CN115505019A - 7-酰胺取代雌甾类化合物及其制备方法和应用 - Google Patents
7-酰胺取代雌甾类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种7‑酰胺取代雌甾类化合物，化学结构式如下：
其中R选自
Description
技术领域
本发明涉及抗肿瘤药物技术领域，更具体地说，本发明涉及一种7-酰胺取代雌甾类化合物及其制备方法和应用。
背景技术
乳腺癌是女性中最常见的癌症，也是全世界女性与癌症相关的死亡的第二大常见原因。全世界每年大约诊断出一百万新病例。ER阳性的早期乳腺癌通常通过手术治疗，相比之下，处于乳腺癌晚期的乳腺癌通常与转移到远处的器官相关，因此通常不再需要手术治疗(Hortobagyi G N.Treatment of breast cancer.N.Engl.J.Med.1998,339(14):974～984.)，而是选择选择性雌激素受体调节剂、芳香化酶抑制剂(AIs)、选择性雌激素受体下调剂等内分泌治疗方法(Sainsbury R.The development of endocrine therapy for womenwith breast cancer.Cancer Treat.Rev.,2013,39(5):507～517.)。
根据最近的研究，ERα雌激素受体参与晚期疾病并促进了AI抵抗性肿瘤的发病机制(McDonnell D P,Wardell S E,Norris J D.Oral selective estrogen receptordownregulators(SERDs),a breakthrough endocrine therapy for breastcancer.J.Med.Chem.,2015,58(12):4883～4887.)。乳腺癌中ERα作用的观点导致了氟维司群的发展，这是唯一批准的靶向蛋白酶体降解受体的SERD(Casa A J,Hochbaum D,Sreekumar S,et al.The estrogen receptor alpha nuclear localization sequenceis critical for fulvestrant-induced degradation of thereceptor.Mol.Cell.Endocrinol.,2015,415:76～86.)。然而，氟维司群的效果较差，仍亟需进一步研究效果更优的产品。
发明内容
本发明的一个目的是解决至少上述缺陷，并提供至少后面将说明的优点。
本发明的另一个目的是提供一种具有抗肿瘤活性的7-酰胺取代雌甾类化合物，解决已有氟维司群的效果较差的问题。
本发明的另一个目的是提供一种7-酰胺取代雌甾类化合物的制备方法。
本发明的另一个目的是提供一种7-酰胺取代雌甾类化合物在制备肿瘤药物中的应用。
为了实现本发明的这些目的和其它优点，本发明提供一种7-酰胺取代雌甾类化合物，其化学结构如下式所示：
其中R选自R1＝
R2＝
R3＝
R4＝
R5＝
R6＝
R7＝
R8＝
中一种。
优选的是，所述7-酰胺取代雌甾类化合物中，所述R选自R4＝
或R5＝
或R6 
或R7＝
优选的是，所述7-酰胺取代雌甾类化合物中，所述R选自R4＝
或R7＝
7-酰胺取代雌甾类化合物的制备方法，其中，包括：
以雌二醇为起始原料，将3，17-C(即3号位，17号位C)进行MOM基团保护得到第一化合物；
接着在雌二醇6-C(即6号位C)引入羟基得到第二化合物；
接着对6-OH(即6号位-OH)进行氧化转变为羰基得到第三化合物；
然后在7-C(即7号位C)引入1，6-二碘己烷得到第四化合物；
使用Gabriel反应将卤素碘转化为氨基得到第五化合物和第六化合物；
再将不同取代的酰胺基团分别引入，再脱去3，17-C保护基团，对6号位羰基进行还原，得到7-酰胺取代雌甾类化合物。
优选的是，所述7-酰胺取代雌甾类化合物的制备方法中，所述第一化合物的结构式如下：
第二化合物的结构式如下：
第三化合物的结构式如下：
第四化合物的结构式如下：
第五化合物的结构式如下：
第六化合物的结构式如下：
优选的是，所述7-酰胺取代雌甾类化合物的制备方法中，将不同取代的酰胺基团分别引入第六化合物，得到不同的化合物7Ⅰ～7Ⅷ；
化合物7Ⅰ～7Ⅷ的结构式如下：
其中R选自R1＝
R2＝
R3＝
R4＝
R5＝
R6＝
R7＝
R8＝
中一种。
优选的是，所述7-酰胺取代雌甾类化合物的制备方法中，将化合物7Ⅰ～7Ⅷ脱去3，17-C(3号位和17号位C)保护基团得到化合物8Ⅰ～8Ⅷ；
化合物8Ⅰ-8Ⅷ的结构式如下：
其中R选自R1＝
R2＝
R3＝
R4＝
R5＝
R6＝
R7＝
R8＝
中一种。
优选的是，所述7-酰胺取代雌甾类化合物的制备方法中，将化合物8Ⅰ-8Ⅷ对6位羰基进行还原，得到化合物9Ⅰ-9Ⅷ，即为7-酰胺取代雌甾类化合物；
化合物9Ⅰ-9Ⅷ的结构式如下：
其中R选自R1＝
R2＝
R3＝
R4＝
R5＝
R6＝
R7＝
R8＝
中一种。
所述7-酰胺取代雌甾类化合物在制备抗肿瘤药物中的应用。
所述7-酰胺取代雌甾类化合物在制备抗乳腺癌药物或抗宫颈癌药物或肝癌药物中的应用，所述7-酰胺取代雌甾类化合物的具体的结构式为：
R为R7＝
所述7-酰胺取代雌甾类化合物在制备抗卵巢腺癌药物或抗乳腺管癌药物中的应用，所述7-酰胺取代雌甾类化合物的具体的结构式为：
本发明至少能达到以下有益效果：
本发明的通过体外抗肿瘤增殖活性试验表明，本发明对肿瘤细胞具有显著的抑制作用。因此，本发明7-酰胺取代雌甾类化合物可用于制备治疗肿瘤的药物，该药物可以制成注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂的形式使用，给药途径可为口服，或经皮下、静脉或肌肉注射。
本发明的7位雌二醇烷烃酰胺支链化合物对广谱的肿瘤细胞具有抑制效果，其中长链活性普遍优于短链；含有吸电子基团如Cl，F等基团的化合物相较于无电子效应基团具有更好的活性，七氟取代的化合物9Ⅶ对MCF-7、HeLa、HepG-2抑制效果最佳分别为10.4±1.02μmol/L、9.72±0.99μmol/L、8.53±0.93μmol/L；一氯取代的化合物9Ⅳ对SKOV-3、T47D抑制效果最佳，分别9.89±0.99μmol/L、1.85±0.27μmol/L，化合物9Ⅳ、9Ⅶ对肿瘤细胞抑制活性均优于阳性对照氟维司群。
本发明的其它优点、目标和特征将部分通过下面的说明体现，部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
具体实施方式
下面结合实施例对本发明做进一步的详细说明，以令本领域技术人员参照说明书文字能够据以实施。
应当理解，本文所使用的诸如“具有”、“包含”以及“包括”术语并不排除一个或多个其它元件或其组合的存在或添加。
需要说明的是，下述实施方案中所述实验方法，如无特殊说明，均为常规方法，所述试剂和材料，如无特殊说明，均可从商业途径获得。
本发明的7-酰胺取代雌甾类化合物的反应路线如下：
实施例1
制备第1化合物3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯
向100mL圆底烧瓶加入2.00g(7.2mmol)雌二醇溶于30mL无水四氢呋喃溶液中，加入6.72mL(14.4mmol)N,N-二异丙基乙胺(DIEPA),搅拌溶解，再加入2.56g(14.4mmol)溴甲基甲基醚，加热至54℃搅拌反应2h，薄层色谱(TLC)监测反应终点，待反应完成后，减压蒸馏旋干溶剂，乙酸乙酯(30mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V石油醚：V乙酸乙酯＝15:1)]，得到白色油状物，得到无色油状物2.48g，产率95.8％。1H NMR(400MHz,CDCl3)δ7.70(d,J＝2.8Hz,1H),7.35(d,J＝8.6Hz,1H),7.21(dd,J＝8.6,2.9Hz,1H),5.20(s,2H),4.69-4.63(m,2H),3.63(t,J＝8.4Hz,1H),3.47(s,3H),3.38(s,3H),2.74(dd,J＝16.9,3.4Hz,1H),2.48(td,J＝11.2,4.6Hz,1H),2.37(dt,J＝13.5,3.6Hz,1H),2.21(dd,J＝16.9,13.4Hz,1H),2.15-2.02(m,2H),1.99-1.88(m,1H),1.76-1.54(m,4H),1.47-1.23(m,4H),0.82(s,3H).
实施例2
制备第2化合物3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-6-醇
向250mL三颈烧瓶加入22mL 1M叔丁醇钾的四氢呋喃溶液，降低温度至-78℃，加入11mL 2M叔丁醇钾的N,N-二异丙基乙胺(DIEPA)溶液,搅拌30min，再加入2g(5.5mmol)化合物1，-78℃下反应3h，加入硼酸三甲酯10mL，转0℃下反应2h，加入30％H2O2室温反应1h，最后于0℃加入10％Na2S2O3反应1h，TLC监测反应终点，待反应完成后，减压蒸馏，旋干溶剂，乙酸乙酯(30mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V石油醚：V乙酸乙酯＝2:1)]，得到白色固态1.87g，产率90.4％。1H NMR(400MHz,CDCl3)δ7.20(d,J＝8.6Hz,1H),6.82(dd,J＝8.5,2.7Hz,1H),6.77(d,J＝2.7Hz,1H),5.14(s,2H),4.69-4.63(m,2H),3.61(t,J＝8.4Hz,1H),3.47(s,3H),3.37(s,3H),2.88-2.81(m,2H),2.33-2.14(m,2H),2.12-1.95(m,2H),1.92-1.83(m,1H),1.73-1.14(m,8H),0.81(s,3H).
实施例3
制备第3化合物3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-6-酮向100mL圆底烧瓶加入1.00g(2.6mmol)化合物2溶于50mL苯溶液中，加入1:1混合的5.6046g PCC-硅藻土粉末，于80℃下搅拌反应6h，TLC监测反应终点，待反应完成后，过滤，减压蒸馏，旋干溶剂，乙酸乙酯(30mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V石油醚：V乙酸乙酯＝6:1)]，得到黄绿色油状物0.81g，产率83.7％。1H NMR(400MHz,CDCl3)δ7.68(d,J＝2.8Hz,1H),7.33(d,J＝8.6Hz,1H),7.19(dd,J＝8.6,2.9Hz,1H),5.20(s,2H),4.70-4.61(m,2H),3.65(t,J＝8.5Hz,1H),3.48(s,3H),3.37(s,3H),3.18(t,J＝7.0Hz,2H),2.77-2.64(m,1H),2.46(dt,J＝11.7,3.3Hz,1H),2.37(dq,J＝11.7,3.6Hz,1H),2.14-1.96(m,2H),1.84-1.75(m,2H),1.66-1.11(m,4H),0.81(s,3H).
实施例4
制备第4化合物3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(6-碘己基)-6-酮向100mL圆底烧瓶加入13mL 1M叔丁醇钾的四氢呋喃溶液，氩气保护下冰浴加入2.4131g(6.45mmol)化合物3，搅拌30min，降低温度至-40℃，加入6.5384g(19.35mmol)1,6-二碘己烷溶液，搅拌30min，转0℃下反应3h，TLC监测反应终点，待反应完成后，减压蒸馏，旋干溶剂，乙酸乙酯(30mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V石油醚：V乙酸乙酯＝20:1)]，得到白色油状物1.73g，产率45.9％。1H NMR(400MHz,CDCl3)δ7.67(d,J＝2.8Hz,1H),7.35-7.31(m,1H),7.19(dd,J＝8.6,2.9Hz,1H),5.20(s,2H),4.68-4.63(m,2H),3.65(t,J＝8.4Hz,1H),3.47(s,3H),3.37(s,3H),3.15(t,J＝7.0Hz,2H),2.71(td,J＝11.2,4.5Hz,1H),2.46(dt,J＝11.6,3.2Hz,1H),2.37(dt,J＝13.1,3.6Hz,1H),2.15-2.04(m,2H),2.04-1.98(m,1H),1.78(p,J＝7.0Hz,2H),1.68-1.17(m,14H),0.81(s,3H).13C NMR(100MHz,CDCl3)δ200.51,155.73,139.64,132.28,127.18,122.31,114.0,96.04,94.42,86.30,56.12,55.18,48.52,45.23,42.94,42.27,37.38,36.99,33.38,30.26,28.48,27.89,27.00,26.59,23.52,22.27,11.53,7.17.
实施例5
制备第5化合物3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(1H-异吲哚-1,3(2H)-二酮,6-己基)-6-酮
向100mL圆底烧瓶依次加入1.6030g(2.74mmol)化合物4，1.5244g(8.23mmol)邻苯二甲酰胺亚胺钾盐，0.1000g(0.82mmol)4-二甲氨基吡啶，溶于20mL N,N-二甲基甲酰胺溶液中，于110℃下搅拌反应过夜，待反应完成后，乙酸乙酯(30mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V石油醚：V乙酸乙酯＝6:1)]，得到白色油状物1004.5mg，产率60.6％。1H NMR(400MHz,CDCl3)δ7.82(dq,J＝5.1,2.8Hz,2H),7.70(ddd,J＝5.4,3.5,2.0Hz,2H),7.66(t,J＝2.4Hz,1H),7.32(dd,J＝8.7,2.7Hz,1H),7.19(dt,J＝8.6,2.5Hz,1H),5.21-5.17(m,2H),4.65(q,J＝2.2Hz,2H),3.68-3.61(m,3H),3.47(s,3H),3.37(s,3H),2.69(td,J＝11.4,5.8Hz,1H),2.44(dd,J＝11.4,3.2Hz,1H),2.40-2.32(m,1H),2.15-2.04(m,2H),2.01(dt,J＝13.4,2.8Hz,1H),1.69-1.18(m,16H),0.80(s,3H).13C NMR(100MHz,CDCl3)δ200.63,168.41,155.71,139.68,133.83,132.31,132.16,127.16,123.14,122.29,114.09,96.06,94.44,86.36,56.12,55.19,48.60,45.23,42.94,42.29,37.94,37.39,37.01,29.27,28.54,27.88,27.16,26.71,26.59,23.63,22.24,11.52.
实施例6
制备第6化合物3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(6-己胺)-6-酮
向100mL圆底烧瓶加入0.697g(1.06mmol)化合物5，9mL水合肼(80％溶液)，14.4mLN,N-二甲基甲酰胺溶液，14.4mL无水乙醇,于90℃下搅拌回流4h，冷却至室温加入14.4mL5％ NaOH溶液，搅拌30min后处理反应，用二氯甲烷(20mL×3)萃取，水(20mL×3)，饱和食盐水20mL依次洗涤，粗产物柱层析分离(洗脱剂V二氯甲烷：V甲醇＝6:1)，得到黄色油状物0.29g，产率为70.8％。1H NMR(400MHz,CDCl3)δ7.63(d,J＝2.9Hz,1H),7.32(d,J＝8.7Hz,1H),7.19(dd,J＝8.6,2.9Hz,1H),5.22-5.16(m,2H),4.69-4.62(m,2H),3.65(t,J＝8.4Hz,1H),3.47(s,3H),3.37(s,3H),2.97(t,J＝7.7Hz,2H),2.69(td,J＝11.2,4.5Hz,1H),2.43(dt,J＝11.6,3.2Hz,1H),2.39-2.33(m,1H),2.09(ddd,J＝14.7,10.7,5.0Hz,2H),2.01(dt,J＝15.1,3.2Hz,1H),1.73(p,J＝8.0,7.6Hz,2H),1.64-1.13(m,15H),0.80(s,3H).13C NMR(100MHz,CDCl3)δ200.97,155.73,139.82,132.16,127.24,122.46,114.02,96.08,94.43,86.39,56.14,55.20,48.52,45.18,42.95,42.30,39.98,37.34,29.70,28.92,27.89,27.42,27.03,26.59,26.42,23.59,22.26,11.53.HREIMS calcd.for C28H44NO5[M+H+]474.3214,found 474.3216.
实施例7
制备第7Ⅰ化合物N-(3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-丙酰胺，结构式为：
取0.400g(0.85mmol)化合物6，溶于10mL二氯甲烷，加入0.5mL三乙胺，再加入93μL丙酰氯，于室温下搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V二氯甲烷：V甲醇＝20:1)]，得到黄色油状物210.3mg，产率46.7％。1H NMR(400MHz,CDCl3)δ7.67(d,J＝2.8Hz,1H),7.33(d,J＝8.7Hz,1H),7.20(dd,J＝8.6,2.8Hz,1H),5.57(s,1H),5.20(d,J＝0.9Hz,2H),4.69-4.63(m,2H),3.65(t,J＝8.5Hz,1H),3.48(s,3H),3.38(s,3H),3.20(td,J＝7.1,5.7Hz,2H),2.70(td,J＝11.3,4.5Hz,1H),2.45(dt,J＝11.6,3.3Hz,1H),2.42-2.34(m,1H),2.18(q,J＝7.6Hz,2H),2.12-2.06(m,1H),2.04-1.98(m,1H),1.66-1.23(m,17H),1.14(t,J＝7.6Hz,3H),0.81(s,3H).13C NMR(100MHz,CDCl3)δ200.79,173.75,155.72,139.75,132.28,127.22,122.37,114.05,96.07,94.44,86.34,56.14,55.20,48.59,45.23,42.94,42.29,39.40,37.39,37.00,29.76,29.48,29.24,27.88,27.16,26.77,26.58,23.62,22.24,11.52,9.95.HREIMS calcd.for C31H48NO6[M+H+]530.3476,found 530.3483.
制备第7Ⅱ化合物N-(3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-己酰胺
制备第7Ⅲ化合物N-(3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-壬酰胺
取0.320g(0.68mmol)化合物6，溶于10mL二氯甲烷，加入0.5mL三乙胺，再加入147μL壬酰氯，于室温下搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V二氯甲烷：V甲醇＝20:1)]，得到黄色油状物396.1mg，产率95.59％。1H NMR(400MHz,CDCl3)δ7.67(d,J＝2.9Hz,1H),7.33(dd,J＝8.7,1.0Hz,1H),7.20(dd,J＝8.6,2.9Hz,1H),5.44(d,J＝5.7Hz,1H),5.22-5.18(m,2H),4.69-4.63(m,2H),3.65(t,J＝8.5Hz,1H),3.48(s,3H),3.38(s,3H),3.20(td,J＝7.2,5.7Hz,2H),2.70(td,J＝11.2,4.6Hz,1H),2.45(dt,J＝11.6,3.3Hz,1H),2.37(dt,J＝11.3,3.7Hz,1H),2.17-2.11(m,2H),2.11-2.04(m,2H),2.01(dt,J＝12.5,3.2Hz,1H),1.75(s,1H),1.65-1.14(m,27H),0.90-0.84(m,3H),0.81(s,3H).13C NMR(100MHz,CDCl3)δ200.74,173.08,155.74,139.74,132.31,127.22,122.35,114.08,96.08,94.46,86.35,56.16,55.22,48.59,45.25,42.95,42.30,39.37,37.40,37.01,36.94,31.83,29.52,29.33,29.26,29.16,27.89,27.17,26.79,26.59,25.84,23.63,22.65,22.25,14.10,11.53.HREIMS calcd.for C37H59NO6[M+H+]614.4415,found 614.4421.
制备第7Ⅳ化合物N-(3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-2-氯乙酰胺
取0.400g(0.85mmol)化合物6，溶于10mL二氯甲烷，加入0.5mL三乙胺，再加入81μL氯乙酰氯，于室温下搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V二氯甲烷：V甲醇＝20:1)]，得到黄色油状物273.1mg，产率58.5％。1H NMR(400MHz,CDCl3)δ7.60(d,J＝2.8Hz,1H),7.26(d,J＝8.6Hz,1H),7.12(dd,J＝8.5,2.9Hz,1H),6.53(d,J＝6.7Hz,1H),5.13(s,2H),4.61-4.55(m,2H),3.96(s,2H),3.58(t,J＝8.5Hz,1H),3.41(s,3H),3.30(s,3H),3.20(td,J＝7.2,5.9Hz,2H),2.63(td,J＝11.3,4.6Hz,1H),2.38(dt,J＝11.5,3.3Hz,1H),2.30(dt,J＝11.4,3.6Hz,1H),2.08-1.97(m,2H),1.94(dt,J＝12.6,3.2Hz,1H),1.59-1.08(m,16H),0.73(s,3H).13C NMR(100MHz,CDCl3)δ200.69,165.76,155.73,139.72,132.28,127.21,122.36,114.07,96.06,94.44,86.33,56.14,55.20,48.57,45.23,42.94,42.69,42.27,39.80,37.39,37.00,29.22,29.18,27.88,27.14,26.69,26.58,23.61,22.25,11.52.HREIMS calcd.for C30H45ClNO6[M+H+]550.2930,found 550.2937.
制备第7Ⅴ化合物N-(3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-4-氯丁酰胺
取0.400g(0.85mmol)化合物6，溶于10mL二氯甲烷，加入0.5mL三乙胺，再加入114μL 4-氯丁酰氯，于室温下搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V二氯甲烷：V甲醇＝20:1)]，得到黄色油状物276.5mg，产率56.2％。1H NMR(400MHz,CDCl3)δ7.67(d,J＝2.8Hz,1H),7.33(dd,J＝8.8,0.9Hz,1H),7.20(dd,J＝8.6,2.9Hz,1H),5.64(t,J＝5.7Hz,1H),5.20(d,J＝1.0Hz,2H),4.69-4.62(m,2H),3.65(t,J＝8.5Hz,1H),3.60(t,J＝6.2Hz,2H),3.48(s,3H),3.38(s,3H),3.21(td,J＝7.1,5.7Hz,2H),2.70(td,J＝11.3,4.6Hz,1H),2.45(dt,J＝11.6,3.3Hz,1H),2.34(t,J＝7.1Hz,2H),2.14-2.07(m,4H),2.01(dt,J＝12.5,3.1Hz,1H),1.68-1.23(m,17H),0.81(s,3H).13C NMR(100MHz,CDCl3)δ200.78,171.57,155.73,139.75,132.29,127.23,122.38,114.06,96.07,94.45,86.34,56.16,55.21,48.58,45.24,44.59,42.95,42.29,39.47,37.40,37.00,33.28,29.42,29.20,28.20,27.89,27.15,26.74,26.58,23.60,22.25,11.52.HREIMS calcd.forC32H49ClNO6[M+H+]578.3243,found 578.3248.
制备第7Ⅵ化合物N-(3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-4-氯丁酰胺
取0.320g(0.68mmol)化合物6，溶于10mL二氯甲烷，加入0.5mL三乙胺，再加入110μL 4,4,4-三氟丁酰氯，于室温下搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V二氯甲烷：V甲醇＝20:1)]，得到黄色油状物347.4mg，产率85.3％。1H NMR(400MHz,CDCl3)δ7.66(d,J＝2.8Hz,1H),7.33(dd,J＝8.8,0.9Hz,1H),7.20(dd,J＝8.6,2.9Hz,1H),5.70(t,J＝5.6Hz,1H),5.23-5.17(m,2H),4.69-4.63(m,2H),3.65(t,J＝8.5Hz,1H),3.48(s,3H),3.38(s,3H),3.22(td,J＝7.2,5.8Hz,2H),2.70(td,J＝11.3,4.6Hz,1H),2.55-2.34(m,6H),2.16-2.06(m,2H),2.01(dt,J＝12.5,3.1Hz,1H),1.82(s,1H),1.67-1.13(m,15H),0.81(s,3H).13C NMR(100MHz,CDCl3)δ200.81,169.59,155.74,139.77,132.28,127.24,122.40,114.04,96.07,94.45,86.33,56.14,55.21,48.55,45.24,42.95,42.29,39.66,37.40,37.00,29.81,29.51,29.29,29.12,28.83,27.88,27.10,26.70,26.58,23.58,22.24,11.51.HREIMS calcd.for C32H47F3NO6[M+H+]596.3350,found 598.3355.
制备第7Ⅶ化合物N-(3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-七氟丁酰胺
取0.435g(0.94mmol)化合物6，溶于10mL二氯甲烷，加入0.5mL三乙胺，再加入178μL 七氟丁酰氯，于室温下搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V二氯甲烷：V甲醇＝20:1)]，得到黄色油状物253.4mg，产率35.1％。1H NMR(400MHz,CDCl3)δ7.66(d,J＝2.8Hz,1H),7.34(d,J＝8.7Hz,1H),7.20(dd,J＝8.6,2.9Hz,1H),6.63(t,J＝6.1Hz,1H),5.24-5.17(m,2H),4.69-4.62(m,2H),3.65(t,J＝8.5Hz,1H),3.48(s,3H),3.38(s,3H),3.37-3.32(m,2H),2.70(td,J＝11.3,4.6Hz,1H),2.46(dt,J＝11.7,3.3Hz,1H),2.42-2.34(m,1H),2.17-2.04(m,2H),2.01(dt,J＝12.7,3.2Hz,1H),1.66-1.50(m,6H),1.44-1.10(m,10H),0.81(s,3H).13C NMR(100MHz,CDCl3)δ200.85,155.73,139.77,132.24,127.25,122.44,114.03,96.06,94.43,86.33,56.14,55.20,48.52,45.22,42.94,42.27,40.09,37.39,36.99,28.98,28.72,27.86,27.02,26.57,26.43,23.54,22.23,11.51.HREIMS calcd.for C32H43NO6F7[M+H+]670.2979,found 670.2982.
制备第7Ⅷ化合物N-(3,17-二(甲氧基甲基醚)-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-4-烯戊酰胺
取0.435g(0.94mmol)化合物6，溶于10mL二氯甲烷，加入0.5mL三乙胺，再加入151μL 4-戊烯酰氯，于室温下搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V二氯甲烷：V甲醇＝20:1)]，得到黄色油状物419.2mg，产率79.8％。1H NMR(400MHz,CDCl3)δ7.67(d,J＝2.8Hz,1H),7.33(d,J＝8.7Hz,1H),7.20(dd,J＝8.6,2.9Hz,1H),5.88-5.76(m,1H),5.61(t,J＝5.7Hz,1H),5.20(s,2H),5.10-4.96(m,2H),4.70-4.63(m,2H),3.65(t,J＝8.5Hz,1H),3.48(s,3H),3.38(s,3H),3.20(q,J＝6.7Hz,2H),2.70(td,J＝11.3,4.6Hz,1H),2.45(dt,J＝11.7,3.3Hz,1H),2.42-2.34(m,3H),2.25(dd,J＝8.7,6.7Hz,2H),2.15-2.04(m,1H),2.04-1.98(m,1H),1.66-1.11(m,17H),0.81(s,3H).13C NMR(100MHz,CDCl3)δ200.78,172.22,155.72,139.74,137.16,132.28,127.23,122.36,115.51,114.05,96.07,94.44,86.34,56.15,55.21,48.59,45.23,42.94,42.29,39.40,37.39,36.99,35.92,29.69,29.45,29.23,27.88,27.17,26.76,26.58,23.62,22.25,11.52.HREIMS calcd.forC33H50NO6[M+H+]556.3638,found 556.3639.
实施例8
制备第8Ⅰ化合物N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-丙酰胺
其中
取0.210g(0.40mmol)化合物7Ⅰ，溶于10mL四氢呋喃，加入10mL 6mol/L HCl，于室温下搅拌，TLC监测反应终点，待反应完成后，加碳酸氢钠淬灭，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝1:3)]，得到黄色油状物113.2mg，产率64.5％。1H NMR(400MHz,CD3OD)δ7.33(d,J＝2.8Hz,1H),7.30(d,J＝8.6Hz,1H),7.00(dd,J＝8.5,2.9Hz,1H),3.70(t,J＝8.6Hz,1H),3.12(t,J＝7.1Hz,2H),2.68(td,J＝11.2,4.5Hz,1H),2.39(ddt,J＝15.0,11.8,3.7Hz,2H),2.17(q,J＝7.7Hz,2H),2.10-1.98(m,2H),1.95(dt,J＝12.4,3.2Hz,1H),1.70-1.18(m,19H),1.10(t,J＝7.6Hz,3H),0.76(s,3H).13C NMR(100MHz,CD3OD)δ202.22,175.58,155.79,137.59,131.83,127.12,121.28,112.41,80.80,48.69,44.98,42.99,42.86,38.89,37.31,36.34,29.13,28.91,28.84,26.96,26.47,26.43,23.27,21.80,10.08,9.25.HREIMS calcd.forC30H46NO4[M+H+]442.2952,found 442.2957.
制备第8Ⅱ化合物N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-己酰胺
其中R＝R2＝
取0.336g(0.59mmol)化合物7Ⅱ，溶于10mL四氢呋喃，加入10mL 6mol/L HCl，于室温下搅拌，TLC监测反应终点，待反应完成后，加碳酸氢钠淬灭，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝1:3)]，得到黄色油状物232.2mg，产率81.4％。1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),7.69(t,J＝5.6Hz,1H),7.30(d,J＝8.6Hz,1H),7.24(d,J＝2.8Hz,1H),6.98(dd,J＝8.5,2.9Hz,1H),4.56(d,J＝4.8Hz,1H),3.57(td,J＝8.5,4.8Hz,1H),2.98(q,J＝6.5Hz,2H),2.60(td,J＝11.0,4.3Hz,1H),2.35(dd,J＝12.4,3.6Hz,1H),2.26(dt,J＝12.0,3.3Hz,1H),2.01(t,J＝7.4Hz,2H),1.91(dtd,J＝14.7,7.6,3.4Hz,2H),1.85-1.79(m,1H),1.52-1.04(m,22H),0.84(t,J＝7.1Hz,3H),0.66(s,3H).13C NMR(100MHz,DMSO-d6)δ200.56,172.34,156.23,137.24,132.10,127.87,121.70,112.74,80.29,48.67,45.06,43.27,42.70,38.74,37.31,36.73,35.85,31.34,30.17,29.57,29.11,27.34,26.79,25.48,23.52,22.33,22.28,14.33,11.45.HREIMS calcd.for C30H46NO4[M+H+]484.3427,found 484.3428.
制备第8Ⅲ化合物N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-壬酰胺
其中R＝R3＝
取0.396g(0.65mmol)化合物7Ⅲ，溶于10mL四氢呋喃，加入10mL 6mol/L HCl，于室温下搅拌，TLC监测反应终点，待反应完成后，加碳酸氢钠淬灭，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝1:3)]，得到黄色油状物274.5mg，产率80.0％。1H NMR(400MHz,CD3OD)δ7.34(d,J＝2.8Hz,1H),7.29(d,J＝8.6Hz,1H),7.00(dd,J＝8.5,2.9Hz,1H),3.70(t,J＝8.5Hz,1H),3.12(t,J＝7.0Hz,2H),2.67(td,J＝11.2,4.5Hz,1H),2.38(ddd,J＝15.0,12.8,3.7Hz,2H),2.15(t,J＝7.5Hz,2H),2.10-2.02(m,1H),1.95(dt,J＝13.0,3.0Hz,1H),1.69-1.15(m,32H),0.88(s,3H),0.76(s,3H).13C NMR(100MHz,CD3OD)δ202.09,174.80,155.81,137.54,131.84,127.10,121.27,112.47,80.80,48.68,44.99,42.99,42.85,38.87,37.30,36.35,35.77,31.61,29.15,29.02,28.95,28.89,27.01,26.50,25.73,23.30,22.34,21.83,13.10,10.11.HREIMS calcd.for C33H52NO4[M+H+]526.3891,found 526.3898.
制备第8Ⅳ化合物N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-2-氯乙酰胺
其中R＝R4＝
取0.230g(0.42mmol)化合物7Ⅳ，溶于10mL四氢呋喃，加入10mL 6mol/L HCl，于室温下搅拌，TLC监测反应终点，待反应完成后，加碳酸氢钠淬灭，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝1:3)]，得到黄色油状物165.2mg，产率85.2％。1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.15(t,J＝5.7Hz,1H),7.30(d,J＝8.5Hz,1H),7.24(d,J＝2.8Hz,1H),6.98(dd,J＝8.5,2.9Hz,1H),5.76(s,1H),4.55(d,J＝4.8Hz,1H),4.01(s,2H),3.57(td,J＝8.5,4.8Hz,1H),3.04(q,J＝6.6Hz,2H),2.61(td,J＝11.0,4.4Hz,1H),2.40-2.32(m,1H),2.27(dt,J＝11.7,3.3Hz,1H),1.91(ddq,J＝12.6,8.6,4.0Hz,2H),1.85-1.79(m,1H),1.42-1.08(m,15H),0.66(s,3H).13C NMR(100MHz,DMSO-d6)δ200.60,166.14,156.22,137.27,132.11,127.91,121.71,112.72,80.28,55.37,48.67,45.04,43.27,43.14,42.69,37.30,36.73,30.17,29.25,29.05,27.29,26.78,26.68,23.52,22.28,11.47.HREIMS calcd.for C26H37ClNO4[M+H+]462.2406,found 462.2411.
制备第8Ⅴ化合物N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-4-氯丁酰胺
其中R＝R5＝
取0.314g(0.54mmol)化合物7Ⅴ，溶于10mL四氢呋喃，加入10mL 6mol/L HCl，于室温下搅拌，TLC监测反应终点，待反应完成后，加碳酸氢钠淬灭，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝1:3)]，得到黄色油状物175.3mg，产率66.7％。1H NMR(400MHz,CD3OD)δ7.34-7.28(m,2H,1-CH),7.00(dd,J＝8.5,3.0Hz,1H),3.70(t,J＝8.6Hz,1H),3.57(t,J＝6.5Hz,2H),3.14(q,J＝7.4,6.8Hz,2H),2.69(td,J＝11.2,4.4Hz,1H),2.47-2.37(m,2H),2.33(t,J＝7.3Hz,2H),2.10-2.02(m,2H),1.96(dt,J＝12.6,3.2Hz,1H),1.73 -1.17(m,22H),0.77(s,3H).13CNMR(100MHz,CD3OD)δ202.20,173.30,155.79,137.60,131.84,127.12,121.27,112.41,80.80,48.72,44.98,43.69,42.99,42.87,38.91,37.31,36.35,32.67,29.13,28.86,28.83,28.51,26.98,26.47,26.43,23.26,21.80,10.08.HREIMS calcd.for C28H41ClNO4[M+H+]490.2719,found 490.2719.
制备第8Ⅵ化合物N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-4，4,4-三氟丁酰胺
取0.347g(0.57mmol)化合物7Ⅵ，溶于10mL四氢呋喃，加入10mL 6mol/L HCl，于室温下搅拌，TLC监测反应终点，待反应完成后，加碳酸氢钠淬灭，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝1:3)]，得到黄色油状物268.9mg，产率91.4％。1H NMR(400MHz,CD3OD)δ7.33(d,J＝2.8Hz,1H),7.30(d,J＝8.5Hz,1H),7.00(dd,J＝8.5,2.8Hz,1H),3.70(t,J＝8.6Hz,1H),3.14(t,J＝7.0Hz,2H),2.67(td,J＝11.2,4.5Hz,1H),2.52-2.40(m,5H),2.37(dt,J＝12.0,3.2Hz,1H),2.11-2.02(m,1H),1.95(dt,J＝12.6,3.1Hz,1H),1.70-1.14(m,20H),0.76(s,3H).13CNMR(100MHz,CD3OD)δ202.18,171.18,155.81,137.57,131.83,127.11,121.28,112.43,80.80,48.68,44.97,42.98,42.85,39.06,37.29,36.34,29.32,29.13,29.02,28.83,28.80,27.91,26.96,26.47,26.42,23.27,21.79,10.08.HREIMS calcd.for C29H30F3NO4[M+H+]510.2826,found 510.2832.
制备第8Ⅶ化合物N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-七氟丁酰胺
其中R＝R7＝
取0.2234g(0.38mmol)化合物7Ⅶ，溶于10mL四氢呋喃，加入10mL 6mol/L HCl，于室温下搅拌，TLC监测反应终点，待反应完成后，加碳酸氢钠淬灭，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝1:3)]，得到黄色油状物218.3mg，产率97.4％。1H NMR(400MHz,CD3OD)δ7.33(d,J＝2.8Hz,1H),7.31(d,J＝8.5Hz,1H),7.00(dd,J＝8.6,2.9Hz,1H),3.70(t,J＝8.6Hz,1H),3.26(t,J＝7.1Hz,2H),2.69(td,J＝11.2,4.5Hz,1H),2.37(dt,J＝11.7,3.3Hz,1H),2.10-2.00(m,2H),1.96(dt,J＝15.6,3.6Hz,1H),1.72-1.12(m,20H),0.77(s,3H).13C NMR(100MHz,CD3OD)δ202.23,155.80,137.59,131.80,127.11,121.28,112.38,80.79,48.68,44.96,42.98,42.85,39.46,37.30,36.33,29.10,28.68,28.31,26.90,26.46,26.17,23.22,21.77,10.05.HREIMS calcd.for C28H35NO4F7[M+H+]582.2454,found 582.2457.
制备第8Ⅷ化合物N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基)-6-酮)-4-戊烯酰胺
取0.410g(0.69mmol)化合物7Ⅷ，溶于10mL四氢呋喃，加入10mL 6mol/L HCl，于室温下搅拌，TLC监测反应终点，待反应完成后，加碳酸氢钠淬灭，二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝1:3)]，得到黄色油状物193.3mg，产率62.9％。1H NMR(400MHz,CD3OD)δ7.34(d,J＝2.8Hz,1H),7.28(d,J＝8.6Hz,1H),6.99(dd,J＝8.5,2.9Hz,1H),5.87-5.74(m,1H),5.08-4.93(m,2H),3.70(t,J＝8.5Hz,1H),3.12(t,J＝7.0Hz,2H),2.64(td,J＝11.2,4.4Hz,1H),2.43-2.20(m,5H),2.10-1.92(m,2H),1.68-1.13(m,21H),0.75(s,3H).13C NMR(100MHz,CD3OD)δ202.09,173.85,155.81,137.54,136.85,131.82,127.14,121.29,114.50,112.48,80.79,48.67,44.97,42.99,42.82,38.90,37.26,36.33,35.09,29.68,29.15,28.93,28.86,27.01,26.49,23.29,21.82,10.14.HREIMS calcd.for C29H42NO4[M+H+]468.3114,found468.3113.
实施例9-各7-酰胺取代雌甾类化合物的合成
(一)N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基))-丙酰胺(9Ⅰ)的合成
取0.100g(0.23mmol)化合物8Ⅰ，溶于10mL干燥二氯甲烷，于氩气保护0℃下，依次滴加735μL三乙基硅烷，2.8mL三氟化硼乙醚，转室温搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，20mL碳酸钾淬灭，过滤除去固体，滤液用二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝2:1)]，得到白色油状物78.7mg，产率78.3％。1H NMR(400MHz,CD3OD)δ7.06(d,J＝8.5Hz,1H),6.54(dd,J＝8.4,2.7Hz,1H),6.46(d,J＝2.6Hz,1H),3.66(t,J＝8.6Hz,1H),3.12(t,J＝7.1Hz,2H),2.81(dd,J＝16.7,5.3Hz,1H),2.67(dd,J＝16.9,1.7Hz,1H),2.34-2.21(m,2H),2.16(q,J＝7.6Hz,2H),2.05(td,J＝9.8,5.5Hz,1H),1.91(dt,J＝12.5,3.1Hz,1H),1.76-1.69(m,1H),1.63-1.16(m,20H),1.10(t,J＝7.6Hz,3H),0.77(s,3H).13C NMR(100MHz,CD3OD)δ175.55,154.61,136.21,130.42,126.51,115.58,112.58,81.20,46.41,43.15,42.30,38.99,38.24,36.88,34.39,33.29,29.37,29.33,29.02,28.86,27.80,27.27,26.65,25.20,22.28,10.40,9.29.HREIMS calcd.for C27H42NO3[M+H+]428.3159,found 428.3158.
(二)N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基))-己酰胺(9Ⅱ)的合成
取0.1522g化合物8Ⅱ(0.31mmol)，溶于10mL干燥二氯甲烷，于氩气保护0℃下，依次滴加1.0mL三乙基硅烷，3.8mL三氟化硼乙醚，转室温搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，20mL碳酸钾淬灭，过滤除去固体，滤液用二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝2:1)]，得到白色油状物75.6mg，产率51.6％。1H NMR(400MHz,DMSO-d6)δ9.03(s,1H),7.75(t,J＝5.5Hz,1H),7.09(d,J＝8.5Hz,1H),6.55(dd,J＝8.4,2.6Hz,1H),6.47(d,J＝2.6Hz,1H),4.55(d,J＝4.8Hz,1H),3.59(td,J＝8.4,4.8Hz,1H),3.04(q,J＝6.5Hz,2H),2.80(dd,J＝16.7,5.2Hz,1H),2.65(d,J＝16.7Hz,1H),2.34-2.18(m,2H),1.94(qd,J＝10.6,9.9,5.9Hz,1H),1.85(dt,J＝12.3,3.0Hz,1H),1.74-1.66(m,1H),1.59-1.13(m,25H),0.90(t,J＝7.1Hz,3H),0.72(s,3H).13C NMR(100MHz,DMSO-d6)δ172.36,155.44,136.42,130.08,127.07,116.24,113.33,80.60,46.48,43.43,42.24,38.78,38.25,37.26,35.87,34.63,33.26,31.35,30.35,29.63,28.09,27.56,26.99,25.59,25.51,22.76,22.35,14.33,11.75.HREIMS calcd.for C30H48NO3[M+H+]470.3629,found 470.3939.
(三)N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基))-壬酰胺(9Ⅲ)的合成
取0.241g化合物8Ⅲ(0.46mmol)，溶于10mL干燥二氯甲烷，于氩气保护0℃下，依次滴加1.5mL三乙基硅烷，5.7mL三氟化硼乙醚，转室温搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，20mL碳酸钾淬灭，过滤除去固体，滤液用二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝2:1)]，得到黄色油状物196.3mg，产率83.5％。1H NMR(400MHz,CD3OD)δ7.07(d,J＝8.5Hz,1H),6.54(dd,J＝8.4,2.7Hz,1H),6.46(d,J＝2.6Hz,1H),3.67(t,J＝8.5Hz,1H),3.13(t,J＝6.9Hz,2H),2.81(dd,J＝16.7,5.2Hz,1H),2.71-2.64(m,1H),2.34-2.22(m,2H),2.14(t,J＝7.4Hz,2H),2.05(td,J＝9.1,4.8Hz,1H),1.91(dt,J＝12.5,3.0Hz,1H),1.77-1.69(m,1H),1.65-1.16(m,32H),0.91-0.87(m,3H),0.77(s,3H).13C NMR(100MHz,CD3OD)δ174.81,154.62,136.19,130.41,126.48,115.56,112.57,81.19,46.41,43.14,42.31,38.91,38.25,36.88,35.76,34.39,33.31,31.61,29.38,29.31,29.02,28.97,28.88,27.84,27.26,26.66,25.74,25.19,22.35,22.27,13.09,10.36.HREIMS calcd.for C31H54NO3[M+H+]512.4098,found 512.4105.
(四)N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基))-2-氯乙酰胺(9Ⅳ)的合成
取0.150g(0.33mmol)化合物8Ⅳ，溶于10mL干燥二氯甲烷，于氩气保护0℃下，依次滴加1.1mL三乙基硅烷，4.1mL三氟化硼乙醚，转室温搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，20mL碳酸钾淬灭，过滤除去固体，滤液用二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝2:1)]，得到白色油状物75.6mg，产率51.5％。1H NMR(400MHz,CD3OD)δ7.07(d,J＝8.5Hz,1H),6.54(dd,J＝8.5,2.7Hz,1H),6.46(d,J＝2.6Hz,1H),3.99(s,2H),3.67(t,J＝8.6Hz,1H),3.18(t,J＝7.1Hz,2H),2.81(dd,J＝16.7,5.2Hz,1H),2.71-2.64(m,1H),2.35-2.21(m,2H),2.05(td,J＝9.0,4.7Hz,1H),1.91(dt,J＝12.5,3.0Hz,1H),1.77-1.68(m,1H),1.63-1.17(m,20H),0.77(s,3H).13C NMR(100MHz,CD3OD)δ167.77,154.59,136.22,130.44,126.50,115.56,112.57,81.20,46.40,43.14,42.30,41.81,39.41,38.24,36.88,34.38,33.28,29.31,28.80,27.75,27.26,26.53,25.17,22.26,10.37.HREIMS calcd.for C26H39ClNO3[M+H+]448.2613,found 448.2621.
(五)N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基))-4-氯丁酰胺(9Ⅴ)的合成
取0.170g(0.35mmol)化合物8Ⅴ，溶于10mL干燥二氯甲烷，于氩气保护0℃下，依次滴加1.1mL三乙基硅烷，4.3mL三氟化硼乙醚，转室温搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，20mL碳酸钾淬灭，过滤除去固体，滤液用二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝2:1)]，得到白色油状物77.8mg，产率45.7％。1H NMR(400MHz,CD3OD)δ7.95(t,J＝5.7Hz,1H),7.07(d,J＝8.4Hz,1H),6.54(dd,J＝8.5,2.7Hz,1H),6.46(d,J＝2.7Hz,1H),3.67(t,J＝8.6Hz,1H),3.56(t,J＝6.4Hz,2H),3.13(tt,J＝8.8,4.5Hz,2H),2.82(dd,J＝16.7,5.3Hz,1H),2.68(d,J＝16.6Hz,1H),2.35-2.22(m,4H),2.09-2.02(m,2H),1.91(dt,J＝12.5,3.1Hz,1H),1.74(d,J＝11.0Hz,1H),1.63-1.16(m,20H),0.77(s,3H).13C NMR(100MHz,CD3OD)δ173.38,154.60,136.23,130.45,126.49,115.54,112.55,81.20,46.40,43.67,43.14,42.31,38.95,38.25,36.88,34.38,33.31,32.68,29.33,29.30,28.94,28.51,27.79,27.25,26.59,25.17,22.25,10.34.HREIMS calcd.for C28H43ClNO3[M+H+]476.2926,found476.2927.
(六)N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基))-4,4,4-三氟丁酰胺(9Ⅵ)的合成
取0.238g(0.47mmol)化合物8Ⅵ，溶于10mL干燥二氯甲烷，于氩气保护0℃下，依次滴加1.5mL三乙基硅烷，5.8mL三氟化硼乙醚，转室温搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，20mL碳酸钾淬灭，过滤除去固体，滤液用二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝2:1)]，得到黄色油状物216.3mg，产率93.1％。1H NMR(400MHz,CD3OD)δ7.07(d,J＝8.5Hz,1H),6.54(dd,J＝8.5,2.7Hz,1H),6.46(d,J＝2.6Hz,1H),3.67(t,J＝8.6Hz,1H),3.14(t,J＝7.0Hz,2H),2.81(dd,J＝16.7,5.3Hz,1H),2.71-2.64(m,1H),2.53-2.38(m,4H),2.35-2.22(m,2H),2.05(td,J＝9.2,4.8Hz,1H),1.91(dt,J＝12.5,3.0Hz,1H),1.76-1.69(m,1H),1.65-1.15(m,20H),0.77(s,3H).13C NMR(100MHz,CD3OD)δ171.18,154.59,136.22,130.44,126.50,115.56,112.57,81.20,46.40,43.14,42.30,39.14,38.24,36.87,34.38,33.29,29.36,29.33,29.31,29.04,28.90,27.92,27.79,27.26,26.60,25.19,22.26,10.37.HREIMS calcd.for C28H41F3NO3[M+H+]496.3033,found 496.3038.
(七)N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基))-七氟丁酰胺(9Ⅶ)的合成
取0.218g(0.37mmol)化合物8Ⅶ，溶于10mL干燥二氯甲烷，于氩气保护0℃下，依次滴加1.18mL三乙基硅烷，4.6mL三氟化硼乙醚，转室温搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，20mL碳酸钾淬灭，过滤除去固体，滤液用二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝2:1)]，得到黄色油状物187.1mg，产率89.2％。1H NMR(400MHz,CD3OD)δ7.07(d,J＝8.5Hz,1H),6.54(dd,J＝8.4,2.7Hz,1H),6.46(d,J＝2.6Hz,1H),3.67(t,J＝8.5Hz,1H),3.26(t,J＝7.1Hz,2H),2.81(dd,J＝16.7,5.3Hz,1H),2.68(d,J＝16.6Hz,1H),2.34-2.21(m,2H),2.11-1.97(m,1H),1.91(dt,J＝12.4,2.9Hz,1H),1.78-1.69(m,2H),1.62-1.14(m,19H),0.77(s,3H).13C NMR(100MHz,CD3OD)δ154.58,136.20,130.43,126.51,115.56,112.57,81.20,46.38,43.14,42.28,39.56,38.22,36.86,34.36,33.28,29.28,29.24,28.41,27.77,27.26,26.40,25.17,22.25,10.38.HREIMS calcd.for C28H37NO3F7[M+H+]568.2662,found 568.2657.
(八)N-(3,17-二羟基-1,3,5(10)-雌甾三烯-7-(6-己基))-4-戊烯酰胺(9Ⅷ)的合成
取0.091g(0.18mmol)化合物8Ⅷ，溶于10mL干燥二氯甲烷，于氩气保护0℃下，依次滴加574μL三乙基硅烷，2.2mL三氟化硼乙醚，转室温搅拌，薄层色谱(TLC)监测反应终点，待反应完成后，20mL碳酸钾淬灭，过滤除去固体，滤液用二氯甲烷(20mL×3)萃取，水洗(30mL×3)，合并有机相，无水硫酸钠干燥，减压蒸馏，柱层析分析纯化[(V乙酸乙酯：V石油醚＝2:1)]，得到白色油状物62.5mg，产率77.8％。1H NMR(400MHz,CD3OD)δ7.07(d,J＝8.5Hz,1H),6.54(dd,J＝8.4,2.6Hz,1H),6.46(d,J＝2.6Hz,1H),5.87-5.75(m,1H),5.08-4.94(m,2H),3.66(t,J＝8.5Hz,1H),3.12(t,J＝7.0Hz,2H),2.81(dd,J＝16.7,5.2Hz,1H),2.68(d,J＝16.6Hz,1H),2.37-2.19(m,6H),1.91(dt,J＝12.5,3.0Hz,1H),1.77-1.68(m,1H),1.65-1.11(m,21H),0.77(s,3H).13C NMR(100MHz,CD3OD)δ173.86,154.61,136.86,136.20,130.41,126.51,115.56,114.46,112.57,81.19,46.40,43.14,42.29,38.95,38.24,36.87,35.08,34.38,33.30,29.68,29.37,29.30,29.01,27.82,27.26,26.63,25.19,22.27,10.38.HREIMS calcd.for C29H44NO3[M+H+]454.3321,found 454.3325.
对比试验
<对比例1>市售药物氟维司群
采用MTT方法，测试体外抗肿瘤活性，测定IC50(半数抑制浓度)值。将细胞以约(3～4)×104/ml的密度置于96孔板中，每孔200μL，放在5％CO2培养箱中培养24h，按照浓度梯度加入需测的样品作为试验组(分别加入本发明实施例实施例中各7-酰胺取代雌甾类化合物(9Ⅰ-9Ⅷ)以及对比例市售药物氟维司群作为试验组)，对照组为含细胞不含药物的培养基，空白组为不含细胞及药物的培养基。将接种后的96孔板移至37℃二氧化碳培养箱中培养72h，然后每孔依次加入20μL的MTT(5mg/mL),继续孵育3小时。吸取上清液，加入200μL的DHRMSO，将其置于摇床上约10min充分混匀，最后用酶标仪在波长为490nm处测定出OD值。计算各组细胞的抑制率：抑制率＝[(对照组OD-空白组OD)-(给药OD-空白组OD)]/(对照OD-空白OD)×100％(使用Graphpad Prism 8软件计算其半数存活浓度IC50值并分析统计)。IC50值见表所示。
表1：7-取代雌甾酰胺化合物的体外抗增殖活性(IC50，μM)
通过表1的体外抗肿瘤增殖活性试验表明，本发明的7-酰胺取代雌甾类化合物对多种肿瘤细胞具有显著的抑制作用，对化合物的构效关系分析的得出：
1)7位雌二醇芳香酰胺支链化合物对肿瘤细胞无抑制效果；
2)7位雌二醇烷烃酰胺支链化合物对广谱的肿瘤细胞具有抑制效果，其中长链活性普遍优于短链；
3)含有吸电子基团如Cl，F等基团的化合物相较于无电子效应基团具有更好的活性，七氟取代化合物9Ⅶ对MCF-7、HeLa、HepG-2抑制效果最佳分别为10.4±1.02μmol/L、9.72±0.99μmol/L、8.53±0.93μmol/L；一氯取代化合物9Ⅳ对T47D、SKOV-3抑制效果最佳，分别9.89±0.99μmol/L、1.85±0.27μmol/L，化合物9Ⅳ、9Ⅶ对肿瘤细胞抑制活性均显著优于阳性对照氟维司群。
尽管本发明的实施方案已公开如上，但其并不仅仅限于说明书和实施方式中所列运用。它完全可以被适用于各种适合本发明的领域。对于熟悉本领域的人员而言，可容易地实现另外的修改。
Claims (10)
1.7-酰胺取代雌甾类化合物，其特征在于，化学结构式如下：
其中R选自
中一种。
2.如权利要求1所述7-酰胺取代雌甾类化合物中，其特征在于，所述R选自
3.如权利要求1所述7-酰胺取代雌甾类化合物中，其特征在于，所述R选自
4.7-酰胺取代雌甾类化合物的制备方法，其特征在于，包括：
以雌二醇为起始原料，将3，17-C进行MOM基团保护得到第一化合物；
接着在雌二醇6-C引入羟基得到第二化合物；
接着对6-OH进行氧化转变为羰基得到第三化合物；
然后在7-C引入1，6-二碘己烷得到第四化合物；
使用Gabriel反应将卤素碘转化为氨基得到第五化合物和第六化合物；
再将不同取代的酰胺基团分别引入，再脱去3，17-C保护基团，对6号位羰基进行还原，得到7-酰胺取代雌甾类化合物。
5.如权利要求4所述7-酰胺取代雌甾类化合物的制备方法，其特征在于，所述第一化合物的结构式如下：
第二化合物的结构式如下：
第三化合物的结构式如下：
第四化合物的结构式如下：
第五化合物的结构式如下：
第六化合物的结构式如下：
6.如权利要求5所述7-酰胺取代雌甾类化合物的制备方法，其特征在于，将不同取代的酰胺基团分别引入第六化合物，得到不同的化合物7Ⅰ～7Ⅷ；
化合物7Ⅰ～7Ⅷ的结构式如下：
其中R选自
中一种。
7.如权利要求6所述7-酰胺取代雌甾类化合物的制备方法，其特征在于，将化合物7Ⅰ～7Ⅷ脱去3，17-C保护基团得到化合物8Ⅰ～8Ⅷ；
化合物8Ⅰ-8Ⅷ的结构式如下：
其中R选自
8.如权利要求7所述7-酰胺取代雌甾类化合物的制备方法，其特征在于，将化合物8Ⅰ-8Ⅷ对6位羰基进行还原，得到化合物9Ⅰ-9Ⅷ，即为7-酰胺取代雌甾类化合物；
化合物9Ⅰ-9Ⅷ的结构式如下：
其中R选自
中一种。
9.权利要求1所述7-酰胺取代雌甾类化合物在制备抗肿瘤药物中的应用。
10.权利要求1所述7-酰胺取代雌甾类化合物在制备抗乳腺癌药物或抗宫颈癌药物或肝癌药物中的应用，所述7-酰胺取代雌甾类化合物的具体的结构式为：
R为
或，所述7-酰胺取代雌甾类化合物在制备抗卵巢腺癌药物或抗乳腺管癌药物中的应用，所述7-酰胺取代雌甾类化合物的具体的结构式为：
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