CN101486703B - 一类具有抗肿瘤活性的黄酮化合物、其制备方法及其用途 - Google Patents
一类具有抗肿瘤活性的黄酮化合物、其制备方法及其用途 Download PDFInfo
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- CN101486703B CN101486703B CN2009100249403A CN200910024940A CN101486703B CN 101486703 B CN101486703 B CN 101486703B CN 2009100249403 A CN2009100249403 A CN 2009100249403A CN 200910024940 A CN200910024940 A CN 200910024940A CN 101486703 B CN101486703 B CN 101486703B
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- phenyl
- chromene
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Abstract
本发明涉及药物化学领域,具体涉及结构式(I)的黄酮类化合物及其药学上可以接受的盐,其中R5、R6、R7、R8和X的定义同说明书,本发明的化合物具有较强的抗肿瘤活性。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类汉黄芩素衍生物的黄酮类化合物,该类黄酮类化合物具有显著的抗肿瘤活性。
背景技术
汉黄芩素是天然产物黄芩中的一个黄酮类化合物。黄芩为唇形科植物黄芩(Scutellariabaicalensis Georgi)的干燥根,主要分布于我国的北部各省,以东北和华北的资源最为丰富,是我国的传统中药,它的抗菌、消炎、解毒、排毒和清热燥湿等功效早就为人所知。另外,黄芩尚有抗乙肝病毒、抗血栓形成、抗半乳糖性白内障等功效。现代药理研究认为黄芩能通过诱导凋亡和刺激NOS(nitric oxide synthase,一氧化氮合酶)活性促使巨噬细胞产生NO等途径抗肿瘤细胞增殖(Cobo JM,Garcia Canero R,Valdez JG et al.,Attenuation of apoptocic DNAfragmentation by amiloride.J Cell Physiol,1998,175:59-67)。
最近生物活性研究表明,汉黄芩素有抗血管平滑肌细胞增殖活性;抑制LPS诱导的NO和PGE-2的产生从而有抗氧化的活性;有效抑制HBV表面抗原的抗乙肝病毒活性;此外汉黄芩素能激活caspase-3的级联反应,诱导肿瘤细胞凋亡。
在HL-60细胞实验中(MTT测定),汉黄芩素(WOG)对HL-60有显著的浓度依赖型(20,40,80μM for12h)抑制作用;随着浓度增大,抑制作用也越强。同时也会破坏其染色体DNA。而且进一步证实这种抑作用是通过caspase-3(Woan-Rouh Lee,Shing-Chuan Shen,Hui-YiLin etal;Biochemical Pharmacology,2002,63:225-236)。
发明内容
本发明公开了一类具有抗肿瘤活性的汉黄芩素衍生物的黄酮类化合物。本发明用汉黄芩素为起始原料,经氧烃化、氮烃化等反应制备了一系列新的黄酮类化合物,这些化合物具有较强的抗肿瘤活性。
本发明的黄酮类化合物结构如下:
其中R5、R6、R7或R8可代表相同基团也可代表不同基团,各自独立地代表H、C1~C6取代烃基;C1~C6取代烃基中的取代基是H、卤素、硝基、氨基、取代氨基、羟基、醚基、羧基、酯基或酰氨基;所述取代氨基为R1NH或R1R2N,其中R1或R2为C1~C6的烃基,R1、R2可以是各自独立,R1和R2还可以连接成环状或者通过1~3个杂原子连接成环状;
R5、R6、R7或R8还各自独立地代表取代的苯基,取代的苯基中的取代基是H、F、Cl、Br、I、C1~10烷基、羟基、C1~C10烷氧基、硝基或氨基;
R5、R6、R7或R8还各自独立地代表取代的杂环基;杂环基指含有从氧、氮、硫原子中任选的一个或一个以上的杂原子的3-7元的饱和杂环基或4-7元的芳香杂环基;取代的杂环基中取代基是H、F、Cl、Br、I、C1~C10烷基、羟基、C1~C10烷氧基、硝基或氨基;
X代表H、卤素、C1~C10烃基、卤素取代的C1~C10烃基、硝基、氨基、腈基、羟基或C1~C10烷氧基。
R5优选表示H、C1~C6的烷基、卤素或羟基取代的C1-C4的烷基。R5进一步优选H或甲基。
R6优选表示H、C1~C7的烷基或C2~C7烯基。R6进一步优选H、甲基、乙基、异丙基或异戊烯基。
R7优选表示H、F、Cl、Br、I、羟基、氨基、取代氨基取代的C1~C6烷基,其中取代氨基为甲基哌嗪、哌嗪、吗啡啉基、哌啶基、四氢吡咯基、R1R2N,其中R1、R2为H或C1~C6的烃基。R7进一步优选甲基哌嗪、哌嗪、吗啡啉、哌啶、四氢吡咯、N,N-二乙氨基或N,N-二羟乙基氨基取代的C2-C4的烷基。
R8优选表示H、C1-C6的烷基、卤素或者羟基取代的C1-C4的烷基。R8进一步优选H或甲基。
X优选代表H、卤素、甲基、乙基、硝基、氨基、腈基、羟基、甲氧基或乙氧基。本发明中部分化合物如下,括号中是其代号:
5-羟基-7,8-二甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-101)
5-羟基-7-乙氧基-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-102)
5-羟基-7-丙氧基-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-103)
5-羟基-7-异丁氧基-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-104)
5-羟基-7-烯丙氧基-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-105)
5-羟基-7-(3-甲基-2-丁烯氧基)-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-106)
5-羟基-7-苄氧基-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-107)
5-羟基-8-甲氧基-7-(3-溴丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-201)
5-羟基-8-甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-202)
5-羟基-8-甲氧基-7-(3-(吗啡啉-1-基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-203)
5-羟基-8-甲氧基-7-(3-(N,N-二(2-羟基乙基)胺基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-204)
5-羟基-8-甲氧基-7-(3-(四氢吡咯-1-基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-205)
5-羟基-8-甲氧基-7-(3-(哌啶-1-基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-206)
5-羟基-8-甲氧基-7-(3-(N,N-二乙胺基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-207)
5-羟基-8-甲氧基-7-(3-(苄胺基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-208)
5-羟基-8-甲氧基-7-(3-(对甲氧苯胺基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-209)
5,8-二甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-210)
5-羟基-8-甲氧基-7-(4-溴丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-301)
5-羟基-8-甲氧基-7-(4-(4-甲基哌嗪-1-基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-302)
5-羟基-8-甲氧基-7-(4-(吗啡啉-1-基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-303)
5-羟基-8-甲氧基-7-(4-(N,N-二(2-羟基乙基)胺基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-304)
5-羟基-8-甲氧基-7-(4-(四氢吡咯-1-基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-305)
5-羟基-8-甲氧基-7-(4-(哌啶-1-基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-306)
5-羟基-8-甲氧基-7-(4-(N,N-二乙胺基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-307)
5-羟基-8-甲氧基-7-((4-苄胺基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-308)
5-羟基-8-甲氧基-7-((4-苯胺基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-309)
5,8-二甲氧基-7-(4-(4-甲基哌嗪-1-基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-310)
5-羟基-8-甲氧基-7-(4-(4-甲氧苯胺基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-311)
5-羟基-8-甲氧基-7-(4-溴丁氧基)-2-(4-硝基苯基)-4H-1-苯并吡喃-4-酮(LYG-401)
5-羟基-8-甲氧基-7-(4-(4-甲基哌嗪-1-基)丁氧基)-(4-硝基苯基)-4H-1-苯并吡喃-4-酮(LYG-402)
5,7-二羟基-8-甲氧基-6-甲基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-501)
5,7-二羟基-8-甲氧基-6-烯丙基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-502)
5,7-二羟基-8-甲氧基-6-(3-甲基-2-丁烯基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-503)
5,7-二羟基-8-甲氧基-6-苄基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-504)
上述化合物对应的化学结构如下:
本发明化合物可以和药学上可接受的盐结合成盐。药学上可以接受的盐可以用有机或无机碱形式。例如与碱金属或碱土金属(如钠、钾、钙或镁)或有机碱和N-四烷基铵盐(如N-四丁基铵)成盐。对于具有碱性基团的式(I)化合物,则可以由有机或无机酸成盐。例如可以由盐酸、硫酸、硫酸、磷酸、甲酸、乙酸、丙酸、乳酸、柠檬酸、酒石酸、琥珀酸、富马酸、马来酸、杏仁酸、苹果酸、樟脑磺酸以及类似的已知可以接受的酸形成盐。
本发明化合物化合物也可以采用制成酯、氨基甲酸酯和其他前药形式,当以这种形式给药时,其在体内转变为活性形式起效。
本发明还公开了一种药用组合物,其中含有有效量的本发明化合物或其药用盐和药学上可接受的载体。
本文中所述的部分化合物可用作制备本发明的其他化合物的中间体。
本发明的化合物可用下列方法制备得到:
R1、R2、R5、R7、R8的定义同前,Y代表氯或者溴原子。
根据不同的取代基选取对应的原料按上述方法制备即可。
本发明的化合物以数项标准药理学检验规程进行评价,结果表明本发明化合物具有显著抗肿瘤活性并且可作为抗肿瘤药。基于所述标准药理学检验程序评价中所显示的活性,本发明化合物因而可以用于抗肿瘤领域,优选乳腺癌、肾癌、膀胱癌、口腔癌、喉癌、食管癌、胃癌、结肠癌、卵巢癌、子宫癌、肺癌、胰腺癌、前列腺癌、肝癌、皮肤癌和白血病等疾病的治疗。
本发明化合物可以作为前药在体内发挥作用。通过化学反应或代谢的结果,本发明化合物可以被转变成可用于治疗肿瘤的化合物。
本发明化合物可以单独或与一种或一种以上的药学上可以接受的载体组合制成制剂以供给药。例如,溶剂、稀释剂等,可以用口服剂型给药,如片剂、胶囊、可分散粉末、颗粒剂等。这些药用制剂中可以含有与载体组合的例如0.05%至90%重量的活性成分,更常见约15%至60%之间重量的活性成分。本发明化合物剂量可以是0.001~100mg/kg/天,也可根据疾病程度的不同或剂型的不同偏离此剂量范围。
对于肿瘤的治疗,可将本发明化合物与其他抗肿瘤物质或放射治疗联合应用。这些其他物质或放射治疗可以与本发明化合物同时或在不同时间给予。这些联合治疗可以产生协同作用并且能改善作用效果。例如,可将本发明化合物与以下药物联合使用:有丝分裂抑制剂(如紫杉醇或长春碱)、烷化剂(如环磷酰胺或顺铂)、抗代谢药(如5-氟尿嘧啶或羟基脲)、DNA插入剂(如阿霉素)、拓扑异构酶抑制剂(如喜树碱)。
下面是本发明部分化合物的药理学试验方法及活性数据:
体外抗人结肠癌细胞(HT-29、HCT-8)、肝癌细胞(Bcl-7402)、非小细胞肺癌(A549)和乳腺癌(MCF-7)的活性测定。
平板打孔法测定KB和HT-29肿瘤细胞抑制活性,实验方法如下:取对数生长期细胞培养于96孔培养板内,每孔100μL(含1000-1200个肿瘤细胞),次日,给药组加入含有不同浓度化合物,每药设4-5个剂量组,每组至少设3个平行孔。对照组加入与化合物等体积的溶剂,置5%CO2温箱中于37℃培养,4d后弃去培养液,每孔加入200μL 0.2%MTT溶液,37℃保温4h.,弃去上清液,每孔加入DMSO 150μL溶解甲簪颗粒,轻度振荡后,用酶标仪,在参考波长450nm,检测波长570nm条件下测定光密度(OD)。以溶剂对照处理的肿瘤细胞为对照组,以拓扑异构酶抑制剂喜树碱和JDC-108作为对照药品。测量结果用以下公式计算药物对肿瘤细胞的抑制率:
由所得细胞抑制率使用LOGIT法进而计算化合物IC50数值。
试验结果显示,本发明的化合物均具有较强的抗肿瘤活性,其活性强于汉黄芩素,化合物的试验结果见表1。
表1 本发明化合物对各种肿瘤细胞的抑制作用(IC50(μM))
MCF7 | HepG2 | A549 | BGC-823 | |
LYG101 | 28.7 | 9.3 | 25.7 | 10.8 |
LYG102 | 54.1 | 6.3 | 40.7 | 38.7 |
LYG103 | 26.2 | 12.9 | 13.4 | 16.7 |
LYG104 | 15.6 | 28.7 | 8.30 | 21.8 |
LYG105 | 34.3 | 16.5 | 5.2 | 57.8 |
LYG106 | 24.7 | 47.3 | 13.0 | 7.1 |
LYG107 | 12.7 | 15.6 | 8.7 | 32.0 |
LYG201 | 28.1 | 8.5 | 55.3 | 35.8 |
LYG202 | 13.4 | 9.24 | 18.6 | 46.6 |
LYG203 | 2.1 | 6.5 | 2.3 | 3.7 |
LYG204 | 7.8 | 5.9 | 9.9 | 2.2 |
LYG205 | 1.98 | 1.2 | 2.1 | 3.3 |
LYG206 | 2.5 | 2.8 | 5.4 | 6.4 |
LYG207 | 5.6 | 6.9 | 10.2 | 10.1 |
LYG208 | 7.9 | 8.4 | 5.6 | 24.0 |
LYG209 | 38.2 | 21.8 | 9.9 | 6.4 |
LYG210 | 36.1 | 31.6 | 9.9 | 52.7 |
LYG301 | 2.8 | 15.2 | 13.2 | 11.1 |
LYG302 | 1.2 | 0.5 | 1.4 | 3.8 |
LYG303 | 2.3 | 3.5 | 2.1 | 3.5 |
LYG304 | 3.5 | 5.2 | 3.6 | 2.4 |
LYG305 | 8.1 | 3.9 | 12.8 | 2.3 |
LYG306 | 1.05 | 7.5 | 1.19 | 1.8 |
LYG307 | 2.7 | 0.82 | 3.47 | 2.5 |
LYG308 | 1.06 | 0.66 | 2.7 | 1.5 |
LYG309 | 1.6 | 1.12 | 1.50 | 5.3 |
LYG310 | 1.6 | 3.3 | 1.52 | 5.3 |
LYG311 | 5.8 | 5.9 | 8.8 | 7.6 |
LYG401 | 29.0 | 35.5 | 26.4 | 8.6 |
LYG402 | 25.9 | 10.4 | 7.5 | 2.5 |
LYG501 | 74.4 | 7.2 | 3.5 | 5.3 |
LYG502 | 8.5 | 26.8 | 8.2 | 5.5 |
LYG503 | 56.2 | 6.5 | 8.2 | 10.2 |
LYG504 | 7.9 | 8.4 | 5.6 | 24.0 |
汉黄芩素 | 16.0 | 12.3 | 15.8 | 16.5 |
具体实施方式
实施例1
5-羟基-7,8-二甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-101)
氮气保护下,将汉黄芩素0.4g(1.4mmol)和10mL无水丙酮加入反应瓶,搅拌溶解后加入0.2g(1.1equiv)碳酸钾,0.1mL(1.1equiv)碘甲烷。加热回流,TLC检测原料消失后过滤除去碳酸钾,滤液浓缩,残留物100~200目硅胶柱层析。展开剂:石油醚∶乙酸乙酯=20∶1。产品为黄色固体。mp 185℃~186℃。
IR(KBr):3451,2975,1664,1621,1589,1450,1377,1277,1124,1036,815,576cm-1
1H-NMR(300MHz,CDCl3),δ:3.96(3H,s,7-OCH3),3.95(3H,s,8-OCH3),6.44(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.94(2H,m,Ar-H),12.57(1H,s,5-OH)ppmMS(EI)m/z:298[M]+,283,255,181,153
E.Anal.:C(%):68.42,H(%)4.35(理论值:C(%):68.45,H(%)4.73)
Formula:C17H14O3
实施例2
5-羟基-7-乙氧基-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-102)
按照LYG-01的制备方法,用0.2mL(过量)溴乙烷替换碘甲烷其余操作同。得产品为黄色固体。mp 192℃~193℃。
IR(KBr):3409,2975,1664,1622,1589,1377,1335,1124,1029,840,815,576cm-1
1H-NMR(300MHz,CDCl3),δ:1.51(3H,t,-CH3-CH2,J=21Hz),3.94,(3H,s,8-OCH3),4.19(2H,m,7-OCH2-CH3,J=21Hz),6.42(1H,s,Ar-H),6.67(1H,s,-CH=),7.56(3H,m,Ar-H),7.94(2H,m,Ar-H),12.55(1H,s,5-OH)ppm
MS(EI)m/z:312[M]+,297,269,241,153,139,102
E.Anal.:C(%):70.10,H(%)5.77 (理论值:C(%):69.22,H(%):5.16)
Formula:C18H16O3
实施例3
5-羟基-7-丙氧基-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-103)
按照LYG-01的制备方法,用溴丙烷替换碘甲烷,其余操作同。产品为黄色固体。mp200℃~202℃。
IR(KBr):3409,3074,2960,1660,1621,1589,1377,1277,1125,1036,817,cm-1
1H-NMR(300MHz,CDCl3),δ:1.09(3H,t,-CH3-CH2,J=14.7Hz),1.91(2H,m,-CH2-CH2-CH3,J1=14.7Hz,J2=12.9Hz),3.94,(3H,s,8-OCH3),4.19(2H,t,7-OCH2-CH2-CH3,J=12.9Hz),6.42(1H,s,Ar-H),6.67(1H,s,-CH=),7.56(3H,m,Ar-H),7.94(2H,m,Ar-H),12.54(1H,s,5-OH)ppmMS(EI)m/z:326[M]+,311,269,241,153,139,102
E.Anal.:C(%):70.10,H(%)5.77 (理论值:C(%):69.93,H(%)5.56)
Formula:C19H19O5
实施例4
5-羟基-7-异丁氧基-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-104)
按照LYG-01的制备方法,用溴代异丁烷替换碘甲烷,其余操作同。产品为黄色固体。
mp 210℃~212℃。
IR(KBr):3409,2953,1664,1614,1587,1512,1379,1276,1111,1012,807,574cm-1
1H-NMR(300MHz,CDCl3),δ:1.09(3H,d,J=6.9Hz,-CH3-CH),1.54(3H,d,J=6.9Hz,-CH3-CH),2.21,(1H,m,J1=6.9Hz,J2=23.7Hz,-OCH2-CH-(CH3)2),3.85(2H,d,J=23.7Hz,7-OCH2),3.94(3H,s,8-OCH3),6.41(1H,s,Ar-H),6.67(1H,s,-CH=),7.56(3H,m,Ar-H),7.94(2H,m,Ar-H),12.53(1H,s,5-OH)ppm
MS(EI)m/z:340[M]+,325,269,241,139,102
E.Anal.C(%):70.35,H(%)5.91 (理论值:C(%):70.57,H(%)5.92)
Formula:C20H20O5
实施例5
5-羟基-7-烯丙氧基-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-105)
按照LYG-01的制备方法,用烯丙基溴替换碘甲烷,其余操作同。产品为黄色固体。mp197℃~199℃。
IR(KBr):3437,2934,1661,1617,1589,1375,1335,1273,1198,1032,817,684cm-1
1H-NMR(300MHz,CDCl3),δ:3.96(3H,s,8-OCH3),4.69(2H,d,J=5.1Hz,7-OCH2-CH=),5.40(2H,dd,J1=10.5Hz,J2=17.1Hz,-CH=CH2),6.15(1H,m,J1=10.5Hz,J2=17.1Hz,J3=5.1Hz,-OCH2-CH=CH2),6.42(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.94(2H,m,Ar-H),12.53(1H,s,5-OH)ppm
MS(EI)m/z:324[M]+,309,281,267,255,239,207,169,153,139,119,102,97
E.Anal.:C(%):70.10,H(%)5.01(理论值:C(%):70.36,H(%)4.97)
Formula:C19H16O5
实施例6
5-羟基-7-(3-甲基-2-丁烯氧基)-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-106)
按照LYG-01的制备方法,用异戊烯基溴替换碘甲烷,其余操作同。产品为黄色固体。
mp 220℃~222℃。
IR(KBr):3437,2944,1661,1618,1509,1375,1335,1273,1112,1032,684,574cm-1
1H-NMR(300MHz,CDCl3),δ:1.79(6H,d,J=10.2Hz,(-CH3)2-CH=),3.93(3H,s,8-OCH3),4.66(2H,d,J=6.9Hz,7-OCH2-CH=),5.51(1H,m,J1=10.2Hz,J2=6.9Hz,-OCH2-CH=(CH3)2),6.43(1H,s,Ar-H),6.67(1H,s,-CH=),7.55(3H,m,Ar-H),7.95(2H,m,Ar-H),12.54(1H,s,5-OH)ppmMS(EI)m/z:352[M]+,335,309,297,281,266,177,133,119,105,97,91
E.Anal.:C(%):71.35,H(%)5.69(理论值:C(%):71.58;H(%)5.72,)
Formula:C21H20O5
实施例7
5-羟基-7-苄氧基-8-甲氧基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-107)
按照LYG-01的制备方法,用溴苄替换碘甲烷,其余操作同。产品为黄色固体。mp 245℃~247℃。
IR(KBr):3449,2928,1661,1613,1586,1506,1452,1431,1413,1375,1336,1275,1230,1115,999,847,755,700,683cm-1
1H-NMR(300MHz,CDCl3),δ:3.97(3H,s,8-OCH3),5.52(2H,s,7-OCH2),6.48(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(8H,m,Ar-H),7.96(2H,m,Ar-H),12.53(1H,s,5-OH)ppm
MS(EI)m/z:374[M]+,359,281,253,207,187,169,151,119,97,91
E.Anal.:C(%):73.60,H(%)4.78(理论值:C(%):73.79,H(%)4.85)
Formula:C23H19O5
实施例8
5-羟基-8-甲氧基-7-(3-溴丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-201)
氮气保护下,将汉黄芩素0.4g(1.4mmol)和10mL无水丙酮加入反应瓶,搅拌溶解后加入0.2g(1.1equiv)碳酸钾,0.12mL(1.1equiv)1,3-二溴丙烷。加热回流,TLC检测原料消失后过滤除去碳酸钾,滤液浓缩,残留物100~200目硅胶柱层析。展开剂:石油醚∶乙酸乙酯=20∶1。产品为黄色固体。mp 220℃~222℃。
IR(KBr):3442,3078,2939,1659,1589,1378,1336,1278,1195,1122,819,578cm-1
1H-NMR(300MHz,CDCl3),δ:2.42(2H,m,J1=12.6Hz,J2=11.7Hz,-BrCH2-CH2-OCH2),3.65(2H,t,J=12.6Hz,-BrCH2-CH2),3.93(3H,s,8-OCH3),4.25(2H,t,J=11.7Hz,7-OCH2-CH2),6.45(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.94(2H,m,Ar-H),12.54(1H,s,5-OH)ppmMS(EI)m/z:407[M+2]+,405[M]+,389,269,241,153,139,102
E.Anal.:C(%):56.68,H(%)4.56 (理论值:C(%):56.31,H(%)4.23)
Formula:C19H17BrO5
实施例9
5-羟基-8-甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-202)
氮气保护下,将LYG-201 30mg(0.07mmol)和5mL无水乙腈加入反应瓶,搅拌溶解加入0.01g碳酸钾,0.02g N-甲基哌嗪。加热回流,TLC检测原料消失后过滤除去碳酸钾,滤液浓缩,残留物100~200目硅胶柱层析。展开剂:石油醚∶乙酸乙酯=8∶1。产品为黄色固体。mp 283℃~285℃。
IR(KBr):3432,2929,2792,1661,1619,1378,1337,1277,1115,1035,815,768,685,579cm-1
1H-NMR(300MHz,CDCl3),δ:2.30(2H,m,-CH2-CH2OAr),2.54(3H,s,N-CH3),2.57(8H,m,4-CH2),3.92(3H,s,8-OCH3),4.16(2H,t,J=12.9Hz,7-OCH2-CH2),6.45(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.96(2H,m,Ar-H),12.53(1H,s,5-OH)ppm
ESI:426(M+2H)+
E.Anal.:C(%):68.1,H(%)6.67,N(%)6.59(理论值:C(%):67.91,H(%)6.65,N(%)6.60)
Formula:C24H29N2O5
实施例10
5-羟基-8-甲氧基-7-(3-(吗啡啉-1-基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-203)
按照LYG-202的制备方法,用吗啡啉替换N-甲基哌嗪,其余操作同。产品为黄色固体。mp 278℃~280℃。
IR(KBr):3439,2813,1664,1587,1376,1336,1277,1116,1038,820,766,684,578cm-1
1H-NMR(300MHz,CDCl3),δ:2.05(2H,m,-CH2-CH2OAr),2.54(4H,m,J=9Hz,2-CH2-CH2),3.73(4H,t,J=9Hz,2-OCH2),3.93(3H,s,8-OCH3),4.19(2H,t,J=12.6Hz,7-OCH2-CH2),6.45(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.96(2H,m,Ar-H),12.53(1H,s,5-OH)ppm
ESI:412(M+H)+,413(M+2H)+
E.Anal.:C(%):67.55,H(%)6.66,N(%)3.18(理论值:C(%):67.14,H(%)6.16,N(%)3.40)
Formula:C23H25NO6
实施例11
5-羟基-8-甲氧基-7-(3-(N,N-二(2-羟基乙基)胺基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-204)
按照LYG-202的制备方法,用二乙醇胺替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.09g,收率为37.7%。mp 114~116℃。
IR(KBr):3994,3659,3413,2941,1656,1614,1443,1379,1337,1120,1033,818,679,628,575cm-1
1H-NMR(300MHz,CDCl3),δ:2.12(2H,m,-CH2-CH2OAr),2.72(4H,m,2-N-CH2),2.82(2H,t,J=13.5Hz,N-CH2),3.69(4H,m,2-CH2-OH),3.93(3H,s,8-OCH3),4.14(2H,t,J=11.7Hz,7-OCH2-CH2),6.45(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.97(2H,m,Ar-H),12.55(1H,s,5-OH)ppmMS(EI)m/z:429(M+H)+,398,380,368,350,315,284,269,241,191
E.Anal.:C(%):64.55,H(%)6.26,N(%)3.20(理论值:C(%):64.32,H(%)6.34,N(%)3.26)
Formular:C23H27NO7
实施例12
5-羟基-8-甲氧基-7-(3-(四氢吡咯-1-基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-205)
按照LYG-202的制备方法,用四氢吡咯替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.13g,收率为59%。mp 147~149℃。
IR(KBr):3440,3069,2948,2806,1659,1612,1506,1450,1376,1122,1036,816,768,683,640,574cm-1
1H-NMR(300MHz,CDCl3),δ:1.82(4H,m,2-CH2),2.12(2H,m,-CH2-CH2OAr),2.58(6H,m,3-N-CH2),3.93(3H,s,8-OCH3),4.17(2H,t,J=12.9Hz,7-OCH2-CH2),6.45(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.97(2H,m,Ar-H),12.55(1H,s,5-OH)ppm
MS(EI)m/z:395[M]+,380,364,345,311,285,269,255,241,184,153,110,84,69,55
E.Anal.:C(%):69.72,H(%)6.26,N(%)3.44(理论值:C(%):69.86,H(%)6.37,N(%)3.54)
Formular:C23H25NO5
实施例13
5-羟基-8-甲氧基-7-(3-(哌啶-1-基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-206)按照LYG-202的制备方法,用哌啶替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.15g,收率为66%。mp 163~165℃。
IR(KBr):3461,3424,2931,1607,1444,1381,1280,1118,1039,822,678,630,575cm-1
1H-NMR(300MHz,CDCl3),δ:1.46(6H,m,3-CH2),2.10(2H,m,-CH2-CH2OAr),2.45(6H,m,3-N-CH2),3.93(3H,s,8-OCH3),4.17(2H,t,J=12.3Hz,7-OCH2-CH2),6.45(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.97(2H,m,Ar-H),12.55(1H,s,5-OH)ppm
MS(EI)m/z:409[M]+,378,377,415,285,269,255,238,224,153,124,98,96,70,55E.Anal.:C(%):70.13,H(%)6.46,N(%)3.44(理论值:C(%):70.40,H(%)6.65,N(%)3.42)
Formular:C24H27NO5
实施例14
5-羟基-8-甲氧基-7-(3-(二乙胺基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-207)5-hydroxy-8-methoxy-7-(3-(diethylamino)propoxy)-2-phenyl-4H-chromen-4-one
按照LYG-202的制备方法,用二乙胺替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.07g,收率为36.9%。mp 121-123℃。
IR(KBr):3477,3450,3415,268,1660,1616,1588,1375,1336,1195,1122,1035,817,765,683,579cm-1
1H-NMR(300MHz,CDCl3),δ:1.25(6H,m,2-CH3),1.58(2H,m,-CH2-CH2OAr),2.36(6H,m,3-N-CH2)3.93(3H,s,8-OCH3),4.14(2H,t,J=11.7Hz,7-OCH2-CH2),6.45(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.96(2H,m,Ar-H),12.55(1H,s,5-OH)ppm
MS(EI)m/z:397[M]+,382,366,360,345,269,255,241,184,153,139,98,86,72,58
Formular:C23H27NO5
实施例15
5-羟基-8-甲氧基-7-(3-(苄胺基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-208)
5-hydroxy-8-methoxy-7-(3-(benzylamino)propoxy)-2-phenyl-4H-chromen-4-one按照LYG-202的制备方法,用苄胺替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.11g,收率为45%。mp 139-141℃。
IR(KBr):3542,3414,1659,1614,1588,1452,1381,1355,1195,1122,819,628,579cm-1
1H-NMR(300MHz,CDCl3),δ:1.95(2H,m,-CH2-CH2OAr),2.70(2H,m,-CH2-NH),3.72(2H,s,Ar-CH2),3.83(3H,s,8-OCH3),4.14(2H,t,J=12.6Hz,7-OCH2-CH2),6.43(1H,s,Ar-H),6.68(1H,s,-CH=),7.34(5H,m,Ar-H),7.64(3H,m,Ar-H),8.09(2H,m,Ar-H),12.55(1H,s,5-OH)ppm
MS(EI)m/z:431[M]+,400,360,345,296,285,269,255,207,148,118,91,70,58
Formular:C26H25NO5
实施例16
5-羟基-8-甲氧基-7-(3-(对甲氧苯胺基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-209)5-hydroxy-8-methoxy-7-(3-(4-methoxyphenylamino)propoxy)-2-phenyl-4H-chromen-4-one按照LYG-202的制备方法,用对甲氧基苯胺替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.07g,收率为30%。mp 136~137℃。
IR(KBr):3469,3413,2946,2925,1662,1609,1511,1451,1377,1338,1246,1193,1123,1034,993,819,773,689,581cm-1
1H-NMR(300MHz,CDCl3),δ:2.23(2H,m,-CH2-CH2OAr),3.38(2H,m,-CH2-NH),3.83(3H,s,CH3-OAr),3.93(3H,s,8-OCH3),4.17(2H,t,J=12.0Hz,7-OCH2-CH2),6.41(1H,s,Ar-H),6.68(3H,m,2-Ar-H,1-CH=),6.81(2H,m,Ar-H),7.60(3H,m,Ar-H),7.97(2H,m,Ar-H),12.55(1H,s,5-OH)ppmMS(EI)m/z:448[M+1]+,447[M]+,284,269,207,163,148,136,123,108,86,77,58
Formular:C26H25NO6
实施例17
5,8-二甲氧基-7-(3-(4-甲基哌嗪基)丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-210)5,8-dimethoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-2-phenyl-4H-chromen-4-one氮气保护下,将5,8-二甲氧基-7-(3-溴丙氧基)-2-苯基-4H-1-苯并吡喃-4-酮(300mg,0.802mmol)和无水乙腈(30ml)加入反应瓶,搅拌溶解后加入甲基哌嗪(0.40g,4.0mmol)和催化量的碘化钠。加热回流,TLC检测原料消失后,过滤除去碘化钠,将反应液浓缩,残留物用聚酰胺柱层析。洗脱剂:乙酸乙酯∶三乙胺=30∶1。产品为黄色固体。得产品0.18g,收率为51.2%。mp 123-124℃。
IR(KBr):3889,3782,3466,2947,2513,2401,2304,1632,1388,1346,1121,1042,815,773,687,621cm-1
1H-NMR(300MHz,CDCl3),δ:1.94(2H,m,-CH2-CH2OAr),2.57(13H,m,5-N-CH2,N-CH3),3.97(3H,s,5-OCH3),3.95(3H,s,8-OCH3),4.20(2H,t,J=12.6Hz,7-OCH2-CH2),6.40(1H,s,Ar-H),6.70(1H,s,-CH=),7.55(3H,m,Ar-H),7.95(2H,m,Ar-H)ppm
MS(EI)m/z:438[M]+,423,407,364,336,299,283,219,167,141,139,113,84,70,
Formular:C25H30N2O5
实施例18
5-羟基-8-甲氧基-7-(4-溴丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-301)
氮气保护下,将汉黄芩素0.4g(1.4mmol)和10mL无水丙酮加入反应瓶,搅拌溶解后加入0.2g(1.1equiv)碳酸钾,0.17mL(1.1equiv)1,4-二溴丁烷。加热回流,TLC检测原料消失后过滤除去碳酸钾,滤液浓缩,残留物100~200目硅胶柱层析。展开剂:石油醚∶乙酸乙酯=20∶1。产品为黄色固体。mp 228℃~229℃。
IR(KBr):3437,3073,2959,1658,1621,1379,1338,1223,1123,1034,816,769,685,584,599cm-1
1H-NMR(300MHz,CDCl3),δ:2.09(4H,m,J1=12.3Hz,J2=6Hz,-OCH2-CH2-CH2-BrCH2),3.53(2H,m,J=12.3Hz,-BrCH2-CH2-CH2),3.93(3H,s,8-OCH3),4.15(2H,t,J=6Hz,7-OCH2-CH2),6.41(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.94(2H,m,Ar-H),12.54(1H,s,5-OH)ppm
MS(EI)m/z:421[M+2H]+,419[M]+,418,405,269,241,153,135,102
E.Anal.:C(%):57.03,H(%)4.52 (理论值:C(%):57.29,H(%)4.57)
Formula:C20H19BrO5
实施例19
5-羟基-8-甲氧基-7-(4-(4-甲基哌嗪-1-基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-302)
氮气保护下,将LYG-301(300mg,0.693mmol)和无水乙腈(30ml)加入反应瓶,搅拌溶解后加入N-甲基哌嗪.(280mg,3.40mmol)。加热回流,TLC检测原料消失后,将反应液浓缩,残留物用聚酰胺柱层析。洗脱剂:乙酸乙酯∶三乙胺=30∶1。得产品0.13g,为黄色固体。mp 292℃~293℃。
IR(KBr):3422,2930,2788,1664,1621,1588,1452,1375,1277,1194,1111,1032,819,763,682,578cm-1
1H-NMR(300MHz,CDCl3),δ:1.70(2H,m,-CH2-CH2-N),1.90(2H,m,-CH2-CH2OAr),2.30(3H,s,N-CH3),2.47(8H,m,4-CH2),3.93(3H,s,8-OCH3),4.13(2H,t,J=12.9Hz,7-OCH2-CH2),6.43(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.96(2H,m,Ar-H),12.53(1H,s,5-OH)ppm
ESI:439(M+H)+,440(M+2H)+
E.Anal.:C(%):68.32,H(%)6.98,N(%)3.42 (理论值:C(%):68.47,H(%)6.90,N(%)6.39)
Formula:C25H30N2O5
实施例20
5-羟基-8-甲氧基-7-(4-(吗啡啉-1-基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-303)
按照LYG-302的制备方法,用吗啡啉替换N-甲基哌嗪.,其余操作同。产品为黄色固体。mp 285℃~287℃。
IR(KBr):3440,2951,1661,1380,1338,1116,1033,682,816,686,580cm-1
1H-NMR(300MHz,CDCl3),δ:1.57(2H,m,-CH2-CH2-N),1.76(2H,m,-CH2-CH2OAr),2.54(6H,m,3-N-CH2),3.73(4H,m,2-OCH2),3.93(3H,s,8-OCH3),4.19(2H,t,J=12.9Hz,7-OCH2-CH2),6.45(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.96(2H,m,Ar-H),12.53(1H,s,5-OH)ppm
ESI:426(M+H)+,427(M+2H)+
E.Anal.:C(%):66.04,H(%)6.49,N(%)3.24 (理论值:C(%):66.50,H(%)6.40,N(%)3.29)
Formula:C24H27NO6
实施例21
5-羟基-8-甲氧基-7-(4-(N,N-二乙醇胺基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-304)按照LYG-302的制备方法,用N,N-二乙醇胺替换N-甲基哌嗪.,其余操作同。产品为黄色固体。得产品0.11g,收率为52%。mp 141-143℃。
IR(KBr):3559,3525,3415,2944,2719,1603,1510,1380,1235,1122,1035,844,773,691cm-1
1H-NMR(300MHz,CDCl3),δ:1.73(2H,m,-CH2-CH2-N),1.94(2H,m,-CH2-CH2OAr),2.72(6H,m,3-N-CH2),3.66(4H,t,J=10.5Hz,2-CH2OH),3.94(3H,s,8-OCH3),4.14(2H,t,J=12.9Hz,7-OCH2-CH2),6.43(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.96(2H,m,Ar-H),12.55(1H,s,5-OH)ppmMS(EI)m/z:427[M]+,412,394,284,269,241,199,174,158,153,128,98,84,77,58
Formular:C24H29NO7
实施例22
5-羟基-8-甲氧基-7-(4-(四氢吡咯-1-基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-305)
按照LYG-302的制备方法,用四氢吡咯替换N-甲基哌嗪.,其余操作同。产品为黄色固体。得产品0.13g,收率为59%。mp 147~149℃。
IR(KBr):3440,3069,2948,2806,1659,1612,1506,1450,1376,1122,1036,816,768,683,640,574cm-1
1H-NMR(300MHz,CDCl3),δ:1.57(2H,m,-CH2-CH2-N),1.82(4H,m,2-CH2),2.12(2H,m,-CH2-CH2OAr),2.58(6H,m,3-N-CH2),3.93(3H,s,8-OCH3),4.17(2H,t,J=12.9Hz,7-OCH2-CH2),6.45(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.97(2H,m,Ar-H),12.55(1H,s,5-OH)ppmMS(EI)m/z:395[M]+,380,364,345,311,285,269,255,241,184,153,110,84,69,55
E.Anal.:C(%):70.15,H(%)6.85,N(%)3.34(理论值:C(%):70.40,H(%)6.65,N(%)3.42)
Formular:C23H27NO5
实施例23
5-羟基-8-甲氧基-7-(4-(哌啶-1-基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-306)
按照LYG-302的制备方法,用哌啶替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.15g,收率为66%。mp 163~165℃。
IR(KBr):3461,3424,2931,1607,1444,1381,1280,1118,1039,822,678,630,575cm-1
1H-NMR(300MHz,CDCl3),δ:1.38(2H,m,-CH2-CH2-N),1.46(6H,m,3-CH2),2.10(2H,m,-CH2-CH2OAr),2.45(6H,m,3-N-CH2),3.93(3H,s,8-OCH3),4.17(2H,t,J=12.3Hz,7-OCH2-CH2),6.45(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.97(2H,m,Ar-H),12.55(1H,s,5-OH)ppmMS(EI)m/z:409[M]+,378,377,415,285,269,255,238,224,153,124,98,96,70,55
E.Anal.:C(%):71.14,H(%)6.75,N(%)3.14(理论值:C(%):70.90,H(%)6.90,N(%)3.31)
Formular:C24H27NO5
实施例24
5-羟基-8-甲氧基-7-(4-(N,N-二乙基胺基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-307)
按照LYG-302的制备方法,用二乙胺替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.14g,收率为68.6%。mp 115~117℃。
IR(KBr):3445,3419,2955,2809,1616,1443,1380,1337,1277,1191,1119,1037,817,769,677,624cm-1
1H-NMR(300MHz,CDCl3),δ:1.06(6H,m,2-CH3),1.88(2H,m,-CH2-CH2-N),1.91(2H,m,-CH2-CH2OAr),2.58(6H,m,3-N-CH2),3.93(3H,s,8-OCH3),4.14(2H,t,J=12.9Hz,7-OCH2-CH2),6.43(1H,s,Ar-H),6.68(1H,s,-CH=),7.93(3H,m,Ar-H),7.97(2H,m,Ar-H),12.55(1H,s,5-OH)ppm
MS(EI)m/z:411[M]+,396,380,296,238,224,207,195,178,152,128,118,102,86,65
E.Anal.:C(%):71.25,H(%)7.75,N(%)3.24(理论值:C(%):71.05,H(%)7.57,N(%)3.19)
Formular:C24H29NO5
实施例25
5-羟基-8-甲氧基-7-((4-苄胺基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-308)
按照LYG-302的制备方法,用苄胺替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.11g,收率为47%。mp 125~127℃。
IR(KBr):3447,3386,3298,3246,3070,2933,1654,1611,1507,1444,1382,1276,1120,1033,817,746,688,582cm-1
1H-NMR(300MHz,CDCl3),δ:1.73(2H,m,-CH2-CH2-NH),1.90(2H,m,-CH2-CH2OAr),2.72(2H,m,CH2-NH),3.83(2H,s,Ar-CH2),3.93(3H,s,8-OCH3),4.14(2H,t,J=12.6Hz,7-OCH2-CH2),6.43(1H,s,Ar-H),6.68(1H,s,-CH=),7.34(5H,m,Ar-H),7.93(3H,m,Ar-H),7.97(2H,m,Ar-H),12.55(1H,s,5-OH)ppm
MS(EI)m/z:445[M]+,414,325,295,284,269,241,195,162,153,139,102,91,70,58
E.Anal.:C(%):73.84,H(%)6.33,N(%)3.08(理论值:C(%):72.79,H(%)6.11,N(%)3.14)
Formular:C27H27NO5
实施例26
5-羟基-8-甲氧基-7-(4-(4-甲氧苯胺基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-309)
按照LYG-302的制备方法,用对甲氧基苯胺替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.12g,收率为49.7%。mp 128~129℃。
IR(KBr):3443,3383,2941,1655,1614,1510,1443,1380,1337,1235,1121,1033,816,764,680,626,581cm-1
1H-NMR(300MHz,CDCl3),δ:1.91(2H,m,-CH2-CH2-N),2.05(2H,m,-CH2-CH2OAr),3.22(2H,m,-CH2-NH),3.75(3H,s,CH3-OAr),3.93(3H,s,8-OCH3),4.17(2H,t,J=12.0Hz,7-OCH2-CH2),6.41(1H,s,Ar-H),6.68(3H,m,2-Ar-H,1-CH=),6.83(2H,m,Ar-H),7.56(3H,m,Ar-H),7.97(2H,m,Ar-H),12.55(1H,s,5-OH)ppm
MS(EI)m/z:462[M+H]+,461[M]+,431,325,296,281,269,254,224,223,178,162,149,136,121,108,93,77,69,55
E.Anal.:C(%):70.32,H(%)5.91,N(%)3.16(理论值:C(%):70.27,H(%)5.90,N(%)3.03)
Formular:C27H27NO6
实施例27
5-羟基-8-甲氧基-7-((4-苯胺基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-310)
按照LYG-302的制备方法,用苯胺替换N-甲基哌嗪,其余操作同。产品为黄色固体。得产品0.10g,收率为44%。mp 145~147℃。
IR(KBr):3772,3653,3414,2927,1659,1614,1505,1443,1379,1334,1268,1190,1119,1030,816,752,682cm-1
1H-NMR(300MHz,CDCl3),δ:1.25(1H,s,Ar-NH),1.91(2H,m,-CH2-CH2-NH),2.08(2H,m,-CH2-CH2OAr),3.33(2H,m,-CH2-NH),3.93(3H,s,8-OCH3),4.17(2H,t,J=12.0Hz,7-OCH2-CH2),6.41(1H,s,Ar-H),6.75(4H,m,3-Ar-H,1-CH=),7.22(2H,m,Ar-H),7.56(3H,m,Ar-H),7.97(2H,m,Ar-H),12.55(1H,s,5-OH)ppm
MS(EI)m/z:431[M]+,315,295,284,269,254,241,224,148,139,106,93,77,69,55
E.Anal.:C(%):72.52,H(%)5.79,N(%)3.18(理论值:C(%):72.37,H(%)5.84,N(%)3.25)
Formular:C26H25NO5
实施例28
5,8-二甲氧基-7-(4-(4-甲基哌嗪-1-基)丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-311)
氮气保护下,将5,8-二甲氧基-7-(4-溴丁氧基)-2-苯基-4H-1-苯并吡喃-4-酮(300mg,0.693mmol)和无水乙腈(30ml)加入反应瓶,搅拌溶解后加入甲基哌嗪(0.340g,3.40mmol)。加热回流,TLC检测原料消失后,将反应液浓缩,残留物用聚酰胺柱层析。洗脱剂:乙酸乙酯∶三乙胺=30∶1。产品为黄色固体。得产品0.22g,收率为70.3%。mp 116~118℃。
IR(KBr):3443,2953,2810,1636,1455,1346,1288,1241,1121,1040,786,686,629,572,523cm-1
1H-NMR(300MHz,CDCl3),δ:1.76(2H,m,-CH2-CH2-N),1.96(2H,m,-CH2-CH2OAr),2.52(13H,m,5-N-CH2,N-CH3),3.97(3H,s,5-OCH3),3.95(3H,s,8-OCH3),4.20(2H,t,J=12.6Hz,7-OCH2-CH2),6.42(1H,s,Ar-H),6.70(1H,s,-CH=),7.53(3H,m,Ar-H),7.94(2H,m,Ar-H)ppm
MS(EI)m/z:452[M]+,437,409,378,377,299,283,269,255,238,155,153,126,113,98,84,70,55
E.Anal.:C(%):68.89,H(%)7.45,N(%)6.34(理论值:C(%):69.01,H(%)7.13,N(%)6.19)
Formular:C26H32N2O5
实施例29
5-羟基-8-甲氧基-7-(4-溴丁氧基)-2-(4-硝基苯基)-4H-1-苯并吡喃-4-酮(LYG-401)
氮气保护下,将5-羟基-8-甲氧基-7-羟基-2-(4-硝基苯基)-4H-1-苯并吡喃-4-酮0.4g(1.25mmol)和10mL无水丙酮加入反应瓶,搅拌溶解后加入0.2g(1.0equiv)碳酸钾,0.15mL(1.1equiv)1,4-二溴丁烷。加热回流,TLC检测原料消失后过滤除去碳酸钾,滤液浓缩,残留物100~200目硅胶柱层析。展开剂:石油醚∶乙酸乙酯=20∶1。产品为黄色固体。mp 245℃~247℃。
IR(KBr):3457,3011,2938,1658,1619,1500,1330,1123,1034,799
1H-NMR(300MHz,CDCl3),δ:2.10(4H,m,J1=12.0Hz,J2=5.9Hz,-OCH2-CH2-CH2-BrCH2),3.61(2H,m,J=12.0Hz,-BrCH2-CH2-CH2),3.95(3H,s,8-OCH3),4.25(2H,t,J=5.9Hz,7-OCH2-CH2),6.43(1H,s,Ar-H),6.70(1H,s,-CH=),7.96(2H,d,Ar-H),8.23(2H,d,Ar-H),12.61(1H,s,5-OH)ppm
MS(EI)m/z:465[M+2H]+,463[M]+
E.Anal.:C(%):51.63,H(%)4.01 (理论值:C(%):51.74,H(%)3.91)
Formula:C20H19BrNO7
实施例30
5-羟基-8-甲氧基-7-(4-(4-甲基哌嗪基)丁氧基)-(4-硝基苯基)-4H-1-苯并吡喃-4-酮(LYG-402)
氮气保护下,将LYG-501 55mg(0.12mmol)和5mL无水乙腈加入反应瓶,搅拌溶解加入0.01g碳酸钾,0.02g甲基哌嗪。加热回流,TLC检测原料消失后过滤除去碳酸钾,滤液浓缩,残留物100~200目硅胶柱层析。展开剂:石油醚∶乙酸乙酯=8∶1。产品为黄色固体。mp 292℃~293℃。
IR(KBr):3400,2915,1661,1611,1568,1445,,118,1023cm-1
1H-NMR(300MHz,CDCl3),δ:1.72(2H,m,-CH2-CH2-N),1.93(2H,m,-CH2-CH2OAr),2.33(3H,s,N-CH3),2.57(8H,m,4-N-CH2),3.95(3H,s,8-OCH3),4.23(2H,t,J=12.9Hz,7-OCH2-CH2),6.46(1H,s,Ar-H),6.78(1H,s,-CH=),7.98(2H,d,Ar-H),8.26(2H,d,Ar-H),12.58(1H,s,5-OH)ppm
ESI:484(M+H)+
E.Anal.:C(%):62.33,H(%)6.25,N(%)8.47(理论值:C(%):62.10,H(%)6.05,N(%)8.69)
Formula:C25H29N3O7
实施例31
5,7-二羟基-8-甲氧基-6-甲基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-501)
氮气保护下,将汉黄芩素0.1g(0.39mmol)和5mL甲醇加入反应瓶,滴加0.6mL25%的四甲基氢氧化胺,搅拌溶解后加入0.1g四甲基碘化胺和0.12mL(5equiv)碘甲烷。加热回流12h后,停止反应,过滤,滤液浓缩,残留物100~200目硅胶柱层析。展开剂:石油醚∶乙酸乙酯=20∶1。产品为黄色固体。mp 183℃~184℃。
IR(KBr):3437,2941,1666,1608,1511,1449,1409,1377,1338,1274,1228,1211,1122,1032,1014,970,934,817,766,688,663,564cm-1
1H-NMR(300MHz,CDCl3),δ:2.03(3H,s,6-CH3),3.97(3H,s,8-OCH3),6.61(1H,s,-CH=),7.83(3H,m,Ar-H),7.86(2H,m,Ar-H)ppm
MS(EI)m/z:298[M]+,283,255,181,153
E.Anal.:C(%):68.93,H(%)4.52 (理论值:C(%):68.45,H(%)4.73)
Formula:C17H14O5
实施例32
5,7-二羟基-8-甲氧基-6-烯丙基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-502)
按照LYG-401的制备方法,用烯丙基溴替换碘甲烷,其余操作同。产品为黄色固体。mp192℃~193℃。
IR(KBr):3441,2961,1653,1593,1479,1449,1405,1350,1222,1123,1019,946,851,808,768,684cm-1
1H-NMR(300MHz,CDCl3),δ:3.47(2H,d,J=5.1Hz,6-CH2-CH=),4.05(3H,s,8-OCH3),5.20(2H,dd,J1=10.5Hz,J2=17.1Hz,-CH=CH2),6.15(1H,m,J1=10.5Hz,J2=17.1Hz,J3=5.1Hz,-OCH2-CH=CH2),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.94(3H,m,Ar-H),12.77(1H,s,5-OH)ppm
MS(EI)m/z:324[M]+,309,281,269,255,239,207,159,153,139,125,102,97
E.Anal.:C(%):69.74,H(%)4.46 (理论值:C(%):70.16,H(%)4.97)
Formula:C19H16O5
实施例33
5,7-二羟基-8-甲氧基-6-(3-甲基-2-丁烯基)-2-苯基-4H-1-苯并吡喃-4-酮(LYG-503)
按照LYG-401的制备方法,用异戊烯基溴替换碘甲烷,其余操作同产品为黄色固体。mp215℃~217℃。
IR(KBr):3195,2923,2854,1649,1581,1451,1351,1260,1204,1116,1032,940,799,770,688cm-1
1H-NMR(300MHz,CDCl3),δ:1.79(6H,d,J=10.2Hz,(CH3)2-CH=),3.43(2H,d,J=6.9Hz,7-OCH2-CH=),4.05(3H,s,8-OCH3),5.21(1H,m,J1=10.2Hz,J2=6.9Hz,-OCH2-CH=(CH3)2),6.74(1H,s,-CH=),7.56(3H,m,Ar-H),7.93(2H,m,Ar-H),12.74(1H,s,5-OH)ppm
MS(EI)m/z:352[M]+,309,297,281,269,243,207,161,149,127,115,105,97,91
E.Anal.:C(%):71.77,H(%)5.80(理论值:C(%):71.58,H(%)5.72)
Formula:C21H20O5
实施例34
5,7-二羟基-8-甲氧基-6-苄基-2-苯基-4H-1-苯并吡喃-4-酮(LYG-504)
按照LYG-401的制备方法,用氯苄替换碘甲烷,其余操作同产品为黄色固体。mp 241℃~242℃。
IR(KBr):3088,2939,1646,1579,1479,1400,1294,1192,1023,940,847,703,679,655,581,556cm-1
1H-NMR(300MHz,CDCl3),δ:4.05(5H,2s,8-OCH3,6-Ar-CH2),6.68(1H,s,-CH=),7.56(8H,m,Ar-H),7.92(2H,m,Ar-H),12.83(1H,s,5-OH)ppm
MS(EI)m/z:374[M]+,259,283,255,207,169,147,119,102,92
E.Anal.:C(%):73.23,H(%)4.47 (理论值:C(%):73.79,H(%)4.85)
Formula:C23H18O5
实施例35
取实施例10中所得化合物0.5g,淀粉2g,糊精1g混合,用适量30%乙醇作湿润剂,制粒,压片。
Claims (4)
2.权利要求1的黄酮类化合物或其药学上可以接受的盐,其中R5是H或甲基;R6是H、甲基、乙基、异丙基或异戊烯基;R7是被甲基哌嗪、哌嗪、吗啡啉、哌啶、四氢吡咯或N,N-二乙氨基取代的C2~C4的烷基;R8是甲基;R5、R8不同时代表甲基。
3.一种药物组合物,其中含有权利要求1的黄酮类化合物或其药学上可以接受的盐及药学上可接受的载体。
4.权利要求1的黄酮类化合物或其药学上可以接受的盐用于制备治疗肿瘤疾病的药物的用途,肿瘤疾病是乳腺癌、结肠癌、肺癌或肝癌。
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