87.5%.Yellowsolid.Mp:202–203℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.07(s,1H,NH,D2Oexchangeable),10.58(s,1H,NH,D2O exchangeable),10.18(s,1H,NH,D2O exchangeable),8.28(s,1H,ArH),8.12–7.69(m,6H,ArH),7.69–7.34(m,4H,ArH),7.13(s,1H,ArH),4.14(s,2H,CH2).13CNMR(100MHz,DMSO-d6,δ,ppm):δ172.92,170.83,167.37,160.54,151.27,150.63,148.63,138.99,138.82,136.72,134.81,131.02,129.97,129.52,129.09,127.73,125.81,123.11,121.69,120.41,120.10,115.93,113.46,86.33,35.91.HRMS(ESI)calcdfor C26H18ClF3N7O2S[M+H]+:584.0883,found:584.0882.
实施例19通式(I)所示,R1=m-CF3,R2=m,p-diF,X=N的衍生物(I-16)的制备
采取实施例1同样的方法制备II-6,R2=m,p-diF;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-6。
将IV-6(461mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间三氟甲基苯胺(322mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-16,用乙醇重结晶得到I-16的纯品。Yield 86.7%.Yellowsolid.Mp:134–135℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.08(s,1H,NH,D2Oexchangeable),10.58(s,1H,NH,D2O exchangeable),10.22(s,1H,NH,D2O exchangeable),8.27(d,J=4.4Hz,1H,ArH), 8.04–7.72(m,6H,ArH),7.56(dt,J=27.0,8.0Hz,3H,ArH),7.25–7.03(m,1H,ArH),4.15(s,2H,CH2).13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.94,170.83,166.29,160.45,151.26,150.56,148.59,138.97,138.75,133.40,130.00,129.84,127.78,126.68,125.80,123.10,121.76,120.42,120.08,118.71,118.52,118.37,118.19,115.82,113.46,86.53,35.92.HRMS(ESI)calcd for C26H17F5N7O2S[M+H]+:586.1085,found:586.1086
实施例20通式(I)所示,R1=m-CF3,R2=m,p,m-triOCH3,X=N的衍生物(I-17)的制备
采取实施例1同样的方法制备II-7,R2=m,p,m-triOCH3;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-7。
将IV-7(515mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间三氟甲基苯胺(322mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-17,用乙醇重结晶得到I-17的纯品。Yield 72.0%.Yellowsolid.Mp:145–146℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.18(s,1H,NH,D2Oexchangeable),10.59(s,1H,NH,D2O exchangeable),10.14(s,1H,NH,D2O exchangeable),8.27(s,1H,ArH),8.07–7.73(m,4H,ArH),7.70–7.39(m,2H,ArH),7.16(d,J=38.9Hz,3H,ArH),4.21(s,2H,CH2),3.83(s,6H,OCH3),3.74(s,3H,OCH3).13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.64,170.62,168.16,160.64,153.15,151.31,150.63,148.58,140.64,138.97,138.93,131.01,130.02,129.82,129.50,127.67,125.83,123.12,121.54,120.30,120.03,116.39,113.42,106.94,86.05,60.65,56.49,36.03.HRMS(ESI)calcd for C29H25F3N7O5S[M+H]+:640.1590,found:640.1588.
实施例21通式(I)所示,R1=p-Br,R2=m,p,m-triOCH3,X=N的衍生物(I-18)的制备
采取实施例1同样的方法制备II-7,R2=m,p,m-triOCH3;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-7。
将IV-7(515mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后, 加热搅拌下加入对溴苯胺(344mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-18,用乙醇重结晶得到I-18的纯品。Yield 75.0%.Yellowsolid.Mp:216–217℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.08(s,1H,NH,D2Oexchangeable),10.58(s,1H,NH,D2O exchangeable),9.92(s,1H,NH,D2O exchangeable),8.29(d,J=4.3Hz,1H,ArH),7.95(d,J=7.2Hz,1H,ArH),7.83(t,J=7.2Hz,1H,ArH),7.62–7.40(m,4H,ArH),7.20(s,2H,ArH),7.17–7.07(m,1H,ArH),4.18(s,2H,CH2),3.83(s,6H,OCH3),3.75(s,3H,OCH3).13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.67,170.64,168.13,160.52,153.15,151.30,150.64,148.62,140.60,139.04,137.41,131.73,131.07,125.92,120.11,117.54,116.49,113.50,106.94,85.86,60.66,56.49,36.10.HRMS(ESI)calcd forC28H25BrN7O5S[M+H]+:650.0821,found:650.0820.
实施例22通式(I)所示,R1=o-Cl,R2=m,p,m-triOCH3,X=N的衍生物(I-19)的制备
采取实施例1同样的方法制备II-7,R2=m,p,m-triOCH3;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-7。
将IV-7(515mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入邻氯苯胺(255mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-19,用乙醇重结晶得到I-19的纯品。Yield 87.5%.Yellowsolid.Mp:206–207℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.17(s,1H,NH,D2Oexchangeable),10.60(s,1H,NH,D2O exchangeable),9.97(s,1H,NH,D2O exchangeable),8.28(d,J=4.1Hz,1H,ArH),8.03–7.71(m,2H,ArH),7.75–7.45(m,2H,ArH),7.39(t,J=8.1Hz,1H,ArH),7.30–7.04(m,4H,ArH),4.21(s,2H,CH2),3.83(s,6H,OCH3),3.75(s,3H,OCH3). 13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.64,170.63,168.14,160.61,153.15,151.34,150.67,148.60,140.65,139.59,138.99,133.15,131.02,130.46,125.08,123.54,122.50,120.04,116.43,113.46,106.96,85.97,60.66,56.50,36.04.HRMS(ESI)calcd forC28H25ClN7O5S[M+H]+:606.1326,found:606.1324.
实施例23通式(I)所示,R1=p-Cl,R2=m,p,m-triOCH3,X=N的衍生物(I-20)的制备
采取实施例1同样的方法制备II-7,R2=m,p,m-triOCH3;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-7。
将IV-7(515mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对氯苯胺(255mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-20,用乙醇重结晶得到I-20的纯品。Yield 80.0%.Yellowsolid.Mp:128–129℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.07(s,1H,NH,D2Oexchangeable),10.57(s,1H,NH,D2O exchangeable),9.93(s,1H,NH,D2O exchangeable),8.29(s,1H,ArH),8.09–7.72(m,2H,ArH),7.55(d,J=7.9Hz,2H,ArH),7.39(d,J=8.0Hz,2H,ArH),7.17(d,J=26.0Hz,3H,ArH),4.17(s,2H,CH2),3.83(s,6H,OCH3),3.75(s,2H,OCH3).13CNMR(100MHz,DMSO-d6,δ,ppm):δ172.67,170.63,168.13,160.59,153.15,151.29,150.64,148.62,140.59,139.04,136.94,131.08,129.37,128.81,125.66,120.11,116.50,113.48,106.92,85.78,60.66,56.48,36.12.HRMS(ESI)calcd for C28H25ClN7O5S[M+H]+:606.1326,found:606.1324.
实施例24通式(I)所示,R1=m-Cl,R2=m,p,m-triOCH3,X=N的衍生物(I-21)的制备
采取实施例1同样的方法制备II-7,R2=m,p,m-triOCH3;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-7。
将IV-7(515mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间氯苯胺(255mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-21,用乙醇重结晶得到I-21的纯品。Yield 76.5%.Yellowsolid.Mp:194–195℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.17(s,1H,NH,D2Oexchangeable),10.60(s,1H,NH,D2O exchangeable),9.97(s,1H,NH,D2O exchangeable),8.28(d,J=4.1Hz,1H,ArH),8.03–7.71(m,2H,ArH),7.75–7.45(m,2H,ArH),7.39(t,J=8.1Hz,1H,ArH),7.30–7.04(m,4H,ArH),4.21(s,2H,CH2),3.83(s,6H,OCH3),3.75(s,3H,OCH3). 13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.64,170.63,168.14,160.61,153.15,151.34,150.67,148.60,140.65,139.59,138.99,133.15,131.02,130.46,125.08,123.54,122.50,120.04,116.43,113.46,106.96,85.97,60.66,56.50,36.04.HRMS(ESI)calcd forC28H24ClN7NaO5S[M+H]+:628.1146,found:628.1147.
实施例25通式(I)所示,R1=m-NO2,R2=m,p,m-triOCH3,X=N的衍生物(I-22)的制备
采取实施例1同样的方法制备II-7,R2=m,p,m-triOCH3;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-7。
将IV-7(515mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间硝基苯胺(276mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-22,用乙醇重结晶得到I-22的纯品。Yield 79.0%.Yellowsolid.Mp:213–214℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.12(s,1H,NH,D2Oexchangeable),10.52(s,1H,NH,D2O exchangeable),10.28(s,1H,NH,D2O exchangeable),8.48(s,1H,ArH),8.27(s,1H,ArH),7.91(ddd,J=36.8,22.0,7.6Hz,4H,ArH),7.64(t,J=7.9Hz,1H,ArH),7.17(d,J=43.4Hz,3H,ArH),4.21(s,2H,CH2),3.79(d,J=35.6Hz,9H,OCH3).13CNMR(100MHz,DMSO-d6,δ,ppm):δ172.71,170.46,168.19,160.67,153.15,151.30,150.59,148.56,148.10,140.63,139.36,138.96,130.96,130.18,130.06,120.01,119.70,118.24,116.37,113.37,106.92,86.18,60.66,56.49,36.22.HRMS(ESI)calcd forC28H25N8O7S[M+H]+:617.1567,found:617.1564.
实施例26通式(I)所示,R1=p-CH3,R2=m,p,m-triOCH3,X=N的衍生物(I-23)的制备
采取实施例1同样的方法制备II-7,R2=m,p,m-triOCH3;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-7。
将IV-7(515mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对甲基苯胺(214mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-23,用乙醇重结晶得到I-23的纯品。Yield 75.5%.Yellowsolid.Mp:204–205℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.00(s,1H,NH,D2Oexchangeable),10.58(s,1H,NH,D2O exchangeable),9.17(s,1H,NH,D2O exchangeable),8.29(s,1H,ArH),7.88(d,J=42.9Hz,2H,ArH),7.61(d,J=6.7Hz,1H,ArH),7.34–6.80(m,6H,ArH),4.12(s,2H,CH2),3.83(s,9H,OCH3),3.75(s,3H,CH3).13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.62,170.56,167.41,160.64,153.17,152.76,151.31,150.64,148.65,140.51,139.05,131.12,127.30,126.33,125.60,120.72,120.08,116.56,113.43,112.10,106.78,85.28,60.64,56.46,56.23,36.06.HRMS(ESI)calcd for C29H28N7O5S[M+H]+:586.1873,found:586.1869.
实施例27通式(I)所示,R1=p-CF3,R2=m,p,m-triOCH3,X=N的衍生物(I-24)的制备
采取实施例1同样的方法制备II-7,R2=m,p,m-triOCH3;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-7。
将IV-7(515mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对三氟甲基苯胺(322mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-24,用乙醇重结晶得到I-24的纯品。Yield 87.5%.Yellowsolid.Mp:201–202℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.10(s,1H,NH,D2Oexchangeable),10.57(s,1H,NH,D2O exchangeable),10.14(s,1H,NH,D2O exchangeable),8.29(d,J=4.2Hz,1H,ArH),7.82(ddd,J=46.5,37.2,8.6Hz,6H,ArH),7.37–7.05(m,3H,ArH),4.21(s,2H,CH2),3.84(s,6H,OCH3),3.75(s,3H,OCH3).13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.78,170.56,168.31,160.56,153.17,151.27,150.61,148.63,143.55,141.92,140.66,139.02,130.98,126.10,123.41,120.12,116.43,113.42,106.97,86.47,60.67,56.49,36.34.HRMS(ESI)calcd for C29H25F3N7O5S[M+H]+:640.1590,found:640.1603.
实施例28通式(I)所示,R1=o-OCH3,R2=m,p,m-triOCH3,X=N的衍生物(I-25)的制备
采取实施例1同样的方法制备II-7,R2=m,p,m-triOCH3;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-7。
将IV-7(515mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入邻甲氧基苯胺(246mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-25,用乙醇重结晶得到I-25的纯品。Yield 74.2%,Yellowsolid.Mp:204-205℃.HRMS(ESI)calcd forC29H28N7O6S[M+H]+:602.1822,found:602.1820.
实施例29通式(I)所示,R1=o-Cl,R2=m,p-diF,X=N的衍生物(I-26)的制备
采取实施例1同样的方法制备II-6,R2=m,p-diF;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-6。
将IV-6(461mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入邻氯苯胺(255mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-26,用乙醇重结晶得到I-26的纯品。Yield 75.5%.Yellowsolid.Mp:106–107℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ10.88(s,1H,NH,D2Oexchangeable),10.56(s,1H,NH,D2O exchangeable),10.05(s,1H,NH,D2O exchangeable),8.29(d,J=4.3Hz,1H,ArH),8.08–7.68(m,4H,ArH),7.63–7.20(m,5H,ArH),7.20–7.02(m,1H,ArH),3.99(s,2H,CH2).13C NMR(100MHz,DMSO-d6,δ,ppm):δ173.06,170.44,166.02,161.18,151.35,150.56,148.67,139.01,134.91,133.39,131.39,130.08,129.66,129.03,128.03,126.73,120.07,118.73,118.54,118.37,118.19,115.85,113.44,85.21,35.96.HRMS(ESI)calcd for C25H17ClF2N7O2S[M+H]+:552.0821,found:552.0818.
实施例30通式(I)所示,R1=p-CH3,R2=m,p-diF,X=N的衍生物(I-27)的制备
采取实施例1同样的方法制备II-6,R2=m,p-diF;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-6。
将IV-6(461mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对甲基苯胺(214mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-27,用乙醇重结晶得到I-27的纯品。Yield 79.0%.Yellowsolid.Mp:185–186℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.02(s,1H,NH,D2Oexchangeable),10.58(s,1H,NH,D2O exchangeable),9.90(s,1H,NH,D2O exchangeable),8.29(d,J=4.4Hz,1H,ArH),8.03–7.49(m,5H,ArH),7.34(d,J=8.0Hz,2H,ArH),7.13(d,J=7.5Hz,3H,ArH),4.10(s,2H,CH2),2.25(s,3H,CH3).13C NMR(100MHz,DMSO-d6,δ,ppm): δ172.94,170.66,166.15,160.46,151.34,150.63,148.65,139.02,135.09,134.95,133.56,129.34,126.67,124.37,120.08,118.67,118.48,118.33,118.16,116.06,113.41,85.67,36.03,21.06.HRMS(ESI)calcd for C26H20F2N7O2S[M+H]+:532.1367,found:532.1368.
实施例31通式(I)所示,R1=m-Cl,R2=m,p-diF,X=N的衍生物(I-28)的制备
采取实施例1同样的方法制备II-6,R2=m,p-diF;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-6。
将IV-6(461mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入间氯苯胺(255mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-28,用乙醇重结晶得到I-28的纯品。Yield 85.0%.Yellowsolid.Mp:192–193℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.08(s,1H,NH,D2Oexchangeable),10.60(s,1H,NH,D2O exchangeable),10.08(s,1H,NH,D2O exchangeable),8.28(d,J=4.4Hz,1H,ArH),8.05–7.69(m,4H,ArH),7.67–7.48(m,3H,ArH),7.38(t,J=8.1Hz,1H,ArH),7.28–7.03(m,2H,ArH),4.15(s,2H,CH2).13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.95,170.83,166.28,160.42,151.29,150.60,148.62,139.41,138.98,133.16,130.45,126.72,126.68,125.27,123.70,122.64,120.09,118.71,118.53,118.36,118.18,115.86,113.48,86.42,35.93.HRMS(ESI)calcd for C25H17ClF2N7O2S[M+H]+:552.0821,found:552.0820.
实施例32通式(I)所示,R1=o-OCH3,R2=m,p-diF,X=N的衍生物(I-29)的制备
采取实施例1同样的方法制备II-6,R2=m,p-diF;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-6。
将IV-6(461mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入邻甲氧基苯胺(246mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-29,用乙醇重结晶得到I-29的纯品。Yield 78.5%.Yellowsolid.Mp:198–199℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.00(s,1H,NH,D2Oexchangeable),10.57(s,1H,NH,D2O exchangeable),9.32(s,1H,NH,D2O exchangeable),8.28(d,J=4.3Hz,1H,ArH),8.09–7.69(m,4H,ArH),7.68–7.44(m,2H,ArH),7.28–6.82(m,4H,ArH),4.08(s,2H,CH2),3.81(s,3H,OCH3).13C NMR(100MHz,DMSO-d6,δ,ppm):δ172.96,170.66,165.54,160.57,153.08,151.33,150.59,148.63,139.00,133.46,127.61,126.56,126.11,126.05,120.69,120.06,118.64,118.45,118.36,118.18,115.99,113.45,112.14,100.00,85.53,56.19,36.02.HRMS(ESI)calcd for C26H20F2N7O3S[M+H]+:548.1316,found:548.1314.
实施例33通式(I)所示,R1=p-Cl,R2=m,p-diF,X=N的衍生物(I-30)的制备
采取实施例1同样的方法制备II-6,R2=m,p-diF;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-6。
将IV-6(461mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对氯苯胺(255mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-30,用乙醇重结晶得到I-30的纯品。Yield 80.9%.Yellowsolid.Mp:213–214℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.09(s,1H,NH,D2Oexchangeable),10.58(s,1H,NH,D2O exchangeable),10.03(s,1H,NH,D2O exchangeable),8.28(d,J=4.1Hz,1H,ArH),8.09–7.71(m,4H,ArH),7.71–7.45(m,3H,ArH),7.39(d,J=8.8Hz,2H,ArH),7.20–7.00(m,1H,ArH),4.15(s,2H,CH2).13C NMR(100MHz,DMSO-d6,δ,ppm):δ173.01,170.71,166.20,160.37,151.29,150.60,148.55,139.01,136.77,133.41,129.53,128.80,126.66,125.73,120.08,118.69,118.51,118.35,118.17,115.93,113.51,86.15,36.09.HRMS(ESI)calcd for C25H17ClF2N7O2S[M+H]+:552.0821,found:552.0819.
实施例34通式(I)所示,R1=p-Cl,R2=p-Cl,X=N的衍生物(I-31)的制备
采取实施例1同样的方法制备II-5,R2=p-Cl;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-5。
将IV-5(459mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对氯苯胺(255mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-31,用乙醇重结晶得到I-31的纯品。Yield 74.5%.Yellowsolid.Mp:212–213℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.07(s,1H,NH,D2Oexchangeable),10.57(s,1H,NH,D2O exchangeable),9.99(s,1H,NH,D2O exchangeable),8.29(d,J=4.1Hz,1H,ArH),8.10–7.71(m,4H,ArH),7.56(dd,J=8.7,7.2Hz,4H,ArH),7.39(d,J=8.8Hz,2H,ArH),7.13(dd,J=6.9,5.3Hz,1H,ArH),4.14(s,2H,CH2).13C NMR(100MHz, DMSO-d6,δ,ppm):δ172.99,170.71,167.31,160.46,151.31,150.66,148.63,139.02,136.84,136.66,134.86,131.01,129.47,129.08,128.80,125.68,120.11,116.05,113.51,85.98,36.08.HRMS(ESI)calcd for C25H18Cl2N7O2S[M+H]+:550.0620,found:550.0617.
实施例35通式(I)所示,R1=p-CF3,R2=p-Cl,X=N的衍生物(I-32)的制备
采取实施例1同样的方法制备II-5,R2=p-Cl;采取实施例2同样的方法用氨基吡啶替代苯胺制备III-2,X=N;采取实施例3同样的方法制备IV-5。
将IV-5(459mg,1mmol)加入50ml圆底烧瓶中,加入20ml乙醇,溶解后,加热搅拌下加入对三氟甲基苯胺(322mg,2mmol),加热回流反应,TLC跟踪监测。待反应完成后,冷凝,析出固体,抽滤即得到化合物I-32,用乙醇重结晶得到I-32的纯品。Yield 78.4%.Yellowsolid.Mp:216–217℃.1H NMR(400MHz,DMSO-d6,δ,ppm)δ11.10(s,1H,NH,D2Oexchangeable),10.58(s,1H,NH,D2O exchangeable),10.19(s,1H,NH,D2O exchangeable),8.29(d,J=4.1Hz,1H,ArH),8.08–7.48(m,10H,ArH),7.24–7.00(m,1H,ArH),4.19(s,2H,CH2).13C NMR(100MHz,DMSO-d6,δ,ppm):δ173.10,170.72,167.50,160.45,151.28,150.63,148.61,141.82,139.01,136.75,134.78,131.07,129.11,126.07,126.04,123.48,120.11,115.96,113.45,86.68,36.14.HRMS(ESI)calcd for C26H18ClF3N7O2S[M+H]+:584.0883,found:584.0880.
实施例36上述化合物的抗肿瘤活性测定:
1.实验方法:
筛选所用化合物均是由本发明实施例合成、纯化而得;样品储备液:称取3-5mg样品置于1.5mL EP管中,然后用DMSO配制成浓度是128×103μg/mL的溶液,4℃保存放置,实验时根据所需浓度利用培养基稀释。
2.初筛
取对数生长期的细胞,消化计数后,用培养基调整细胞密度,以4000-5000个cell/孔接种至96孔板中,每孔150μL,培养24h后,弃去培养基,加入用培养基稀释好的药物(50μg/mL、100μg/mL),每个浓度设6个复孔,另设空白对照组及阴性对照组。药物作用72h后,每孔加入20μLMTT,继续培养4h后, 吸去液体,加入150mL的DMSO,振荡均匀,酶标仪490nm处检测吸光度值,计算抑制率,计算公式如下:
抑制率(%)=(1-给药组吸光度值/空白组吸光度值)×100%
3、细筛
50μg/mL时抑制率大于50%的样品,重新设置浓度进行细筛。即将待测样品以0.25μg/mL、0.5μg/mL、1μg/mL、2μg/mL、4μg/mL、8μg/mL、16μg/mL、32μg/mL浓度加入96孔板中,培养72h后,检测。试验结果采用SPSS软件计算IC50值和相关系数。
4、实验结果:
表1 上述化合物对四种肿瘤细胞的抗肿瘤活性评价数据:
a人类胃癌细胞b人类乳腺癌细胞c人类前列腺癌细胞d小鼠黑色素瘤细胞
实验结果表明,本发明所提供的含脲结构单元的4-取代-5-氰基-6-氨基嘧啶衍生物对EC109,MCF-7,MGC-803和B16-F10四种肿瘤细胞具有一定的抑制作用,其中多数化合物的体外抗肿瘤活性明显优于或者与5-氟脲嘧啶相当,可作为进一步开发的候选或者先导化合物,应用于制备抗肿瘤药物。
Claims (5)
1.含酰脲结构单元的-5-氰基嘧啶衍生物,特征在于,具有通式Ⅰ所述结构:
通式Ⅰ中X为C或N;
R1为不同位置单取代的氟、氯、溴、甲基、甲氧基、三氟甲基、硝基或异丙基中的任意一种;
R2为氢、不同位置单取代的氯、甲基、异丙基任意一种或R2为3,4,5-三甲氧基或3,4-二氟。
2.如权利要求1所述的含酰脲结构单元的-5-氰基嘧啶衍生物,其特征在于,
优选:X为C;
R1为不同位置单取代的氟、氯、甲基、甲氧基、三氟甲基、硝基或异丙基其中之一;
R2为氢或3,4,5-三甲氧基。
3.如权利要求1所述的含酰脲结构单元的-5-氰基嘧啶衍生物,其特征在于,
优选:X为N;
R1为不同位置单取代的氯、溴、甲基、甲氧基、三氟甲基或硝基其中之一;
R2为不同位置单取代的氯、甲基、异丙基或R2为3,4,5-三甲氧基、3,4-二氟其中之一。
4.如权利要求1所述的含酰脲结构单元的-5-氰基嘧啶衍生物,其特征在于,选如下化合物之一:
X=C时,
I-1 R1= m-CF3,R2=m,p,m-triOCH3;
I-2 R1= o-OCH3,R2=m,p,m-triOCH3;
I-3 R1= p-Cl,R2=m,p,m-triOCH3;
I-4 R1= m-Cl,R2=m,p,m-triOCH3;
I-5 R1= m-NO2,R2=m,p,m-triOCH3;
I-6 R1= p-CH3,R2=m,p,m-triOCH3;
I-7 R1= p-F,R2=m,p,m-triOCH3;
I-8 R1=p-CH(CH3)2,R2=m,p,m-triOCH3;
X=N时,
I-9 R1=p-CH3,R2=H;
I-10 R1= p-CH3,R2=p-CH(CH3)2;
I-11 R1= p-OCH3,R2=p-CH(CH3)2;
I-12 R1= m-CH3,R2=p-CH(CH3)2;
I-13 R1= m-CF3,R2=p-CH(CH3)2;
I-14 R1= m-CF3,R2= p-CH3;
I-15 R1= m-CF3,R2= p-Cl;
I-16 R1= m-CF3,R2=m,p-diF;
I-17 R1= m-CF3,R2=m,p,m-triOCH3;
I-18 R1= p-Br,R2=m,p,m-triOCH3;
I-19 R1= o-Cl,R2=m,p,m-triOCH3;
I-20 R1= p-Cl,R2=m,p,m-triOCH3;
I-21 R1= m-Cl,R2=m,p,m-triOCH3;
I-22 R1= m-NO2,R2=m,p,m-triOCH3;
I-23 R1= p-CH3,R2=m,p,m-triOCH3;
I-24 R1= p-CF3,R2=m,p,m-triOCH3;
I-25 R1=o-OCH3,R2=m,p,m-triOCH3;
I-26 R1=o-Cl,R2=m,p-diF;
I-27 R1= p-CH3,R2=m,p-diF;
I-28 R1= m-Cl,R2=m,p-diF;
I-29 R1=o-OCH3,R2=m,p-diF;
I-30 R1= p-Cl,R2=m,p-diF;
I-31 R1= p-Cl,R2= p-Cl;
I-32 R1= p-CF3,R2= p-Cl。
5.如权利要求1-4其中之一所述的含酰脲结构单元的-5-氰基嘧啶衍生物在制备药物中的应用,其特征在于,做为活性成分用于制备抗肿瘤药物。
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