CN113582949B - 一种含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物及其制备与应用 - Google Patents
一种含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物及其制备与应用 Download PDFInfo
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- CN113582949B CN113582949B CN202110954032.5A CN202110954032A CN113582949B CN 113582949 B CN113582949 B CN 113582949B CN 202110954032 A CN202110954032 A CN 202110954032A CN 113582949 B CN113582949 B CN 113582949B
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- hydroxyphenyl
- bicyclo
- phenyl
- oxo
- hept
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Abstract
Description
技术领域
本发明属于属于靶向药物技术领域,涉及基于氧桥双环-[2.2.1]-庚烯类结构的化合物,具体涉及一种含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物及其制备方法与在抗乳腺癌中的应用。
背景技术
乳腺癌是女性高发性的恶性肿瘤之一,是35-55岁女性的头号杀手。据WHO统计,全球每年170万妇女罹患乳腺癌,且有50万死于该病,发病率占全身各种恶性肿瘤的7-10%。乳腺癌的发病率在全球范围内逐年增加,并且年轻化趋势。其中雌激素受体阳性的患者占三分之二。雌激素的作用机制主要是通过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。尽管以他莫西芬为首的内分泌治疗可以显著降低其复发几率,但仍有约三分之一的患者会耐药而复发转移。
传统的小分子药物抑制酶或受体的一般机制是通过小分子药物与目标蛋白结合,降低其活性。药物与靶蛋白结合的典型模式是通过非共价相互作用。然而这些非共价结合是可逆的,会被内源性底物竞争下来,影响药效。共价药物是通过共价作用与目标蛋白结合而发挥其生物作用的一类药物。共价药物的结合力强,结合时间长,因而具有强效的生物活性,可以减少给药剂量和给药次数,进而增强患者的依从性。这是因为共价键键能远大于非共价相互作用,且不能被内源性底物竞争下来,属于非可逆性结合。因此共价型小分子抑制剂更具有优势。
介于目前针对乳腺癌内分泌疗法耐药问题,亟需发展新一代靶向突变型雌激素受体的药物。共价型药物是解决这一问题的方法。
发明内容
本发明首要目的是提供一类含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物,该类化合物是将氧桥双环庚烯类结构的化合物和共价弹头相结合,得到具有三维立体结构共价抗肿瘤药物,合成的目标化合物在测试其生物活性中,表现了良好的抗乳腺癌细胞活性,并且具有下调雌激素受体水平的能力,更重要的是针对突变型雌激素受体表现出的活性是4-羟基他莫昔芬的6~10倍。
本发明的另一目的是提供上述含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物的制备方法,这类目标化合物是由两种底物:含有不同共价弹头的呋喃衍生物和乙烯磺酰胺衍生物或乙烯磺酸酯衍生物,通过Diels-Alder反应制备得到含有共价弹头结构的氧桥双环庚烯类化合物。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。
本发明的再一目的是提供上述含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物在制备抗乳腺癌药物中的应用。
为了实现上述目的,本发明采用如下技术方案:
第一方面,提供一类含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物,结构如通式(I)或通式(II)所示:
其中,
X为O、NCH2CH3或NCH2CF3;
R2为H、OH、OMe、Cl或F。
优选地,所述的含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物选自如下化合物:
4-丙烯酰胺苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂(17a);
4-(2-丁烯酰胺基)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂(17b);
4-(3-甲基-2-丁烯酰胺基)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂(17c);
4-丙炔酰胺基苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂(17d);
4-(2-氯乙酰胺)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂(17e);
4-(2-溴乙酰胺基)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂(17f);
4-(6-溴己酰胺基)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂(17g);
4-(8-溴辛酰胺基)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂(17h);
4-((5,6-双(4-羟基苯基)-N-(2,2,2-三氟乙基)-7-氧杂双环-[2.2.1]-庚-5-烯)-2-磺酰氨基)苯基3-甲基丁-2-烯酸酯(17i);
苯基-5-(4-丙烯酰胺苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯(18a);
苯基-5-(4-(2-丁烯酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯(18b);
苯基-5-(4-(3-甲基-2-丁烯酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯(18c);
苯基-5-(4-(2-氯乙酰胺)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯(18d);
苯基-5-(4-(8-溴癸酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯(18e);
N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-2-丁烯酰胺(18f);
N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18g);
N-(4-(3-(4-羟基苯基)-5-(N-(4-甲氧基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基2-丁烯酰胺(18h);
N-(4-(3-(4-羟基苯基)-5-(N-(3-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18i);
N-(4-(5-(N-乙基-N-(4-羟基苯基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18j);
N-(4-(5-(N-(4-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺(18k);
6-溴-N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7)-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)己酰胺(18l);
N-(4-(5-(N-(3-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺(18m)。
第二方面,提供一种上述含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物的制备方法。
3,4-二(4-羟基苯基)-呋喃化合物4与含有共价弹头的乙烯磺酰胺衍生物或乙烯磺酸酯衍生物13,通过Diels-Alder反应制备得到结构如通式(I)所示的化合物;
含有共价弹头的呋喃衍生物9与含有R2基团的乙烯磺酰胺衍生物或乙烯磺酸酯衍生物16,通过Diels-Alder反应制备得到结构如通式(II)所示的化合物;
所述的3,4-二(4-羟基苯基)-呋喃化合物4的结构式为:
所述的含有共价弹头的乙烯磺酰胺衍生物或乙烯磺酸酯衍生物13的结构式为:
含有共价弹头的乙烯磺酸酯衍生物13可由含氨基的乙烯基磺酸酯衍生物或含氨基的乙烯基磺酰胺衍生物与含有共价弹头的羧酸或酰氯经缩合得到。
所述的含有共价弹头的呋喃衍生物9的结构式为:
含有共价弹头的呋喃衍生物9可由含有氨基的呋喃衍生物与含有共价弹头的羧酸或酰氯经缩合得到。
所述的含有R2基团的乙烯磺酰胺衍生物或乙烯磺酸酯衍生物16的结构式为:
上述结构式中,X、R1、R2的限定同上。
所述的Diels-Alder反应的条件为90~100℃反应12~18小时。
第三方面,提供上述含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物药学上可接受的盐。
按照本发明所属技术领域的一些通常方法,本发明的氧桥双环-[2.2.1]-庚烯类化合物可以与酸生成它的药学上可接受的盐,酸可以包括无机酸或有机酸,例如盐酸、氢溴酸、氢碘酸、硫酸、磷酸、甲酸、乙酸、丙酸、三氟乙酸、马来酸、酒石酸、甲磺酸、苯磺酸、对甲苯磺酸等。本发明的药物可以是化合物本身与药学上可接受的稀释剂、辅助剂和/或载体混合的药物,也可以是以本发明化合物或其在药学上可接受的盐、溶剂化物、光学异构体或多晶型物作为活性成分之一的组合物与药学上可接受的稀释剂、辅助剂和/或载体混合的药物。
将本发明的药物加入常规辅料,按照常规工艺,可以制成药学上可接受的各种剂型,如片剂、胶囊剂、口服液剂、注射剂、颗粒剂或各种缓控释制剂等。
本发明药物的载体是药学领域中可得到的常见类型,包括:黏合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂或基质等。
第四方面,提供上述含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物及其药学上可接受的盐在制备抗乳腺癌药物中的应用。
优选地,所述的应用中,含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物为:
苯基-5-(4-丙烯酰胺苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯(18a);
苯基-5-(4-(2-丁烯酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯(18b);
苯基-5-(4-(3-甲基-2-丁烯酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯(18c);
苯基-5-(4-(2-氯乙酰胺)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯(18d);
苯基-5-(4-(8-溴癸酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯(18e);
N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-2-丁烯酰胺(18f);
N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18g);
N-(4-(3-(4-羟基苯基)-5-(N-(4-甲氧基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基2-丁烯酰胺(18h);
N-(4-(3-(4-羟基苯基)-5-(N-(3-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18i);
N-(4-(5-(N-乙基-N-(4-羟基苯基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18j);
N-(4-(5-(N-(4-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺(18k);
6-溴-N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7)-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)己酰胺(18l);
N-(4-(5-(N-(3-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺(18m)。
第五方面,上述含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物及其药学上可接受的盐在制备降解雌激素受体的药物中的应用。
优选地,所述的应用中,含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物为:
N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-2-丁烯酰胺(18f);
N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18g);
N-(4-(3-(4-羟基苯基)-5-(N-(4-甲氧基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基2-丁烯酰胺(18h);
N-(4-(3-(4-羟基苯基)-5-(N-(3-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18i);
N-(4-(5-(N-乙基-N-(4-羟基苯基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18j);
N-(4-(5-(N-(4-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺(18k);
6-溴-N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7)-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)己酰胺(18l);
N-(4-(5-(N-(3-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺(18m)。
第六方面,上述含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物及其药学上可接受的盐在制备靶向突变型雌激素受体的药物中的应用。
优选地,所述的应用中,含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物为:
N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-2-丁烯酰胺(18f);
N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18g);
N-(4-(3-(4-羟基苯基)-5-(N-(4-甲氧基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基2-丁烯酰胺(18h);
N-(4-(3-(4-羟基苯基)-5-(N-(3-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18i);
N-(4-(5-(N-乙基-N-(4-羟基苯基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺(18j);
N-(4-(5-(N-(4-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺(18k);
6-溴-N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7)-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)己酰胺(18l);
N-(4-(5-(N-(3-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺(18m)。
第七方面,提供一种抗乳腺癌药物组合物,包含上述含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物或其药学上可接受的盐,以及一种或多种药学上可接受的助剂。
第八方面,提供一种降解雌激素受体或突变型雌激素受体的药物组合物,包含上述含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物或其药学上可接受的盐,以及一种或多种药学上可接受的助剂。
第九方面,提供一种针对乳腺癌内分泌疗法耐药的药物组合物,包含上述含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物或其药学上可接受的盐,以及一种或多种药学上可接受的助剂。
和现有技术相比,本发明的有益效果是:通过含有共价弹头的呋喃衍生物和乙烯磺酸酯或磺酰胺衍生物为原料,无需溶剂和催化剂,在90~100℃反应12~18小时一步制备得到含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物。体外实验表明,大多数新型磺酰胺类氧桥双环-[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,并且具有下调雌激素受体水平的能力,更重要的是针对突变型雌激素受体表现出的活性是4-羟基他莫昔芬的5~10倍。
附图说明
图1是本发明合成的代表性目标化合物18g与4-羟基他莫昔芬4OHT对不同乳腺细胞的抑制活性比较结果图。
图2是本发明合成的代表性目标化合物的ERα蛋白降解活性结果图。其中,C是空白对照,Ful是阳性对照,OBHSA是5,6-双(4-羟基苯基)-N-苯基-N-(2,2,2-三氟乙基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺胺。
具体实施方式
下面结合实施例对本发明做进一步详细的描述,所提供的实施例仅是对本发明方法的说明,而不以任何方式限制本发明揭示的其余内容。
本发明的含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物由3,4-二(4-羟基苯基)呋喃化合物4或3-(4-氨基苯基)-4-(4-羟基苯基)-呋喃衍生物9a~9g中任意一种与乙烯磺酸酯衍生物13a~13l或乙烯磺酰胺衍生物16a~16i中任意一种溶解在四氢呋喃中,在90℃反应12小时一步制备得含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物17a~17i、18a~18m,反应式如下所示:
其中,X为O、NCH2CH3或NCH2CF3;
R2为H、OH、OMe、Cl或F。
上述各反应底物的合成如下:
1、3,4-二(4-羟基苯基)-呋喃化合物4的合成
(1)2-(4-甲氧基苯基)-2-氧乙基-2-(4-甲氧基苯基)乙酸酯化合物1的合成
称取1.0eq.2-溴-4-甲氧基苯乙酮和1.0eq.对甲氧基苯乙酸于50mL的圆底烧瓶中,加入25mL的无水乙腈,缓慢滴加1.0eq.无水三乙胺后,室温继续反应2h。TLC监测反应完全后,旋干后得黄色固体化合物1。
(2)3,4-二(4-甲氧基苯基)呋喃-2-酮化合物2的合成
称取1.0eq.化合物1于25mL两口瓶中,加入10mL的无水DMSO,氩气保护下分批加入2.0eq.60%NaH后,25℃反应2h。TLC监测反应完全,在0℃下加入4.0eq.2N HC1淬灭反应,用乙酸乙酯萃取,有机层经无水NaSO4干燥,减压脱溶得到粗产物,柱层析(洗脱剂,石油醚/乙酸乙酯=9:1)得到化合物2。
(3)3,4-二(4-羟基苯基)呋喃-2-酮化合物3的合成
称取1.0eq.化合物2于100mL的双口瓶,加入25mLDCM,氩气置换三次,-20℃下滴加入6.0eq.BBr3,反应12h后,0℃加入10mL水淬灭反应,用乙酸乙酯萃取,饱和NaHCO3溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,柱层析(洗脱剂,石油醚/乙酸乙酯=7:3)得到化合物3。
(4)3,4-二(4-羟基苯基)呋喃化合物4的合成
称取1.0eq.化合物3于50mL的双口瓶中,加入15mL无水THF中,氩气置换三次,-78℃下加入4.0eq.二异丁基氢化铝(DIBAL-H)反应12h。TLC监测反应完全后加入5%H2SO4淬灭反应,乙酸乙酯萃取,饱和NaCl溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,经柱层析(洗脱剂,石油醚/乙酸乙酯=6:4)得到化合物4。
2、3-(4-氨基苯基)-4-(4-羟基苯基)-呋喃衍生物9a~9g的合成
(1)3-(4-氨基苯基)-4-(4-羟基苯基)-呋喃化合物8的合成:
(1.1)2-(4-甲氧基苯基)-2-氧乙基2-(4-((叔丁氧基羰基)氨基)苯基)乙酸酯化合物5的合成
称取1.0eq.2-溴-4-甲氧基苯乙酮和1.0eq.2-(4-((叔丁氧羰基)氨基)苯基)乙酸于50mL的圆底烧瓶中,加入25mL的无水乙腈,缓慢滴加1.0eq.无水三乙胺后,室温继续反应2h后,TLC监测反应完全后,旋干后得黄色固体化合物5。
(1.2)3-(4-叔丁氧羰基氨基苯基)-4-(4-甲氧基苯基)呋喃-6-酮化合物6的合成
称取1.0eq.化合物5于25mL两口瓶中,加入10mL的无水DMSO,氩气保护下分批加入2.0eq.60%NaH后,25℃反应2h。TLC监测反应完全,在0℃下加入水淬灭反应,用乙酸乙酯萃取,有机层经无水NaSO4干燥,减压脱溶得到粗产物,柱层析(洗脱剂,石油醚/乙酸乙酯=15:1)得到化合物6。
(1.3)3-(4-氨基苯基)-4-(4-甲氧基苯基)呋喃-6-酮化合物7的合成
称取1.0eq.化合物6于100mL的双口瓶,加入25mL DCM,氩气置换三次,-20℃下滴加入6.0eq.BBr3,反应12h后,0℃加入10mL水淬灭反应,用乙酸乙酯萃取,饱和NaHCO3溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,柱层析(洗脱剂,石油醚/乙酸乙酯=7:3)得到化合物7。
(1.4)3-(4-氨基苯基)-4-(4-羟基苯基)-呋喃化合物8的合成
称取1.0eq.化合物3于50mL的双口瓶中,加入15mL无水THF中,氩气置换三次,-78℃下加入4.0eq.二异丁基氢化铝(DIBAL-H)反应12h。TLC监测反应完全后加入5%H2SO4淬灭反应,乙酸乙酯萃取,饱和NaCl溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,经柱层析(洗脱剂,石油醚/乙酸乙酯=6:4)得到化合物8。
(2)3-(4-氨基苯基)-4-(4-羟基苯基)-呋喃衍生物9a~9g的合成
称取1.0eq.化合物8于50mL的双口瓶中,加入2.0eq.丙烯酸与15mL无水DCM,0℃下加入1.0eq.2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、3.5eq.N,N-二异丙基乙胺(DIPEA)后反应2h。TLC监测反应完全后乙酸乙酯萃取,饱和NaCl溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,经柱层析(洗脱剂,石油醚/乙酸乙酯=3:1)得到化合物9a。
3-(4-氨基苯基)-4-(4-羟基苯基)-呋喃衍生物9b~9l的制备
3、乙烯磺酸酯衍生物13a~13l的合成:
(1)称取1.0eq.对氨基苯酚于100mL的双口瓶中,加入25mL DCM,加入1.0eq.三乙胺后,缓慢滴加二碳酸二叔丁酯,反应12h后,加入10mL水淬灭反应,用DCM萃取,饱和NaCl溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,柱层析(洗脱剂,石油醚/乙酸乙酯=5:1)得到化合物10。
(2)称取1.0eq.化合物10于50mL的双口瓶,加入20mL DCM,加入1.3eq.氯乙烷磺酰氯,然后缓慢滴加3.0eq.三乙胺,反应12h。TLC监测反应完全后DCM萃取,饱和NaCl溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,经柱层析(洗脱剂,石油醚/乙酸乙酯=10:1)得到化合物11。
(3)称取1.0eq.化合物11于10mL的单口瓶,加入5mL DCM,加入2.5mL三氟乙酸,反应12h。TLC监测反应完全后减压蒸除溶剂,用乙酸乙酯稀释,饱和NaHCO3溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,经柱层析(洗脱剂,石油醚/乙酸乙酯=5:1)得到化合物12。
(4)称取1.0eq.化合物12于50mL的双口瓶,加入20mL DCM,加入1.3eq.丙烯酸和1.3eq.2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、3.5eq.N,N-二异丙基乙胺(DIPEA),反应12h。TLC监测反应完全后DCM萃取,饱和NaCl溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,经柱层析(洗脱剂,石油醚/乙酸乙酯=10:1)得到化合物13a。
乙烯磺酸酯衍生物13b~13l的制备
4、乙烯磺酰胺衍生物16a~16j的合成:
(1)分别称取1.0eq.氨基苯基衍生物于100mL的单口瓶中,加入25mL DCM,滴加1.2eq.三氟乙酸酐后(14g的合成为加入乙酸酐),室温反应12h后,加入10mL水淬灭反应,用DCM萃取,饱和NaHCO3溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,柱层析(洗脱剂,石油醚/乙酸乙酯=10:1~1:1)得到化合物14a~14g。
(2)称取1.0eq.化合物14a~14g与50mL的双口瓶中,加入20mL DCM,氩气置换三次,于-78℃下缓慢滴加2.0eq.2N硼烷二甲硫醚。TLC监测反应完全后DCM萃取,饱和NaCl溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,经柱层析(洗脱剂,石油醚/乙酸乙酯=10:1~1:1)得到化合物15a~15g。
(3)称取1.0eq.化合物15a~15f与50mL的双口瓶中,加入20mL DCM,1.3eq.氯乙烷磺酰氯,然后缓慢滴加3.0eq.三乙胺,反应12h。TLC监测反应完全后DCM萃取,饱和NaCl溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,经柱层析(洗脱剂,石油醚/乙酸乙酯=10:1~1:1)得到化合物16a~16f和16j。
(4)称取1.0eq.化合物16b/16c于100mL的双口瓶,加入25mL DCM,氩气置换三次,-20℃下滴加入6.0eq.BBr3,反应12h后,0℃加入10mL水淬灭反应,用乙酸乙酯萃取,饱和NaHCO3溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,柱层析(洗脱剂,石油醚/乙酸乙酯=7:3)得到化合物16g/16h。
(5)称取1.0eq.化合物16h于100mL的单口瓶中,加入25mL DCM,滴加加入1.2eq.三乙胺后,加入1.2eq.丙烯酰氯,室温反应12h后,加入10mL水淬灭反应,用DCM萃取,饱和NaHCO3溶液洗涤,有机层无水NaSO4干燥,减压脱溶得到粗产物,柱层析(洗脱剂,石油醚/乙酸乙酯=5:1)得到化合物16i。
【实施例1】4-丙烯酰胺苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂17a的制备
称取3,4-二(4-羟基苯基)呋喃1.0e.q和4-丙烯酰胺苯基乙烯磺酸脂(13a)1.0e.q置于25mL的单口瓶圆底瓶,加入1mL四氢呋喃,然后缓慢升温至90℃,反应12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,得到黄色的固体,产率61%。
1H NMR(400MHz,Acetone-d6)δ9.59(s,1H),8.82(d,J=3.2Hz,1H),8.75(d,J=3.0Hz,1H),7.81–7.67(m,2H),7.30–7.13(m,6H),6.89–6.74(m,4H),6.39(m,J=16.9,6.0Hz,2H),5.72(dd,J=9.7,2.3Hz,1H),5.64–5.62(m,1H),5.43(d,J=4.3Hz,1H),3.77(dd,J=8.3,4.5Hz,1H),2.40(dt,J=12.0,4.4Hz,1H),2.27(dd,J=12.1,8.4Hz,1H).
13C NMR(101MHz,Acetone-d6)δ163.46,162.32,157.71,157.56,145.09,141.29,138.19,136.96,131.64,129.17,128.55,126.69,123.97,123.18,122.60,120.56,115.74,115.51,84.39,82.75,54.10,19.77.
【实施例2】4-(2-丁烯酰胺基)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂17b的制备
参照实施例1的制备方法,以3,4-二(4-羟基苯基)呋喃和乙烯磺酸酯衍生物13b为原料,产物为黄色固体,收率53%。
1H NMR(400MHz,Acetone-d6)δ9.39(s,1H),8.76(s,2H),7.77(dd,J=34.6,9.0Hz,2H),7.38–7.12(m,6H),6.97–6.88(m,1H),6.87–6.74(m,4H),6.12(dd,J=15.1,1.5Hz,1H),5.65–5.60(m,1H),5.40(t,J=18.0Hz,1H),3.80–3.56(m,1H),2.40(dt,J=12.0,4.4Hz,1H),2.27(dd,J=12.1,8.4Hz,1H),1.85(dd,J=6.9,1.2Hz,3H).
13C NMR(101MHz,Acetone-d6)δ163.76,157.58,157.44,144.89,141.34,140.61,138.45,137.02,129.20,128.60,125.70,124.12,123.32,122.57,120.39,115.73,115.51,84.38,82.77,60.50,30.60,16.94.
【实施例3】4-丙炔酰胺基苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂17c的制备
参照实施例1的制备方法,以3,4-二(4-羟基苯基)呋喃和乙烯磺酸酯衍生物13c为原料,产物为黄色固体,收率55%。
1H NMR(400MHz,MeOD)δ7.54(d,J=9.0Hz,2H),7.18–7.06(m,6H),6.72(dd,J=16.8,8.7Hz,4H),5.83(s,1H),5.59(d,J=0.9Hz,1H),5.34(d,J=3.8Hz,1H),3.67(dd,J=8.4,4.4Hz,1H),2.39(dt,J=12.0,4.4Hz,1H),2.19–2.11(m,4H),1.87(s,3H).
13C NMR(101MHz,MeOD)δ166.24,157.42,157.29,153.32,144.88,141.10,137.86,136.58,128.96,128.37,123.74,123.01,122.29,120.77,118.23,115.45,115.21,84.39,82.78,60.21,53.48,30.24,26.25,18.88.
【实施例4】4-丙炔酰胺基苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂17d的制备
参照实施例1的制备方法,以3,4-二(4-羟基苯基)呋喃和乙烯磺酸酯衍生物13d为原料,产物为黄色固体,收率45%。
1H NMR(400MHz,Acetone-d6)δ10.04(s,1H),8.80(s,1H),8.75(s,1H),7.70(d,J=9.0Hz,2H),7.34–7.14(m,6H),6.89–6.72(m,4H),5.64–5.62(m,1H),5.43(d,J=4.3Hz,1H),3.81–3.77(m,1H),3.76(s,1H),2.40(dt,J=12.0,4.4Hz,1H),2.27(dd,J=12.1,8.3Hz,1H).
13C NMR(101MHz,Acetone-d6)δ157.61,157.48,149.75,145.61,141.35,137.28,137.00,129.17,128.60,124.08,123.28,122.78,120.89,115.69,115.50,84.36,82.77,77.71,74.99,60.64,30.60.
【实施例5】4-(2-氯乙酰胺)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂17e的制备
参照实施例1的制备方法,以3,4-二(4-羟基苯基)呋喃和乙烯磺酸酯衍生物13e为原料,产物为黄色固体,收率52%。
1H NMR(400MHz,Acetone-d6)δ9.60(s,1H),8.72(s,1H),8.67(s,1H),7.69(d,J=9.0Hz,2H),7.43–7.10(m,6H),6.94–6.61(m,4H),5.63(d,J=3.3Hz,1H),5.50–5.33(m,1H),4.24(s,2H),3.77(dd,J=8.3,4.5Hz,1H),2.40(dt,J=12.0,4.4Hz,1H),2.27(dd,J=12.1,8.4Hz,1H).
13C NMR(101MHz,Acetone-d6)δ164.76,157.62,157.49,145.45,141.34,137.47,136.98,129.18,128.59,124.06,123.26,122.70,120.80,115.72,115.52,84.37,82.77,60.59,43.19,30.60.
【实施例6】4-(2-溴乙酰胺基)苯基-(1R,4R)-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂17f的制备
参照实施例1的制备方法,以3,4-二(4-羟基苯基)呋喃和乙烯磺酸酯衍生物13f为原料,产物为黄色固体,收率54%。
1H NMR(400MHz,Acetone-d6)δ9.75(s,1H),8.74(s,1H),8.68(s,1H),7.68(d,J=9.0Hz,2H),7.23(dd,J=8.3,5.8Hz,6H),6.81(dd,J=13.1,8.6Hz,4H),5.63(d,J=5.0Hz,1H),5.43(d,J=4.2Hz,1H),4.03(s,2H),3.77(dd,J=8.3,4.5Hz,1H),2.40(dt,J=12.0,4.4Hz,1H),2.27(dd,J=12.1,8.4Hz,1H).
13C NMR(101MHz,Acetone-d6)δ164.77,157.56,157.43,145.40,141.35,137.71,137.02,129.38,129.20,128.60,124.13,123.33,122.73,120.51,115.71,115.50,84.37,82.77,60.57,30.60.
【实施例7】4-(6-溴己酰胺基)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂17g的制备
参照实施例1的制备方法,以3,4-二(4-羟基苯基)呋喃和乙烯磺酸酯衍生物13g为原料,产物为黄色固体,收率52%。
1H NMR(400MHz,Acetone-d6)δ9.34(s,1H),8.71(s,1H),7.68(d,J=8.9Hz,2H),7.36–7.14(m,6H),6.81(dd,J=12.4,8.6Hz,4H),5.63(s,1H),5.42(d,J=4.2Hz,1H),3.76(dd,J=8.3,4.4Hz,1H),3.48(t,J=6.7Hz,2H),2.47–2.33(m,3H),2.26(dd,J=12.0,8.4Hz,1H),1.92–1.82(m,2H),1.70(dt,J=15.2,7.5Hz,2H),1.48(dt,J=15.1,7.7Hz,2H).
13C NMR(101MHz,Acetone-d6)δ171.12,157.55,157.42,144.76,141.34,138.46,137.03,129.19,128.61,124.15,123.34,122.53,120.14,115.71,115.51,84.36,82.77,60.49,36.52,33.75,32.49,30.61,27.53,24.40.
【实施例8】4-(8-溴辛酰胺基)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸脂17h的制备
参照实施例1的制备方法,以3,4-二(4-羟基苯基)呋喃和乙烯磺酸酯衍生物13h为原料,产物为黄色固体,收率54%。
1H NMR(400MHz,Acetone-d6)δ9.28(s,1H),8.65(s,2H),7.67(d,J=9.0Hz,2H),7.35–7.11(m,6H),6.81(dd,J=11.4,8.6Hz,4H),5.63(d,J=0.9Hz,1H),5.42(d,J=3.6Hz,1H),3.76(dd,J=8.3,4.4Hz,1H),3.47(t,J=6.8Hz,2H),2.39(m,J=15.0,10.3,6.0Hz,3H),2.26(dd,J=12.1,8.4Hz,1H),1.89–1.76(m,2H),1.73–1.62(m,2H),1.42(dd,J=13.3,6.6Hz,2H),1.35(dd,J=7.3,3.6Hz,4H).
13C NMR(101MHz,Acetone-d6)δ171.47,157.53,157.41,144.77,141.34,138.43,137.02,129.19,128.62,124.13,123.34,122.55,120.21,115.71,115.52,84.37,82.79,60.53,36.76,33.96,32.68,31.77,30.63,27.80,25.22,22.48,13.56.
【实施例9】4-((5,6-双(4-羟基苯基)-N-(2,2,2-三氟乙基)-7-氧桥双环-[2.2.1]庚-5-烯)-2-磺酰氨基)苯基3-甲基丁-2-烯酸酯17i的制备
参照实施例1的制备方法,以3,4-二(4-羟基苯基)呋喃和乙烯磺酸酯衍生物13i为原料,产物为黄色固体,收率53%。
1H NMR(400MHz,MeOD)δ7.56–7.31(m,2H),7.12(dd,J=11.1,8.7Hz,4H),7.02(d,J=8.9Hz,2H),6.76(d,J=8.7Hz,2H),6.69(d,J=8.8Hz,2H),5.99–5.83(m,1H),5.45(d,J=0.9Hz,1H),5.28(d,J=3.7Hz,1H),4.45(dd,J=17.5,8.8Hz,2H),3.50(dd,J=8.3,4.4Hz,1H),2.24–2.13(m,4H),2.06–1.92(m,4H).
13C NMR(101MHz,MeOD)δ164.50,161.28,157.44,157.21,150.51,141.03,136.65,136.29,129.93,129.45,129.38,129.16,128.98,128.16,123.80,123.12,122.74,122.62,115.43,115.14,114.81,114.54,114.20,84.39,82.68,61.72,52.19,30.22,26.35,19.33.
【实施例10】苯基-5-(4-丙烯酰胺苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯18a的制备
参照实施例1的制备方法,以呋喃衍生物9a和乙烯基磺酸苯酯为原料,产物为黄色固体,收率33%。
1H NMR(400MHz,Acetone-d6)δ9.53(d,J=11.7Hz,1H),8.68(d,J=19.1Hz,1H),7.65(dd,J=10.0,7.8Hz,2H),7.44–7.30(m,6H),7.29–7.17(m,4H),6.86–6.78(m,2H),5.70(dd,J=5.0,1.0Hz,1H),5.47(dd,J=5.7,2.2Hz,1H),4.25–4.23(m,2H),3.81(m,J=34.0,8.3,4.5Hz,1H),2.44(m,J=10.9,6.3,4.5Hz,1H),2.30(m,J=25.8,12.1,8.4Hz,1H).
13C NMR(101MHz,Acetone-d6)δ164.58,157.83,157.70,149.65,143.12,140.90,138.90,138.36,138.25,136.57,129.93,129.91,129.44,128.84,128.22,127.64,127.10,122.26,122.23,119.87,119.65,115.80,115.61,114.98,84.30,82.81,54.09,43.27,30.63.
【实施例11】苯基-5-(4-(2-丁烯酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯18b的制备
参照实施例1的制备方法,以呋喃衍生物9b和乙烯基磺酸苯酯为原料,产物为黄色固体,收率43%。
1H NMR(400MHz,MeOD)δ7.51(t,J=8.2Hz,2H),7.34–7.15(m,6H),7.11(d,J=8.3Hz,3H),6.95–6.81(m,1H),6.69(dd,J=14.3,8.6Hz,2H),6.15–5.93(m,1H),5.58(d,J=1.8Hz,1H),5.52(s,1H),5.32(s,1H),5.23(s,1H),3.66(ddd,J=35.0,8.3,4.4Hz,1H),2.36(dd,J=12.1,4.5Hz,1H),2.24–2.01(m,1H),1.83(d,J=5.8Hz,3H).
13C NMR(101MHz,MeOD)δ166.58,157.83,153.70,149.65,143.12,140.90,138.90,138.36,138.25,136.57,129.93,129.91,129.44,128.84,128.22,127.64,127.10,122.26,122.23,119.87,119.65,115.80,115.61,114.98,84.30,82.81,54.09,43.27,30.63,18.81.
【实施例12】苯基-5-(4-(3-甲基-2-丁烯酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯18c的制备
参照实施例1的制备方法,以呋喃衍生物9c和乙烯基磺酸苯酯为原料,产物为黄色固体,收率55%。
1H NMR(400MHz,MeOD)δ7.47(t,J=9.1Hz,2H),7.29–7.16(m,6H),7.15–7.07(m,3H),6.68(dd,J=15.8,8.5Hz,2H),5.81(d,J=5.2Hz,1H),5.57(d,J=2.5Hz,1H),5.33(t,J=3.9Hz,1H),3.64(m,J=32.9,8.3,4.5Hz,1H),2.43–2.29(m,1H),2.20–2.06(m,4H),1.85(s,3H).
13C NMR(101MHz,MeOD)δ166.26,157.77,153.09,149.44,142.69,140.70,138.79,138.29,136.20,129.66,129.63,129.15,128.57,127.84,127.29,126.93,121.92,121.90,119.87,119.62,118.37,115.50,115.27,84.29,82.81,60.11,26.20,18.82.
【实施例13】苯基-5-(4-(2-氯乙酰胺)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯18d的制备
参照实施例1的制备方法,以呋喃衍生物9d和乙烯基磺酸苯酯为原料,产物为黄色固体,收率23%。
1H NMR(400MHz,MeOD)δ7.60(t,J=8.3Hz,2H),7.28(dddd,J=15.3,11.1,8.0,1.7Hz,6H),7.21–7.14(m,3H),6.81–6.69(m,2H),6.48–6.33(m,2H),5.77(ddd,J=9.3,3.9,2.6Hz,1H),5.65(d,J=1.9Hz,1H),5.39(t,J=4.3Hz,1H),3.72(ddd,J=37.8,8.4,4.4Hz,1H),2.43(ddd,J=14.7,10.0,4.6Hz,1H),2.18(ddd,J=20.6,12.2,8.5Hz,1H).
13C NMR(101MHz,MeOD)δ164.74,157.66,149.35,142.99,138.23,136.06,130.96,129.69,129.66,129.22,128.63,128.05,127.93,127.38,126.98,123.24,121.93,120.17,119.92,115.55,115.32,84.26,82.82,60.42,29.35.
【实施例14】苯基-5-(4-(8-溴癸酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯18e的制备
参照实施例1的制备方法,以呋喃衍生物9l和乙烯基磺酸苯酯为原料,产物为黄色固体,收率33%。
1HNMR(400MHz,MeOD)δ7.51(t,J=8.4Hz,2H),7.29(dt,J=12.2,6.1Hz,3H),7.19(ddd,J=23.1,12.0,5.1Hz,6H),6.72(dd,J=14.7,8.6Hz,2H),5.61(d,J=4.8Hz,1H),5.36(dd,J=7.5,4.3Hz,1H),3.68(ddd,J=33.2,8.3,4.4Hz,1H),3.44(dt,J=48.2,6.7Hz,2H),2.49–2.28(m,3H),2.16(ddd,J=15.4,12.2,8.5Hz,1H),1.84–1.71(m,2H),1.71–1.63(m,2H),1.39(dd,J=19.2,12.3Hz,6H).
13C NMR(101MHz,MeOD)δ173.26,157.63,149.37,142.78,140.60,138.47,138.40,136.12,129.68,129.65,129.17,128.59,127.89,127.34,126.94,121.93,120.02,119.75,115.53,115.30,84.29,82.70,60.11,44.43,36.62,33.15,32.55,28.77,28.19,27.68,25.39.
【实施例15】N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-2-丁烯酰胺18f的制备
参照实施例1的制备方法,以呋喃衍生物9b和乙烯基磺酰胺衍生物16h为原料,产物为黄色固体,收率58%。
1H NMR(400MHz,MeOD)δ7.59(d,J=8.6Hz,2H),7.24(d,J=8.7Hz,2H),7.12(d,J=8.7Hz,4H),6.94(dd,J=15.2,6.9Hz,1H),6.68(t,J=9.0Hz,4H),6.13(dd,J=15.2,1.7Hz,1H),5.49–5.46(m,1H),5.31(d,J=3.9Hz,1H),4.37(q,J=8.5Hz,2H),3.52(dd,J=8.3,4.4Hz,1H),2.21(dt,J=12.0,4.4Hz,1H),2.00(dd,J=12.2,8.4Hz,1H),1.91(dd,J=6.9,1.5Hz,3H).
13C NMR(101MHz,MeOD)δ165.37,157.56,157.47,142.72,141.40,138.41,136.24,130.30,130.17,128.39,128.14,127.96,125.57,125.04,123.44,122.78,120.21,115.64,115.26,84.34,82.75,61.30,52.38,30.10,16.74.
【实施例16】N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺18g的制备
参照实施例1的制备方法,以呋喃衍生物9c和乙烯基磺酰胺衍生物16h为原料产物为黄色固体,收率68%。
1H NMR(400MHz,MeOD)δ7.56(d,J=8.6Hz,2H),7.23(d,J=8.6Hz,2H),7.12(d,J=8.8Hz,4H),6.68(t,J=8.7Hz,4H),5.88(s,1H),5.31(d,J=4.1Hz,1H),4.37(q,J=8.5Hz,2H),3.52(dd,J=8.3,4.4Hz,1H),2.24–2.15(m,4H),2.03(s,1H),1.92(s,3H).
13C NMR(101MHz,MeOD)δ166.34,157.59,157.49,153.20,142.56,138.74,136.34,130.26,130.17,128.33,128.07,127.59,123.47,119.95,118.33,115.59,115.20,84.33,82.73,61.27,53.44,30.09,26.20,18.81.
【实施例17】N-(4-(-3-(4-羟基苯基)-5-(N-(4-甲氧基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基2-丁烯酰胺18h的制备
参照实施例1的制备方法,以呋喃衍生物9c和乙烯基磺酰胺衍生物16c为原料产物为黄色固体,收率73%。
1H NMR(400MHz,CDCl3)δ8.16(s,1H),7.92(s,1H),7.56–7.40(m,2H),7.25–7.02(m,6H),6.85–6.69(m,4H),5.80(s,1H),5.56(s,1H),5.37–5.24(m,1H),4.28(m,J=16.8,13.0,6.9Hz,2H),3.75(d,J=4.8Hz,3H),3.56–3.35(m,1H),2.32(s,1H),2.19(s,3H),2.01(s,1H),1.85(d,J=2.2Hz,4H).
13C NMR(101MHz,CDCl3)δ166.05,159.70,156.86,154.52,142.47,140.53,138.27,136.49,132.34,130.60,129.32,128.87,128.62,128.19,127.50,125.20,123.70,122.94,122.42,120.27,118.51,115.91,114.87,84.36,82.97,68.36,62.20,55.47,29.73,27.46,20.17.
【实施例18】N-(4-(3-(4-羟基苯基)-5-(N-(3-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺18i的制备
参照实施例1的制备方法,以呋喃衍生物9b和乙烯基磺酰胺衍生物16g为原料产物为黄色固体,收率57%。
1H NMR(400MHz,MeOD)δ7.53(d,J=8.5Hz,2H),7.19(d,J=8.6Hz,2H),7.10(dd,J=16.4,8.3Hz,3H),6.92(t,J=2.1Hz,1H),6.83–6.64(m,4H),5.87(s,1H),5.49(s,1H),5.31(d,J=4.2Hz,1H),4.50–4.37(m,2H),3.55(dd,J=8.3,4.3Hz,1H),2.25–2.13(m,4H),2.02–1.95(m,1H),1.91(s,3H).
13C NMR(101MHz,MeOD)δ166.32,158.03,157.53,153.15,142.63,140.13,138.68,136.34,129.84,128.45,127.82,127.55,125.49,123.39,122.71,119.87,118.69,118.32,115.94,115.30,115.22,84.27,82.76,61.74,51.82,30.09,26.20,18.80.
【实施例19】N-(4-(5-(N-乙基-N-(4-羟基苯基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺18j的制备
参照实施例1的制备方法,以呋喃衍生物9b和乙烯基磺酰胺衍生物16j为原料,产物为黄色固体,收率63%。
1H NMR(400MHz,MeOD)δ7.55(d,J=8.5Hz,2H),7.23(d,J=8.6Hz,2H),7.13(d,J=8.6Hz,2H),7.07(d,J=8.8Hz,2H),6.70(d,J=8.7Hz,4H),5.87(s,1H),5.45(d,J=0.8Hz,1H),5.31(d,J=3.9Hz,1H),3.71(q,J=7.0Hz,2H),3.48(dd,J=8.3,4.4Hz,1H),2.27–2.14(m,4H),2.07–1.97(m,1H),1.90(s,3H),1.03(t,J=7.0Hz,3H).
13C NMR(101MHz,MeOD)δ166.31,157.45,157.07,153.22,142.34,138.67,136.53,130.52,129.81,128.44,127.90,127.71,123.57,119.88,118.33,115.39,115.22,84.37,82.79,60.96,46.60,29.98,26.24,18.83,13.62.
【实施例20】N-(4-(5-(N-(4-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺18k的制备
参照实施例1的制备方法,以呋喃衍生物9b和乙烯基磺酰胺衍生物16e为原料,产物为黄色固体,收率52%。
1H NMR(400MHz,CDCl3)δ7.99(d,J=12.9Hz,1H),7.76(s,1H),7.45(dd,J=14.1,8.2Hz,2H),7.33–7.21(m,2H),7.21–6.91(m,6H),6.74(dd,J=19.8,8.3Hz,2H),5.79(d,J=7.1Hz,1H),5.54(s,1H),5.31(d,J=9.0Hz,1H),4.48–4.11(m,2H),3.53–3.36(m,1H),2.29(s,1H),2.20(s,3H),2.00(s,1H),1.87(d,J=1.9Hz,3H).
13C NMR(101MHz,CDCl3)δ165.99,163.59,161.10,156.98,156.80,154.78,142.51,140.52,138.20,136.37,134.82,131.28,129.28,128.63,128.15,127.52,125.05,123.63,122.88,122.27,120.30,118.41,116.83,115.90,84.28,82.95,62.64,52.54,29.73,27.48,20.18.
【实施例21】6-溴-N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7)-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)己酰胺18l的制备
参照实施例1的制备方法,以呋喃衍生物9j和乙烯基磺酰胺衍生物16h为原料,产物为黄色固体,收率44%。
1H NMR(400MHz,MeOD)δ7.55(d,J=8.6Hz,2H),7.24(d,J=8.6Hz,2H),7.12(dd,J=8.5,6.8Hz,4H),6.68(dd,J=11.6,8.7Hz,4H),5.48(d,J=5.6Hz,1H),5.33(d,J=4.1Hz,1H),4.37(q,J=8.5Hz,2H),3.51(dd,J=8.3,4.3Hz,1H),3.46(t,J=6.7Hz,2H),2.41(t,J=7.4Hz,2H),2.21(dt,J=11.9,4.3Hz,1H),2.01(dd,J=12.2,8.5Hz,1H),1.89(dd,J=14.5,7.0Hz,2H),1.78–1.70(m,2H),1.54(dd,J=15.2,8.1Hz,2H).
13C NMR(101MHz,MeOD)δ173.09,157.61,157.54,142.70,138.42,136.30,130.24,130.17,128.30,128.07,127.91,123.42,120.11,115.56,115.18,84.34,82.72,61.26,36.34,32.73,32.29,30.03,29.35,27.40,24.57.
【实施例22】N-(4-(5-(N-(3-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺18m的制备
参照实施例1的制备方法,以呋喃衍生物9j和乙烯基磺酰胺衍生物16f为原料,产物为黄色固体,收率50%。
1H NMR(400MHz,CDCl3)δ7.99(d,J=12.9Hz,1H),7.76(s,1H),7.45(dd,J=14.1,8.2Hz,2H),7.33–7.21(m,2H),7.21–6.91(m,6H),6.74(dd,J=19.8,8.3Hz,2H),5.79(d,J=7.1Hz,1H),5.54(s,1H),5.31(d,J=9.0Hz,1H),4.48–4.11(m,2H),3.53–3.36(m,1H),2.29(s,1H),2.20(s,3H),2.00(s,1H),1.87(d,J=1.9Hz,3H).
13C NMR(101MHz,CDCl3)δ165.99,163.59,161.10,156.98,156.80,154.78,142.51,140.52,138.20,136.37,134.82,131.28,129.28,128.63,128.15,127.52,125.05,123.63,122.88,122.27,120.30,118.41,116.83,115.90,84.28,82.95,62.64,52.54,29.73,27.48,20.18.
【实施例23】不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物的抗肿瘤活性实验
MCF-7人乳腺癌细胞系和MCF-10A正常的乳腺细胞获自ATCC。将细胞培养在具有10%FBS和1%双抗的含酚红DMEM中。将测试化合物溶解在DMSO中,药物浓度为100mol/L。将细胞接种在96孔板(Nest Biotech Co,中国)中,在培养箱中培育24h。将不同浓度的测试化合物加入96孔板中,每个浓度平行3个孔,并将溶媒DMSO作为阴性对照,4-羟基他莫昔芬作为阳性对照药。72h后,向每个孔中加入10μL 2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺酸苯)-2H-四唑单钠盐(CCK-8)溶液并再培养2h。在WellscanMK-2酶标仪上于490nm处读取吸光度(OD)。通过Logit方法测定IC50(诱导50%细胞凋亡的浓度)。所有化合物至少平行重复检测3次,结果见表1。化合物活性普遍优于4-羟基他莫昔芬,其中18g、18h、18j、18k的活性是4-羟基他莫昔芬10倍,其药物安全选择性指数SI值远大于4-羟基他莫昔芬(表1)。
表1
【实施例24】不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物的针对突变株的抗肿瘤活性实验
T47D人乳腺癌细胞系、T47DY537S和T47DD538G突变型乳腺细胞获自ATCC。将细胞培养RPMI 1640培养基中。将测试化合物溶解在DMSO中,药物浓度为100mol/L。将细胞接种在96孔板(Nest Biotech Co,中国)中,在培养箱中培育24h。将不同浓度的测试化合物加入96孔板中,每个浓度平行3个孔,并将溶媒DMSO作为阴性对照,4-羟基他莫昔芬作为阳性对照药。72h后,向每个孔中加入10μL 2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺酸苯)-2H-四唑单钠盐(CCK-8)溶液并再培养2h。在WellscanMK-2酶标仪上于490nm处读取吸光度(OD)。通过Logit方法测定IC50(诱导50%细胞凋亡的浓度)。所有化合物至少平行重复检测3次,结果见表2。化合物18f、18g、18i、18j针对T47DY537S和T47DD538G突变型乳腺的细胞活性明显优于4-羟基他莫昔芬,其中18g针对T47DY537S和T47DD538G的细胞抑制活性分别是4-羟基他莫昔芬的5倍和10倍(图1)。
表2
【实施例25】不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物的蛋白降解活性实验将MCF-7细胞接种于6孔板中培育24h,然后将细胞与DMSO或化合物(1μM和5μM)共培育20h。提取全蛋白,通过蛋白质印迹分析雌激素受体ERα蛋白水平。使用8%SDS-PAGE凝胶电泳分离细胞裂解液中的蛋白质。然后将凝胶电印迹到聚偏二氟乙烯(PVDF)膜(LifeTechnologies)上,用5%脱脂牛奶封闭2h,再与兔anti-ERα抗体(1:1000,CST)和小鼠Anti-β-Actin抗体(1:10000,ABclonal Technology)孵育过夜。随即用0.1%Tween-20的TBS溶液把膜洗涤三次。室温下将膜与山羊抗兔辣根过氧化物酶偶联的二抗(Thermo)一起孵育1h。用0.1%Tween-20的TBS溶液把膜洗涤三次后,通过ECL化学发光法进行显影。结果见图2,其中,C是空白对照,Ful是阳性对照,OBHSA是5,6-双(4-羟基苯基)-N-苯基-N-(2,2,2-三氟乙基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺胺。结果表明18h、18f、18g、18j在5μM时可使ER蛋白高效降解。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (9)
1.一种含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物,其特征在于:结构如通式(I)或通式(II)所示:
(I) (II)
其中,
X 为O、NCH2CH3或NCH2CF3;
R2为H、OH、OMe 或F;
所述通式(I)或通式(II)所示化合物选自如下具体化合物:
4-丙炔酰胺基苯基-5,6-双(4-羟基苯基)-7-氧桥双环[2.2.1]庚-5-烯-2-磺酸酯;
4-(2-氯乙酰胺)苯基-5,6-双(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯;
苯基-5-(4-丙烯酰胺苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯;
苯基-5-(4-(2-丁烯酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯;
苯基-5-(4-(3-甲基-2-丁烯酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯;
苯基-5-(4-(2-氯乙酰胺)苯基) -6-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-5-烯-2-磺酸酯;
苯基-5-(4-(8-溴癸酰胺基)苯基)-6-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-5-烯-2-磺酸酯;
N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-2-丁烯酰胺;
N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺;
N-(4-(3-(4-羟基苯基)-5-(N- (4-甲氧基苯基)-N-(2,2,2-三氟乙基)氨磺酰基) -7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基2-丁烯酰胺;
N-(4-(3-(4-羟基苯基)-5-(N- (3-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺;
N-(4-(5-(N-乙基-N-(4-羟基苯基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基-2-丁烯酰胺;
N-(4-(5-(N- (4-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环[2.2.1]庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺;
6-溴-N-(4-(3-(4-羟基苯基)-5-(N-(4-羟基苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-7)-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)己酰胺;
N-(4-(5-(N-(3-氟苯基)-N-(2,2,2-三氟乙基)氨磺酰基)-3-(4-羟基苯基)-7-氧桥双环-[2.2.1]-庚-2-烯-2-基)苯基)-3-甲基丁-2-烯酰胺。
2.权利要求1所述的含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物的制备方法,其特征在于:
3,4-二(4-羟基苯基)-呋喃化合物4与含有共价弹头的乙烯磺酰胺衍生物或乙烯磺酸酯衍生物13,通过Diels-Alder反应制备得到结构如通式(I)所示的化合物;
含有共价弹头的呋喃衍生物9与含有R2基团的乙烯磺酰胺衍生物或乙烯磺酸酯衍生物16,通过Diels-Alder反应制备得到结构如通式(II)所示的化合物;
3,4-二(4-羟基苯基)-呋喃化合物4的结构式为:
含有共价弹头的乙烯磺酰胺衍生物或乙烯磺酸酯衍生物13的结构式为:
含有共价弹头的呋喃衍生物9的结构式为:
含有R2基团的乙烯磺酰胺衍生物或乙烯磺酸酯衍生物16的结构式为:
上述结构式中,X、R1、R2为权利要求1中所述具体化合物中的相应基团。
3.根据权利要求2所述的制备方法,其特征在于:所述的Diels-Alder反应的条件为90~100℃反应12~18小时。
4.一种权利要求1所述的含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物药理或生理上可接受的盐。
5.权利要求1所述的含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物或权利要求4所述的盐在制备药物中的应用,其特征在于:所述的药物为抗乳腺癌药物、降解雌激素受体的药物或靶向突变型雌激素受体的药物。
6.一种抗乳腺癌药物组合物,其特征在于:包含权利要求1所述的含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物或权利要求4所述的盐。
7.一种降解雌激素受体或突变型雌激素受体的药物组合物,其特征在于:包含权利要求1所述的含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物或权利要求4所述的盐。
8.一种针对乳腺癌内分泌疗法耐药的药物组合物,其特征在于:包含权利要求1所述的含有不同共价弹头结构的氧桥双环-[2.2.1]-庚烯类化合物或权利要求4所述的盐。
9.根据权利要求6-8任一项所述的药物组合物,其特征在于:还包含一种或多种药学上可接受的助剂。
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