CN112898260A - 3-羰基-2h-苯并吡喃类化合物或其可药用的盐、制备方法和用途 - Google Patents
3-羰基-2h-苯并吡喃类化合物或其可药用的盐、制备方法和用途 Download PDFInfo
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- CN112898260A CN112898260A CN202110085617.8A CN202110085617A CN112898260A CN 112898260 A CN112898260 A CN 112898260A CN 202110085617 A CN202110085617 A CN 202110085617A CN 112898260 A CN112898260 A CN 112898260A
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Abstract
Description
技术领域
本发明涉及药物化学,特别涉及3-羰基-2H-苯并吡喃类化合物或其可药用的盐、制备方法和用途。
背景技术
据统计,2018年全球女性确诊癌症患者中,乳腺癌的发病率位居第一位,已经严重威胁女性的身体健康。研究发现,乳腺癌与雌激素及雌激素信号通路有着异常密切的联系。在正常情况下,雌激素与雌激素受体(ER)结合后,对生殖系统的发育与维持起着至关重要的作用,如促进乳腺内皮细胞和子宫内膜细胞的生长、分化;对骨骼、心血管系统、神经系统也有一定的影响:如保持骨密度和减少骨质疏松症发生的风险,通过降低胆固醇水平来保护心血管系统,并能调节认知功能和行为。
而在病理条件下,在雌激素的作用下,乳腺细胞异常增殖,最终恶化为肿瘤细胞。ER-(+)型乳腺癌一种雌激素依赖性的多发性肿瘤,严重危害女性健康。相关研究揭示雌激素与ER结合会促进乳腺癌细胞生长。经典的ER介导信号传导通路如下:雌激素在胞浆中与ER结合后,促使ER从热休克蛋白上解离,然后雌激素与其受体形成的复合物[Estradiol(E2)-ER]构象发生变化并使受体发生同源二聚体化,这种同源二聚体复合物与靶基因上雌激素反应元件(ERE)结合,并募集相关共激活因子,启动靶基因的转录,促进乳腺癌细胞的增殖。
选择性雌激素受体调节剂(Selective Estrogen Receptor Modulators,SERMs)是具有胺乙氧基侧链,结构多样性的非甾体化合物,作为配体与雌二醇(Estradiol,E2)竞争性地结合于ER,根据作用的靶器官不同,可表现为ER激动剂或者拮抗剂。SERMs具有组织选择性,例如在骨组织和心血管系统表现为ER激动活性,具有预防骨质疏松和保护心血管系统的作用;而在乳腺组织则表现为ER拮抗剂,可用于治疗ERα+乳腺癌。SERMs的组织选择特性与多种因素有关,如不同组织中ER亚型表达量不同,SERMs与ER结合时招募的协激活因子或协抑制因子不同、诱导受体产生的构象变化不同。他莫昔芬(Tamoxifen)作为三苯乙烯的结构的SERM,首次报道于二十世纪60年代,并于1977年被FDA批准用于ER+乳腺癌的预防和治疗,随后于1989年被批准用于绝经后妇女晚期ER+乳腺癌的治疗。尽管Tamoxifen作为治疗乳腺癌一线用药并具有良好的治疗效果。但长期服用容易使患者产生原发性或者获得性耐药,同时由于其在子宫组织表现为ER激动活性,长期使用会刺激子宫内膜增生从而诱发子宫内膜癌。多种作用机制可导致肿瘤耐药的发生,例如ERα能通过非配体依赖激活途径,导致肿瘤的复发;ERα产生突变,使Tamoxifen由拮抗剂转换为激动剂,或者突变的ERα即使在没有E2存在的情况下,可以与热休克蛋白(Heat shock protein,Hsp)预先形成激动构象,最终导致耐药,而无论哪种作用机制所导致的肿瘤耐药,ERα都在其中起着具有至关重要的作用。因此,以ERα为靶标,发展新型的能下调ERα水平的药物,将能有效地治疗ERα+乳腺癌,并能克服耐药。
选择性雌激素受体降解剂(Selective Estrogen Receptor Degraders,SERDs)是一类靶向ERα的小分子,也可以称为ERα的完全拮抗剂(Pure antagonists),它们不具有组织选择性,可以完全抑制ERα活性并通过降解ERα降低其表达水平。氟维司群(Fulvestrant)作为目前唯一被批准上市的SERD,于1992年被首次报道,并于2002年被FDA批准用于绝经后妇女经抗雌激素疗法治疗无效的晚期转移性ERα+乳腺癌的治疗。Fulvestrant作为E2结构类似物,7α-位长链的引入使分子产生ERα抑制活性同时能稳定其构象,促使ERα通过体内的泛素化途径被降解,从而降低其表达水平。除Fulvestrant外,还有一些其他甾体类ERα完全拮抗剂的报道,但都未能进入临床研究,分析原因可能是因为这类分子的母核为刚性甾体结构,导致它们水溶性较差;Fulvestrant也由于水溶性差的原因无法口服给药,只能通过肌肉注射给药,并且Fulvestrant在体内的生物利用度较低,即使给药剂量已由最初批准的每月250mg增加为每月500mg,该药物在体内对ERα的降解活性仍然弱于体外研究,从而限制其在临床上进一步的应用。
发明内容
发明目的:本发明目的是提供3-羰基-2H-苯并吡喃类化合物或其可药用的盐。
本发明另一目的是提供所述3-羰基-2H-苯并吡喃类化合物或其可药用的盐的制备方法和用途。
技术方案:本发明提供一种3-羰基-2H-苯并吡喃类化合物或其可药用的盐,结构如下:
其中R2代表-H,-F,-Me,-OMe,-OSEM。
进一步地,所述的3-羰基-2H-苯并吡喃类化合物或其可药用的盐,为如下任一种:
(E)-3-(3-甲苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH01);
(E)-3-(4-甲苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH02);
(E)-3-(3-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH03);
(E)-3-(4-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH04);
(E)-3-(3-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH05);
(E)-3-(4-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH06);
(E)-3-(2-(2-三甲硅乙氧基)-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH07);
(E)-3-(3-甲基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH08);
(E)-3-(4-甲基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH09);
(E)-3-(3-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH10);
(E)-3-(4-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH11);
(E)-3-(3-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH12);
(E)-3-(4-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH13);
(E)-3-(2-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH14);
(E)-3-(2-(2-三甲硅乙氧基)-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-2H-色满烯(XH15);
(E)-3-苯甲酰基-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH16)。
所述的3-羰基-2H-苯并吡喃类化合物或其可药用的盐的制备方法,工艺如下:
路线1:
以间苯二酚1为原料,先与3-氯丙酸发生付克酰基化反应,随后分子内醚化构建出苯并吡喃酮结构2,之后与氯化苄反应得到中间体3,再进行Vilsmeier-Hacck-Arnold反应构建出关键中间体化合物4。随后中间体4与不同的芳基格氏试剂反应,产物不经纯化再通过IBX氧化得到中间体5a~g,之后与三溴化硼反应脱去苄基得到中间6a~g,再与2-(三甲基硅烷基)乙氧甲基氯反应得到中间7a~g。然后与4-羟基肉桂酸甲酯反应得到中间体8a~g,随后利用四丁基氟化铵脱去保护基得到中间体9a~g,最终通过酯水解即得;
路线2:
以2,3-二氢苯并吡喃-4-酮10为原料,首先利用Vilsmeier-Hacck-Arnold反应构建出关键中间体11,随后与不同的格氏试剂反应合成中间体12a~12i,中间体12h则是以中间体12g为原料,与三溴化硼反应脱去苄基,随后在与2-(三甲基硅烷基)乙氧甲基氯反应合成得到。中间体12a~12i与4-羟基肉桂酸甲酯反应得到中间体13a~13i,最终酯水解得到通式II所示的化合物。
一种药物组合物,其含有治疗有效量的一种或多种如权利要求1或2所述的3-羰基-2H-苯并吡喃类化合物或其可药用的盐,及药学上可接受的载体。
一种药物组合物,其含有治疗有效量的一种或多种如权利要求1或2所述的3-羰基-2H-苯并吡喃类化合物或其可药用的盐,及药学上可接受的辅料。
所述的3-羰基-2H-苯并吡喃类化合物或其可药用的盐在制备治疗或预防多种与绝经后综合症相关的医学适应症,以及治疗ER(+)乳腺癌药物方面的用途。
有益效果:本发明以SERDs分子构效关系为基础,设计并合成了一类3-羰基-2H-苯并吡喃化合物,该类起到SERDs类分子作用,在制备治疗或预防多种与绝经后综合症相关的医学适应症,以及治疗ER(+)乳腺癌药物方面的用途。
附图说明
图1为ERα抑制活性结果;
图2为ERα降解活性结果,其中,(A)fulvestrant和XH04对MCF-7细胞内ERα降解情况;(B)XH04降解条带灰度值统计。
具体实施方式
本发明化合物的结构及编号如下:
编号 | R<sub>1</sub> | R<sub>2</sub> | 编号 | R<sub>1</sub> | R<sub>2</sub> |
XH01 | -OH | 3’-Me | XH09 | -H | 4’-Me |
XH02 | -OH | 4’-Me | XH10 | -H | 3’-OMe |
XH03 | -OH | 3’-OMe | XH11 | -H | 4’-OMe |
XH04 | -OH | 4’-OMe | XH12 | -H | 3’-F |
XH05 | -OH | 3’-F | XH13 | -H | 4’-F |
XH06 | -OH | 4’-F | XH14 | -H | 2’-OMe |
XH07 | -OH | 2’-OSEM | XH15 | -H | 2’-OSEM |
XH08 | -H | 3’-Me | XH16 | -H | -H |
部分化合物的制备实施如下:
1H-NMR核磁共振由Bruker AV300型(300MHz)核磁共振仪测定(TMS为内标物),质谱分别由岛津GC/MS-QP2010型质谱仪(EI-MS)、Agilent1100LC-MSD-Trap/SL型质谱仪(ESI-MS)测定。
柱层析用硅胶为100-200目、200-300目或300-400目硅胶(青岛海洋化工厂),洗脱剂为石油醚-乙酸乙酯体系或氯仿-甲醇体系。薄层层析(TLC)用GF254薄层层析板(烟台江友硅胶开发有限公司);TLC展开体系为石油醚-乙酸乙酯系统或氯仿-甲醇系统,必要时加入少量乙酸;TLC在ZF7型三用紫外分析仪(河南巩义予华仪器有限公司)下照射显示。部分化合物纯度使用岛津HPLC在254nm下检测,流动相为甲醇/水系统。
实施例1
7-羟基-4-色满酮(2)的合成
化合物2的合成分为两步。间苯二酚(5g,45.4mmol)和3-氯丙酸(5.35g,50mmol)溶于15ml三氟甲烷磺酸中,60℃加热条件下反应2h。冷却至室温,倒入100ml二氯甲烷中,随后有机相倒入100ml水中,萃取。水相再用有机相萃取两次,合并有机相,无水硫酸钠干燥。蒸干溶剂得粗品,粗品溶于2M NaOH浓溶液中,室温反应2h。停止反应,冰浴条件下,加入浓盐酸调pH为2,抽滤得红棕色固体2(3.5g,48%)。
实施例2
7-苄氧基-4-色满酮(3)的合成
化合物2(5g,30.1mmol)溶于无水DMF(30ml)中,加入无水碳酸钾(4.41g,69mmol)和苄氯(3.85ml,33mmol),60℃条件下反应2h。停止反应,冰浴下加水稀释,抽滤得棕色固体,柱层析得白色固体3(6.5g,85%)。1H NMR(300MHz,CDCl3)δ7.87(d,J=8.8Hz,1H),7.52-7.33(m,5H),6.68(dd,J=8.8,2.4Hz,1H),6.51(d,J=2.4Hz,1H),5.11(s,2H),4.53(t,J=6.4Hz,2H),2.78(t,J=6.4Hz,2H).
实施例3
3-甲酰基-4-氯-7-苄氧基-2H-色满烯(4)的合成
冰浴条件下,将三氯氧磷(6.6ml,70.8mmol)加入到无水DMF(6.85ml,88.5mmol)中,冰浴下反应1h。随后将化合物3(3g,11.8mmol)溶于无水二氯甲烷,缓慢滴加到体系中,滴加完毕后,升至室温反应3h。停止反应,将体系置于冰浴条件下,缓慢加入冰水,蒸去二氯甲烷。加入乙酸乙酯萃取两次,合并有机相,再用饱和食盐水萃取一次,无水硫酸钠干燥。柱层析得黄色固体4(2.12g,60%)。1H NMR(300MHz,CDCl3)δ10.13(s,1H),7.64(d,J=8.8Hz,1H),7.52-7.34(m,5H),6.71(dd,J=8.7,2.5Hz,1H),6.54(d,J=2.5Hz,1H),5.11(s,2H),5.02(s,2H).
实施例4
3-(3-甲基苯甲酰基)-4-氯-7-苄氧基-2H-色满烯(5a)的合成
化合物4(0.5g,1.67mmol)溶于无水四氢呋喃(5ml)中,冰浴条件下加入3-甲基苯基溴化镁(2.2ml,1.837mmol),随后升至室温过夜反应。停止反应,将体系置于冰浴条件下,缓慢加入10%氯化铵溶液(5ml),乙酸乙酯萃取两次,合并有机相,再用饱和食盐水萃取一次,无水硫酸钠干燥。浓缩得粗品,溶于DMSO中,加入IBX(2eq),室温反应2h。随后冰浴下加水,抽滤,乙酸乙酯和水分别洗涤滤饼。萃取滤液,合并有机相,再用饱和食盐水萃取一次,无水硫酸钠干燥。柱层析得黄色固体5a(0.39g,60%)。
实施例5
3-(4-甲基苯甲酰基)-4-氯-7-苄氧基-2H-色满烯(5b)的合成
合成方法同实施例4得黄色固体5b(0.42g,65%)。1H NMR(400MHz,CDCl3)δ7.87(d,J=8.2Hz,2H),7.53(d,J=8.7Hz,1H),7.48-7.36(m,5H),7.31(d,J=7.9Hz,2H),6.69(dd,J=8.7,2.5Hz,1H),6.59(d,J=2.5Hz,1H),5.12(s,2H),5.01(s,2H),2.46(s,3H).
实施例6
3-(3-甲氧基苯甲酰基)-4-氯-7-苄氧基-2H-色满烯(5c)的合成
合成方法同实施例4得黄色固体5c(0.40g,60%)。1H NMR(300MHz,CDCB)δ7.58-7.51(m,4H),7.50-7.37(m,5H),7.21-7.14(m,1H),6.70(dt,J=8.7,2.1Hz,1H),6.60(q,J=1.9Hz,1H),5.12(d,J=2.1Hz,2H),5.02(d,J=1.8Hz,2H),3.89(d,J=2.0Hz,3H).
实施例7
3-(4-甲氧基苯甲酰基)-4-氯-7-苄氧基-2H-色满烯(5d)的合成
合成方法同实施例4得黄色固体5d(0.42g,68%)。1H NMR(400MHz,CDCl3)δ7.97(d,J=8.9Hz,2H),7.52(d,J=8.7Hz,2H),7.49-7.37(m,5H),6.99(d,J=8.9Hz,1H),6.69(dd,J=8.7,2.5Hz,1H),6.59(d,J=2.4Hz,1H),5.11(s,2H),5.00(s,2H),3.91(s,3H).
实施例8
3-(3-氟苯甲酰基)-4-氯-7-苄氧基-2H-色满烯(5e)的合成
合成方法同实施例4得黄色固体5e(0.42g,65%)。1H NMR(300MHz,CDCl3)δ7.74(dt,J=7.7,1.3Hz,1H),7.64(ddd,J=9.2,2.6,1.5Hz,1H),7.57(d,J=8.7Hz,1H),7.54-7.33(m,6H),6.73(dd,J=8.7,2.5Hz,1H),6.62(d,J=2.5Hz,1H),5.15(s,2H),5.05(s,2H).
实施例9
3-(2-甲氧基苯甲酰基)-4-氯-7-苄氧基-2H-色满烯(5f)的合成
合成方法同实施例4得黄色固体5f(0.39g,60%)。1H NMR(300MHz,CDCl3)δ7.60-7.35(m,8H),7.07(t,J=7.5Hz,1H),6.97(d,J=8.3Hz,1H),6.67(dd,J=8.8,2.5Hz,1H),6.57(d,J=2.6Hz,1H),5.11(s,2H),5.08(s,2H),3.85(s,3H).
实施例10
3-(4-氟苯甲酰基)-4-氯-7-苄氧基-2H-色满烯(5g)的合成
合成方法同实施例4得黄色固体5g(0.43g,65%)。1H NMR(400MHz,CDCl3)δ7.98(dd,J=8.8,5.4Hz,2H),7.53(d,J=8.7Hz,1H),7.48-7.35(m,5H),7.19(t,J=8.6Hz,2H),6.70(dd,J=8.7,2.5Hz,1H),6.59(d,J=2.5Hz,1H),5.12(s,2H),5.02(s,2H).
实施例11
3-(3-甲基苯甲酰基)-4-氯-7-羟基-2H-色满烯(6a)的合成
化合物5a(0.5g,1.28mmol)溶于无水二氯甲烷(7ml)中,冰浴条件下,缓慢加入1MBBr3(1.5ml,1.53mmol),冰浴下反应10min。停止反应,缓慢加入10%氯化铵溶液(10ml),二氯甲烷萃取两次,合并有机相,再用饱和食盐水萃取一次,无水硫酸钠干燥。柱层析得黄色固体6a(0.23g,60%)。1H NMR(300MHz,CDCl3)δ7.83(s,2H),7.56-7.39(m,3H),6.62-6.50(m,1H),6.47(d,J=2.4Hz,1H),4.96(s,2H),2.47(s,3H).
实施例12
3-(4-甲基苯甲酰基)-4-氯-7-羟基-2H-色满烯(6b)的合成
合成方法同实施例11得黄色固体6b(0.25g,61%)。1H NMR(300MHz,CDCl3)δ7.87(m,2H),7.53(d,J=8.7Hz,1H),7.01(d,J=7.9Hz,2H),6.53(dd,J=8.7,2.5Hz,1H),6.49(d,J=2.5Hz,1H),5.01(s,2H),2.46(s,3H).
实施例13
3-(3-甲氧基苯甲酰基)-4-氯-7-羟基-2H-色满烯(6c)的合成
合成方法同实施例11得黄色固体6c(0.25g,66%)。1H NMR(300MHz,CDCl3)δ7.59(dt,J=7.6,1.2Hz,1H),7.53-7.50(m,1H),7.48-7.39(m,2H),7.23-7.16(m,1H),6.55(dd,J=8.6,2.4Hz,1H),6.45(d,J=2.4Hz,1H),4.93(s,2H),3.89(s,3H).
实施例14
3-(4-甲氧基苯甲酰基)-4-氯-7-羟基-2H-色满烯(6d)的合成
合成方法同实施例11得黄色固体6d(0.23g,60%)。1H NMR(400MHz,CDCl3)δ8.04-7.94(m,2H),7.47(t,J=8.4Hz,1H),7.03-6.96(m,2H),6.54(dt,J=8.5,2.4Hz,1H),6.45(dd,J=6.5,2.5Hz,1H),4.94(s,2H),3.92(s,3H).
实施例15
3-(3-氟基苯甲酰基)-4-氯-7-羟基-2H-色满烯(6e)的合成
合成方法同实施例11得黄色固体6e(0.22g,58%)。1H NMR(300MHz,CDCl3)δ7.80(dt,J=7.8,1.2Hz,1H),7.69(ddd,J=9.1,2.6,1.5Hz,1H),7.58-7.47(m,2H),7.36(tdd,J=8.3,2.7,1.0Hz,1H),6.58(dd,J=8.6,2.5Hz,1H),6.48(d,J=2.4Hz,1H),4.97(s,2H).
实施例16
3-(2-羟基苯甲酰基)-4-氯-7-羟基-2H-色满烯(6f)的合成
合成方法同实施例11得黄色固体6f(0.25g,70%)。1H NMR(300MHz,CDCl3)δ11.78(s,1H),7.85(t,J=7.4Hz,1H),7.55(d,J=7.9Hz,2H),7.09(d,J=8.5Hz,1H),6.99(t,J=7.8Hz,1H),6.58(d,J=8.7Hz,1H),6.49(dd,J=4.9,2.5Hz,1H),5.66(s,1H),5.01(d,J=2.1Hz,2H).
实施例17
3-(4-氟苯甲酰基)-4-氯-7-羟基-2H-色满烯(6g)的合成
合成方法同实施例11得黄色固体6g(0.20g,55%)。1H NMR(300MHz,CDCl3)δ8.05(dd,J=8.5,5.5Hz,2H),7.48(d,J=8.5Hz,1H),7.22(t,J=8.4Hz,2H),6.62-6.54(m,1H),6.48(d,J=2.4Hz,1H),4.95(s,2H).
实施例18
3-(3-甲基苯甲酰基)-4-氯-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(7a)的合成
化合物6a(0.5g,1.6mmol)与DIPEA(0.6ml,3.2mmol)溶解于无水二氯甲烷(10ml)中,随后冰浴下缓慢加入SEMCl(0.4ml,1.76mmol),室温反应2h。停止反应,体系中加水稀释,二氯甲烷萃取两次,合并有机相,再用饱和食盐水萃取一次,无水硫酸钠干燥。柱层析得黄色油状液体7a(0.65g,90%)。1H NMR(300MHz,CDCl3)δ7.85-7.73(m,2H),7.59-7.38(m,3H),6.76(dd,J=8.7,2.4Hz,1H),6.68(t,J=2.4Hz,1H),5.28(s,2H),4.97(s,2H),3.87-3.74(m,2H),1.07-0.95(m,2H),0.06(s,9H).
实施例19
3-(4-甲基苯甲酰基)-4-氯-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(7b)的合成
合成方法同实施例18得黄色油状液体7b(0.62g,85%)。1H NMR(300MHz,CDCl3)δ7.94(d,J=7.9Hz,2H),7.53(d,J=8.6Hz,1H),7.41-7.26(m,2H),6.76(dd,J=8.8,2.3Hz,1H),6.69(t,J=2.4Hz,1H),5.29(s,2H),4.97(s,2H),3.81(t,J=8.3Hz,2H),2.49(s,2H),1.02(t,J=8.4Hz,2H),0.07(s,9H).
实施例20
3-(3-甲氧基苯甲酰基)-4-氯-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(7c)的合成
合成方法同实施例18得黄色油状液体7c(0.62g,87%)。1H NMR(300MHz,CDCl3)δ7.63-7.39(m,4H),7.23-7.17(m,1H),6.76(dd,J=8.7,2.3Hz,1H),6.68(dd,J=4.9,2.4Hz,1H),5.28(s,2H),4.97(s,2H),3.91(s,3H),3.88-3.74(m,2H),1.10-0.91(m,2H),0.06(s,9H).
实施例21
3-(4-甲氧基苯甲酰基)-4-氯-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(7d)的合成
合成方法同实施例18得黄色油状液体7d(0.62g,88%)。1H NMR(300MHz,CDCl3)δ8.07-7.90(m,2H),7.51(dd,J=8.7,6.4Hz,1H),7.00(dd,J=8.9,2.2Hz,2H),6.78-6.69(m,1H),6.66(dd,J=5.0,2.4Hz,1H),5.26(s,2H),4.94(s,2H),3.92(s,3H),3.83-3.71(m,2H),1.04-0.94(m,2H),0.04(s,9H).
实施例22
3-(3-氟苯甲酰基)-4-氯-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(7e)的合成
合成方法同实施例18得黄色油状液体7e(0.64g,90%)。1H NMR(300MHz,CDCl3)δ7.79(dt,J=7.7,1.3Hz,1H),7.68(ddd,J=9.1,2.7,1.6Hz,1H),7.55-7.48(m,2H),7.39-7.32(m,1H),6.76(dd,J=8.7,2.4Hz,1H),6.68(d,J=2.4Hz,1H),5.28(s,2H),4.97(s,2H),3.84-3.74(m,2H),1.06-0.94(m,2H),0.05(s,9H).
实施例23
3-(2-(2-三甲硅乙氧基)-甲氧基苯甲酰基)-4-氯-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(7f)的合成
合成方法同实施例18得黄色油状液体7f(0.79g,85%)。1H NMR(300MHz,CDCl3)δ7.67-7.43(m,3H),7.29-7.20(m,1H),7.16-7.07(m,1H),6.76-6.69(m,1H),6.64(dd,J=5.8,2.5Hz,4H),5.25(d,J=4.3Hz,2H),5.10(d,J=2.3Hz,2H),3.79(t,J=8.4Hz,2H),3.70(t,J=8.3Hz,2H),0.97(dt,J=23.1,8.3Hz,4H),0.05(d,J=2.3Hz,9H),-0.02(d,J=2.4Hz,9H).
实施例24
3-(4-氟苯甲酰基)-4-氯-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(7g)的合成
合成方法同实施例18得黄色油状液体7g(0.63g,88%)。1H NMR(300MHz,CDCl3)δ8.07(dd,J=8.5,5.5Hz,2H),7.54(d,J=8.6Hz,1H),7.23(t,J=8.5Hz,2H),6.78(dd,J=8.4,2.2Hz,1H),6.69(d,J=2.3Hz,1H),5.30(s,1H),4.98(s,2H),3.82(t,J=8.4Hz,2H),1.03(t,J=8.3Hz,2H),0.08(s,9H).
实施例25
(E)-3-(3-甲基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(8a)的合成
化合物7a(0.3g,0.6mmol),对羟基苯丙烯酸甲酯78(0.15g,0.66mmol)和碳酸铯(0.39g,1.2mmol)溶于乙腈中,60℃下反应2h。停止反应,冷却至室温,体系倒入水中,乙酸乙酯萃取两次,合并有机相,再用饱和食盐水萃取一次,无水硫酸钠干燥。柱层析得黄色油状液体8a(0.31g,80%)。1H NMR(300MHz,CDCl3)δ7.60(d,J=16.0Hz,1H),7.42(d,J=7.3Hz,1H),7.29-7.14(m,4H),6.75(d,J=2.3Hz,1H),6.65-6.52(m,3H),6.31(d,J=15.8Hz,1H),5.27(s,2H),5.23(s,2H),3.84(s,3H),3.78(d,J=8.4Hz,2H),2.24(s,3H),1.01(t,J=8.3Hz,2H),0.06(d,J=1.8Hz,9H).
实施例26
(E)-3-(4-甲基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(8b)的合成
合成方法同实施例25得黄色油状液体8b(0.28g,75%)。1H NMR(300MHz,CDCl3)δ7.65-7.50(m,3H),7.34-7.25(m,3H),7.21(d,J=8.7Hz,1H),7.13(d,J=7.9Hz,2H),6.74(d,J=2.3Hz,1H),6.66-6.53(m,3H),6.29(d,J=15.9Hz,1H),5.26(s,2H),5.22(s,2H),3.83(s,3H),3.78(d,J=8.4Hz,2H),2.41(s,3H),1.00(t,J=8.3Hz,2H),0.05(s,9H).
实施例27
(E)-3-(3-甲氧基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(8c)的合成
合成方法同实施例25得黄色油状液体8c(0.30g,78%)。
实施例28
(E)-3-(4-甲氧基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(8d)的合成
合成方法同实施例25得黄色油状液体8d(0.32g,83%)。1H NMR(300MHz,CDCl3)δ7.72-7.64(m,2H),7.59(d,J=15.9Hz,1H),7.28-7.20(m,2H),6.88-6.80(m,2H),6.74(d,J=2.4Hz,1H),6.67-6.57(m,2H),6.29(d,J=16.0Hz,1H),5.27(s,2H),5.21(s,2H),3.89(s,3H),3.83(s,3H),3.78(d,J=8.5Hz,2H),1.00(t,J=8.3Hz,2H),0.05(s,9H).
实施例29
(E)-3-(3-氟苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(8e)的合成
合成方法同实施例25得黄色油状液体8e(0.28g,75%)。1H NMR(300MHz,CDCl3)δ7.59(d,J=16.0Hz,1H),7.37(dt,J=7.6,1.3Hz,1H),7.29-7.11(m,5H),6.74(d,J=2.3Hz,1H),6.62(dd,J=8.7,2.4Hz,1H),6.59-6.54(m,2H),6.30(d,J=16.0Hz,1H),5.27(s,2H),5.23(s,2H),3.83(s,2H),3.80-3.74(m,1H),1.06-0.96(m,2H),0.05(s,9H).
实施例30
(E)-3-(2-(2-三甲硅乙氧基)-甲氧基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(8f)的合成
合成方法同实施例25得黄色油状液体8f(0.32g,80%)。1H NMR(300MHz,CDCl3)δ7.59(d,J=16.0Hz,1H),7.29-7.20(m,3H),7.09-6.97(m,3H),6.79-6.73(m,1H),6.70(d,J=2.3Hz,1H),6.56-6.46(m,3H),6.29(d,J=16.0Hz,1H),5.30(s,2H),5.23(s,2H),5.06(s,2H),3.82(s,3H),3.80-3.69(m,4H),0.97(dt,J=9.7,7.7Hz,4H),0.03(s,9H),0.01(s,9H).
实施例31
(E)-3-(4-氟苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-((2-三甲硅乙氧基)-甲氧基)-2H-色满烯(8g)的合成
合成方法同实施例25得黄色油状液体8g(0.27g,73%)。1H NMR(300MHz,CDCl3)δ7.68-7.55(m,3H),7.25(m,3H),7.00(t,J=8.5Hz,2H),6.74(d,J=2.3Hz,1H),6.63(dd,J=8.7,2.2Hz,1H),6.57(d,J=8.5Hz,2H),6.30(d,J=15.9Hz,1H),5.27(s,2H),5.23(s,2H),3.83(s,3H),3.77(d,J=8.5Hz,2H),1.00(t,J=8.3Hz,2H),0.05(s,9H).
实施例32
(E)-3-(3-甲基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-羟基-2H-色满烯(9a)的合成
化合物8a(0.3g,0.5mmol)溶解于四氢呋喃溶液中(6ml),加入1M TBAF溶液(6ml),80℃条件下反应4h。停止反应,体系冷却至室温,加水稀释,乙酸乙酯萃取两次,合并有机相,无水硫酸钠干燥。柱层析得黄色固体9a(0.14g,60%)。1H NMR(300MHz,CDCl3)δ7.60(d,J=15.9Hz,1H),7.44(d,7.7Hz,1H),7.28-7.09(m,5H),6.89(d,J=8.1Hz,1H),6.54(d,J=8.2Hz,3H),6.42(d,J=8.5Hz,1H),6.30(d,J=15.8Hz,1H),5.21(s,2H),3.84(d,J=2.3Hz,3H),2.23(s,3H).
实施例33
(E)-3-(4-甲基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-羟基-2H-色满烯(9b)的合成
合成方法同实施例32得黄色固体9b(0.2g,59%)。1H NMR(300MHz,DMSO-d6)δ7.53(m,5H),7.20(d,J=7.9Hz,2H),7.03(d,J=8.4Hz,1H),6.63(d,J=8.7Hz,2H),6.53-6.38(m,3H),5.13(s,2H),3.72(s,3H),2.36(s,3H).
实施例34
(E)-3-(3-甲氧基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-羟基-2H-色满烯(9c)的合成
合成方法同实施例32得黄色固体9c(0.24g,55%)。1H NMR(400MHz,CDCl3)δ7.57(d,J=16.0Hz,1H),7.26(d,J=8.8Hz,2H),7.22-7.19(m,2H),7.16(d,J=8.5Hz,1H),7.00(qd,J=4.0,1.9Hz,1H),6.96(dd,J=2.8,1.1Hz,1H),6.57-6.52(m,2H),6.51(d,J=2.4Hz,1H),6.42(dd,J=8.5,2.4Hz,1H),6.28(d,J=16.0Hz,1H),5.19(s,2H),3.81(s,3H),3.69(s,3H).
实施例35
(E)-3-(4-甲氧基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-羟基-2H-色满烯(9d)的合成
合成方法同实施例32得黄色固体9d(0.32g,60%)。1H NMR(400MHz,DMSO-d6)δ7.60(d,J=8.8Hz,2H),7.57-7.50(m,3H),7.02(d,J=8.4Hz,1H),6.92(d,J=8.9Hz,2H),6.63(d,J=8.8Hz,2H),6.46(d,J=16.1Hz,1H),6.43-6.37(m,2H),5.09(s,2H),3.81(s,3H),3.70(s,3H).
实施例36
(E)-3-(3-氟基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-羟基-2H-色满烯(9e)的合成
合成方法同实施例32得黄色固体9e(0.21g,50%)。1H NMR(300MHz,DMSO-d6)δ7.68-7.50(m,3H),7.38(q,J=5.7,4.3Hz,3H),7.26(dd,J=9.6,2.2Hz,1H),7.03(d,J=8.5Hz,1H),6.63(d,J=8.6Hz,2H),6.56-6.38(m,3H),5.17(s,2H),3.73(s,3H).
实施例37
(E)-3-(2-(2-三甲硅乙氧基)-甲氧基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-羟基-2H-色满烯(9f)的合成
合成方法同实施例32得黄色固体9f(0.18g,40%)。1H NMR(300MHz,CDCl3)δ7.59(d,J=16.0Hz,1H),7.29-7.19(m,3H),7.10-6.92(m,3H),6.76(td,J=7.4,1.0Hz,1H),6.54-6.45(m,3H),6.35(dd,J=8.6,2.4Hz,1H),6.29(d,J=16.0Hz,1H),5.28(s,2H),5.05(s,2H),3.83(s,3H),3.79-3.68(m,2H),1.04-0.89(m,2H),0.01(s,9H).
实施例38
(E)-3-(4-氟苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-7-羟基-2H-色满烯(9g)的合成
合成方法同实施例32得黄色固体9g(0.2g,45%)。1H NMR(300MHz,DMSO-d6)δ7.68-7.50(m,5H),7.19(t,J=8.7Hz,2H),7.04(d,J=8.5Hz,1H),6.66-6.57(m,2H),6.55-6.39(m,3H),5.15(s,2H),3.72(s,3H).
实施例39
(E)-3-(3-甲苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH01)的合成
化合物9a(0.15g,0.3mmol)溶于四氢呋喃(2ml)中,加入10%LiOH溶液(2ml),60℃条件下反应1 h。停止反应,体系冷却至室温,置于冰浴条件下,加稀盐酸调pH为2,柱层析得黄色固体XH01(0.07g,50%)。mp:188~190℃.1HNMR(300MHz,DMSO-d6)δ7.54-7.43(m,3H),7.38-7.20(m,4H),7.00(d,J=8.5Hz,1 H),6.64-6.56(m,2H),6.48-6.34(m,1H),5.12(s,2H),2.18(s,3H).13C NMR(75MHz,DMSO-d6)δ192.81,174.71,164.19,156.65,153.95,152.99,136.48,132.25,130.76,130.52,129.21,128.53,128.17,128.06,127.93,127.31,122.34,116.91,102.88,68.46,20.74.HRMS(ESI)for C26H20O6-H calcd 427.1187,found427.1181.
实施例40
(E)-3-(4-甲苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH02)的合成
合成方法同实施例39得黄色固体XH02(0.08g,52%)。mp:183~184℃.1H NMR(300MHz,DMSO-d6)δ7.57-7.43(m,3H),7.39-7.17(m,4H),7.00(d,J=8.5Hz,1H),6.65-6.56(m,2H),6.50-6.33(m,3H),5.12(s,2H),2.18(s,3H).13C NMR(75MHz,DMSO-d6)δ192.95,168.18,162.61,159.54,158.82,151.40,139.38,137.72,130.26,128.98,125.57,116.15,113.65,110.12,21.03.HRMS(ESI)for C26H20O6-H calcd 427.1187,found427.1180.
实施例41
(E)-3-(3-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH03)的合成
合成方法同实施例39得黄色固体XH03(0.07g,48%)。mp:139~140℃.1H NMR(400MHz,DMSO-d6)δ7.52-7.43(m,3H),7.26(t,J=7.9Hz,1H),7.13(dt,J=7.5,1.3Hz,1H),7.05(dd,J=8.0,2.6Hz,1H),7.01(d,J=8.5Hz,1H),6.93(dd,J=2.6,1.5Hz,1H),6.63-6.56(m,2H),6.45-6.31(m,3H),5.11(s,2H),3.64(s,3H).13C NMR(101MHz,DMSO-d6)δ192.51,168.15,162.69,159.57,159.31,158.88,151.71,143.47,140.80,130.24,129.59,129.01,126.79,120.88,118.57,118.31,116.06,113.46,112.76,110.46,110.19,103.60,67.09,55.58.HRMS(ESI)for C26H20O7-H calcd 443.1136,found 443.1131.
实施例42
(E)-3-(4-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH04)的合成
合成方法同实施例39得黄色固体XH04(0.1g,45%)。mp:172~174℃.1H NMR(300MHz,DMSO-d6)δ7.63(d,J=8.8Hz,2H),7.55-7.41(m,3H),7.04(d,J=8.3Hz,1H),6.97-6.90(m,2H),6.65(d,J=8.5Hz,2H),6.47-6.31(m,3H),5.11(s,2H),3.83(s,3H).13CNMR(75MHz,DMSO-d6)δ191.21,168.23,163.38,162.27,159.13,158.88,149.58,131.43,131.15,130.32,129.04,116.00,113.94,110.42,55.96.HRMS(ESI)for C26H20O7-H calcd443.1136,found 443.1130.
实施例43
(E)-3-(3-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH05)的合成
合成方法同实施例39得黄色固体XH05(0.06g,40%)。mp:128~130℃.1H NMR(300MHz,DMSO-d6)δ7.54-7.44(m,3H),7.40-7.30(m,3H),7.27-7.21(m,1H),7.02(d,J=8.5Hz,1H),6.63-6.56(m,2H),6.47-6.34(m,3H),5.15(s,2H)13C NMR(75MHz,DMSO-d6)δ191.37,162.92,159.79,158.70,152.44,143.49,141.82,130.34,129.10,126.98,124.41,119.18,118.31,115.91,113.25,110.54,109.95,103.59,66.88..HRMS(ESI)for C25H17FO6-H calcd 431.0936,found 431.0930.
实施例44
(E)-3-(4-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH06)的合成
合成方法同实施例39得黄色固体XH06(0.04g,35%)。mp:153~154℃.1H NMR(300MHz,DMSO-d6)δ7.63(t,J=6.9Hz,2H),7.56-7.44(m,3H),7.20(t,J=8.8Hz,2H),7.05(d,J=8.4Hz,1H),6.61(d,J=8.2Hz,2H),6.49-6.32(m,3H),5.16(s,2H).13C NMR(75MHz,DMSO-d6)δ191.31,168.16,162.78,159.59,158.78,151.54,135.80,131.58,130.37,129.10,115.83,113.24,110.16,68.96.HRMS(ESI)for C25H17FO6+H calcd 433.1081,found433.1080.
实施例45
(E)-3-(2-(2-三甲硅乙氧基)-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH07)的合成
合成方法同实施例39得黄色固体XH07(0.06g,53%)。mp:119~120℃.1H NMR(400MHz,DMSO-d6)δ7.44(tt,J=7.9,4.7,4.2Hz,3H),7.23(q,J=7.4Hz,1H),7.06-6.98(m,1H),6.93(d,J=6.9Hz,1H),6.88-6.81(m,1H),6.72(dq,J=7.5,4.5,2.8Hz,1H),6.54-6.45(m,2H),6.44-6.28(m,3H),5.17-5.11(s,2H),5.10-5.05(s,2H),0.01(s,9H).13C NMR(75MHz,DMSO)δ191.26,168.57,163.12,159.97,158.54,154.22,153.23,132.30,129.94,128.98,115.55,115.39,109.75,66.15,17.99,-0.96.HRMS(ESI)for C31H32O8Si-H calcd559.1793.found 559.1789.
实施例46
3-甲酰基-4-氯-2H-色满烯(11)的合成
冰浴条件下,将三氯氧磷(4.76ml,50.7mmol)加入到化合物110(5g,33.8mmol)的无水DMF溶液中,冰浴下反应0.5h。随后移至室温反应3h,TLC监测原料反应完全。将体系倒入碎冰中,搅拌至冰块全融,抽滤得黄色固体10(5.8g,90%)。1HNMR(300MHz,CDCl3)δ10.22(s,1H),7.75(dd,J=7.8,1.6Hz,1H),7.51-7.35(m,1H),7.11(td,J=7.6,1.2Hz,1H),6.96(dd,J=8.2,1.1Hz,1H),5.06(s,2H).
实施例47
3-(3-甲基苯甲酰基)-4-氯一2H-色满烯(12a)的合成
合成方法同实施例4得黄色油状液体12a(0.3g,75%)。1H NMR(300MHz,CDCl3)δ7.82(dt,J=6.3,1.9Hz,2H),7.64(dd,J=7.8,1.6Hz,1H),7.52-7.42(m,2H),7.37(td,J=7.8,1.6Hz,1H),7.10(td,J=7.6,1.2Hz,1H),6.99(dd,J=8.1,1.2Hz,1H),5.06(s,2H),2.48(s,3H).
实施例48
3-(4-甲基苯甲酰基)-4-氯-2H-色满烯(12b)的合成
合成方法同实施例4得黄色固体12b(0.2g,65%)。1H NMR(300MHz,CDCl3)δ7.93(d,J=8.3Hz,2H),7.63(dd,J=7.7,1.6Hz,1H),7.40-7.32(m,3H),7.09(td,J=7.6,1.2Hz,1H),6.98(dd,J=8.2,1.1Hz,1H),5.04(s,2H),2.49(s,3H).
实施例48
3-(3-甲氧基苯甲酰基)-4-氯-2H-色满烯(12c)的合成
合成方法同实施例4得黄色油状液体12c(0.3g,75%)。1H NMR(300MHz,CDCl3)δ7.64-7.56(m,2H),7.51(dd,J=2.7,1.5Hz,1H),7.43(t,J=7.9Hz,1H),7.34(ddd,J=8.1,7.4,1.6Hz,1H),7.19(ddd,J=8.2,2.7,1.0Hz,1H),7.07(td,J=7.6,1.2Hz,1H),6.96(dd,J=8.2,1.2Hz,1H),5.03(s,2H),3.90(s,3H).
实施例49
3-(4-甲氧基苯甲酰基)-4-氯-2H-色满烯(12d)的合成
采合成方法同实施例4得黄色油状液体12d(0.3g,60%)。1H NMR(300MHz,CDCl3)δ8.04-7.95(m,2H),7.60(dd,J=7.8,1.6Hz,1H),7.33(ddd,J=8.1,7.5,1.7Hz,1H),7.06(td,J=7.6,1.2Hz,1H),7.03-6.98(m,2H),6.95(dd,J=8.1,1.2Hz,1H),5.02(s,2H),3.92(s,3H).
实施例50
3-(3-氟苯甲酰基)-4-氯-2H-色满烯(12e)的合成
合成方法同实施例4得黄色油状液体12e(0.3g,80%)。1H NMR(300MHz,CDCl3)δ7.80(dt,J=7.7,1.3Hz,1H),7.72-7.62(m,2H),7.53(td,J=8.0,5.4Hz,1H),7.43-7.32(m,2H),7.11(td,J=7.6,1.2Hz,1H),7.00(dd,J=8.2,1.2Hz,1H),5.06(s,2H).
实施例51
3-(4-氟苯甲酰基)-4-氯-2H-色满烯(12f)的合成
合成方法同实施例4得黄色油状液体12f(0.3g,80%)。1H NMR(300MHz,CDCl3)δ8.10-8.00(m,2H),7.63(dd,J=7.8,1.6Hz,1H),7.37(ddd,J=8.1,7.4,1.6Hz,1H),7.27-7.17(m,2H),7.10(td,J=7.6,1.2Hz,1H),6.99(dd,J=8.2,1.2Hz,1H),5.05(s,2H).
实施例52
3-(2-甲氧基苯甲酰基)-4-氯-2H-色满烯(12g)的合成
合成方法同实施例4得黄色固体12g(0.3g,80%)。1H NMR(300MHz,CDCl3)δ7.61(dd,J=7.7,1.7Hz,2H),7.52(ddd,J=8.9,7.5,1.8Hz,1H),7.31(td,J=7.8,1.7Hz,1H),7.06(dtd,J=15.2,7.5,1.0Hz,2H),6.99-6.91(m,2H),5.07(s,2H),3.85(s,3H).
实施例53
3-(2-(2-三甲硅乙氧基)-甲氧基)-4-氯--2H-色满烯(12h)的合成
合成方法同实施例11得黄色油状液体(0.25g,61%)。1H NMR(300MHz,CDCl3)δ11.77(s,1H),7.85(dd,J=8.0,1.7Hz,1H),7.69-7.55(m,2H),7.37(td,J=7.8,1.6Hz,1H),7.17-7.07(m,2H),6.99(dtd,J=8.1,3.5,2.9,1.1Hz,2H),5.04(s,2H).
采合成方法同实施例18得黄色固体12h(0.27g,86%)。1H NMR(300MHz,CDCl3)δ7.58(d,J=7.2Hz,2),7.48(t,J=7.7Hz,1),7.31(d,J=8.8Hz,1H),7.22(d,J=8.3Hz,1),7.10(t,J=7.2Hz,1),7.01(t,J=7.5Hz,1),6.92(d,J=8.0Hz,1),5.23(s,2),5.07(s,2H),3.65(t,J=8.3Hz,2H),0.89(d,J=8.6Hz,2),-0.06(s,9H).
实施例54
3-苯甲酰基-4-氯-2H-色满烯(12i)的合成
合成方法同实施例4得黄色固体12i(0.3g,85%)。1H NMR(300MHz,CDCl3)δ8.03-7.96(m,2H),7.68-7.59(m,2H),7.57-7.50(m,2H),7.34(ddd,J=8.2,7.4,1.6Hz,1H),7.07(td,J=7.6,1.2Hz,1H),6.97(dd,J=8.1,1.2Hz,1H),5.04(s,2H).
实施例55
(E)-3-(3-甲基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-2H-色满烯(13a)的合成
合成方法同实施例25得黄色固体13a(0.27g,86%)。1H NMR(300MHz,CDCl3)δ7.55(d,J=16.0Hz,1H),7.43(dt,J=7.3,1.8Hz,1H),7.36-7.28(m,2H),7.00(dd,J=8.2,1.1Hz,1H),6.90(td,J=7.6,1.1Hz,1H),6.54(d,J=8.8Hz,2H),6.26(d,J=16.0Hz,1H),5.18(s,2H),3.78(s,3H),2.21(s,3H).
实施例56
(E)-3-(4-甲基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-2H-色满烯(13b)的合成
合成方法同实施例25得黄色固体13b(0.2g,60%)。1H NMR(300MHz,CDCl3)δ7.62-7.52(m,3H),7.33(ddd,J=8.2,7.3,1.7Hz,1H),7.14(d,J=8.0Hz,2H),7.01(dd,J=8.2,1.1Hz,1H),6.93(td,J=7.6,1.1Hz,1H),6.60(d,J=8.8Hz,2H),6.27(d,J=16.0Hz,1H),5.20(s,2H),3.80(s,3H),2.40(s,3H).
实施例57
(E)-3-(3-甲氧基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-2H-色满烯(13c)的合成
合成方法同实施例25得淡黄色固体13c(0.25g,80%)。1H NMR(300MHz,DMSO-d6)δ7.62-7.53(m,3H),7.40(ddd,J=8.1,7.4,1.6Hz,1H),7.35-7.24(m,2H),7.21-7.03(m,4H),6.98(td,J=7.5,1.1Hz,1H),6.73-6.68(m,2H),6.51(d,J=16.1Hz,1H),5.20(s,2H),3.72(s,3H),3.70(s,3H).
实施例58
(E)-3-(4-甲氧基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-2H-色满烯(13d)的合成
合成方法同实施例25得黄色固体13d(0.20g,75%)。1H NMR(300MHz,DMSO-d6)δ7.76-7.70(m,2H),7.61-7.52(m,3H),7.42-7.35(m,1H),7.19(dd,J=7.7,1.6Hz,1H),7.06(dd,J=8.2,1.1Hz,1H),7.02-6.95(m,3H),6.76-6.70(m,2H),6.50(d,J=16.1Hz,1H),5.18(s,2H),3.85(s,3H),3.71(s,3H).
实施例59
(E)-3-(3-氟苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-2H-色满烯(13e)的合成
合成方法同实施例25得黄色固体13e(0.25g,80%)。1H NMR(300MHz,DMSO-d6)δ7.60-7.51(m,3H),7.48-7.31(m,5H),7.16(dd,J=7.8,1.6Hz,1H),7.05(dd,J=8.3,1.1Hz,1H),6.95(td,J=7.6,1.1Hz,1H),6.71-6.63(m,2H),6.48(d,J=16.1Hz,1H),5.20(s,2H),3.70(s,3H).
实施例60
(E)-3-(4-氟苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-2H-色满烯(13f)的合成
合成方法同实施例25得黄色油状液体13f(0.20g,70%)。1H NMR(300MHz,DMSO-d6)δ7.75-7.68(m,2H),7.58-7.50(m,3H),7.43-7.34(m,1H),7.27-7.14(m,3H),7.05(dd,J=8.3,1.1Hz,1H),6.96(td,J=7.5,1.1Hz,1H),6.67(d,J=8.8Hz,2H),6.48(d,J=16.1Hz,1H),5.20(s,2H),3.70(s,3H).
实施例61
(E)-3-(2-甲氧基苯甲酰基)-4-(4-丙烯酸甲酯基-1-苯氧基)-2H-色满烯(13g)的合成
合成方法同实施例25得黄色油状液体13g(0.20g,76%)。1H NMR(300MHz,DMSO-d6)δ7.60-7.50(m,3H),7.36(ddd,J=8.4,7.4,1.7Hz,1H),7.33-7.27(m,1H),7.08(dd,J=7.4,1.8Hz,1H),7.03(dt,J=7.8,1.4Hz,2H),6.94-6.84(m,2H),6.80(td,J=7.5,0.9Hz,1H),6.59-6.53(m,2H),6.48(d,J=16.1Hz,1H),5.18(s,2H),3.70(s,3H),3.56(s,3H).
实施例62
(E)-3-(2-(2-三甲硅乙氧基)-甲氧基苯甲酰基))-4-(4-丙烯酸甲酯基-1-苯氧基)-2H-色满烯(13h)的合成
合成方法同实施例25得黄色油状液体13h(0.18g,70%)。1H NMR(300MHz,DMSO-d6)δ7.61-7.52(m,3H),7.39(ddd,J=8.2,7.3,1.7Hz,1H),7.31(ddd,J=9.0,7.4,1.8Hz,1H),7.05(dddd,J=9.3,5.0,4.1,1.3Hz,4H),6.92(d,J=1.2Hz,1H),6.78(td,J=7.4,0.9Hz,1H),6.62-6.57(m,2H),6.50(d,J=16.1Hz,1H),5.22(s,2H),5.14(s,2H),3.72(s,1H),3.70-3.62(m,2H),0.91-0.82(m,2H),-0.06(s,9H).
实施例63
(E)-3-苯甲酰基-4-(4-丙烯酸甲酯基-1-苯氧基)-2H-色满烯(13i)的合成
合成方法同实施例25得黄色油状液体13i(0.20g,70%)。1H NMR(300MHz,DMSO-d6)δ7.67-7.61(m,2H),7.58-7.49(m,4H),7.43-7.34(m,3H),7.16(dd,J=7.7,1.6Hz,1H),7.05(dd,J=8.3,1.1Hz,1H),6.95(td,J=7.6,1.1Hz,1H),6.69-6.60(m,2H),6.47(d,J=16.0Hz,1H),5.20(s,2H),3.69(s,3H).
实施例64
(E)-3-(3-甲基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH08)的合成
合成方法同实施例39得黄色固体XH08(0.24g,80%)。mp:136~138℃。1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),7.53-7.42(m,4H),7.41-7.31(m,3H),7.28(t,J=7.5Hz,1H),7.14(dd,J=7.8,1.6Hz,1H),7.05(d,J=8.2Hz,1H),6.94(t,J=7.5Hz,1H),6.66(d,J=8.4Hz,2H),6.37(d,J=16.0Hz,1H),5.17(s,2H),2.19(s,3H).13C NMR(101 MHz,DMSO-d6)δ193.09,168.10,158.59,157.30,148.95,143.51,138.36,138.01,133.80,133.08,130.33,129.18,129.14,128.62,125.90,124.92,122.41,118.91,118.33,118.06,117.06,116.26,66.92,21.04.HRMS(ESI)for C26H20O5+H calcd 413.1384,found 413.1378.
实施例65
(E)-3-(4-甲基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH09)的合成
合成方法同实施例39得黄色固体XH09(0.05g,50%)。mp:162~164℃。1H NMR(400MHz,DMSO-d6)δ12.32(s,1H),7.60(d,J=7.9Hz,2H),7.54-7.43(m,3H),7.36(td,J=7.7,1.7Hz,1H),7.23(d,J=7.9Hz,2H),7.16(dd,J=7.7,1.6Hz,1H),7.04(d,J=8.1Hz,1H),6.95(t,J=7.5Hz,1H),6.69(d,J=8.5Hz,2H),6.36(d,J=16.0Hz,1H),5.17(s,2H),2.35(s,3H).13C NMR(101MHz,DMSO-d6)δ192.39,168.09,158.65,157.13,148.04,144.02,143.50,135.29,132.91,130.39,129.34,129.23,124.72,122.43,119.05,118.37,118.34,116.97,116.16,66.89,21.71.HRMS(ESI)for C26H20O5+H calcd 413.1384,found413.1382.
实施例66
(E)-3-(3-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH10)的合成
合成方法同实施例39得黄色固体XH10(0.05g,45%)。mp:140~142℃。1H NMR(400MHz,DMSO-d6)δ12.31(s,1H),7.54-7.44(m,3H),7.38(td,J=7.8,1.6Hz,1H),7.31(t,J=7.8Hz,1H),7.25(dt,J=7.6,1.3Hz,1H),7.17(dd,J=7.8,1.6Hz,1H),7.14-7.08(m,1H),7.07-7.01(m,2H),6.95(t,J=7.5Hz,1H),6.67(d,J=8.6Hz,2H),6.37(d,J=16.0Hz,1H),5.18(s,2H),3.68(s,3H).13C NMR(101MHz,DMSO-d6)δ192.70,168.10,159.47,158.67,157.32,149.25,143.49,139.76,133.16,130.36,129.87,129.22,124.91,122.44,121.31,119.36,118.97,118.35,117.88,117.04,116.20,112.92,66.83,55.67.HRMS(ESI)forC26H20O6+H calcd 429.1333,found 429.1331.
实施例67
(E)-3-(4-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH11)的合成
合成方法同实施例39得黄色固体XH11.09g,55%)。mp:86~88℃。1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),7.71(d,J=8.4Hz,2H),7.55-7.47(m,3H),7.39-7.33(m,1H),7.03(d,J=8.3Hz,2H),6.99-6.94(m,3H),6.71(d,J=8.4Hz,2H),6.36(d,J=16.0Hz,1H),5.16(s,2H),3.83(s,3H).13C NMR(101MHz,DMSO-d6)δ191.18,168.09,163.83,158.66,156.97,147.14,143.51,132.73,131.71,130.41,130.30,129.20,124.55,122.42,119.14,118.54,118.31,116.91,116.13,114.14,66.97,56.04.HRMS(ESI)for C26H20O6+H calcd 429.1333,found 429.1332.
实施例68
(E)-3-(3-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH12)的合成
合成方法同实施例39得黄色固体XH12(0.04g,40%)。mp:144~146℃。1H NMR(400MHz,DMSO-d6)δ7.48-7.31(m,8H),7.17(dd,J=7.7,1.6Hz,1H),7.05(dd,J=8.3,1.0Hz,1H),6.95(td,J=7.5,1.2Hz,1H),6.66(d,J=8.7Hz,2H),6.37(d,J=16.0Hz,1H),5.20(s,2H)..13C NMR(75MHz,DMSO-d6)δ168.08,158.50,157.52,150.15,143.44,140.92,140.83,133.46,130.41,129.31,125.06,124.78,122.46,116.05,66.65.HRMS(ESI)forC25H17FO5+H calcd 417.1133,found 417.1330.
实施例69
(E)-3-(4-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH13)的合成
合成方法同实施例39得黄色固体XH13(0.05g,55%)。mp:160~162℃。1H NMR(300MHz,DMSO-d6)δ12.36(s,1H),7.78-7.70(m,2H),7.56-7.46(m,3H),7.40(td,J=7.7,1.6Hz,1H),7.28-7.17(m,3H),7.07(d,J=8.1Hz,1H),6.98(t,J=7.6Hz,1H),6.68(d,J=8.4Hz,2H),6.39(d,J=16.0Hz,1H).5.22(s,1H).13C NMR(75MHz,DMSO)δ191.48,168.13,158.59,157.36,149.24,143.47,134.91,133.28,131.94,131.82,130.44,129.30,124.88,122.47,118.93,118.44,117.57,117.03,115.99,115.60,66.79.HRMS(ESI)for C25H17FO5+Hcalcd 417.1133,found 417.1330.
实施例70
(E)-3-(2-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH14)的合成
合成方法同实施例39得黄色固体XH14(0.1g,70%)。mp:118~120℃.1H NMR(500MHz,DMSO-d6)δ12.29(s,1H),7.50-7.43(m,3H),7.36(ddd,J=8.2,7.3,1.6Hz,1H),7.30(ddd,J=8.4,7.4,1.8Hz,1H),7.08(dd,J=7.5,1.8Hz,1H),7.03(dt,J=7.7,0.8Hz,2H),6.93-6.86(m,2H),6.80(td,J=7.4,0.9Hz,1H),6.57-6.53(m,2H),6.36(d,J=16.0Hz,1H),5.17(s,2H),3.56(s,3H).13C NMR(126MHz,DMSO-d6)δ158.42,157.72,156.79,150.98,143.59,133.47,131.99,130.79,130.11,128.98,128.00,125.31,122.42,120.40,119.64,118.71,118.18,117.15,115.78,111.59,65.91,55.84.HRMS(ESI)forC26H20O6+H calcd 429.1333,found 429.1327.
实施例71
(E)-3-(2-(2-三甲硅乙氧基)-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-2H-色满烯(XH15)的合成
合成方法同实施例39得黄色固体XH15(0.8g,65%)。mp:76~78℃。1H NMR(400MHz,DMSO-d6)δ7.49-7.43(m,3H),7.36(td,J=7.8,1.7Hz,1H),7.28(td,J=7.9,1.8Hz,1H),7.07-7.00(m,4H),6.90(t,J=7.5Hz,1H),6.76(t,J=7.5Hz,1H),6.56(d,J=8.7Hz,2H),6.35(d,J=16.0Hz,1H),5.20(s,2H),5.11(s,2H),3.68-3.60(m,2H),0.90-0.79(m,2H),-0.08(s,9H).13C NMR(101MHz,DMSO-d6)δ191.80,168.09,158.50,157.71,154.61,151.00,143.56,133.53,131.86,131.52,130.18,129.02,128.03,125.24,122.42,121.21,119.58,118.68,118.20,117.13,115.60,114.39,93.21,66.25,65.86,17.99,-0.96HRMS(ESI)for C31H32O7Si+H calcd 567.1810,found 567.1804。
实施例72
(E)-3-苯甲酰基-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH16)的合成
合成方法同实施例39得黄色固体XH16(0.1g,70%)。mp:104~106℃。1H NMR(400MHz,DMSO-d6)δ7.66-7.61(m,2H),7.59-7.52(m,2H),7.40-7.34(m,3H),7.18-7.14(m,1H),7.07-7.02(m,2H),6.66-6.61(m,1H),6.39-6.32(m,2H),5.20(s,2H).13C NMR(101MHz,DMSO-d6)δ192.92,168.08,158.61,157.32,149.05,143.48,138.24,133.30,133.17,130.38,129.20,128.85,128.74,128.66,124.87,122.46,118.95,118.36,117.95,117.03,116.07,66.82.HRMS(ESI)for C25H18O5+H calcd 399.1227,found 399.1225.
下面是本发明化合物的部分药理学试验及结果:
MTT法测试MCF-7乳腺癌细胞增殖试验:
测试方法:MCF-7乳腺癌细胞以含10%胎牛血清的RPMI1640培养液培养,取对数生长期细胞用于实验,调整细胞密度为2×104个/mL,接种于96孔板,培养12小时后,加入100μl/孔的含药培养基,样品最终浓度为2×10-4mol/L、1×10-4mol/L、1×10-5mol/L、1×10- 6mol/L和1×10-7mol/L,每个浓度3个复孔,以相同体积的培养基代替测试药物作为对照组,继续培养48小时后加入20μl/孔MTT(浓度为5mg/m1),培养4h后,弃上清液,加入DMSO 150μl/孔,用酶标检测仪于492nm波长处测定每孔吸光度(A)值,按公式计算细胞增殖抑制率:抑制率=(对照组A值-实验组A值)/(对照组A值-空白组A值)×100%,并计算出ICs0。MCF-7细胞抗增殖实验结果:
以Tamoxifen为阳性对照,对合成的苯并吡喃类化合物进行了MCF-7细胞抗增殖实验,研究结果表明,大部分化合物对MCF-7细胞表现出较好的抑制活性,并且7-羟基化合物XH04活性最好。
ERα受体亲和力测试
测试方法:待测化合物每种精确称量,加入DMSO溶剂成母液,然后使用ES2Screening Buffer配制待测化合物溶液至浓度为100μM。使用ES2 Screening Buffer配制2X荧光配基与ERα混合液使最终荧光配基浓度为9nM,ERα浓度为30nM。于384孔黑色微孔板先每孔加入50μl化合物,再每孔加入50ul 2X荧光配基与ERα混合溶液。同时加入50ul雌二醇溶液(100μM),50ul 2X荧光配基与ERα混合溶液作为100%竞争结合对照、加入50ulBuffer,50ul 2X荧光配基与ERα混合溶液作为0%竞争结合对照以及加入100ul Buffer作为空白对照。避光操作。室温(20-25℃)孵育2h,测得荧光偏振值mP。ERα受体相对亲和力=(空白组mP-实验组mP)/(空白组mP-雌二醇组mP)×100%。ERα亲和力结果如下:
在以Fulvestrant为对照的ERα受体亲和力实验中,7-羟基化合物在1 μM的浓度下,对于ERα受体有较好的亲和力。
ERα抑制活性实验:
测试方法:经化合物处理的MCF-7细胞胰酶消化后加入适量的RNAiso p1us即trizol,室温静置10min,加入1/5RNAiso plus体积量的氯仿,震荡混匀,室温静置5min,12000g,4℃离心15min;将上清转移至新的离心管中,加入与上清等体积的异丙醇上下颠倒,充分混匀,静置10min(冰上),12000g,4℃离心10min(可见管底侧壁有少量白色RNA沉淀);小心弃上清,沿离心管壁加入75%乙醇1ml,12000g,4℃离心5min,弃上清,留沉淀,空气干燥(5-10min),使乙醇挥发。随后加入20ul的RNase-free水溶解,即得到20ul RNA溶液。取2ul样品,使用Nanodrop 2000测定microRNA浓度和纯度。之后按照PrimeScript RTReagent Kit with gDNA Eraser(Perfect Real Time)和SYBR qPCR mix说明书操作。
PgR引物序列:
Sense:5’-CGTGCCTATCCTGCCTCTCAA-3,
Anti-sense:5’-CCGCCGTCGTAACTTTCGT-3’。ERα抑制活性结果如图1。
孕激素受体(progestron receptor,PgR)作为雌激素的靶基因,其mRNA的表达水平可以用来检测ER配体的拮抗与激动活性。我们选择活性MCF-7抗增殖活性较好的化合物XH04,以Tamoxifen和Fulvestrant为阳性对照检测MCF-7细胞中PgR mRNA表达,结果显示在1μM浓度下,化合物XH04具有由于对照Tamoxifen和Fulvestrant的ERα抑制活性。
ERα降解活性实验:
测试方法:1、上样。两端孔道分别加入5μL上样缓冲液,中间孔道加入5μL Marker。样品固定上样量为20μg,并由上样缓冲液补充至5μL。
2、电泳。SDS-PAGE凝胶置于电泳液中,恒压80V电泳30min。条带从浓缩胶进入分离胶之后,改为120V,继续电泳至条带跑至底端停止。
3、转膜。将PVDF膜放置甲醇和超纯水中各活化2min。将棉花,滤纸和预活化的PVDF膜按顺序放置于转印夹中,随后放置于转膜液中。以恒流(300mA)转膜100min。
4、封闭。将转印完毕的PVDF膜放置于5%脱脂牛奶溶液中,4℃下封闭过夜。
5、洗膜。用1×TBST溶液洗涤封闭完毕的PVDF膜,洗涤三次,每次置于脱色摇床5min。
6、一抗封闭。最后一次洗涤完毕后,完全弃去洗涤液。加入预先配制好的一抗(兔源)室温封闭2.5h。ERα配制比例1∶1000,GADPH为1∶10000。
7、洗膜。用1×TBST溶液洗涤一抗封闭完毕的PVDF膜,洗涤三次,每次置于脱色摇床5min。
8、二抗封闭。最后一次洗涤完毕后,完全弃去洗涤液。加入预先配制好的二抗(兔源,1∶10000)室温封闭1h。
9、洗膜。用1×TBST溶液洗涤二抗封闭完毕的PVDF膜,洗涤三次,每次置于脱色摇床5min。
10、曝光。将A液:B液(1∶1)配制成ECL发光液。曝光前,将PVDF水分吸干,滴加预先配制ECL发光液至全膜覆盖。随后曝光拍照。
ERα降解活性结果如图2。
以Fulvestrant为阳性对照,对化合物XH04进行了ERα的Western Blot实验,结果显示化合物XH04具有良好的ERα降解活性。通过MCF-7抗增殖实验,ERα亲和力实验,ERα抑制活性实验和降解实验结果表明3-羰基-2H-苯并吡喃类化合物可作为选择性雌激素受体下调剂,用于治疗或预防多种与绝经后综合症相关的医学适应症,特别是适用于治疗ER-(+)型乳腺癌。
Claims (6)
2.根据权利要求1所述的3-羰基-2H-苯并吡喃类化合物或其可药用的盐,为如下任一种:
(E)-3-(3-甲苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH01);
(E)-3-(4-甲苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH02);
(E)-3-(3-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH03);
(E)-3-(4-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH04);
(E)-3-(3-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH05);
(E)-3-(4-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH06);
(E)-3-(2-(2-三甲硅乙氧基)-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH07);
(E)-3-(3-甲基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH08);
(E)-3-(4-甲基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH09);
(E)-3-(3-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH10);
(E)-3-(4-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH11);
(E)-3-(3-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH12);
(E)-3-(4-氟苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH13);
(E)-3-(2-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH14);
(E)-3-(2-(2-三甲硅乙氧基)-甲氧基苯甲酰基)-4-(4-丙烯酸基-1-苯氧基)-2H-色满烯(XH15);
(E)-3-苯甲酰基-4-(4-丙烯酸基-1-苯氧基)-7-羟基-2H-色满烯(XH16)。
3.权利要求1所述的3-羰基-2H-苯并吡喃类化合物或其可药用的盐的制备方法,其特征在于:工艺如下:
路线1:
以间苯二酚1为原料,先与3-氯丙酸发生付克酰基化反应,随后分子内醚化构建出苯并吡喃酮结构2,之后与氯化苄反应得到中间体3,再进行Vilsmeier-Hacck-Arnold反应构建出关键中间体化合物4,随后中间体4与不同的芳基格氏试剂反应,产物不经纯化再通过IBX氧化得到中间体5a~g,之后与三溴化硼反应脱去苄基得到中间6a~g,再与2-(三甲基硅烷基)乙氧甲基氯反应得到中间7a~g,然后与4-羟基肉桂酸甲酯反应得到中间体8a~g,随后利用四丁基氟化铵脱去保护基得到中间体9a~g,最终通过酯水解即得;
路线2:
以2,3-二氢苯并吡喃-4-酮10为原料,首先利用Vilsmeier-Hacck-Arnold反应构建出关键中间体11,随后与不同的格氏试剂反应合成中间体12a~12i,中间体12h则是以中间体12g为原料,与三溴化硼反应脱去苄基,随后在与2-(三甲基硅烷基)乙氧甲基氯反应合成得到,中间体12a~12i与4-羟基肉桂酸甲酯反应得到中间体13a~13i,最终酯水解得到通式II所示的化合物。
4.一种药物组合物,其含有治疗有效量的一种或多种如权利要求1或2所述的3-羰基-2H-苯并吡喃类化合物或其可药用的盐,及药学上可接受的载体。
5.一种药物组合物,其含有治疗有效量的一种或多种如权利要求1或2所述的3-羰基-2H-苯并吡喃类化合物或其可药用的盐,及药学上可接受的辅料。
6.权利要求1所述的3-羰基-2H-苯并吡喃类化合物或其可药用的盐在制备治疗或预防多种与绝经后综合症相关的医学适应症,以及治疗ER(+)乳腺癌药物方面的用途。
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