CN109776556A - 吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物及其制备方法及应用 - Google Patents
吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物及其制备方法及应用 Download PDFInfo
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Abstract
本发明公开了一种吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物,该类化合物包含潜在的生物活性山酮素骨架、螺环吡唑啉酮骨架和螺环氧化吲哚或螺环苯并呋喃酮骨架,可以为生物活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值。本发明操作简单易行,原料合成便宜易得,可以在各种有机溶剂中进行,也具有较好的空气稳定性,适用性广,对于各种取代基都有很好的兼容性。且该类骨架化合物对人白血病细胞(K562)具有肿瘤生长抑制活性作用。
Description
技术领域
本发明涉及化学技术和药学技术领域,尤其是一种吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物及其制备方法及应用。
背景技术
根据药物设计的活性骨架拼接和迁越原理,把两个或多个具有生物活性骨架拼接成一个潜在生物活性的多骨架分子在有机化学和医药化学中是极其重要的研究领域。(1)山酮素骨架也普遍存在天然产物和药物分子中。例如:天然产物分子Ergochrome DD,Diversonol,Desoxydiversonol,Applanatin B和Isocochlioquinone A共享一个山酮素分子单元,这些化合物在解除病痛、经济发展中起着重大作用。(2)螺环吡唑啉酮广泛存在天然产物和合成药物分子中,吸引了许多化学工作者及医药化学团队的广泛关注,例如附图8中,天然产物或活性小分子螺环吡唑啉酮phosphodiesterase inhibitor和anti-inflammatory agent表现明显的生物活性。(3)螺六元碳环氧化吲哚广泛存在天然产物和合成药物分子中,例如附图8中,天然产物或活性小分子螺六元碳环氧化吲哚Satavaptan和progesterone receptor agonist II表现明显的生物活性。(4)螺六元碳环苯并呋喃酮化合物也广泛存在天然产物和合成药物分子中,例如附图8中,天然产物或活性小分子螺六元碳环苯并呋喃酮rosmadial和ferrubietolide表现明显的生物活性。
鉴于山酮素骨架、螺环吡唑啉酮、螺六元碳环氧化吲哚骨架和螺六元碳环苯并呋喃酮具有潜在的生物活性。因此,把螺六元碳环氧化吲哚骨架或螺六元碳环苯并呋喃酮拼接到吡唑啉酮山酮素骨架,合成一系列新的潜在多活性官能团的吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物,可以为生物活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值(如图8所示)。
发明内容
本发明的目的是:提供一种吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物及其制备方法与应用,它是一类重要的医药中间体类似物和药物分子类似物,对药物筛选和制药行业具有重要的应用价值,且其合成方法非常经济简便。
本发明还发现该类化合物在制备防治肿瘤疾病药物中的应用。
本发明是这样实现的:一种吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物,该化合物具有如下通式(Ⅰ)的结构:
式中,R1为甲基或异丙基或氟或氢;R2为甲基或氟或氯或溴或氢;X为氮取代或氧取代。
吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物的制备方法,将各种取代的双功能吡唑啉酮-色酮合成子、各种取代的3-烯氧化吲哚或3-烯苯并呋喃酮在有机溶剂中,在有机小分子催化剂作用下,进行Michael/Michael环加成反应,获得吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物3或5。
合成路线举例如下:
其中合成路线中的化合物,其取代基满足R1为甲基或异丙基或氟或氢;R2为甲基或氟或氯或溴或氢;X为氮取代或氧取代。
反应机理举例如下:
所述的有机溶剂为乙腈、甲苯、二氯甲烷、或氯仿。
所述的有机小分子碱性催化剂为手性双功能金鸡纳碱衍生的硫脲或芳酰胺、环己基二胺衍生的硫脲或芳酰胺、1,2-二苯基二胺衍生的的硫脲或芳酰胺。
所述的有机小分子碱性催化剂举例如下:
各种取代的双功能吡唑啉酮-色酮合成子、各种取代的3-烯氧化吲哚或3-烯苯并呋喃酮在有机溶剂中的反应温度为-10℃至40℃,反应时间为1至5天。
吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物在制备防治肿瘤疾病药物中的应用。
通过采用上述技术方案,以各种取代的双功能吡唑啉酮-色酮合成子1、各种取代的3-烯键氧化吲哚2或3-烯苯并呋喃酮4在有机溶剂中,在有机小分子催化剂作用下,进行Michael/Michael环加成反应,获得吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物3或5,该类化合物包含潜在的生物活性吡唑啉酮山酮素骨架和螺环氧化吲哚或螺环苯并呋喃酮骨架,可以为生物活性筛选提供化合物源,对药物的筛选和制药行业具有重要的应用价值。且该新型骨架化合物对人白血病细胞(K562)具有抑制活性的作用。本发明操作简单易行,原料合成便宜易得,可以在各种有机溶剂中进行,也具有较好的空气稳定性,适用性广,对于各种取代基都有很好的兼容性。
附图说明
附图1及附图2为本发明的实施例的化合物3a谱图数据;
附图3为化合物3a液相谱图数据;
附图4及附图5为本发明的实施例的化合物5a谱图数据;
附图6为化合物5a液相谱图数据;
附图7为本发明的实施例的化合物3b和5a单晶图。
附图8为本发明的化合物创造性设计图。
具体实施方式
本发明的实施例:在反应管中依次加入32.2mg双功能吡唑啉酮-色酮合成子1a(0.10mmol),37.3mg 3-烯键氧化吲哚2a(0.13mmol),11.8mg奎宁衍生的硫脲催化剂C2(20mol%,0.02mmol)和1.0mL新蒸馏的***溶液,室温中搅拌反应4天,TLC检测基本反应完全,直接上样经柱层析(洗脱剂:V(石油醚):V(乙酸乙酯)=4:1)纯化得53.8mg化合物3a,白色固体,熔点:115.1-116.3℃;53.8mg,产率87%;96%ee,>20:1dr,[α]D 20=+123.34(c0.15,CH2Cl2);The ee was determined by HPLC analysis using a Chiralpak IAcolumn(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=15.56min;τminor=26.56min)。核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,600MHz)δ:0.87(s,8H),2.19(s,3H),2.43-2.47(m,1H),2.51-2.55(m,1H),2.78(s,3H),3.82-3.87(m,1H),5.95(d,J=13.8Hz,1H),6.71(d,J=8.4Hz,1H),6.99-7.02(m,1H),7.21-7.25(m,2H),7.37-7.42(m,2H),7.42-7.46(m,2H),7.84-7.86(m,1H),7.96(d,J=7.8Hz,2H),8.01(d,J=7.8Hz,1H),8.34(d,J=7.8Hz,1H);13C NMR(CDCl3,150MHz)δ:13.1,25.9,26.8,26.9,38.4,52.2,52.9,53.5,80.4,83.1,115.7,117.8,119.5,120.3,122.1,125.4,125.9,126.8,127.3,128.0,128.8,129.3,136.2,138.1,141.6,160.1,160.4,166.0,170.6,175.3,179.4,192.3;HRMS(ESI-TOF)m/z:Calcd.for C36H33N3NaO7[M+Na]+:642.2211;Found:642.2216.
化合物3b至3p和化合物5a至5h的制备方法同化合物3a,投料比与化合物3a相同,可得到化合物3b至3p和化合物5a至5h,反应产率和dr值,ee值见表1-3,但需强调的是本发明的化合物不限于表1-3所表示的内容。
表1为一种吡唑啉酮山酮素骨架拼接氧化吲哚类化合物的制备方法的化学结构
表2为一种吡唑啉酮山酮素骨架拼接氧化吲哚类化合物的化学结构
表3为一种吡唑啉酮山酮素骨架拼接苯并呋喃酮类化合物的制备方法的化学结构
本实施例制备化合物3b(C1'S,C2'R,C4'S,C5'R,C6'S):白色固体,熔点:121.6-122.4℃;47.7mg,产率75%;96%ee,>20:1dr,[α]D 20=+110.95(c 0.21,CH2Cl2);The eewas determined by HPLC analysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=13.94min;τminor=28.95min);核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,600MHz)δ:0.93(s,9H),2.19(s,3H),2.43-2.52(m,2H),2.77(s,3H),3.80-3.86(m,2H),5.91(d,J=13.8Hz,1H),6.73(d,J=7.8Hz,1H),7.02-7.05(m,1H),7.09-7.13(m,1H),7.23-7.26(m,1H),7.41-7.47(m,3H),7.85-7.88(m,2H),7.96(d,J=7.8Hz,2H),8.33-8.35(m,1H);13C NMR(CDCl3,150MHz)δ:13.1,25.9,26.7,27.0,38.3,52.0,52.8,53.8,80.3,83.4,114.7(d,JCF=26.5Hz),115.8(d,JCF=24.0Hz),117.0,117.8,119.4,120.2,122.3,125.4,127.3,128.9,129.9,136.3,137.6,138.0,159.7,160.3,160.5(d,JCF=249.1Hz),165.8,170.4,175.3,178.9,192.0;HRMS(ESI-TOF)m/z:Calcd.for C36H32FN3NaO7[M+Na]+:660.2116;Found:660.2117.
本实施例制备化合物3c:白色固体,熔点:231.3-232.6℃;56.4mg,产率81%;97%ee,>20:1dr,[α]D 20=+221.56(c 0.32,CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=13.60min;τminor=28.12min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,600MHz)δ:0.94(s,9H),2.20(s,3H),2.42-2.46(m,1H),2.49-2.53(m,1H),2.77(s,3H),3.78-3.84(m,2H),5.94(d,J=14.4Hz,1H),6.73(d,J=8.4Hz,1H),7.02-7.05(m,1H),7.22-7.25(m,1H),7.41-7.47(m,3H),7.54-7.56(m,1H),7.84-7.86(m,1H),7.96-7.98(m,2H),8.20-8.25(m,2H);13C NMR(CDCl3,150MHz)δ:13.2,25.9,26.8,27.0,38.3,52.2,52.9,53.5,80.2,83.7,117.3,117.8,118.9,119.2,120.2,122.3,125.3,127.3,128.9,130.0,130.1,132.4,136.3,138.0,140.6,159.9,160.3,165.8,170.4,175.2,178.5,192.0;HRMS(ESI-TOF)m/z:Calcd.for C36H32BrN3NaO7[M+Na]+:720.1316;Found:720.1316.
本实施例制备化合物3d:白色固体,熔点:128.9-129.7℃;52.2mg,产率80%;98%ee,>20:1dr,[α]D 20=+101.11(c 0.27,CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=12.22min;τminor=36.93min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,600MHz)δ:0.92(s,9H),2.18(s,3H),2.43-2.53(m,2H),2.77(s,3H),3.79-3.84(m,2H),5.89(d,J=13.8Hz,1H),6.74(d,J=8.4Hz,1H),7.02-7.05(m,1H),7.23-7.26(m,2H),7.41-7.46(m,3H),7.85-7.87(m,1H),7.93(d,J=7.8Hz,2H),7.97(d,J=8.4Hz,1H),8.41(s,1H);13C NMR(CDCl3,150MHz)δ:13.1,25.9,26.7,27.0,38.3,52.0,52.8,53.4,80.3,83.4,116.3,117.8,119.5,120.2,122.3,125.5,125.9,126.4,127.3,127.9,128.9,135.2,136.3,138.0,142.3,159.9,160.3,165.9,170.4,175.4,179.0,192.1;HRMS(ESI-TOF)m/z:Calcd.for C36H32ClN3NaO7[M+Na]+:676.1821;Found:676.1823.
本实施例制备化合物3e:白色固体,熔点:126.4-127.8℃;53.6mg,产率77%;92%ee,>20:1dr,[α]D 20=+199.52(c 0.21,CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IF column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=14.97min;τminor=29.05min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,600MHz)δ:0.92(s,9H),2.18(s,3H),2.43-2.53(m,2H),2.77(s,3H),3.79-3.84(m,2H),5.88(d,J=14.4Hz,1H),6.74-6.75(m,1H),7.02-7.05(m,1H),7.23-7.26(m,1H),7.39-7.46(m,4H),7.85-7.86(m,1H),7.91-7.94(m,3H),8.56(s,1H);13C NMR(CDCl3,150MHz)δ:13.1,25.9,26.7,27.0,38.3,52.0,52.8,53.4,80.2,83.4,117.8,119.0,119.6,120.2,122.3,123.2,125.5,127.0,127.3,128.2,128.9,136.3,137.9,142.5,159.9,160.3,165.8,170.4,175.4,178.9,192.1;HRMS(ESI-TOF)m/z:Calcd.for C36H32BrN3NaO7[M+Na]+:720.1316;Found:720.1316.
本实施例制备化合物3f:白色固体,熔点:96.3-97.4℃;46.8mg,产率74%;97%ee,>20:1dr,[α]D 20=+81.15(c 0.26,CH2Cl2);The ee was determined by HPLC analysisusing a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=17.58min;τminor=41.41min);核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,600MHz)δ:0.87(s,9H),2.18(s,3H),2.28(s,3H),2.43-2.52(m,2H),2.77(s,3H),3.79-3.84(m,2H),5.89(d,J=13.8Hz,1H),6.61(d,J=8.4Hz,1H),7.20-7.25(m,3H),7.38-7.41(m,1H),7.43-7.46(m,2H),7.63(s,1H),7.96(d,J=7.8Hz,2H),8.00(d,J=7.8Hz,1H),8.33(d,J=7.8Hz,1H);13C NMR(CDCl3,150MHz)δ:13.1,20.4,26.0,26.8,26.9,38.4,52.2,52.8,53.6,80.4,83.0,115.6,117.6,119.5,119.8,125.3,125.9,126.8,128.1,128.8,129.3,131.6,137.2,138.1,141.6,158.2,160.4,166.0,170.6,175.4,179.4,192.5;HRMS(ESI-TOF)m/z:Calcd.for C37H35N3NaO7[M+Na]+:656.2367;Found:656.2365.
本实施例制备化合物3g:白色固体,熔点:107.3-108.4℃;54.0mg,产率83%;95%ee,>20:1dr,[α]D 20=+94.85(c 0.32,CH2Cl2);The ee was determined by HPLC analysisusing a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=15.67min;τminor=46.08min);核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,600MHz)δ:0.92(s,9H),2.19(s,3H),2.29(s,3H),2.45-2.48(m,2H),2.76(s,3H),3.77-3.82(m,2H),5.85(d,J=14.4Hz,1H),6.62(d,J=8.4Hz,1H),7.09-7.12(m,1H),7.22-7.25(m,2H),7.44-7.47(m,2H),7.64(s,1H),7.86-7.88(m,1H),7.96(d,J=8.4Hz,2H),8.32-8.34(m,1H);13C NMR(CDCl3,150MHz)δ:13.1,20.4,26.0,26.7,27.0,38.3,51.9,52.8,53.8,80.3,83.4,114.7(d,JCF=27.0Hz),115.7(d,JCF=22.5Hz),116.9,117.0,117.6,119.4,119.8,125.4,126.8,128.9,130.1,131.8,137.3,137.7,138.0,158.0,160.4,160.5(d,JCF=243.0Hz),165.8,170.4,175.4,179.0,192.3;HRMS(ESI-TOF)m/z:Calcd.for C37H34FN3NaO7[M+Na]+:674.2273;Found:674.2277.
本实施例制备化合物3h:白色固体,熔点:103.4-104.6℃;57.3mg,产率86%;95%ee,>20:1dr,[α]D 20=+66.00(c 0.25,CH2Cl2);The ee was determined by HPLC analysisusing a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=13.94min;τminor=40.79min);核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,600MHz)δ:0.93(s,9H),2.19(s,3H),2.29(s,3H),2.43-2.51(m,2H),2.76(s,3H),3.76-3.81(m,2H),5.88(d,J=14.4Hz,1H),6.63(d,J=8.4Hz,1H),7.22-7.25(m,2H),7.37-7.40(m,1H),7.44-7.47(m,2H),7.64(s,1H),7.96-7.98(m,2H),8.07(s,1H),8.29(d,J=9.0Hz,1H);13C NMR(CDCl3,150MHz)δ:13.1,20.4,26.0,26.7,27.0,38.2,52.0,52.9,53.7,80.2,83.6,116.9,117.6,119.2,119.8,125.3,126.8,127.2,128.9,129.4,129.9,131.2,131.8,137.3,138.0,140.1,158.0,160.3,165.8,170.4,175.3,178.7,192.3;HRMS(ESI-TOF)m/z:Calcd.for C37H34ClN3NaO7[M+Na]+:690.1977;Found:690.1981.
本实施例制备化合物3i:白色固体,熔点:104.3-105.2℃;49.7mg,产率70%;92%ee,>20:1dr,[α]D 20=+130.40(c 0.25,CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=13.92min;τminor=41.39min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,600MHz)δ:0.94(s,9H),2.19(s,3H),2.29(s,3H),2.41-2.51(m,2H),2.76(s,3H),3.76-3.81(m,2H),5.88(d,J=14.4Hz,1H),6.63(d,J=9.0Hz,1H),7.22-7.25(m,2H),7.44-7.47(m,2H),7.53-7.55(m,1H),7.64(s,1H),7.97(d,J=7.8Hz,1H),8.21-8.24(m,2H);13C NMR(CDCl3,150MHz)δ:13.1,22.7,26.0,26.8,27.0,38.2,52.1,52.9,53.6,80.2,83.6,117.3,117.6,118.8,119.2,119.8,125.3,126.8,128.9,130.0,130.2,131.8,132.3,137.3,138.1,140.6,158.0,160.3,165.8,170.4,175.2,178.6,192.2;HRMS(ESI-TOF)m/z:Calcd.for C37H34BrN3NaO7[M+Na]+:734.1472;Found:734.1475.
本实施例制备化合物3j:白色固体,熔点:92.3-93.5℃;47.2mg,产率73%;90%ee,>20:1dr,[α]D 20=+74.29(c 0.21,CH2Cl2);The ee was determined by HPLC analysisusing a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=12.69min;τminor=31.01min);核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,600MHz)δ:0.88(s,9H),2.18(s,3H),2.28(s,3H),2.34(s,3H),2.40-2.45(m,1H),2.49-2.53(m,1H),2.76(s,3H),3.77-3.83(m,2H),5.90(d,J=13.8Hz,1H),6.62(d,J=8.4Hz,1H),7.19-7.25(m,3H),7.44-7.47(m,2H),7.63(s,1H),7.78(s,1H),7.97(d,J=7.8Hz,2H),8.19(d,J=8.4Hz,1H);13C NMR(CDCl3,150MHz)δ:13.1,20.4,21.4,25.9,26.7,26.9,38.4,52.2,53.0,53.5,80.3,83.0,115.5,117.6,119.3,119.9,125.2,126.8,127.2,127.9,128.8,129.6,131.5,135.5,137.1,138.2,139.2,158.3,160.4,166.1,170.5,175.3,179.5,192.6;HRMS(ESI-TOF)m/z:Calcd.for C38H37N3NaO7[M+Na]+:670.2524;Found:670.2527.
本实施例制备化合物3k:白色固体,熔点:143.8-144.6℃;56.2mg,产率85%;91%ee,>20:1dr,[α]D 20=+149.31(c 0.29,CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=10.31min;τminor=27.40min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,600MHz)δ:0.87(s,9H),1.19(s,3H),1.20(s,3H),2.19(s,3H),2.43-2.47(m,1H),2.49-2.53(m,1H),2.77(s,3H),3.79-3.85(m,2H),5.90(d,J=14.4Hz,1H),6.65(d,J=8.4Hz,1H),7.22-7.27(m,2H),7.27-7.29(m,1H),7.38-7.41(m,1H),7.43-7.46(m,2H),7.70(s,1H),7.95(d,J=8.4Hz,2H),8.00(d,J=7.8Hz,1H),8.32(d,J=7.8Hz,1H);13C NMR(CDCl3,150MHz)δ:13.1,23.9,26.0,26.8,26.9,33.3,38.4,52.2,52.9,53.6,80.4,83.0,115.6,117.7,119.5,124.2,125.3,125.9,126.8,128.1,128.8,129.3,134.9,138.1,141.6,142.8,158.4,160.4,166.0,170.6,175.3,179.4,192.6;HRMS(ESI-TOF)m/z:Calcd.for C39H39N3NaO7[M+Na]+:684.2680;Found:684.2681.
本实施例制备化合物3l:白色固体,熔点:127.6-128.4℃;47.5mg,产率70%;92%ee,>20:1dr,[α]D 20=+188.57(c 0.21,CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=13.92min;τminor=41.39min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,600MHz)δ:0.92(s,9H),1.20(s,3H),1.21(s,3H),2.19(s,3H),2.45-2.51(m,2H),2.76(s,3H),2.83-2.89(m,1H),3.78-3.83(m,2H),5.86(d,J=14.4Hz,1H),6.66(d,J=9.0Hz,1H),7.09-7.12(m,1H),7.22-7.25(m,1H),7.29-7.31(m,1H),7.43-7.46(m,2H),7.70(s,1H),7.85-7.87(m,1H),7.96(d,J=7.8Hz,2H),8.32-8.35(m,1H);13C NMR(CDCl3,150MHz)δ:13.1,23.8,23.9,26.0,26.7,27.0,33.3,38.3,52.0,52.8,53.8,80.3,83.4,114.7(d,JCF=25.5Hz),115.7(d,JCF=22.5Hz),117.0,117.7,119.3,119.9,124.3,125.4,128.9,135.0,137.7,138.0,143.0,158.3,160.4,160.5(d,JCF=243.0Hz),165.9,170.4,175.3,178.9,192.4;HRMS(ESI-TOF)m/z:Calcd.for C39H38FN3NaO7[M+Na]+:702.2586;Found:702.2589.
本实施例制备化合物3m:白色固体,熔点:123.7-124.6℃;50.0mg,产率72%;90%ee,>20:1dr,[α]D 20=+267.06(c 0.17,CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=8.76min;τminor=24.31min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,600MHz)δ:0.93(s,9H),1.20(s,3H),1.21(s,3H),2.19(s,3H),2.42-2.52(m,2H),2.76(s,3H),2.84-2.89(m,1H),3.76-3.82(m,2H),5.89(d,J=14.4Hz,1H),6.66(d,J=9.0Hz,1H),7.22-7.25(m,1H),7.29-7.31(m,1H),7.37-7.40(m,1H),7.44-7.47(m,2H),7.70(s,1H),7.97(d,J=7.8Hz,2H),8.06(s,1H),8.29(d,J=9.0Hz,1H);13C NMR(CDCl3,150MHz)δ:13.1,23.9,26.0,26.7,27.0,33.3,38.3,52.1,52.9,53.6,80.2,83.6,116.9,117.7,119.2,119.9,124.3,125.3,127.1,128.9,129.3,129.9,131.2,135.0,138.1,140.1,143.0,158.3,160.3,165.8,170.4,175.3,178.7,192.3;HRMS(ESI-TOF)m/z:Calcd.for C39H38ClN3NaO7[M+Na]+:718.2290;Found:718.2293.
本实施例制备化合物3n:白色固体,熔点:117.8-118.6℃;51.0mg,产率69%;91%ee,>20:1dr,[α]D 20=+195.26(c 0.19,CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=9.62min;τminor=26.31min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,600MHz)δ:0.94(s,9H),1.20(s,3H),1.21(s,3H),2.19(s,3H),2.42-2.52(m,2H),2.76(s,3H),2.84-2.89(m,1H),3.76-3.81(m,2H),5.89(d,J=14.4Hz,1H),6.66(d,J=9.0Hz,1H),7.22-7.25(m,1H),7.28-7.31(m,2H),7.44-7.47(m,2H),7.53-7.55(m,1H),7.70(s,1H),7.97(d,J=7.8Hz,2H),8.20(s,1H),8.24(d,J=8.4Hz,1H);13C NMR(CDCl3,150MHz)δ:13.1,23.8,23.9,26.0,26.8,27.0,33.3,38.3,52.1,52.9,53.6,80.2,83.6,117.3,117.7,118.8,119.1,119.9,124.3,125.3,128.9,129.9,130.2,132.3,135.0,138.1,140.6,143.0,158.2,160.3,165.8,170.5,175.2,178.5,192.3;HRMS(ESI-TOF)m/z:Calcd.for C39H38BrN3NaO7[M+Na]+:762.1785;Found:762.1789.
本实施例制备化合物3o:白色固体,熔点:128.5-129.7℃;52.3mg,产率78%;90%ee,>20:1dr,[α]D 20=+154.85(c 0.33,CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=10.96min;τminor=20.10min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,600MHz)δ:0.93(s,9H),2.19(s,3H),2.45-2.50(m,2H),2.77(s,3H),3.78-3.82(m,2H),5.94(d,J=14.4Hz,1H),6.71-6.73(m,1H),7.13-7.16(m,1H),7.23-7.26(m,1H),7.38-7.40(m,1H),7.45-7.47(m,2H),7.49-7.51(m,1H),7.96-7.97(m,2H),8.05(s,1H),8.29(d,J=8.4Hz,1H);13C NMR(CDCl3,150MHz)δ:13.1,25.8,26.7,27.0,38.3,52.2,52.9,53.5,80.4,83.7,112.3(d,JCF=12.6Hz),117.0,119.2,119.6,120.8,123.7(d,JCF=24.0Hz),125.4,127.1,128.9,129.5,129.6,131.3,138.0,140.0,156.2,157.7(d,JCF=242.4Hz),160.2,165.7,170.4,175.2,178.6,191.4;HRMS(ESI-TOF)m/z:Calcd.forC36H31ClFN3NaO7[M+Na]+:694.1727;Found:694.1729.
本实施例制备化合物3p:白色固体,熔点:137.2-138.4℃;51.7mg,产率79%;91%ee,>20:1dr,[α]D 20=+160.00(c 0.23,CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=11.40min;τminor=21.25min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,600MHz)δ:0.93(m,9H),2.19(s,3H),2.45-2.48(m,2H),2.77(s,3H),3.81-3.83(m,2H),5.91(d,J=14.4Hz,1H),6.71-6.73(m,1H),7.10-7.16(m,2H),7.23-7.26(m,1H),7.44-7.47(m,2H),7.49-7.51(m,1H),7.83-7.86(m,1H),7.94-7.96(m,2H),8.32-8.34(m,1H);13C NMR(CDCl3,150MHz)δ:13.1,25.9,26.7,27.0,38.3,52.1,52.8,53.6,80.5,83.5,112.3(d,JCF=22.5Hz),114.7(d,JCF=25.5Hz),115.9(d,JCF=24.0Hz),117.1,119.4,119.5,119.6,123.7(d,JCF=24.0Hz),125.5,128.9,137.6,137.9,156.2,157.6(d,JCF=259.5Hz),160.2,160.4(d,JCF=238.5Hz),165.7,170.4,175.3,178.8,191.4;HRMS(ESI-TOF)m/z:Calcd.for C36H31F2N3NaO7[M+Na]+:678.2022;Found:678.2025.
本实施例制备化合物5a(C1'S,C2'R,C4'S,C5'R,C6'S):白色固体,熔点:150.2-151.2℃;37.0mg,产率64%;>99%ee,>20:1dr,[α]D 20=+59.59(c 0.24CH2Cl2);The ee wasdetermined by HPLC analysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=19.99min;τminor=25.03min);核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,400MHz)δ:0.90(s,9H),2.15(s,3H),2.44(d,J=10.0Hz,1H),3.71-3.77(m,1H),3.78(s,1H),5.85(d,J=14.4Hz,1H),6.73(d,J=8.4Hz,1H),6.96-7.00(m,1H),7.15-7.23(m,3H),7.36-7.44(m,4H),7.80-7.83(m,1H),7.91(d,J=7.6Hz,3H);13C NMR(CDCl3,100MHz)δ:13.1,26.0,26.9,38.2,51.6,52.4,52.7,83.4,109.9,117.9,119.4,122.1,125.0,125.3,126.8,127.1,127.7,128.8,129.9,136.2,137.9,154.6,159.8,160.3,165.7,175.3,177.6,192.0;HRMS(ESI-TOF)m/z:Calcd.forC34H30N2NaO7[M+Na]+:601.1945;Found:601.1951.
本实施例制备化合物5b:白色固体,熔点:131.5-132.4℃;34.9mg,产率59%;>99%ee,>20:1dr,[α]D 20=+157.39(c 0.17CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=25.19min;τminor=38.22min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,400MHz)δ:0.89(s,9H),2.14(s,3H),2.25(s,3H),2.40-2.44(m,2H),3.67-3.76(m,1H),3.77(s,1H),5.80(d,J=14.4Hz,1H),6.62(d,J=8.4Hz,1H),7.14-7.22(m,4H),7.35-7.44(m,4H),7.59(s,1H),7.91(d,J=8.4Hz,3H);13C NMR(CDCl3,100MHz)δ:13.1,20.3,26.1,27.0,38.2,51.6,52.4,52.8,79.5,83.4,109.9,117.7,119.4,119.6,125.0,125.3,126.6,126.9,127.7,128.8,129.9,131.6,137.2,154.6,157.9,160.3,165.8,175.3,177.7,192.3;HRMS(ESI-TOF)m/z:Calcd.for C35H32N2NaO7[M+Na]+:615.2102;Found:615.2107.
本实施例制备化合物5c:白色固体,熔点:122.5-123.4℃;39.0mg,产率63%;99%ee,>20:1dr,[α]D 20=+156.70(c 0.24CH2Cl2);The ee was determined by HPLC analysisusing a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=13.38min;τminor=21.50min);核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,400MHz)δ:0.89(s,9H),1.15(s,3H),1.17(s,3H),2.14(s,3H),2.40-2.44(m,2H),2.78-2.85(m,1H),3.68-3.73(m,1H),3.67(s,1H),5.81(d,J=14.4Hz,1H),6.65(d,J=8.8Hz,1H),7.13-7.26(m,4H),7.34-7.42(m,3H),7.64(d,J=2.4Hz,1H),7.89-7.92(m,3H);13C NMR(CDCl3,100MHz)δ:13.1,23.8,26.1,26.9,33.2,38.2,51.6,52.5,52.7,79.5,83.4,109.9,117.8,119.4,119.7,124.0,124.9,125.3,126.9,127.7,128.8,129.8,134.9,142.7,154.6,158.1,160.3,165.8,175.3,177.6,192.3;HRMS(ESI-TOF)m/z:Calcd.forC37H36N2NaO7[M+Na]+:643.2415;Found:643.2418.
本实施例制备化合物5d:白色固体,熔点:195.6-196.5℃;35.5mg,产率60%;>99%ee,>20:1dr,[α]D 20=+218.89(c 0.17CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=15.32min;τminor=19.65min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,400MHz)δ:0.90(s,9H),2.14(s,3H),2.31(s,3H),2.43(d,J=9.6Hz,1H),3.69-3.76(m,1H),3.78(s,1H),5.86(d,J=14.4Hz,1H),6.73(d,J=8.4Hz,1H),6.95-6.99(m,1H),7.07(d,J=8.4Hz,1H),7.15-7.25(m,2H),7.35-7.44(m,3H),7.67(s,1H),7.79-7.81(m,1H),7.93(d,J=8.0Hz,2H);13C NMR(CDCl3,100MHz)δ:13.1,21.3,26.0,26.9,38.2,51.7,52.6,52.7,79.4,83.3,109.6,117.9,119.2,122.0,125.2,126.6,127.0,127.9,128.8,130.2,134.6,136.1,152.5,159.8,160.3,165.8,175.2,177.9,192.1;HRMS(ESI-TOF)m/z:Calcd.for C35H32N2NaO7[M+Na]+:615.2102;Found:615.2105.
本实施例制备化合物5e:白色固体,熔点:128.5-129.2℃;38.1mg,产率63%;>99%ee,>20:1dr,[α]D 20=+219.49(c 0.13CH2Cl2);The ee was determined by HPLCanalysis using a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=18.41min;τminor=26.65min);核磁共振和高分辨质谱测试等结果如下:1HNMR(CDCl3,400MHz)δ:0.90(s,9H),2.14(s,3H),2.24(s,3H),2.31(s,3H),2.41(d,J=9.6Hz,2H),3.66-3.73(m,1H),3.75(s,1H),5.80(d,J=14.4Hz,1H),6.63(d,J=8.4Hz,1H),7.06(d,J=8.0Hz,1H),7.14-7.22(m,3H),7.40-7.44(m,2H),7.59(s,1H),7.68(s,1H),7.93(d,J=8.4Hz,2H);13C NMR(CDCl3,100MHz)δ:13.1,20.3,21.3,26.1,26.9,38.2,51.6,52.6,52.8,79.4,83.3,109.6,117.7,119.2,119.6,125.2,126.6,126.7,128.0,130.1,131.5,134.5,137.2,152.5,157.9,160.3,165.8,175.2,178.0,192.3;HRMS(ESI-TOF)m/z:Calcd.for C36H34N2NaO7[M+Na]+:629.2258;Found:629.2252.
本实施例制备化合物5f:白色固体,熔点:128.3-129.2℃;34.9mg,产率55%;97%ee,>20:1dr,[α]D 20=+170.77(c 0.20CH2Cl2);The ee was determined by HPLC analysisusing a Chiralpak IA column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=13.59min;τminor=18.63min);核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,400MHz)δ:0.90(s,9H),1.16(s,3H),1.17(s,3H),2.14(s,3H),2.31(s,3H),2.42(d,J=9.6Hz,2H),2.78-2.86(m,1H),3.67-3.73(m,1H),3.75(s,1H),5.82(d,J=14.4Hz,1H),6.67(d,J=8.8Hz,1H),7.06(d,J=8.0Hz,1H),7.14-7.22(m,2H),7.24-7.27(m,1H),7.40-7.44(m,2H),7.65-7.67(m,2H),7.92-7.94(m,2H);13C NMR(CDCl3,100MHz)δ:13.1,21.3,23.8,26.1,26.9,33.3,38.2,51.7,52.6,52.7,79.4,83.3,109.6,117.8,119.2,119.7,124.0,125.2,126.7,127.9,128.8,130.1,134.5,134.9,142.7,152.5,158.2,160.3,165.8,175.2,178.0,192.4;HRMS(ESI-TOF)m/z:Calcd.for C38H38N2NaO7[M+Na]+:657.2571;Found:657.2574.
本实施例制备化合物5g:白色固体,熔点:165.2-166.1℃;39.9mg,产率67%;96%ee,>20:1dr,[α]D 20=+225.38(c 0.19CH2Cl2);The ee was determined by HPLC analysisusing a Chiralpak IF column(95/5hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=22.17min;τminor=33.05min);核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,400MHz)δ:0.91(s,9H),2.16(s,3H),2.38-2.50(m,2H),3.71-3.78(m,2H),5.87(d,J=14.4Hz,1H),6.72-6.75(m,1H),7.10-7.14(m,1H),7.17-7.27(m,3H),7.37-7.48(m,4H),7.91-7.93(m,3H);13C NMR(CDCl3,100MHz)δ:13.1,26.0,26.9,38.1,51.7,52.4,52.6,79.7,83.5,110.0,112.0(d,JCF=23.2Hz),119.4,119.6(d,JCF=8.3Hz),123.7(d,JCF=25.1Hz),125.4,127.7,128.8,130.0,137.9,154.6,157.5(d,JCF=242.4Hz),160.2,165.6,166.2,175.3,177.6,191.3;HRMS(ESI-TOF)m/z:Calcd.for C34H29FN2NaO7[M+Na]+:619.1851;Found:619.1848.
本实施例制备化合物5h:白色固体,熔点:156.2-157.2℃;42.7mg,产率70%;97%ee,>20:1dr,[α]D 20=+157.73(c 0.16CH2Cl2);The ee was determined by HPLC analysisusing a Chiralpak IE column(96/4hexane/i-PrOH;flow rate:1.0mL/min;λ=254nm;τmajor=24.99min;τminor=37.43min);核磁共振和高分辨质谱测试等结果如下:1H NMR(CDCl3,400MHz)δ:0.92(s,9H),2.16(s,3H),2.33(s,3H),2.43(d,J=9.2Hz,2H),3.70-3.78(m,2H),5.87(d,J=14.4Hz,1H),6.73-6.76(m,1H),7.07-7.14(m,2H),7.17-7.27(m,2H),7.42-7.48(m,3H),7.68(s,1H),7.94(d,J=8.4Hz,2H);13C NMR(CDCl3,100MHz)δ:13.1,21.3,25.9,26.9,38.2,51.7,52.6,52.7,79.7,83.4,109.6,112.1(d,JCF=23.0Hz),119.3,123.6(d,JCF=25.2Hz),125.3,126.5,127.9,128.8,130.3,134.7,138.0,152.5,156.1,157.5(d,JCF=244.1Hz),160.2,165.7,166.2,175.2,177.9,191.4;HRMS(ESI-TOF)m/z:Calcd.for C35H31FN2NaO7[M+Na]+:633.2008;Found:633.2012.
本发明的式(1)化合物具有重要的生物活性,体外对人白血病细胞(K562)的细胞毒性试验表明:此类式(1)所示结构的吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物对肿瘤细胞生长具有抑制作用,有可能发展成为新的防治肿瘤药物。但需强调的是本发明的化合物不限于人白血病细胞(K562)表示的细胞毒性。
药理实施例:化合物3d,3h和5g,5h对K562细胞的细胞毒性
K562(人慢性髓系白血病细胞)用RPMI-1640培养基培养,培养基中含10%的胎牛血清,100U/mL的青霉素和100U/mL链霉素。细胞以每孔5000个细胞的浓度加入到96孔中,在37℃含5%CO2潮湿空气的培养箱中培养24小时。
细胞存活率的测定用改良MTT法。细胞经过24小时的孵育后,分别将新配的化合物3d,3h和5g,5h的二甲基亚砜溶液以浓度梯度加入到各孔中,使孔中化合物最终浓度分别为5μmol/L,10μmol/L,20μmol/L,40μmol/L和80μmol/L。48小时后,每孔加入10μL MTT(5mg/mL)的磷酸盐缓冲液,再继续在37℃培养4小时后,离心5分钟除去未转化的MTT,每孔中加入150μL二甲基亚砜。以溶解还原的MTT晶体甲臜(formazan),用酶标仪在490nm波长测定OD值。其中化合物化合物3d,3h和5g,5h对K562细胞半抑制浓度IC50由spss软件(19版本)分析得到。化合物3d对K562肿瘤细胞的IC50为51.09μmol/L;化合物3h对K562肿瘤细胞的IC50为45.17μmol/L;化合物5g对K562肿瘤细胞的IC50为51.21μmol/L;化合物5h对K562肿瘤细胞的IC50为47.08μmol/L;而阳性对照顺铂对PC-3肿瘤细胞的IC50为20.57μmol/L。
实验结论:K562细胞是测试化合物对肿瘤细胞的细胞毒性的有效工具和评价指标。本实验表明此类式(1)所示的山吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物对K562细胞具有较强的细胞毒性,和肿瘤治疗一线用药顺铂同一数量级,有可能发展成新的具有抗肿瘤作用的药物。
从以上药理实施例中我们可以看出这些吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物具有开发成为抗肿瘤药物的潜力,值得继续深入研究下去。
Claims (6)
1.一种吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物,其特征在于:该化合物具有如通式(Ⅰ)所示的结构:
式中,R1为甲基、异丙基、氟或氢;R2为甲基、氟、氯、溴或氢;X为氮取代或氧取代。
2.一种如权利要求1所述的吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物的制备方法,其特征在于:将各种取代的双功能吡唑啉酮-色酮合成子与各种取代的3-烯氧化吲哚或3-烯苯并呋喃酮加入有机溶剂中,通过有机小分子催化剂作用,进行Michael/Michael环加成反应,获得吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物。
3.根据权利要求2所述的吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物的制备方法,其特征在于:所述的有机溶剂为乙腈、甲苯、二氯甲烷、或氯仿。
4.根据权利要求2所述的吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物的制备方法,其特征在于:所述的有机小分子碱性催化剂为手性双功能金鸡纳碱衍生的硫脲或芳酰胺、环己基二胺衍生的硫脲或芳酰胺、1,2-二苯基二胺衍生的硫脲或芳酰胺。
5.根据权利要求2所述的吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物的制备方法,其特征在于:各种取代的双功能吡唑啉酮-色酮合成子与各种取代的3-烯氧化吲哚或3-烯苯并呋喃酮在有机溶剂中的反应温度为-10℃至40℃,反应时间为1至5天。
6.一种如权利要求1所述的吡唑啉酮山酮素骨架拼接氧化吲哚或苯并呋喃酮类化合物在制备防治肿瘤疾病药物中的应用。
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