CN104230948B - 一种氧桥双环-[2.2.1]-庚烯类化合物及其用途 - Google Patents
一种氧桥双环-[2.2.1]-庚烯类化合物及其用途 Download PDFInfo
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- KCPGVKOVOLPGGY-UHFFFAOYSA-N COc1cccc(OS(C(C2)C3OC2C(c(cc2)ccc2O)=C3c(cc2)ccc2NC(CCCCCCC(O)=O)O)(=O)=O)c1 Chemical compound COc1cccc(OS(C(C2)C3OC2C(c(cc2)ccc2O)=C3c(cc2)ccc2NC(CCCCCCC(O)=O)O)(=O)=O)c1 KCPGVKOVOLPGGY-UHFFFAOYSA-N 0.000 description 1
- QXOXWUFTWHQRAB-UHFFFAOYSA-O Oc(cc1)ccc1C(C(C1)OC2C1S(O)(Oc1cc(O)ccc1)=O)=C2c(cc1)ccc1NC(CCCCCCC([OH2+])=O)=O Chemical compound Oc(cc1)ccc1C(C(C1)OC2C1S(O)(Oc1cc(O)ccc1)=O)=C2c(cc1)ccc1NC(CCCCCCC([OH2+])=O)=O QXOXWUFTWHQRAB-UHFFFAOYSA-O 0.000 description 1
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Abstract
本发明属于医药技术领域,具体公开了一种具有抗乳腺癌活性的含有<i>N</i>-羟基-<i>N</i>’-苯基辛二酰胺基(SAHA)或其类似结构的氧桥双环-[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-呋喃和乙烯磺酸酯衍生物为原料,无需溶剂和催化剂,在90oC反应3小时一步制备得到含有辛二酸单酰苯胺基团的氧桥双环-[2.2.1]-庚烯类化合物,该化合物再和盐酸羟肟反应得到含有<i>N</i>-羟基-<i>N</i>’-苯基辛二酰胺基团的氧桥双环-[2.2.1]-庚烯类化合物。体外实验表明,这类新型氧桥双环-[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MCF-7细胞具有更强的抑制活性。
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
乳腺癌是女性最常见的恶性肿瘤,据资料统计,全球每年120万妇女罹患乳腺癌,且有50万死于该病,发病率占全身各种恶性肿瘤的7-10%。一方面,研究表明乳腺癌与雌激素和雌激素受体(EstrogenReceptor,ER)有着十分密切的关系。雌激素通过ER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。选择性雌激素受体调节剂(selectiveestrogenreceptormodulators,SERMs)是一类典型的通过内分泌疗法来阻止雌激素的合成的抗乳腺癌的药物。目前广泛用于乳腺癌治疗的药物是他莫昔芬(Tamoxifen,TAM,式1所示),它主要是用于治疗激素依赖型即雌激素受体呈阳性(ER+)乳腺癌。但是,TAM治疗效果并不理想:在雌激素受体呈阴性(ER-)的病人中(约占乳腺癌病人总数的1/3),仅有5%的人受益于内分泌治疗;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,Molecularbasisofagonismandantagonismintheestrogenreceptor,Nature,389(1997)753-758.)。另外,患者对SERMs的耐药性问题是目前乳腺癌内分泌疗法存在的一个严重不足。所以,开发新的抗肿瘤药物是迫在眉睫的科学任务,增加药物靶向,减少患者对药物的耐药性和降低对机体正常细胞的损伤将是研究的重点所在。
另一方面,乳腺癌细胞中除了含有ER以外,还含有组蛋白去乙酰化酶(HistoneDeacetylases,HDAC),它与肿瘤的发生和转移密切相关,对肿瘤细胞的生长调控具有普遍生物学意义,因此有可能成为广谱低毒抗肿瘤药物的作用靶点。组蛋白去乙酰化酶抑制剂(HDACinhibitors,HDACis)被用于血液系统肿瘤和一些实体肿瘤的研究中,显示出对肿瘤生长的抑制作用(参考文献:P.Marks,R.A.Rifkind,V.M.Richon,R.Breslow,T.Miller,W.K.Kelly,Histonedeacetylasesandcancer:causesandtherapies,NatuerRev.Cancer.1(2001)194-202.)。SAHA(式2所示)是最有代表性的HDACi,SAHA作为一类新的抗肿瘤药物,它可引起肿瘤细胞的生长停滞和凋亡,而且对其他药物产生耐药性的肿瘤细胞仍然有较好的反应性,其抑制作用有一定的肿瘤特异性,对一些正常细胞并无影响。并且在体外实验发现,SAHA对乳腺癌细胞增殖有较强的抑制效应(参考文献:P.N.Munster,M.Lacevic,S.Thomas,R.Ismail-Khan,H.Rugo,M.Melisko,S.E.Minton,ClinicalphaseIIstudyofvorinostat,ahydroxamictypehistonedeacetylaeinhibitor,incombinationwithtamoxifentoreverseacpuiredhormoneresistanceinbreastcancerpatientswhoprogressedonhormonetherapy,CancerRes,69(2009)856S-856S.)。
2005年我们成功设计并合成出了一类基于氧桥双环-[2.2.1]-庚烯类结构的化合物(式3所示),由于分子结构具有特殊三维结构,可以更好地与雌激素受体上的结合位点作用,所以这类化合物显示出了很好的受体结合力和选择性,生物活性也表明这类化合物具有良好的潜在的抗乳腺癌活性。(参考文献:H.B.Zhou,J.S.Comninos,F.Stossi,B.S.Katzenllenbogen,J.A.Katzenllenbogen,Synthesisandevaluationofestrogenreceptorligandswithbridgedoxabicycliccorescontainingadiarylethylenemotif:estrogenantagonistsofunusualstructure,J.Med.Chem,48(2005)7261-7274.)我们欲将氧桥双庚烯类结构的化合物和SAHA相结合,得到既具有三维立体结构、又具有双重靶标的新型高效抗肿瘤药物,合成的目标化合物在测试其生物活性中,表现了良好的潜在的抗乳腺癌活性。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5,6-二(4-羟基苯基)-呋喃和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氧桥双庚烯类化合物,该化合物再和盐酸羟肟反应得到含有N-羟基-N’-苯基辛二酰胺基团的氧桥双庚烯类化合物。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。
发明内容
本发明所要解决的技术问题是提供前述的含有N-羟基-N’-苯基辛二酰胺基团的氧桥双环-[2.2.1]-庚烯类化合物的合成方法。
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,
R1为Me、OH、NHOH;
R2为
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:
5,6-二(4-羟基)-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-4-(7-苯胺基甲酰基庚酸甲酯)-酯(1)、
5,6-二(4-羟基)-7-氧桥双环[2.2.1]-5-庚烯-2-磺酸-(3-苯胺基甲酰基庚酸甲酯)-酯(2)、
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-甲氧基苯基)-酯(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-(2-萘基)-酯(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-(1-萘基)-酯(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-氟苯基)-酯(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-甲基苯基)-酯(7)、
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-(4-三氟甲基苯基)-酯(8)
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氧桥双环-[2.2.1]-庚烯类化合物的制备方法。
通过下面所示反应合成5,6-二(4-羟基苯基)-呋喃、3-(4-羟基苯基)-4-辛二酸单酰苯胺基-呋喃和乙烯磺酸酯衍生物。具体操作步骤可以为:
5,6-二(4-羟基苯基)-呋喃:
对甲氧基溴代苯乙酮化合物2的合成
称取对甲氧基苯乙酮1(3.469g,23.13mmol)、对甲苯磺酸(878.8mg,4.62mmol)和N-溴代琥珀酰亚(NBS,4.94g,27.72mmol)于50mL的圆底烧瓶中,加入20mL的CH3Cl,室温反应9h后,TLC监测反应完全,减压脱溶,加入50mL乙酸乙酯溶解,用2NHCl(30mL)、饱和NaHCO3(2×30mL)溶液和饱和NaCl(30mL)洗涤,有机层无水NaSO4干燥,过滤旋干得粗品,经柱层析纯化后得4.825g白色固体化合物2,产率为91.5%。
2-(4-甲氧基苯基)-2-羰基乙基-2-(4-甲氧基苯基)乙酸酯化合物4的合成
称取化合物2(1.5896g,6.94mmol)和对甲氧基苯乙酸3(1.1532g,6.94mmol)于50mL的圆底烧瓶中,加入25mL的无水乙腈,缓慢滴加无水三乙胺(702.3g,6.94mmol)后,室温继续反应2h后,TLC监测反应完全,反应结束之后蒸除乙腈和三乙胺,加入乙酸乙酯溶解,先后用稀盐酸(2N,30mL),饱和碳酸氢钠(2×30mL)和饱和氯化钠(30mL)洗涤,有机层用无水硫酸钠干燥,过滤旋干得粗品,经柱层析纯化后得黄色固体化合物4,产率为88%。
3,4-二(4-甲氧基-苯基)呋喃-2-酮化合物5的合成
将25mL的两口瓶、磁子在105℃下烘烤15min后,趁热装置,无水无氧操作,在通Ar下,称取化合物4(786.2mg,2.5mmol)其中,加入10mL的无水DMSO,缓慢滴加80%NaH(150.1mg,5.0mmol)后,25℃反应2h后,TLC监测反应完全,加入5mL2NHCl淬灭反应,用乙酸乙酯(3×25mL)萃取,有机层无水NaSO4干燥,减压脱溶得到粗产物,硅胶柱纯化(石油醚/乙酸乙酯=9:1)得到475.9mg(64.3%)化合物5。
3,4-二(4-羟基-苯基)呋喃-2-酮化合物6的合成
将100mL的单口瓶、磁子在105℃下烘烤15min后,趁热装置,无水无氧操作,在通Ar下,称取化合物5(1.345g,4.56mmol),其中,加入25mLDCM,-20℃下加入BBr3(2.6mL,27.33mmol)反应12h后,加入10mL水淬灭反应,用乙酸乙酯(3×20mL)萃取,饱和NaHCO3(15mL)溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,硅胶柱纯化(石油醚/乙酸乙酯=7:3)得到1.06g(86.7%)化合物6。
3,4-二(4-羟基-苯基)呋喃化合物7的合成
将50mL的单口瓶、磁子在105℃下烘烤15min后,趁热装置,无水无氧操作,在通Ar下,称取化合物11(560mg,1.98mmol)其中,-78℃下加入二异丁基氢化铝(DIBAl-H,8mL,7.93mmol)反应12h后,加入4%H2SO4淬灭反应,用乙酸乙酯(3×25mL)萃取,饱和NaCl(30mL)溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,硅胶柱纯化(石油醚/乙酸乙酯=6:4)得到203.1mg(40.7%)化合物7。(参考文献:H.B.Zhou,J.S.Comninos,F.Stossi,B.S.Katzenllenbogen,J.A.Katzenllenbogen,Synthesisandevaluationofestrogenreceptorligandswithbridgedoxabicycliccorescontainingadiarylethylenemotif:estrogenantagonistsofunusualstructure,J.Med.Chem,48(2005)7261-7274.)1HNMR(400MHz,CDCl3):δ7.41(2H,s),6.94(2H,d,J=8.4Hz,Ar-H),6.87(2H,d,J=8.8Hz,Ar-H)。
3-(4-羟基苯基)-4-辛二酸单酰苯胺基-呋喃:
2-(4-甲氧基苯基)-2-羰基乙基-2-(4-氨基苯基)乙酸酯化合物9的合成
称取对氨基苯乙酸(662mg,4.36mmol)溶于25mL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(442g,4.36mmol),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(400MHz,CDCl3)δ7.83(d,J=8.5Hz,2H),7.71(d,J=8.5Hz,2H),7.58(d,J=8.5Hz,2H),6.95(d,J=8.5Hz,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10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(3.143g,10.5mmol溶于无水DMSO,缓慢加入NaH(含量为60%,840.6mg,21.0mmol),在25℃下搅拌2个小时后用水萃灭反应,然后用乙酸乙酯萃取(3×30mL),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%。1HNMR(400MHz,CDCl3)δ7.34(d,J=8.8Hz,2H),7.26(d,J=8.4Hz,2H),6.85(d,J=8.8Hz,2H),6.68(d,J=8.4Hz,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11的合成
称取3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃-2-酮(1.001g,3.56mmol)溶于无水四氢呋喃15mL,在-78℃下缓慢加入DIBAL-H(14.2mL,14.24mmol),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%。1HNMR(400MHz,CDCl3)δ7.37(s,2H),7.09(d,J=8.8Hz,2H),6.94(d,J=8.4Hz,2H),6.74(d,J=8.8Hz,2H),6.51(d,J=8.4Hz,2H),3.69(s,3H).
3-(4-氨基苯基)-4-(4-羟基苯基)呋喃化合物12的合成
称取3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃(560mg,2.11mmol)溶于无水二氯甲烷,-20℃下加入三溴化硼(1.570g,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(3×45mL),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%。1HNMR(400MHz,CDCl3)δ7.39(s,2H),6.94(d,J=8.8Hz,2H),6.86(d,J=8.4Hz,2H),6.60(d,J=8.8Hz,2H),6.53(d,J=8.4Hz,2H).
3-(4-羟基苯基)-4-辛二酸单酰苯胺基-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,1.75mmol)和辛二酸酐(410.5mg,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,产率51.6%。1HNMR(400MHz,CDCl3)δ12.03(1H,s,-COOH),9.90(1H,s,-NH-),9.56(1H,s,-OH),7.83(d,J=1.6Hz,1H),7.78(d,J=1.6Hz,1H),7.54(d,J=8.4Hz,2H),7.13(d,J=8.4Hz,2H),7.02(d,J=8.0Hz,2H),6.72(d,J=8.8Hz,2H),2.30(t,J=7.2Hz,2H),2.21(t,J=7.6Hz,2H),1.59(m,2H),1.52(m,2H),1.31(m,4H).13CNMR(101MHz,CDCl3)δ177.74,174.65,157.79,141.71,141.46,138.75,130.86,129.86,129.56,126.77,124.62,121.16,116.28,37.94,34.92,30.02,29.95,26.78,25.96.
乙烯磺酸酯衍生物:
化合物15的合成
称取辛二酸(5g,28.7mmol)于10mL的单口瓶中,加入5mL乙酸酐,加热回流1h后冷却至室温,减压脱溶得到4.26g粗产物2(95.1%)。
化合物16的合成
将250mL的两口瓶,磁子在105℃下烘烤15min后,趁热装上,无水无氧处理并保持通Ar。称取2.001g(12.8mmol)化合物2于其中,加入60mLTHF,搅拌溶解后加入对甲氧基苯胺(1.5876g,12.9mmol),室温下继续反应30min,TCL监测反应完全后,减压过滤,滤液减压脱溶后得到的粗产物用硅胶柱纯化(DCM/MeOH,60:1),得到7.003g(98.0%)白色粉末[39]。
1HNMR(400MHz,DMSO-d6):δ11.98(1H,s,-COOH),9.70(1H,s,-NH),7.51(2H,d,J=8.8Hz,Ar-H),6.87(2H,d,J=9.2Hz,Ar-H),3.37(3H,s,-OCH3),2.28(4H,m,2×CH2),1.56(4H,m,2×CH2),1.49(4H,m,2×CH2).
化合物17的合成
将100mL的单口瓶、磁子在105℃下烘烤15min后,趁热装置,无水无氧操作,在通Ar下,称取化合物3(1g,1.79mol)于其中,加入25mLDCM,-20℃下加入BBr3(0.52mL,5.37mmol)反应12h后,加入1mL水淬灭反应,用乙酸乙酯(3×30mL)萃取,饱和NaHCO3(25mL)溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,硅胶柱纯化(DCM/MeOH,20:1)得到389.2mg(82.0%)化合物4。
1HNMR(400MHz,DMSO-d6):δ11.96(1H,s,-COOH),9.59(1H,s,-NH),9.16(1H,s,-OH),7.37(2H,d,J=8.8Hz,Ar-H),6.69(2H,d,J=9.2Hz,Ar-H),2.25(4H,m,2×CH2),1.54(4H,m,2×CH2),1.29(4H,m,2×CH2).
13CNMR(125MHz,CDCl3):δ174.46,170.44,153.03,131.00,120.81,114.92,36.16,33.59,28.39,28.30,25.08,24.36.
化合物18的合成
将100mL的单口瓶、磁子在105℃下烘烤15min后,趁热装置,无水无氧操作,在通Ar下,称取化合物4(301mg,1.13mol)于其中,加入25mLTHF,0℃下加入氯乙磺酰氯(219.9mg,1.36mmol)和无水三乙胺(171.4mg,1.70mmol)反应24h后,减压脱溶,用乙酸乙酯(50mL)溶解,加入30mL2NHCl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(DCM/MeOH,50:1),得到160.5mg(40.0%)淡黄色粉末。
1HNMR(400MHz,DMSO-d6):δ8.08(1H,s,-NH),7.55(2H,d,J=8.8Hz,Ar-H),7.11(2H,d,J=8.8Hz,Ar-H),6.66(1H,m,=CH-),6.32(2H,d,J=16.4Hz,=CH2),6.16(2H,d,J=9.6Hz,=CH2),3.63(3H,s,-OCH3),2.27(4H,m,2×CH2),1.68(4H,m,2×CH2),1.32(4H,m,2×CH2).
乙烯磺酸酯衍生物:
将50mL的单口瓶、磁子在105℃下烘烤15min后,趁热装置,无水无氧操作,在通Ar下,称取相应的酚(1mol)于其中,加入25mLDCM,0℃下加入氯乙磺酰氯(219.9mg,1.36mmol)和无水三乙胺(171.4mg,1.70mmol)反应24h后,减压脱溶,用乙酸乙酯(50mL)溶解,加入30mL2NHCl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(DCM/MeOH,50:1),得到相应的乙烯磺酸酯衍生物。
通过合成得到的3,4-二(4-羟基-苯基)呋喃化合物7或3-(4-羟基苯基)-4-辛二酸单酰苯胺基-呋喃化合物13和乙烯磺酸酯衍生物溶解在四氢呋喃中,在90℃反应3小时一步制备得含有辛二酸单酰苯胺基团的氧桥双环-[2.2.1]-庚烯类化合物,该化合物再和盐酸羟肟反应得到含有N-羟基-N’-苯基辛二酰胺(SAHA)基团的氧桥双庚烯类化合物,反应式如下面i、ii所示:
其中,
R为
具体实施方式
实施例1:5,6-二(4-羟基)-7-氧桥双环-[2.2.1]-5-庚烯-2-磺酸-4-(7-苯胺基甲酰基庚酸甲酯)-酯(1)的制备
称取3,4-二(4-羟基-苯基)呋喃(200mg,0.793mmol)和乙烯磺酸-4-(7-苯胺基甲酰基庚酸甲酯)-酯(351.4mg,0.952mmol)置于50mL的两口瓶圆底瓶然后缓慢升温至90℃,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413.6mg白色的固体,产率90.1%。1HNMR(400MHz,Acetone-d6)δ7.53(d,J=9.2Hz,2H),7.12(m,6H),6.74(d,J=8.4Hz,2H),6.66(d,J=8.8Hz,2H),5.57(s,1H),5.34(d,J=4.0Hz,1H),4.09(m,2H),3.66(m,1H),3.60(m,3H),2.31(m,4H),1.65(m,2H),1.58(m,2H),1.34(m,4H).13CNMR(101MHz,CDCl3)δ175.98,174.63,158.91,158.77,146.51,142.52,139.02,138.02,130.33,129.73,125.13,124.40,123.69,122.25,116.81,116.56,85.82,84.18,61.58,52.03,37.86,34.73,31.63,29.95,29.89,25.87,20.93;HRMS(ESI)calcdforC33H36NO9S,622.2107(M+H+);found622.2105.
实施例2:5,6-二(4-羟基)-7-氧桥双环-[2.2.1]-5-庚烯-2-磺酸-(3-苯胺基甲酰基庚酸甲酯)-酯(2)的制备
制备方法如实施例1,产物为白色固体,产率为65.3%。1HNMR(400MHz,Acetone-d6)δ9.30(s,1H,-CONH-),8.63(s,2H,-OH),7.79(s,1H),7.60(d,J=8.0Hz,1H),7.30(d,J=8.4Hz,1H),7.22(m,4H),6.95(d,J=8.4Hz,1H),6.83(m,4H),5.64(s,1H),5.45(d,J=4.0Hz,1H),3.83(m,1H),3.60(s,-OMe),2.45(m,1H),2.40(t,J=7.6Hz,2H),2.30(m,3H),1.65(m,2H),1.55(m,2H),1.35(m,4H).13CNMR(101MHz,Acetone-d6)δ174.18,172.38,158.36,158.32,150.65,142.32,141.86,137.98,130.71,129.96,129.62,125.03,124.30,118.33,117.35,116.57,116.42,113.89,85.20,83.71,61.79,51.53,37.62,34.27,31.54,29.57,29.32,25.92,25.51;HRMS(ESI)calcdforC33H36NO9S,622.2128(M+H+);found622.2105.
实施例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-(4-甲氧基苯基)-酯(3)的制备
制备方法如实施例1,产物为淡黄色粉末,产率为67.6%。1HNMR(400MHz,MeO-d4)δ7.54(t,J=8.4Hz,2H),7.24(d,J=8.4Hz,2H),7.16(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,1H),7.06(d,J=9.6Hz,1H),6.80(m,4H),5.61(s,1H),5.39(t,J=4.8Hz,1H),3.73(s,3H,-OMe),3.62(m,1H),2.38(m,3H),2.26(t,J=7.2Hz,2H),2.19(m,1H),1.69(m,2H),1.61(m,2H),1.38(m,4H).13CNMR(101MHz,MeO-d4)δ174.75,174.72,159.84,159.29,159.05,144.03,142.00,139.93,137.48,130.65,129.93,129.39,128.68,124.28,123.86,121.45,121.17,116.96,116.71,115.85,115.82,85.85,84.16,61.28,56.20,38.22,35.86,31.65,30.08,27.15,26.80;HRMS(ESI)calcdforC33H36NO9S,622.2101(M+H+);found622.2105.
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-(2-萘基)-酯(4)的制备
制备方法如实施例1,产物为黄色粉末,产率为81.7%。1HNMR(400MHz,MeOH-d4)δ7.85(m,2H),7.69(t,J=9.2Hz,1H),7.59(d,J=8.8Hz,1H),7.51(m,4H),7.34(m,1H),7.26(t,J=8.4Hz,2H),7.18(t,J=8.0Hz,1H),7.15(d,J=8.4Hz,1H),6.76(d,J=7.6Hz,1H),6.69(d,J=8.0Hz,1H),5.70(s,1H),5.39(t,J=4.0Hz,1H),3.80(m,1H),2.48(m,1H),2.40(m,2H),2.23(m,2H),1.68(t,J=7.2Hz,2H),1.60(m,2H),1.38(m,4H).13CNMR(101MHz,MeOH-d4)δ173.30,173.26,157.86,147.00,142.77,140.65,138.57,138.36,136.05,133.48,131.90,129.74,129.20,128.35,127.99,127.14,126.67,126.16,123.26,122.47,120.72,120.00,119.66,119.10,115.52,115.16,84.44,82.72,60.08,36.54,34.94,29.92,28.68,28.63,25.39,25.07;HRMS(ESI)calcdforC36H34NO8S,640.2021(M-H+);found640.2011.
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-(1-萘基)-酯(5)的制备
制备方法如实施例1,产物为黄色粉末,产率为81.4%。1HNMR(400MHz,MeOH-d4)δ7.99(m,1H),7.89(m,1H),7.79(d,J=8.0Hz,1H),7.56(m,3H),7.45(m,3H),7.33(m,3H),7.24(d,J=8.8Hz,1H),6.74(d,J=8.4Hz,1H),6.65(d,J=8.8Hz,1H),5.71(s,1H),5.35(s,1H),4.49(m,1H),2.63(m,1H),2.37(t,J=6.0Hz,2H),2.30(t,J=6.4Hz,2H),2.06(m,1H),1.69(m,2H),1.60(t,J=6.4Hz,2H),1.38(m,4H).13CNMR(101MHz,MeOH-d4)δ176.20,173.35,157.55,144.63,142.76,140.45,138.27,137.79,135.43,134.83,129.46,129.07,128.25,127.89,127.19,126.80,126.61,126.53,124.94,123.62,121.39,119.75,119.13,118.28,115.17,114.57,84.27,82.93,60.11,36.48,33.42,29.41,28.55,28.50,25.34,24.49;HRMS(ESI)calcdforC36H34NO8S,640.2023(M-H+);found640.2011.
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-氟苯基)-酯(6)的制备
制备方法如实施例1,产物为黄色粉末,产率为36.4%。1HNMR(400MHz,Acetone-d6)δ7.56(t,J=9.6Hz,2H),7.21(m,4H),7.11(t,J=8.4Hz,2H),7.05(m,2H),6.72(d,J=8.8Hz,1H),6.96(d,J=8.8Hz,1H),5.55(s,1H),5.34(t,J=3.2Hz,1H),3.71(m,1H),2.28(m,3H),2.22(t,J=7.6Hz,2H),1.95(m,1H),1.55(t,J=6.8Hz,2H),1.47(t,J=7.6Hz,2H),1.23(m,4H).13CNMR(101MHz,Acetone-d6)δ174.17,172.38,162.98,158.51,146.41,143.49,141.91,140.28,139.18,137.54,130.26,129.65,129.05,128.45,125.15,120.20,119.95,117.46,117.22,116.58,116.40,85.26,83.69,61.67,51.52,37.62,34.28,31.54,31.34,26.06,25.52;HRMS(ESI)calcdforC32H31FNO8S,608.1762(M-H+);found608.1760.
实施例7:3-(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-甲基苯基)-酯(7)的制备
制备方法如实施例1,产物为淡黄色粉末,产率为65.9%。1HNMR(400MHz,Acetone-d6)δ9.33(s,1H),7.67(t,J=8.8Hz,2H),7.31(d,J=8.4Hz,2H),7.26(t,J=8.0Hz,2H),7.16(m,4H),5.67(s,1H),5.46(t,J=3.2Hz,1H),3.80(m,1H),2.39(m,3H),2.30(s,3H),2.28(m,2H),1.69(m,2H),1.60(t,J=6.4Hz,2H),1.37(m,4H).13CNMR(101MHz,Acetone-d6)δ175.04,172.49,158.60,158.41,148.45,143.48,141.82,139.34,137.83,131.21,130.20,129.61,129.07,128.43,124.68,123.88,122.58,120.40,116.64,116.45,85.29,83.63,61.21,37.79,34.34,31.53,31.34,29.65,26.27,25.62,20.69;HRMS(ESI)calcdforC33H34NO8S,604.2015(M-H+);found604.2011.
实施例8:3-(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-(4-三氟甲基苯基)-酯(8)的制备
制备方法如实施例1,产物为黄色粉末,产率为45.9%。1HNMR(400MHz,Acetone-d6)δ9.35(s,1H),7.78(d,J=8.0Hz,2H),7.66(m,2H),7.53(t,J=7.6Hz,1H),7.45(d,J=8.8Hz,1H),7.33(t,J=8.8Hz,2H),7.26(t,J=7.6Hz,2H),6.87(m,2H),5.75(s,1H),5.53(t,J=3.2Hz,1H),4.00(m,1H),2.49(m,1H),2.46(t,J=6.8Hz,2H),2.31(t,J=7.6Hz,2H),2.06(m,1H),1.71(t,J=6.4Hz,2H),1.61(t,J=6.8Hz,2H),1.38(m,4H).13CNMR(101MHz,Acetone-d6)δ175.37,172.74,158.60,153.09,143.62,141.97,140.19,139.17,137.44,130.56,130.27,129.54,129.04,128.51,128.23,126.22,124.59,124.01,120.46,120.28,116.70,116.55,85.26,83.76,62.13,37.76,34.26,31.56,29.66,26.18,25.53,20.68;HRMS(ESI)calcdforC33H31FNO8S,658.1753(M-H+);found658.1728.
实施例9:5,6-二(4-羟基)-7-氧桥双环-[2.2.1]-5-庚烯-2-磺酸-(N-羟基-N’-苯基辛二酸酐)-酯(9)的制备
称取5,6-二(4-羟基)-7-氧桥双环-[2.2.1]-5-庚烯-2-磺酸-(7-苯胺基甲酰基庚酸)-酯(100mg,0.16mmol)置于50mL圆底瓶然中,加入KOH(18.4mg,0.32mmol)和25mL甲醇,冰浴下搅拌10min。另去50mL的圆底瓶,加入盐酸羟肟(220mg,3.2mmol),KOH(184mg,3.2mmol)和15mL甲醇,40℃下搅拌15min后冷却至室温,过滤,上滤液倒入上述的反应液中,室温反应3个小时后,用10%HCl调节Ph6,用乙酸乙酯萃取(3×30mL),合并有机层,无水硫酸钠干燥,柱层析分离,洗脱剂比例为二氯甲烷:甲醇=10:1,得到70.9mg白色的固体,产率为71.2%。1HNMR(400MHz,MeOH-d4)δ7.54(d,J=8.8Hz,2H),7.16(m,6H),6.75(d,J=8.4Hz,2H),6.70(d,J=8.4Hz,2H),5.58(s,1H),5.38(d,J=3.6Hz,1H),3.64(m,1H),2.37(m,3H),2.18(m,1H),2.08(t,J=7.6Hz,2H),1.66(m,2H),1.62(m,2H),1.37(m,4H).13CNMR(101MHz,MeOH-d4)δ173.21,171.91,158.12,157.51,145.09,141.02,137.57,136.36,130.70,128.85,128.19,123.43,122.19,120.81,115.59,115.56,115.26,115.23,84.40,82.72,60.09,36.36,32.24,30.18,28.45,28.37,25.19,25.16;HRMS(ESI)calcdforC32H34NNaO9S,645.1897(M+H+);found645.1877.
实施例10:5,6-二(4-羟基)-7-氧桥双环-[2.2.1]-5-庚烯-2-磺酸-(7-苯胺基甲酰基庚酸)-酯(10)的制备
称取5,6-二(4-羟基)-7-氧桥双环-[2.2.1]-5-庚烯-2-磺酸-(7-苯胺基甲酰基庚酸甲酯)-酯(60mg,0.097mmol)置于50mL圆底瓶然中,加入20%的NaOH水溶液,回流反应3个小时后用乙酸乙酯萃取(3×20mL),合并有机层,无水硫酸钠干燥,柱层析分离,洗脱剂比例为二氯甲烷:甲醇=40:1,得到40.6mg白色的固体,产率为68.9%。1HNMR(400MHz,Acetone-d6)δ7.55(d,J=8.8Hz,2H),7.17(m,6H),6.77(d,J=8.0Hz,2H),6.72(d,J=8.4Hz,2H),5.59(s,1H),5.38(d,J=4.4Hz,1H),3.67(m,1H),2.41(m,3H),2.26(m,2H),2.16(m,1H),1.69(m,2H),1.61(m,2H),1.40(m,4H).13CNMR(101MHz,CDCl3)δ176.28,173.23,157.47,157.32,145.09,141.11,137.57,136.59,128.85,128.24,123,68,122.95,122.18,120.84,115.35,115.09,84.39,82.73,60.15,36.4,33.47,30.17,28.54,28.48,25.22,24.50;HRMS(ESI)calcdforC32H34NO9S,608.1953(M+H+);found608.1949.
实施例11:5,6-二(4-羟基)-7-氧桥双环-[2.2.1]-5-庚烯-2-磺酸-(3-苯胺基甲酰基庚酸)-酯(11)的制备
制备方法如实施例10,产物为白色固体,产率为55.96%。1HNMR(400MHz,Acetone-d6)δ9.30(s,1H,-CONH-),7.79(s,1H),7.57(d,J=8.0Hz,1H),7.30(d,J=8.4Hz,1H),7.25(m,4H),6.97(d,J=8.0Hz,1H),6.81(m,4H),5.64(s,1H),5.44(d,J=4.0Hz,1H),3.85(m,1H),2.44(m,1H),2.42(t,J=7.6Hz,2H),2.28(m,3H),1.71(m,2H),1.61(m,2H),1.39(m,4H).13CNMR(101MHz,Acetone-d6)δ174.72,172.32,158.36,158.32,150.66,142.35,141.90,137.99,130.69,129.95,129.61,125.04,124.30,118.28,117.30,116.56,116.40,113.85,85.19,83.70,61.77,37.62,34.12,31.54,29.63,29.57,25.94,25.50;HRMS(ESI)calcdforC32H34NO9S,608.1958(M+H+);found608.1949.
实施例12:3-(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-(苯基)-酯(12)的制备
制备方法如实施例1,产物为黄色的油状物,产率为64.8%。1HNMR(400MHz,Acetone-d6)δ9.42(s,1H,-CONH-),7.68(t,J=8.8Hz,2H),7.41(m,1H),6.86(d,J=8.4Hz,7H),6.83(d,J=8.4Hz,1H),5.69(s,1H),5.46(t,J=3.2Hz,1H),3.60(s,1H),3.34(s,1H),2.42(m,2H),2.27(m,2H),1.69(m,2H),1.59(m,2H),1.37(m,4H).13CNMR(101MHz,Acetone-d6)δ174.40,172.61,158.84158.60,150.53,141.85,139.25,137.47,131.04,130.13,129.66,129.03,128.41,128.13,124.52,123.17,123.15,120.34,120.13,116.83,116.47,85.28,83.81,61.63,51.84,37.69,34.33,31.43,31.33,26.17,25.53;HRMS(ESI)calcdforC32H32NO8S,590.1862(M-H+);found590.1854.
实施例13:3-(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-甲氧基苯基)-酯(13)的制备
制备方法如实施例1,产物为淡黄色粉末,产率为70.6%。1HNMR(400MHz,Acetone-d6)δ9.36(s,1H),7.69(t,J=8.0Hz,2H),7.32(t,J=8.0Hz,2H),7.28(m,3H),6.88(m,5H),5.73(s,1H),5.47(t,J=3.6Hz,1H),3.89(m,1H),3.75(s,3H,-OMe),2.49(m,1H),2.42(t,J=7.2Hz,2H),2.33(t,J=7.6Hz,2H),2.07(m,1H),1.71(m,2H),1.62(m,2H),1.37(m,4H).13CNMR(101MHz,Acetone-d6)δ175.65,172.99,161.72,158.63,151.32,143.67,141.95,139.31,137.51,131.25,130.27,129.74,129.04,125.52,124.68,123.85,120.47,116.73,116.56,114.98,113.72,109.09,85.26,83.69,61.25,56.12,37.81,34.33,29.68,29.59,26.24,25.55,20.68;HRMS(ESI)calcdforC33H34NO9S,620.1970(M-H+);found620.1960.
实施例14:3-(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-(2-甲氧基苯基)-酯(14)的制备
制备方法如实施例1,产物为淡黄色粉末,产率为68.6%。1HNMR(400MHz,Acetone-d6)δ9.31(s,1H),7.67(t,J=8.0Hz,2H),7.33(m,6H),7.11(d,J=8.0Hz,1H),6.98(t,J=8.0Hz,1H),6.82(t,J=8.0Hz,2H),5.69(s,1H),5.44(t,J=3.2Hz,1H),3.74(m,1H),3.71(s,3H,-OMe),2.51(m,1H),2.41(t,J=7.6Hz,2H),2.31(t,J=7.6Hz,2H),2.07(m,1H),1.71(t,J=6.8Hz,2H),1.61(t,J=6.8Hz,2H),1.37(m,4H).13CNMR(101MHz,Acetone-d6)δ175.03,172.51,158.62,158.56,152.72,143.73,142.14,139.31,137.69,130.12,139.78,128.95,128.88,128.56,124.74,124.70,121.61,120.35,120.17,116.68,116.53,114.15,85.32,83.66,62.60,56.25,37.72,34.23,31.72,30.70,29.76,26.14,25.54;HRMS(ESI)calcdforC33H34NO9S,620.1985(M-H+);found620.1960.
实施例15:3-(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-甲基苯基)-酯(15)的制备
制备方法如实施例1,产物为淡黄色粉末,产率为76.8%。1HNMR(400MHz,MeOH-d4)δ7.52(d,J=8.4Hz,2H),7.27(m,4H),7.18(d,J=8.4Hz,2H),7.06(t,J=8.4Hz,1H),6.93(m,1H),6.76(t,J=8.4Hz,2H),5.65(s,1H),5.38(t,J=4.4Hz,1H),3.85(m,1H),3.62(d,J=11.2Hz,3H),2.48(m,1H),2.36(t,J=7.2Hz,2H),2.25(m,3H),1.71(t,J=6.8Hz,2H),1.61(t,J=6.8Hz,2H),1.39(m,4H).13CNMR(101MHz,MeOH-d4)δ173.98,173.36,157.52,151.79,142.47,140.42,142.90,138.38,136.23,128.89,128.56,127.88,127.65,127.34,123.51,120.44,119.99,119.75,115.41,115.21,112.91,112.88,84.31,82.72,61.37,54.90,36.51,34.99,30.35,28.59,28.37,25.32,25.06;HRMS(ESI)calcdforC33H34NO8S,604.2012(M-H+);found606.2011.
实施例16:3-(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-(2-甲基苯基)-酯(16)的制备
制备方法如实施例1,产物为淡黄色粉末,产率为74.6%。1HNMR(400MHz,Acetone-d6)δ9.32(s,1H),7.68(t,J=8.0Hz,2H),7.35(m,6H),7.26(m,2H),6.82(t,J=8.4Hz,2H),5.72(s,1H),5.50(t,J=3.6Hz,1H),3.91(m,1H),2.56(m,1H),2.41(t,J=7.2Hz,2H),2.32(d,J=2.8Hz,3H),2.29(t,J=7.2Hz,2H),2.06(m,1H),1.71(t,J=6.8Hz,2H),1.58(t,J=6.8Hz,2H),1.38(m,4H).13CNMR(101MHz,Acetone-d6)δ175.58,172.51,158.66,148.88,143.62,141.99,140.23,139.32,137.63,132.64,130.17,129.79,128.93,128.56,128.09,127.88,124.68,123.94,123.08,120.35,116.69,116.53,85.31,83.26,62.43,37.74,34.26,31.62,30.16,29.66,26.16,25.55,16.92;HRMS(ESI)calcdforC33H35NO8S,606.2174(M+H+);found606.2156.
实施例17:3-(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-羟基苯基)-酯(17)的制备
制备方法如实施例1,产物为黄色粉末,产率为47.9%。1HNMR(400MHz,Acetone-d6)δ9.36(s,1H),7.65(t,J=8.4Hz,2H),7.33(t,J=8.8Hz,2H),7.28(t,J=8.4Hz,2H),7.11(t,J=9.2Hz,2H),6.85(d,J=8.8Hz,1H),6.84(m,3H),5.69(s,1H),5.46(s,1H),3.81(m,1H),2.40(m,3H),2.30(t,J=7.2Hz,3H),1.70(t,J=6.4Hz,2H),1.61(t,J=6.4Hz,2H),1.37(m,4H).13CNMR(101MHz,Acetone-d6)δ175.44,172.91,158.58,157.08,143.57,143.00,141.87,139.91,139.37,137.57,130.37,129.68,129.13,128.46,124.71,124.23,120.29,116.95,116.68,116.49,85.32,83.68,61.14,37.74,34.27,31.53,30.80,29.67,26.20,25.53;HRMS(ESI)calcdforC32H32NO9S,606.1796(M-H+);found606.1803.
实施例18:3-(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-羟基苯基)-酯(18)的制备
制备方法如实施例1,产物为黄色粉末,产率为47.9%。1HNMR(400MHz,Acetone-d6)δ9.38(s,1H),7.67(t,J=8.4Hz,2H),7.33(d,J=8.8Hz,2H),7.24(d,J=8.4Hz,2H),7.19(m,1H),6.87(t,J=8.0Hz,4H),6.75(t,J=8.4Hz,1H),5.71(s,1H),5.46(t,J=3.6Hz,1H),3.88(m,1H),2.49(m,1H),2.46(t,J=7.2Hz,2H),2.29(t,J=7.2Hz,2H),2.08(m,1H),1.72(t,J=6.8Hz,2H),1.61(t,J=6.8Hz,2H),1.37(m,4H).13CNMR(101MHz,Acetone-d6)δ175.80,173.23,159.49,158.61,151.28,143.69,141.90,139.90,139.38,137.56,131.25,130.20,129.79,128.97,128.57,124.62,123.86,120.51,116.74,115.23,113.78,110.47,85.25,83.69,61.52,37.81,34.35,31.60,29.65,26.25,25.54,20.84;HRMS(ESI)calcdforC32H32NO9S,606.1805(M-H+);found606.1803.
实施例19:3-(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-(2-羟基苯基)-酯(19)的制备
制备方法如实施例1,产物为黄色粉末,产率为55.7%。1HNMR(400MHz,Acetone-d6)δ9.36(s,1H),7.65(d,J=8.8Hz,2H),7.32(m,5H),7.13(t,J=8.4Hz,1H),7.03(d,J=8.0Hz,1H),6.88(m,3H),5.76(s,1H),5.48(t,J=4.0Hz,1H),4.02(m,1H),2.51(m,1H),2.40(t,J=7.6Hz,2H),2.31(t,J=7.2Hz,2H),2.24(m,1H),1.71(t,J=6.8Hz,2H),1.61(t,J=6.8Hz,2H),1.37(m,4H).13CNMR(101MHz,Acetone-d6)δ175.56,173.04,158.55,150.15,143.67,141.90,139.91,139.38,138.26,137.60,130.03,129.88,128.86,128.66,124.81,124.59,123.96,120.87,118.45,116.66,116.57,85.79,83.75,62.55,37.77,34.30,31.71,29.48,26.22,25.53,20.76;HRMS(ESI)calcdforC32H32NO9S,606.1804(M-H+);found606.1803.
实施例20:3-(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-(3-三氟甲基苯基)-酯(20)的制备
制备方法如实施例1,产物为黄色粉末,产率为50.9%。1HNMR(400MHz,Acetone-d6)δ7.68(d,J=8.0Hz,2H),7.60(t,J=7.6Hz,2H),7.52(d,J=8.4Hz,2H),7.40(m,1H),7.19(m,2H),7.14(m,2H),6.70(d,J=8.4Hz,2H),5.63(s,1H),5.38(t,J=3.6Hz,1H),3.91(m,1H),2.41(m,1H),2.26(m,3H),2.16(t,J=7.6Hz,2H),1.57(t,J=6.8Hz,2H),1.49(t,J=7.2Hz,2H),1.23(m,4H).13CNMR(101MHz,Acetone-d6)δ175.12,172.52,158.54,147.63,143.74,142.19,140.20,139.20,137.44,135.13,131.68,129.88,128.73,128.62,127.83,124.52,123.74,120.17,116.54,85.08,83.70,63.14,37.68,34.19,31.20,30.13,26.14,25.51,20.59;HRMS(ESI)calcdforC33H31FNO8S,658.1738(M-H+);found658.1728.
实施例21:3-(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-氯苯基)-酯(21)的制备
制备方法如实施例1,产物为黄色粉末,产率为71.2%。1HNMR(400MHz,Acetone-d6)δ9.32(s,1H),7.65(t,J=9.2Hz,2H),7.42(d,J=9.6Hz,2H),7.35(m,4H),7.25(d,J=7.6Hz,2H),6.86(d,J=8.0Hz,1H),6.82(d,J=8.8Hz,1H),5.70(s,1H),5.52(t,J=3.2Hz,1H),3.94(m,1H),2.39(m,3H),2.31(t,J=7.6Hz,2H),2.09(m,1H),1.69(m,2H),1.54(t,J=7.2Hz,2H),1.38(m,4H).13CNMR(101MHz,Acetone-d6)δ175.13,172.52,158.47,149.10,143.53,141.95,140.03,139.18,137.49,133.03,130.78,130.29,129.69,129.07,128.48,124.92,120.32,120.11,116.62,85.21,83.67,61.96,37.70,34.20,31.56,31.53,26.15,25.52,20.63;HRMS(ESI)calcdforC32H31ClNO8S,624.1490(M-H+);found624.1464.
实施例22:3-(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-溴苯基)-酯(22)的制备
制备方法如实施例1,产物为黄色粉末,产率为68.3%。1HNMR(400MHz,Acetone-d6)δ9.32(s,1H),7.67(t,J=9.2Hz,2H),7.57(d,J=8.4Hz,2H),7.32(t,J=8.0Hz,2H),7.26(m,4H),6.86(d,J=8.8Hz,1H),6.82(d,J=8.8Hz,1H),5.69(s,1H),5.47(t,J=2.8Hz,1H),3.86(m,1H),2.45(m,3H),2.31(t,J=7.2Hz,2H),2.06(m,1H),1.70(m,2H),1.60(t,J=6.8Hz,2H),1.37(m,4H).13CNMR(101MHz,Acetone-d6)δ175.13,172.42,158.61,149.67,143.50,141.96,139.16,137.50,133.83,130.27,129.67,129.07,128.47,125.29,124.55,123.95,120.81,120.24,120.01,116.60,116.42,85.21,83.70,61.87,37.67,34.18,31.55,31.35,29.65,26.13,25.52;HRMS(ESI)calcdforC32H31BrNO8S,668.0981(M-H+);found668.0959.
实施例23:3-(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-(2,6-二甲基苯基)-酯(23)的制备
制备方法如实施例1,产物为白色粉末,产率为76.7%。1HNMR(400MHz,Acetone-d6)δ9.33(s,1H),7.69(t,J=8.0Hz,2H),7.38(d,J=8.8Hz,1H),7.34(d,J=9.2Hz,1H),7.30(t,J=8.4Hz,2H),7.10(m,3H),6.86(t,J=8.4Hz,2H),5.81(s,1H),5.51(t,J=3.6Hz,1H),4.01(m,1H),2.64(m,1H),2.44(t,J=7.6Hz,2H),2.34(s,3H),2.31(s,3H),2.29(t,J=7.2Hz,2H),2.04(m,1H),1.69(m,2H),1.61(t,J=6.0Hz,2H),1.37(m,4H).13CNMR(101MHz,Acetone-d6)δ175.30,172.57,158.88,147.45,143.68,142.04,140.23,139.37,137.68,133.25,130.18,129.80,128.71,128.56,127.71,124.70,123.97,120.34,120.21,116.69,116.54,85.44,83.79,62.91,37.74,34.28,31.71,31.49,29.66,26.16,25.54,17.90,17.88;HRMS(ESI)calcdforC34H36NO8S,618.2176(M-H+);found618.2167.
实施例24:3-(4-羟基苯基)-4-(N-羟基-N’-苯基辛二酰胺)-7-氧桥双环-[2.2.1]-5-庚烯-2-磺酸-(2-萘基)-酯(24)的制备
制备方法如实施例3,产物为红棕色油状物,产率为26.9%。1HNMR(400MHz,Acetone-d6)δ9.80(s,1H),7.93(d,J=8.4Hz,2H),7.71(m,4H),7.52(d,J=8.8Hz,2H),7.42(d,J=8.8Hz,1H),7.31(d,J=7.2Hz,1H),7.26(m,3H),6.87(m,2H),5.75(s,1H),5.47(s,1H),3.97(m,1H),3.18(m,1H),2.44(m,4H),2.15(m,1H),1.65(m,4H),1.31(m,4H).13CNMR(101MHz,Acetone-d6)δ172.84,171.62,158.96,148.11,143.54,141.91,139.20,137.44,134.50,132.84,131.01,130.29,129.53,129.11,128.81,128.69,128.33,127.99,127.41,124.49,123.67,122.25,120.45,120.42,116.83,116.59,85.29,83.67,61.54,46.94,37.64,33.29,31.59,31.35,26.11,9.10;HRMS(ESI)calcdforC36H36ClN2O8S,691.1919(M+Cl+);found691.1886.
实施例24:N-羟基-N’-苯基辛二酰胺基团或其类似结构的的氧桥双环-[2.2.1]-庚烯类化合物的抗肿瘤活性实验
MCF-7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100μl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:1×10-7M,1×10-6M,1×10-5M,5×10- 5M,1×10-4M。药物处理培养3至5天后,取出培养板,每孔加入20μl5mg/mLMTT工作液,置于37℃、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100μL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490nm处波长为主波长,630nm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的氧桥双环-[2.2.1]-庚烯类化合物体外实验表明,化合物1-8对MCF-7细胞的抑制活性强于同类型的其它化合物,其抑制活性见表1。
表1本发明合成的代表性目标化合物1-8的MCF-7细胞抑制活性结果
Compounds | Effect on the growth of MCF-7cells(IC50[μM]) |
1 | 25.5 |
2 | 19.5 |
3 | 20.8 |
4 | 21.4 |
5 | 8.8 |
6 | 45.4 |
7 | 41.6 |
8 | 31.119 --> |
TAM | 19.0 |
上述实验结果表明:合成的化合物大多数都具有很好抗乳腺癌活性,例如化合物7(IC50=8.8μM)的抗乳腺癌活性是上市药物他莫昔芬的2倍。
Claims (5)
1.一种含有N-羟基-N’-苯基辛二酰胺基或其类似结构的氧桥双环-[2.2.1]-庚烯类化合物,结构式如下:
其中,
R1为Me、OH或NHOH;
R2为 或
2.根据权利要求1所述的化合物,其特征在于,其为
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-甲氧基苯基)-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-(2-萘基)-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-(1-萘基)-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-氟苯基)-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-甲基苯基)-酯或
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-(4-三氟甲基苯基)-酯。
3.权利要求1所述的氧桥双环-[2.2.1]-庚烯类化合物在制备抗乳腺癌药物中的应用。
4.根据权利要求3所述的应用,其特征在于,所述氧桥双环-[2.2.1]-庚烯类化合物为:
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-甲氧基苯基)-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-(2-萘基)-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-(1-萘基)-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-氟苯基)-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-甲基苯基)-酯或
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-(4-三氟甲基苯基)-酯。
5.一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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