CN105111244B - 二茂铁氧桥双环‑[2.2.1]‑庚烯类化合物 - Google Patents
二茂铁氧桥双环‑[2.2.1]‑庚烯类化合物 Download PDFInfo
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- CN105111244B CN105111244B CN201510501650.9A CN201510501650A CN105111244B CN 105111244 B CN105111244 B CN 105111244B CN 201510501650 A CN201510501650 A CN 201510501650A CN 105111244 B CN105111244 B CN 105111244B
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- acid
- hydroxyphenyl
- anhydrous
- furan
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- -1 vinyl compound Chemical class 0.000 title claims abstract description 60
- 239000001301 oxygen Substances 0.000 title claims abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 title abstract 5
- 125000002619 bicyclic group Chemical group 0.000 title abstract 5
- 229920002554 vinyl polymer Polymers 0.000 title abstract 5
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 44
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 41
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
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- 238000004440 column chromatography Methods 0.000 claims description 19
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- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 12
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- TWYYFYNJOJGNFP-CUXYNZQBSA-N (2s,4r,5s,6s)-2-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-2-carbamoyl-4-[[(e,4s,6s)-4,6-dimethyloct-2-enoyl]oxymethyl]-5-hydroxy-1,3-dioxane-4,5,6-tricarboxylic acid Chemical compound O1[C@H](C(O)=O)[C@](C(O)=O)(O)[C@](COC(=O)/C=C/[C@@H](C)C[C@@H](C)CC)(C(O)=O)O[C@]1(C(N)=O)CCC(=C)[C@@H](OC(C)=O)[C@H](C)CC1=CC=CC=C1 TWYYFYNJOJGNFP-CUXYNZQBSA-N 0.000 claims description 5
- CSEWAUGPAQPMDC-UHFFFAOYSA-N 2-(4-aminophenyl)acetic acid Chemical compound NC1=CC=C(CC(O)=O)C=C1 CSEWAUGPAQPMDC-UHFFFAOYSA-N 0.000 claims description 5
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- VHCSBTPOPKFYIU-UHFFFAOYSA-N 2-chloroethanesulfonyl chloride Chemical compound ClCCS(Cl)(=O)=O VHCSBTPOPKFYIU-UHFFFAOYSA-N 0.000 claims description 5
- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 claims description 5
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 claims description 5
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
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- NASLUVAZTLRWAJ-UHFFFAOYSA-N 4-[4-(4-aminophenyl)furan-3-yl]phenol Chemical compound NC1=CC=C(C=C1)C1=COC=C1C1=CC=C(C=C1)O NASLUVAZTLRWAJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本发明公开了一种含有N‑羟基‑N’‑苯基辛二酰胺基或其类似结构的二茂铁氧桥双环‑[2.2.1]‑庚烯类化合物。以3‑(4‑羟基苯基)‑4‑辛二酸单酰苯胺基‑呋喃或其类似物和二茂铁乙烯磺酸酯衍生物为原料,无需溶剂和催化剂,在90 oC反应3小时一步制备得到含有辛二酸单酰苯胺基团的二茂铁氧桥双环‑[2.2.1]‑庚烯类化合物。体外实验表明,这类新型二茂铁氧桥双环‑[2.2.1]‑庚烯类化合物与现有抗乳腺癌药物他莫昔芬比较,对荷尔蒙依赖型乳腺癌MCF‑7细胞和非荷尔蒙依赖型乳腺癌MDA‑MB‑231细胞均具有更强的抑制活性,而且这些新型二茂铁氧桥双环‑[2.2.1]‑庚烯类化合物对正常细胞VERO细胞没有毒性,而现有抗乳腺癌药物他莫昔芬对正常细胞VERO细胞有毒性。
Description
技术领域
本发明涉及一类具有抗乳腺癌活性的含有N-羟基-N’-苯基辛二酰胺基(SAHA)或其类似结构的二茂铁氧桥双环-[2.2.1]-庚烯类化合物的制备与应用。
背景技术
乳腺癌是全世界女性最常见的恶性肿瘤之一,且近年来发病率正逐年的上升,严重威胁着妇女的生命和健康。按照目前乳腺癌发展趋势,预计到2030年乳腺癌的发病率将达到264万,因乳腺癌引起的死亡人数将达到170万。现认为乳腺癌是一种前身性的恶性肿瘤,其生长与内分泌激素有着十分密切的关系。尤其是雌激素在乳腺癌的发展过程中起着非常重要的作用。雌激素是通过与靶组织中的雌激素受体(Estrogen Receptor, ER)结合来调控乳腺的生长、分化以及功能化,ER信号转导系统对乳腺组织的发育、成熟、退缩等正常生理功能以及癌发生过程都起着十分重要的作用。目前临床上常常采用激素替代治疗法来治疗乳腺癌。选择性雌激素受体调节剂(selective estrogen receptor modulators,SERMs) 是一类典型的通过内分泌治疗法来阻止雌激素合成的抗乳腺癌药物。其中选择性雌激素受体调节剂他莫昔芬(Tamoxifen,TAM,式1所示)是目前用于乳腺癌治疗的一线药物,但是他莫昔芬主要是用于治疗荷尔蒙依赖型即雌激素受体呈阳性(ER+)的乳腺癌;而对非荷尔蒙依赖型即雌激素受体呈阴性(ER-)的病人 (约占乳腺癌病人总数的1/3)无效;即使雌激素受体呈阳性(ER-)的病人(约占乳腺癌病人总数的2/3),也仅有50%的人受益于内分泌治疗(参考文献:A. M. Brzozowski, A. C. Pike, Z. Dauter, R. E. Hubbarde, T.Bonn, O. Engstrom, L. Ohman, G. L. Greene, J . A. Gustafsson, M. Carquist,Molecular basis of agonism and antagonism in the estrogen receptor, Nature,389 (1997) 753-758.)。此外,虽然SERMs在乳腺癌的治疗中取得了成功,但是在长期使用中耐药性问题和诸如增加子宫内膜癌的风险等问题是目前乳腺癌内分泌疗法存在的一个严重不足。所以,开发出不仅对ER+和ER-乳腺癌都均有较强抑制作用,而且副作用较少的新型、高效的抗乳腺癌是迫在眉睫的任务。
发明内容
本发明所要解决的技术问题是提供一种具有抗乳腺癌活性的含有N-羟基-N’-苯基辛二酰胺基团或其类似结构的二茂铁氧桥双环-[2.2.1]-庚烯类化合物及其合成方法和用途。
本发明所提供的含有N-羟基-N’-苯基辛二酰胺基(SAHA)或辛二酸单酰苯胺基基团的二茂铁氧桥双环-[2.2.1]-庚烯类化合物,具有以下通式所示的结构:
其中,
n为 5、6、7;
X为 CH2或CO。
本发明通过体外乳腺癌细胞抑制活性实验,发现上述含有N-羟基-N’-苯基辛二酰胺基团的二茂铁氧桥双环-[2.2.1]-庚烯类化合物可进一步用于抗乳腺癌药物研究。优选的,尤其是下列化合物:
3-(4-羟基苯基)-4-庚二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(3-二茂铁羰基苯基)-酯 (TC1)、
3-(4-羟基苯基)-4-庚二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁羰基苯基)-酯 (TC 2)、
3-(4-羟基苯基)-4-庚二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁基苄基)-酯 (TC 3)、
3-(4-羟基苯基)-4-辛二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(3-二茂铁羰基苯基)-酯 (TC 4)、
3-(4-羟基苯基)-4-辛二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁羰基苯基)-酯 (TC 5)、
3-(4-羟基苯基)-4-辛二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁基苄基)-酯 (TC 6)、
3-(4-羟基苯基)-4-壬二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(3-二茂铁羰基苯基)-酯 (TC 7)、
3-(4-羟基苯基)-4-壬二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁羰基苯基)-酯 (TC 8) 或
3-(4-羟基苯基)-4-壬二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁基苄基)-酯 (TC 9)。
本发明还提供前面结构式所表示的含有N-羟基-N’-苯基辛二酰胺基团的二茂铁氧桥双环-[2.2.1]-庚烯类化合物的制备方法,包括以下步骤:
(1)将对氨基苯乙酸溶于无水乙腈中,然后加入α-溴代对甲氧基苯乙酮和无水三乙胺,室温下搅拌12小时;反应结束之后蒸除乙腈和三乙胺得粗品,经柱层析纯化后得黄色固体2-(4-甲氧基苯基)-2-羰基乙基-2-(4-氨基苯基)乙酸酯化合物;对氨基苯乙酸、α-溴代对甲氧基苯乙酮和无水三乙胺的物质的量比为1:1:1;
(2)将2-(4-甲氧基苯基)-2-羰基乙基-2-(4-氨基苯基)乙酸酯溶于无水二甲基亚砜中,加入NaH,在25°C下搅拌2个小时后用水萃灭反应,然后用乙酸乙酯萃取,水洗后,用无水硫酸钠干燥;旋干后用柱层析分离,得到化合物3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃-2-酮化合物;2-(4-甲氧基苯基)-2-羰基乙基-2-(4-氨基苯基)乙酸酯与NaH的物质的量比为1:2;
(3)将3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃-2-酮溶于无水四氢呋喃中,在-78°C下加入二异丁基氢化铝,反应12个小时;乙醚萃取,先后用水和饱和氯化钠洗涤,无水硫酸钠干燥,旋干,柱层析分离,得白色固体3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃化合物;3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃-2-与二异丁基氢化铝的物质的量比为1:4;
(4)将3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃 (560 mg, 2.11 mmol)溶于无水二氯甲烷中,-20 °C下加入三溴化硼(1.570 g, 6.34mmol),反应12h后,加入水萃灭反应,用饱和碳酸氢钠洗涤,用乙酸乙酯萃取,无水硫酸钠干燥,柱层析分离,得3-(4-氨基苯基)-4-(4-羟基苯基)呋喃化合物,3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃与三溴化硼的物质的量比为1:3;
(5)将物质的量比为1:1.5的3-(4-氨基苯基)-4-(4-羟基苯基)呋喃和庚(辛、壬)二酸酐溶于四氢呋喃中,室温反应2h,过滤后蒸干有机相得到粗品,粗品用硅胶柱层析分离,得3-(4-羟基苯基)-4-庚(辛、壬)二酸单酰苯胺基-呋喃化合物13a-c;
(6)将AlCl3溶解于二氯甲烷中,冰浴下加入3-甲氧基苯甲酰氯或4-甲氧基苯甲酰氯,搅拌反应30 min后加入二茂铁,在0 oC下反应12h后,加水淬灭反应,用饱和碳酸氢钠洗涤,用二氯甲烷萃取,无水硫酸钠干燥,柱层析分离,得深红色的化合物16a或16b;AlCl3、3-甲氧基苯甲酰氯或4-甲氧基苯甲酰氯与二茂铁物质的量比为4:1.2 :1;
(7)将二茂铁和对甲氧基苯甲醇溶解于二氯甲烷中,冰浴下加入三氟乙酸,在0 oC下反应2h,加入水淬灭反应,用二氯甲烷萃取,无水硫酸钠干燥,柱层析分离,得深红色的化合物16c,二茂铁、对甲氧基苯甲醇和三氟乙酸物质的量比为1:1.2 :4;
(8)在无水无氧和通氩气下,将化合物16a、16b或16c溶解于二氯甲烷中,-20 °C下加入BBr3,反应24 h后,加入水淬灭反应,用乙酸乙酯萃取,无水NaSO4干燥,减压脱溶后得到的粗产物用硅胶柱纯化,得到化合物17a、17b或17c;化合物16a、16b或16c 与BBr3物质的量比为1:3;
(9)在无水无氧和通氩气下,将化合物17a、17b或17c溶解于二氯甲烷中,0°C下加入氯乙磺酰氯和无水三乙胺反应24 h后,减压脱溶,用乙酸乙酯溶解,加入2 N HCl洗涤,有机层无水NaSO4干燥,减压脱溶后得到的粗产物用硅胶柱纯化,得到化合物18a、18b或18c;化合物17a、17b或17c、氯乙磺酰氯和无水三乙胺物质的量比为8:6 :5;
(10) 将3-(4-羟基苯基)-4-辛二酸单酰苯胺基-呋喃化合物13和二茂铁乙烯磺酸酯衍生物18a、18b或18c溶解在四氢呋喃中,在90oC反应3小时一步制备得权利要求1结构式所示的含有N-羟基-N’-苯基辛二酰胺基或其类似结构的二茂铁氧桥双环-[2.2.1]-庚烯类化合物;
化合物13a、13b、13c,化合物16a、16b、16c,化合物17a、17b、17c,化合物18a、18b、18c结构式如下:
。
本发明得到的上述具有抗乳腺癌活性的含有N-羟基-N’-苯基辛二酰胺基团或其类似结构的二茂铁氧桥双环-[2.2.1]-庚烯类化合物对ER+乳腺癌细胞较强的抑制活性,而且能够对ER-乳腺癌细胞也有较好的抑制活性。体外活性实验表明,这类新型二茂铁氧桥双环-[2.2.1]-庚烯类化合物对荷尔蒙依赖型乳腺癌MCF-7细胞和非荷尔蒙依赖型乳腺癌MDA-MB-231细胞均具有更强的抑制活性;与现有抗乳腺癌药物他莫昔芬相比,这些新型二茂铁氧桥双环-[2.2.1]-庚烯类化合物对正常细胞Vero细胞没有毒性,而他莫昔芬有毒性。这类目标化合物是由两种底物:3-(4-羟基苯基)-4-辛二酸单酰苯胺基-呋喃或其类似物和二茂铁乙烯磺酸酯衍生物通过Diels-Alder反应制备得含有辛二酸单酰苯胺基团的二茂铁氧桥双庚烯类化合物或其类似物。该Diels-Alder反应无需溶剂,也无需贵重金属的催化,反应条件温和。
具体实施方式
一、3-(4-羟基苯基)-4-辛二酸单酰苯胺基-呋喃的合成路线:
2-(4-甲氧基苯基)-2-羰基乙基-2-(4-氨基苯基)乙酸酯化合物8的合成
称取对氨基苯乙酸(662mg, 4.36mmol)溶于25 mL无水乙腈,加入α-溴代对甲氧基苯乙酮(1.001g, 4.36mmol), 后滴加入无水三乙胺(442 g, 4.36 mmol),室温下搅拌12小时。反应结束之后蒸除乙腈和三乙胺得粗品,经柱层析纯化后得黄色固体。产率为61.3%。1HNMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H),7.58 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H), 5.12 (s, 2H), 3.76 (s,3H), 3.72 (s, 2H).
3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃-2-酮化合物9的合成
称取2-(4-甲氧基苯基)-2-羰基乙基-2-(4-氨基苯基)乙酸酯(3.143 g, 10.5mmol溶于无水DMSO,缓慢加入NaH(含量为60% , 840.6mg, 21.0 mmol),在25°C下搅拌2个小时后用水萃灭反应,然后用乙酸乙酯萃取(3×30 mL),合并有机层,水洗后,用无水硫酸钠干燥。旋干后用柱层析分离,洗脱剂比例为石油醚 : 乙酸乙酯 = 1: 1,得到化合物1.808g,产率为64.5%。1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.8 Hz, 2H), 7.26(d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.4 Hz, 2H), 5.10(s, 2H), 3.81 (s, 3H).
3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃化合物10的合成
称取3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃-2-酮(1.001g, 3.56 mmol)溶于无水四氢呋喃15 mL,在-78°C下缓慢加入DIBAL-H (14.2mL, 14.24 mmol),此温度下反应12个小时。缓慢加入4%的稀硫酸淬灭反应,乙醚萃取,合并有机层,先后用水和饱和氯化钠洗涤,无水硫酸钠干燥,旋干,柱层析分离,洗脱剂比例为石油醚 : 乙酸乙酯 = 1: 1,得白色固体,产率为62.1%。1H NMR (400 MHz, CDCl3) δ 7.37 (s, 2H), 7.09 (d, J = 8.8 Hz,2H), 6.94 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 8.4 Hz,2H), 3.69 (s, 3H).
3-(4-氨基苯基)-4-(4-羟基苯基)呋喃化合物11的合成
称取3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃 (560 mg, 2.11 mmol)溶于无水二氯甲烷,-20 °C下加入三溴化硼(1.570 g, 6.34mmol),继续反应12h后,加入水萃灭反应,用饱和碳酸氢钠洗涤,用乙酸乙酯萃取(3×45 mL),合并有机层,无水硫酸钠干燥,柱层析分离,洗脱剂比例为石油醚 : 乙酸乙酯 = 4: 6,产率为45.1%。1H NMR (400 MHz, CDCl3)δ 7.39 (s, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.60 (d,J = 8.8 Hz, 2H), 6.53 (d, J = 8.4 Hz, 2H).
3-(4-羟基苯基)-4-庚(辛、壬)二酸单酰苯胺基-呋喃化合物13的合成
称取3-(4-氨基苯基)-4-(4-羟基苯基)呋喃(440mg, 1.75 mmol)和庚(辛、壬)二酸酐(2.63mmol)溶于四氢呋喃,室温反应2h,过滤后蒸干有机相得到粗品,粗品用硅胶柱层析分离,洗脱剂比例为二氯甲烷: 甲醇=60: 1。
3-(4-羟基苯基)-4-庚二酸单酰苯胺基-呋喃(13a): 产率51.6%。1H NMR (400MHz, CDCl3) δ 12.03 (1H, s, -COOH), 9.09 (1H, s), 7.56 (d, J = 1.6 Hz, 1H),7.51 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 2.26 (t, J = 7.6 Hz, 2H), 2.19 (t, J = 7.6 Hz, 2H) , 1.59 (t, J = 7.6 Hz, 2H), 1.50 (t, J = 7.6 Hz,2H), 1.28 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 174.924, 172.14, 157.50, 141.49,141.24, 139.28, 130.55, 129.52, 128.07, 126.54, 126.36, 124.09, 119.96,116.12, 37. 54, 34.07,29.44, 26.02, 25.39.
3-(4-羟基苯基)-4-辛二酸单酰苯胺基-呋喃(13b): 产率67.2%。1H NMR (400MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 12.03 (1H, s, -COOH), 9.90 (1H, s, -NH-), 9.56 (1H, s, -OH), 7.83 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H),7.54 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H),6.72 (d, J = 8.8 Hz, 2H), 2.30 (t, J = 7.2 Hz, 2H) , 2.21 (t, J = 7.6 Hz, 2H), 1.59 (m, 2H), 1.52 (m, 2H), 1.31 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 177.74,174.65, 157.79, 141.71, 141.46, 138.75, 130.86, 129.86, 129.56, 126.77,124.62, 121.16, 116.28, 37.94, 34.92, 30.02, 29.95, 26.78, 25.96.
3-(4-羟基苯基)-4-壬二酸单酰苯胺基-呋喃(13c): 产率62.9%。1H NMR (400MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 9.25 (1H, s), 7.69 (d, J = 1.6 Hz,1H), 7.64 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz,2H), 7.10 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 2.40 (t, J = 7.6 Hz,2H) , 2.31 (t, J = 7.6 Hz, 2H) , 1.71 (t, J = 6.8 Hz, 2H), 1.61 (t, J = 6.8Hz, 2H), 1.31 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 175.26, 172.51, 157.52,141.50, 141.24, 139.19, 130.56, 129.54, 128.17, 126.35, 124.10, 120.17,120.08, 116.17, 37.75, 34.25, 29.85, 29.84, 29.73, 26.32, 25.64.
二、二茂铁乙烯磺酸酯衍生物:
化合物16a、16b的合成
称取AlCl3(11.6 g, 88.0 mmol) 于100 mL的单口瓶中,加入40 mL二氯甲烷溶解,冰浴下缓慢加入3-甲氧基苯甲酰氯或4-甲氧基苯甲酰氯(4.5 g, 26.5 mmol),搅拌反应30 min后缓慢加入二茂铁(4.1 g, 22.0 mmol),在0 oC下反应12h后,加入20 mL水淬灭反应,用饱和碳酸氢钠洗涤,用二氯甲烷(3 × 35 mL),合并有机层,无水硫酸钠干燥,柱层析分离,洗脱剂比例为石油醚 : 乙酸乙酯 = 9: 1,得深红色的化合物16a或16b,产率分别为89.1%和84.3%。
化合物16c的合成
称取二茂铁(4.1 g, 22.0 mmol)和对甲氧基苯甲醇(3.6 g, 26.4 mmol)于50 mL的单口瓶中,加入30 mL二氯甲烷溶解,冰浴下缓慢加入三氟乙酸(10.0 g, 88.0 mmol),在0 oC下反应2h,加入10 mL水淬灭反应,用二氯甲烷(3 × 30 mL)萃取,合并有机层,无水硫酸钠干燥,柱层析分离,洗脱剂比例为石油醚 : 乙酸乙酯 = 9: 1,得深红色的化合物16c,产率分别为40.8%。
化合物17的合成
将50 mL的单口瓶、磁子在105 °C下烘烤15 min后,趁热装置,无水无氧操作,在通Ar下,称取化合物16(8.0 mmol)于其中,加入25 mL 二氯甲烷溶解,-20 °C下缓慢加入BBr3(2.3 mL, 24.4 mmol),-20 °C下继续反应24 h后,加入2 mL 水淬灭反应,用乙酸乙酯(3× 35 mL)萃取,有机层无水NaSO4干燥,减压脱溶后得到的粗产物用硅胶柱纯化,洗脱剂比例为石油醚 : 乙酸乙酯 = 4: 1,得到化合物17。
化合物18的合成
将100 mL的单口瓶、磁子在105 °C下烘烤15 min后,趁热装置,无水无氧操作,在通Ar下,称取化合物17(5.0 mmol)于其中,加入25 mL 二氯甲烷溶解,0 °C下加入氯乙磺酰氯(970.1 mg, 6.0 mmol)和无水三乙胺(1.5 g, 15.0 mmol) 反应24 h后,减压脱溶,用乙酸乙酯(50mL)溶解,加入30 mL 2 N HCl洗涤,有机层无水NaSO4干燥,减压脱溶后得到的粗产物用硅胶柱纯化,洗脱剂比例为石油醚 : 乙酸乙酯 = 8: 1,得到相应的乙烯磺酸酯衍生物18。
三、含有辛二酸单酰苯胺基团的二茂铁氧桥双环-[2.2.1]-庚烯类化合物或其类似物的制备
通过合成得到的3-(4-羟基苯基)-4-庚(辛、壬)二酸单酰苯胺基-呋喃或其类似物13a-c和二茂铁乙烯磺酸酯衍生物18溶解在四氢呋喃中,在90oC反应3小时一步制备得含有辛二酸单酰苯胺基团的二茂铁氧桥双环-[2.2.1]-庚烯类化合物或其类似物,反应式如下所示:
其中,
n为 5、6、7;
X为 CH2或CO。
实施例1:3-(4-羟基苯基)-4-庚二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(3-二茂铁羰基苯基)-酯 (TC1)的制备
称取3-(4-羟基苯基)-4-庚二酸单酰苯胺-呋喃(200 mg, 0.509 mmol)和乙烯磺酸-3-(二茂铁羰基苯基)-酯(241.7 mg, 0.160 mmol)置于50 mL的两口瓶圆底瓶然后缓慢升温至90 °C,反应3个小时后旋干,直接柱层析分离纯化,洗脱剂比例为二氯甲烷: 甲醇=60: 1,得到374.5 mg红色的固体,产率93.2%, m.p. 111-114°C; 1H NMR (400 MHz,Acetone-d 6) δ 9.34 (s, 1H), 8.01 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.65 (t,J = 7.2 Hz, 2H), 7.55 (m, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.8 Hz,2H), 7.27 (t, J = 8.8 Hz, 2H), 6.86 (t, J = 8.4 Hz, 2H), 5.78 (s, 1H), 5.51(s, 1H), 4.89 (s, 2H), 4.66 (s, 2H), 4.24 (s, 5H), 3.98 (m, 1H), 2.52 (m,1H), 2.40 (m, 3H), 2.29 (t, J = 6.8 Hz, 2H), 1.71 (t, J = 6.8 Hz, 2H), 1.62(t, J = 7.2 Hz, 2H), 1.41 (m, 2H). 13C NMR (100 MHz, Acetone-d 6) δ 197.45,175.10, 172.50, 158.66, 158.59, 149.98, 143.61, 142.30, 141.97, 140.15,139.23, 137.53, 131.12, 130.19, 129.80, 128.98, 128.59, 127.58, 125.99.124.61, 122.98, 120.40, 116.56, 85.19, 83.82, 78.71, 73.91, 72.16, 71.17,62.11, 37.64, 34.18, 31.68, 31.47, 26.02, 25.42; HRMS (ESI) calcd forC42H38 54FeNO9S [M - H]-, 786.6621; found 786.6624.
实施例2:3-(4-羟基苯基)-4-庚二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁羰基苯基)-酯 (TC2)的制备
制备方法如实施例1,产物为红色固体,产率为90.6%, m.p. 108-110°C。1H NMR(400 MHz, Acetone-d 6) δ 9.31 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7. 67 (d, J =8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.36 (d, J =8.0 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H), 6.88 (d, J =8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.76 (s, 1H), 5.50 (s, 1H), 4.84 (s,2H), 4.66 (s, 2H), 4.23 (s, 5H), 3.95 (m, 1H), 2.51 (m, 1H), 2.39 (m, 3H),2.32 (t, J = 7.2 Hz, 2H), 1.70 (m, 2H), 1.62 (t, J = 7.2 Hz, 2H), 1.41 (m,2H). 13C NMR (100 MHz, Acetone-d 6) δ 197.40, 174.90, 172.30, 158.70, 158.56,152.60, 143.55, 142.00, 140.35, 140.21, 139.32, 137.54, 130.92, 130.34,129.78, 129.12, 128.47, 127.94, 123.87. 123.03, 120.29, 120.10, 116.71,116.51, 85.28, 83.73, 78.93, 73.66, 72.17, 71.07, 61.81, 37.61, 34.12, 31.57,31.36, 25.98, 25.41; HRMS (ESI) calcd for C42H38 54FeNO9S [M - H]-, 786.6627;found 786.6624.
实施例3:3-(4-羟基苯基)-4-庚二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁基苄基)-酯 (TC3)的制备
制备方法如实施例1,产物为红色固体,产率为85.2%, m.p. 96-98°C。1H NMR(400 MHz, Acetone-d 6) δ 9.14 (s, 1H), 7.53 (t, J = 8.8 Hz, 2H), 7. 17 (d, J =7.6 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.09 (d, J =7.6 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 7.2 Hz, 1H), 6.99 (d, J =7.2 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 5.53 (s,1H), 5.31 (t, J = 3.2 Hz, 1H), 3.97 (s, 7H), 3.92 (s, 2H), 3.64 (m, 1H), 3.60(m, 2H), 2.27 (m, 3H), 2.17 (m, 3H), 1.58 (t, J = 7.6 Hz, 2H), 1.46 (t, J =7.6 Hz, 2H), 1.30 (m, 2H). 13C NMR (100 MHz, Acetone-d 6) δ 174.83, 172.18,158.56, 158.42, 148.63, 142.13, 141.90, 140.21, 140.09, 139.24, 137.59,130.60, 130.29, 129.11, 128.46, 127.95, 124.71, 123.90, 122.84, 120.23,116.40, 88.54, 85.22, 83.64, 69.43, 69.36, 68.39, 61.21, 37.55, 35.90, 34.08,31.51, 31.31, 25.98, 25.39; HRMS (ESI) calcd for C42H40 54FeNO8S [M - H]-,772.1820; found 772.1824.
实施例4:3-(4-羟基苯基)-4-辛二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(3-二茂铁羰基苯基)-酯 (TC4)的制备
制备方法如实施例1,产物为红色粉末,产率为88.4%, m.p. 106-109°C; 1H NMR(400 MHz, Acetone-d 6) δ 9.27 (s, 1H), 8.00 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H),7.65 (t, J = 7.2 Hz, 2H), 7.55 (m, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.34 (t, J= 8.0 Hz, 2H), 7.24 (t, J = 8.4 Hz, 2H), 6.83 (t, J = 8.4 Hz, 2H), 5.76 (s,1H), 5.50 (s, 1H), 4.86 (s, 2H), 4.66 (s, 2H), 4.25 (s, 5H), 3.93 (m, 1H),2.52 (m, 1H), 2.38 (t, J = 7.2 Hz, 3H), 2.29 (t, J = 7.2 Hz, 2H), 1.69 (t, J= 6.8 Hz, 2H), 1.61 (t, J = 6.4 Hz, 2H), 1.37 (m, 4H). 13C NMR (100 MHz,Acetone-d 6) δ 197.30, 175.06, 172.44, 158.62, 158.56, 150.01, 143.57, 142.32,142.02, 140.26, 139.20, 137.57, 131.08, 129.77, 128.57, 127.53, 125.95,124.65, 123.94, 123.01, 122.95, 120.32, 85.19, 83.77, 78.74, 73.83, 72.08,71.07, 61.94, 55.92, 37.74, 34.21, 31.45, 26.15, 25.54, 29.63; HRMS (ESI)calcd for C43H40 54FeNO9S [M - H]-, 800.1829; found 800.1825.
实施例5:3-(4-羟基苯基)-4-辛二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁羰基苯基)-酯 (TC5)的制备
制备方法如实施例1,产物为红色粉末,产率为83.7 %, m.p. 104-106°C; 1H NMR(400 MHz, Acetone-d 6) δ 9.34 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.64 (m, 2H),7.41 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 2H),7.24 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H),5.76 (s, 1H), 5.50 (s, 1H), 4.84 (s, 2H), 4.65 (s, 2H), 4.23 (s, 5H), 3.96(m, 1H), 2.50 (m, 1H), 2.39 (m, 2H), 2.31 (m, 2H), 1.68 (m, 2H), 1.61 (t, J =6.0 Hz, 2H), 1.36 (m, 4H). 13C NMR (100 MHz, Acetone-d 6) δ 197.58, 175.19,172.59, 158.73, 158.59, 152.59, 141.97, 139.25, 137.50, 130.95, 130.35,129.72, 129.12, 128.51, 128.00, 124.64, 123.84, 123.09, 123.06, 120.39,120.20, 116.75, 116.56, 85.22, 83.70, 78.88, 73.74, 72.21, 71.11, 61.84,37.77, 34.28, 31.59, 31.38, 29.68, 26.16, 25.66; HRMS (ESI) calcd forC43H40 54FeNO9S [M - H]-, 800.1825; found 800.1825.
实施例6:3-(4-羟基苯基)-4-辛二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁基苄基)-酯 (TC6)的制备
制备方法如实施例1,产物为红色粉末,产率为86.4 %, m.p. 101-103°C;1H NMR(400 MHz, Acetone-d 6) δ 9.31 (s, 1H), 7.67 (t, J = 8.8 Hz, 2H), 7.30 (m, 2H),7.23 (t, J = 7.6 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H),7.12 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H),5.67 (s, 1H), 5.44 (s, 1H), 4.15 (s, 7H), 4.10 (s, 2H), 3.76 (m, 1H), 3.65(s, 2H), 2.40 (m, 3H), 2.29 (m, 3H), 1.70 (t, J = 6.0 Hz, 2H), 1.59 (m, 2H),1.37 (m, 4H). 13C NMR (100 MHz, Acetone-d 6) δ 175.13, 172.50, 158.66, 158.52,148.61, 142.11, 139.26, 137.56, 130.63, 130.61, 130.30, 129.66, 129.11,128.47, 124.69, 123.89, 122.90, 122.80, 120.39, 120.15, 116.72, 116.51,85.25, 83.64, 69.56, 69.47, 68.51, 61.25, 55.04, 37.77, 35.90, 31.52, 31.32,26.18, 25.63; HRMS (ESI) calcd for C43H42 54FeNO8S [M - H]-, 786.1976; found786.1951.
实施例7:3-(4-羟基苯基)-4-壬二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(3-二茂铁羰基苯基)-酯 (TC7)的制备
制备方法如实施例1,产物为红色粉末,产率92.8%, m.p. 121-124°C; 1H NMR(400 MHz, Acetone-d 6) δ 9.30 (s, 1H), 8.00 (s, 1H), 7.86 (d, J = 7.6 Hz, 1H),7.65 (t, J = 7.6 Hz, 2H), 7.56 (m, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.35 (t, J= 8.8 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.27 (t, J = 8.8 Hz, 2H), 6.85 (t, J= 8.8 Hz, 2H), 5.77(s, 1H), 5.51 (t, J = 3.6 Hz, 1H), 4.86 (s, 2H), 4.66 (s,2H), 4.25 (s, 5H), 3.99 (m, 1H), 2.52 (m, 1H), 2.39 (m, 3H), 2.29 (m, 2H),1.68 (t, J = 7.2 Hz, 3H), 1.58 (t, J = 6.8 Hz, 3H), 1.34 (m, 4H). 13C NMR (100MHz, Acetone-d 6) δ 197.38, 175.10, 172.54, 158.61, 158.55, 149.99, 143.59,142.30, 141.99, 142.30, 141.99, 140.24, 139.21, 137.56, 131.10, 130.19,129.80, 128.97, 128.59, 127.56, 125.97, 124.65, 122.98, 120.37, 116.54,85.20, 83.81, 78.73, 73.87, 72.11, 71.15, 61.97, 37.81, 37.78, 34.27, 31.68,31.47, 29.73, 26.27, 25.65; HRMS (ESI) calcd for C44H42 54FeNO9S [M - H]-,814.1928; found 814.1930.
实施例8:3-(4-羟基苯基)-4-壬二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁羰基苯基)-酯 (TC8)的制备
制备方法如实施例1,产物为红色粉末,产率为89.2 %, m.p. 114-116°C; 1H NMR(400 MHz, Acetone-d 6) δ 9.29 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.69 (d, J =8.4 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.43 (t, J = 8.4 Hz, 2H), 7.35 (d, J =8.4 Hz, 2H), 7.32 (t, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.88 (d, J =8.0 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.77 (s, 1H), 5.50 (s, 1H), 4.84 (s,2H), 4.65 (s, 2H), 4.23 (s, 5H), 3.95 (m, 1H), 2.51 (m, 1H), 2.39 (m, 3H),2.31 (t, J = 7.6 Hz, 2H), 1.68 (m, 3H), 1.59 (t, J = 6.4 Hz, 3H), 1.33 (m,4H). 13C NMR (100 MHz, Acetone-d 6) δ 197.50, 175.11, 172.56, 158.67, 158.53,152.60, 143.56, 141.63, 139.30, 137.53, 130.94, 130.36, 129.72, 129.13,128.51, 124.68, 123.89, 123.05, 116.72, 116.53, 85.23, 83.75, 78.91, 73.70,72.20, 71.09, 62.03, 37.81, 34.27, 31.58, 31.37, 29.84, 29.73, 26.26, 25.65;HRMS (ESI) calcd for C44H42 54FeNO9S [M - H]-, 814.1926; found 814.1930.
实施例9:3-(4-羟基苯基)-4-壬二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁基苄基)-酯 (TC9)的制备
制备方法如实施例1,产物为红色粉末,产率为89.9 %, m.p. 106-108°C;1H NMR(400 MHz, Acetone-d 6) δ 9.25 (s, 1H), 7.65 (t, J = 8.8 Hz, 2H), 7.30 (d, J =8.0 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 8.4 Hz, 2H), 7.18 (t, J =8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.79 (d, J =8.4 Hz, 1H), 5.67 (s, 1H), 5.45 (t, J = 3.6 Hz, 1H), 4.11 (s, 7H), 4.06 (s,2H), 3.77 (m, 1H), 3.69 (m, 2H), 2.43 (m, 3H), 2.31 (t, J = 7.6 Hz, 3H), 1.68(t, J = 6.4 Hz, 3H), 1.59 (m, 3H), 1.34 (m, 4H). 13C NMR (100 MHz, Acetone-d 6)δ 174.95, 172.34, 158.54, 158.41, 148.58, 143.42, 142.24, 142.13, 141.90,139.24, 137.59, 130.60, 130.30, 129.66, 129.12, 128.47, 124.73, 123.92,122.79, 120.24, 116.41, 88.56, 85.22, 83.60, 69.44, 69.37, 68.40, 61.32,37.74, 35.91, 34.21, 31.52, 31.30, 29.83, 26.26, 25.64; HRMS (ESI) calcd forC44H44 54FeNO8S [M - H]-, 800.21379; found 800.2137.
实施例10:N-羟基-N’-苯基辛二酰胺基团或其类似结构的的二茂铁氧桥双环-[2.2.1]-庚烯类化合物的抗肿瘤活性实验
MCF-7、MDA-MB-231和VERO细胞在含10%胎牛血清的有酚红DMEM液体培养基中培养。细胞密度至80%~90%时,消化细胞,并用含10%胎牛血清的无酚红DMEM培养基将细胞悬浮液铺至96孔细胞培养板中。待细胞完全贴壁后,弃去原培养液,每孔加入100 μl新鲜的用含10%胎牛血清的DMEM培养基配制的化合物溶液,化合物浓度梯度为:1×10-7 M, 1×10-6 M,1×10-5 M, 5×10-5M, 1×10-4 M。药物处理培养3至5天后,取出培养板,每孔加入20 μl5mg/mL MTT工作液,置于37 oC、5% CO2培养箱中孵育4小时。之后吸去每孔液体,然后每孔加入100 μL 二甲亚砜(DMSO),放在微量搅拌器上震荡10~15分钟使结晶物充分溶解。在酶标仪上读板,选取490 nm处波长为主波长,630 nm处波长为参照波长,分析实验结果,并计算出IC50。
这类新型N-羟基-N’-苯基辛二酰胺基团或其类似结构的二茂铁氧桥双环-[2.2.1]-庚烯类化合物体外实验表明,对MCF-7和MDA-MB-231乳腺癌细胞均有较强的抑制活性,尤其是对非荷尔蒙依赖型 (MDA-MB-231)乳腺癌有较好的抑制作用;同时化合物TC1-9对正常细胞Vero没有毒性,但是他莫昔芬有毒性。化合物TC1-9的抑制活性见表1。
表1. 本发明合成的代表性目标化合物1-9的MCF-7、MDA-MB-231和VERO细胞细胞抑制活性结果(IC50, μM)
上述实验结果表明:合成的化合物都具有很好抗乳腺癌活性,尤其是侧链为SAHA的衍生物(化合物TC4-6)不仅对荷尔蒙依赖型(MCF-7)乳腺癌,而且对非荷尔蒙依赖型(MDA-MB-231)乳腺癌均显示出了较好的抗乳腺癌活性。化合物TC1-9(IC50 < 34 μM)对非荷尔蒙依赖型(MDA-MB-231)乳腺癌的抑制活性明显的强于药物他莫昔芬(IC50 > 100 μM)。
Claims (4)
1.一种含有N-羟基-N’-苯基辛二酰胺基或其类似结构的二茂铁氧桥双环-[2.2.1]-庚烯类化合物,结构式如下:
其中,
n为 5、6、7;
X为 CH2或CO;
所述化合物为
3-(4-羟基苯基)-4-庚二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(3-二茂铁羰基苯基)-酯 、
3-(4-羟基苯基)-4-庚二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁羰基苯基)-酯 、
3-(4-羟基苯基)-4-庚二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁基苄基)-酯 、
3-(4-羟基苯基)-4-辛二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(3-二茂铁羰基苯基)-酯 、
3-(4-羟基苯基)-4-辛二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁羰基苯基)-酯 、
3-(4-羟基苯基)-4-辛二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁基苄基)-酯 、
3-(4-羟基苯基)-4-壬二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(3-二茂铁羰基苯基)-酯 、
3-(4-羟基苯基)-4-壬二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁羰基苯基)-酯 或
3-(4-羟基苯基)-4-壬二酸单酰苯胺-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(4-二茂铁基苄基)-酯 。
2.权利要求1所述含有N-羟基-N’-苯基辛二酰胺基或其类似结构的二茂铁氧桥双环-[2.2.1]-庚烯类化合物的制备方法,包括以下步骤:
(1)将对氨基苯乙酸溶于无水乙腈中,然后加入α-溴代对甲氧基苯乙酮和无水三乙胺,室温下搅拌12小时;反应结束之后蒸除乙腈和三乙胺得粗品,经柱层析纯化后得黄色固体2-(4-甲氧基苯基)-2-羰基乙基-2-(4-氨基苯基)乙酸酯化合物;对氨基苯乙酸、α-溴代对甲氧基苯乙酮和无水三乙胺的物质的量比为1:1:1;
(2)将2-(4-甲氧基苯基)-2-羰基乙基-2-(4-氨基苯基)乙酸酯溶于无水二甲基亚砜中,加入NaH,在25°C下搅拌2个小时后用水萃灭反应,然后用乙酸乙酯萃取,水洗后,用无水硫酸钠干燥;旋干后用柱层析分离,得到化合物3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃-2-酮化合物;2-(4-甲氧基苯基)-2-羰基乙基-2-(4-氨基苯基)乙酸酯与NaH的物质的量比为1:2;
(3)将3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃-2-酮溶于无水四氢呋喃中,在-78°C下加入二异丁基氢化铝,反应12个小时;乙醚萃取,先后用水和饱和氯化钠洗涤,无水硫酸钠干燥,旋干,柱层析分离,得白色固体3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃化合物;3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃-2-酮与二异丁基氢化铝的物质的量比为1:4;
(4)将3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃 (560 mg, 2.11 mmol)溶于无水二氯甲烷中,-20 °C下加入三溴化硼(1.570 g, 6.34mmol),反应12h后,加入水萃灭反应,用饱和碳酸氢钠洗涤,用乙酸乙酯萃取,无水硫酸钠干燥,柱层析分离,得3-(4-氨基苯基)-4-(4-羟基苯基)呋喃化合物,3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃 与三溴化硼的物质的量比为1:3;
(5)将物质的量比为1:1.5的3-(4-氨基苯基)-4-(4-羟基苯基)呋喃和庚二酸酐、辛二酸酐或壬二酸酐溶于四氢呋喃中,室温反应2h,过滤后蒸干有机相得到粗品,粗品用硅胶柱层析分离,得3-(4-羟基苯基)-4-庚二酸单酰苯胺基-呋喃化合物13a、3-(4-羟基苯基)-4-辛二酸单酰苯胺基-呋喃化合物13b或3-(4-羟基苯基)-4-壬二酸单酰苯胺基-呋喃化合物13c;
(6)将AlCl3溶解于二氯甲烷中,冰浴下加入3-甲氧基苯甲酰氯或4-甲氧基苯甲酰氯,搅拌反应30 min后加入二茂铁,在0 oC下反应12h后,加水淬灭反应,用饱和碳酸氢钠洗涤,用二氯甲烷萃取,无水硫酸钠干燥,柱层析分离,得深红色的化合物16a或16b;AlCl3、3-甲氧基苯甲酰氯或4-甲氧基苯甲酰氯与二茂铁物质的量比为4:1.2 :1;
(7)将二茂铁和对甲氧基苯甲醇溶解于二氯甲烷中,冰浴下加入三氟乙酸,在0 oC下反应2h,加入水淬灭反应,用二氯甲烷萃取,无水硫酸钠干燥,柱层析分离,得深红色的化合物16c,二茂铁、对甲氧基苯甲醇和三氟乙酸物质的量比为1:1.2 :4;
(8)在无水无氧和通氩气下,将化合物16a、16b或16c溶解于二氯甲烷中,-20 °C下加入BBr3,反应24 h后,加入水淬灭反应,用乙酸乙酯萃取,无水NaSO4干燥,减压脱溶后得到的粗产物用硅胶柱纯化,得到化合物17a、17b或17c;化合物16a、16b或16c 与BBr3物质的量比为1:3;
(9)在无水无氧和通氩气下,将化合物17a、17b或17c溶解于二氯甲烷中,0°C下加入氯乙磺酰氯和无水三乙胺反应24 h后,减压脱溶,用乙酸乙酯溶解,加入2 N HCl洗涤,有机层无水NaSO4干燥,减压脱溶后得到的粗产物用硅胶柱纯化,得到化合物18a、18b或18c;化合物17a、17b或17c、氯乙磺酰氯和无水三乙胺物质的量比为8:6 :5;
(10)将3-(4-羟基苯基)-4-庚二酸单酰苯胺基-呋喃化合物13a、3-(4-羟基苯基)-4-辛二酸单酰苯胺基-呋喃化合物13b或3-(4-羟基苯基)-4-壬二酸单酰苯胺基-呋喃化合物13c和二茂铁乙烯磺酸酯衍生物18a、18b或18c溶解在四氢呋喃中,在90oC反应3小时一步制备得权利要求1结构式所示的含有N-羟基-N’-苯基辛二酰胺基或其类似结构的二茂铁氧桥双环-[2.2.1]-庚烯类化合物;
化合物13a、13b、13c,化合物16a、16b、16c,化合物17a、17b、17c,化合物18a、18b、18c结构式如下:
、、、。
3.权利要求1所述的N-羟基-N’-苯基辛二酰胺基或其类似结构的二茂铁氧桥双环-[2.2.1]-庚烯类化合物在制备抗乳腺癌药物中的应用。
4.一种抗乳腺癌药物组合物,包含权利要求1所述的化合物和一种或多种药学上可接受的助剂。
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