CN114656449A - 一种含氨基甲酸结构的水飞蓟宾衍生物及其用途 - Google Patents
一种含氨基甲酸结构的水飞蓟宾衍生物及其用途 Download PDFInfo
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- CN114656449A CN114656449A CN202210188512.XA CN202210188512A CN114656449A CN 114656449 A CN114656449 A CN 114656449A CN 202210188512 A CN202210188512 A CN 202210188512A CN 114656449 A CN114656449 A CN 114656449A
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- carbamic acid
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- silibinin
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- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical class C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 title claims abstract description 63
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbamic acid group Chemical group C(N)(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 title claims abstract description 19
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- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 10
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- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 8
- -1 isotope Chemical group 0.000 claims abstract description 8
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims abstract description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
Description
技术领域
本发明涉及医药技术领域,具体涉及一种含氨基甲酸结构的水飞蓟宾衍生物及其用途。
背景技术
癌症是一种由人体细胞异常增殖引起的致死率极高的恶性疾病。据估计,2020年全球新发癌症病例约为1930万,到2040年这一数字将激增至2840万。天然产物因其分子多样性和新颖性而被广泛研究并最终开发成药物,尤其是抗癌化疗药物。
水飞蓟素是从水飞蓟植物的种子中分离出来的一种活性提取物,其中含有大约65-80%的黄酮木脂素(水飞蓟宾、异水飞蓟宾、水飞蓟亭、水飞蓟宁、2,3-脱氢水飞蓟宾),以及少量的类黄酮和约20-30%的不明聚合酚类成分。水飞蓟宾是水飞蓟素的主要活性成分,是水飞蓟宾A(SLB A)和水飞蓟宾B(SLB B)两种非对映异构体的大致1:1混合物,而2,3-脱氢水飞蓟宾(DHS)由以下混合物组成两种对映异构体,即DHS A和DHS B。
水飞蓟宾具有清除自由基、维持细胞膜稳定性、抗脂质过氧化、降血脂等药理活性,它可促进肝细胞再生,改善肝功能,具有较强的肝脏保护作用,临床上常用来治疗肝纤维化、非酒精性脂肪肝、酒精性肝病等肝损伤疾病。肝纤维化是指肝结缔组织异常增生,其可发生在任意肝脏损伤的修复愈合过程,是肝脏损伤与慢性炎症进展的必然结果。肝星状细胞(HSC)的激活和增殖是肝纤维化发生、发展的中心环节。研究发现,水飞蓟宾对HSC增殖和迁移具有明显的抑制作用。李伟甲在乙醇诱导的肝纤维化模型小鼠中发现,水飞蓟宾的治疗可以通过调控Wnt/β-catenin信号通路以及减少小鼠血清中透明质酸、层黏连蛋白、谷丙转氨酶、羟脯氨酸的含量,降低肝细胞损伤并逆转肝纤维化进程((1)杨兴平,蒋丽琳.茵栀黄颗粒联合水飞蓟宾胶囊治疗酒精性肝病的疗效观察.现代药物与临床,2019,34(3):701-704.(2)黄家明.水飞蓟宾对肝星状细胞增殖的抑制和促凋亡作用.临床合理用药杂志,2017,10:83-84.)。
水飞蓟宾和DHS已被证明在体外和体内都具有抗癌和促凋亡活性(Agarwal R,Agarwal C,Ichikawa H et al.Anticancer potential of silymarin:from bench tobed side.Anticancer Res.2006;26:4457-4498.)。近期大量研究发现水飞蓟宾对乳腺癌、肺癌、结肠癌、前列腺癌、胰腺癌、肝癌、宫颈癌等多种肿瘤细胞具有较好的抑制作用,并受到广泛关注。目前其作为治疗前列腺癌、EGFR突变型肺腺癌和乳腺癌放射性皮炎进入Ⅱ期临床试验,治疗晚期肝癌进入Ⅰ期临床试验(Siegel AB,et al.Integr Cancer Ther,2014,13:46-53)。
近年来,高效低毒的抗肿瘤药物水飞蓟宾及其衍生物引起了国内外学者的广泛关注。但有报道指出,由于水飞蓟宾的水溶性和脂溶性均较差,水飞蓟宾原料药在人体内的生物利用度不足5%。这严重限制了水飞蓟宾在抗肿瘤方面的应用。因此,各医药企业开始将对水飞蓟宾原料药结构的修饰及剂型的改造作为研制水飞蓟宾新药的重点。随着关于水飞蓟宾的药理学研究的不断深入,高效低毒的抗肿瘤药物水飞蓟宾及其衍生物在临床上的应用前景将会越来越广阔。
发明内容
本发明旨在提供一种含氨基甲酸结构的水飞蓟宾衍生物及其用途,相比于水飞蓟宾,本发明的化合物具有更好的药效。
本发明的技术方案如下:
一种含氨基甲酸结构的水飞蓟宾衍生物及其药学上可接受的盐,结构如通式Ⅰ所示:
R1和R2各自独立地选自:氢原子、氨基、酰基、烷基、烷氧基、烯基、炔基、同位素、卤代烯基、杂烷基、芳基、杂芳基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、同位素、=O、-CF3、烷基、链烯基、链炔基、羧基、羟基、羟烷基、烷氧基、烷氧烷基、≡N;
R3、R4和R5各自独立地选自:氢原子、烷基、杂烷基、烯基、炔基、芳基烷基、环烷基、芳基、杂芳基、杂芳基烷基、杂环烷基、烷基氨基羰基、环烷基氨基羰基、杂芳基氨基羰基、杂芳基氨基羰基;
上述基团中的任一基团各自独立地可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、同位素、氨基、羧基、苯基、苄基、苯基氧基、=O、CF3、卤代烷基、烷基、烯基、炔基、羟基、羟烷基、烷氧基、烷氧基烷基、杂烷基、芳基烷基、环烷基、芳基、杂芳基、杂芳基烷基、杂环烷基、杂环烯基、烷氧基烷基、烯氧基、炔氧基、烷基氨基、氨基烷基、烷基氨基羰基、磺酰基、烷基磺酰基、烷基亚磺酰基、或氨基磺酰基。
优选的,R1和R2各自独立地选自:相连氮原子一起构成的3-8元杂环基或5-10元杂芳基。
优选的,所述的含氨基甲酸结构的水飞蓟宾衍生物及其药学上可接受的盐,选自以下化合物:
其中,经药效学实验研究表明,上述化合物中,化合物1、化合物2、化合物4、化合物10、化合物11、化合物14、化合物19、化合物20具有更好的活性,对癌症具有更好的治疗效果。
本发明还公开了上述的水飞蓟宾衍生物的制备方法,制备方法包括:
本发明还公开了通式Ⅰ的含氨基甲酸结构的水飞蓟宾衍生物及其药学上可接受的盐在制备治疗增生性疾病药物中的用途。
本发明还公开了通式Ⅰ的含氨基甲酸结构的水飞蓟宾衍生物及其药学上可接受的盐在制备抗肿瘤药物中的用途。
所述肿瘤为人甲状腺导管癌细胞或人结肠癌。
本发明还公开了通式Ⅰ的含氨基甲酸结构的水飞蓟宾衍生物及其药学上可接受的盐在制备抑制激酶药物中的用途。
所述抑制激酶的活性是值抑制Hsp90,BCL-2,ERK,Akt,COX-2,MMP-9,CDK或者EGFR的活性。
本发明的含氨基甲酸结构的水飞蓟宾衍生物,经药理实验证实具有很好的抗肿瘤活性,从而可预期其发展成为防治肿瘤疾病药物的制药用途,具有潜在的巨大社会效益和经济效益。
本发明中通式Ⅰ的化合物由天然药物为母体制备而得,合成方法简单,成本低,污染小,适于产业化。
具体实施方式
为更好地理解本发明的实质,下面首先用实施例的形式说明化合物的制备过程,实施例给出了化合物的部分物理和化学及波谱学数据。必须说明,本发明的实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
实施例1
化合物1的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(465.9mg,0.97mmol,1.0eq)和四氢呋喃(7.0mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将N,N-二异丙基乙胺(249.6mg,1.93mmol,2.0eq)和4-二甲氨基吡啶(23.6mg,0.19mmol,0.2eq)加入反应瓶中,氩气置换6次,将[1,4']联哌啶-1'-甲酰氯(234.0mg,1.01mmol,1.05eq)加入反应瓶中,氩气置换6次,将体系控温0-5℃搅拌反应24小时。TLC检测反应完毕后,向体系中加入30mL水和30mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入30mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入50mL水洗涤,分离有机相,加入50mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到560.0mg浅黄色固体,加入6.0mL二氯甲烷及0.8mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=8/1展开剂的展缸中进行展开1次,吹干后再放入事先配好二氯甲烷/甲醇=6.5/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到71.3mg白色固体,mp 146-149℃。
经检测得化合物1,1H NMR(DMSO-d6,400MHz):δ11.69(s,1H),9.21(s,1H),7.11(s,1H),7.06-702(m,2H),7.00(d,J=6.96,1H),6.87(dd,J=6.32,1H),6.81(d,J=6.32,1H),6.37(s,1H),6.33(s,1H),5.99(d,J=4.60,1H),5.23(d,J=9.24,1H),5.00(br,1H),4.92(d,J=6.44,1H),4.79-4.75(m,1H),4.18(br,1H),4.10(br,1H),4.03(br,1H),3.78(s,3H),3.55-3.53(m,1H),3.53-3.35(m,3H),3.00(t,J=10.04,1H),2.87(t,J=9.92,1H),2.50(m,3H),1.79-1.76(m,2H),1.50-1.39(m,8H).13C NMR(DMSO-d6,126MHz)δ199.8,162.3,162.1,159.4,151.8,148.0,147.4,144.2,143.7,130.2,127.8,121.9,120.9,117.1,116.8,115.7,111.9,104.6,103.0,101.8,83.1,78.5,76.3,72.1,61.7,60.5,56.0,50.0,44.3,43.8,27.8,27.3,26.1,24.6.MS(ESI+)m/z calcd for C36H41N2O11 677.27,found 677.60(M+H)+.
实施例2
化合物2的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和四氢呋喃(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将N,N-二异丙基乙胺(193.8mg,1.50mmol,3.0eq)和4-二甲氨基吡啶(18.3mg,0.15mmol,0.3eq)加入反应瓶中,氩气置换6次,将二异丙基甲胺酰氯(163.7mg,1.00mmol,2.0eq)加入反应瓶中,氩气置换6次,将体系控温0-5℃搅拌反应24小时。TLC检测反应完毕后,向体系中加入20mL水和20mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入20mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入30mL水洗涤,分离有机相,加入30mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到400.0mg浅黄色固体,加入4.0mL二氯甲烷及0.8mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=20/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到121.2mg白色固体,mp 138-141℃。
经检测得化合物2,1H NMR(DMSO-d6,400MHz):δ11.69(s,1H),9.16(s,1H),7.12(d,J=1.00,1H),7.05(d,1H),7.02(s,1H),7.00(dd,J=8.36,0.68,1H),6.88(dd,J=8.16,1.68,1H),6.81(d,J=8.08,1H),6.32(d,J=2.08,1H),6.28(d,J=2.32,1H),5.96(d,J=6.36,1H),5.23(d,J=11.60,1H),4.98(t,J=4.92,1H),4.92(d,J=7.92,1H),4.78-4.73(m,1H),4.20-4.16(m,1H),3.91(br,2H),3.78(s,3H),3.55-3.52(m,1H),3.37-3.31(m,1H),1.22(br,12H).13C NMR(DMSO-d6,126MHz)δ199.8,162.4,162.2,159.5,151.8,148.0,147.4,144.2,143.7,130.2,127.8,121.8,120.9,117.1,116.8,115.7,112.0,104.4,102.4,101.3,83.1,78.5,76.3,72.2,60.6,56.0,47.0,46.4,21.7,20.4.MS(ESI+)m/zcalcd for C32H35NO11Na 632.21,found 632.40(M+Na)+.
实施例3
化合物3的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和四氢呋喃(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将N,N-二异丙基乙胺(129.2mg,1.0mmol,2.0eq)和4-二甲氨基吡啶(12.2mg,0.10mmol,0.2eq)加入反应瓶中,氩气置换6次,将二乙氨基甲酰氯(71.2mg,0.53mmol,1.05eq)加入反应瓶中,氩气置换6次,将体系控温0-5℃搅拌反应24小时。TLC检测反应完毕后,向体系中加入20mL水和20mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入20mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入30mL水洗涤,分离有机相,加入30mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到385.5mg黄色固体,加入4.0mL二氯甲烷及0.8mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=12/1展开剂的展缸中进行展开1次,吹干后再放入事先配好二氯甲烷/甲醇=20/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到140.6mg白色固体,mp 129-132℃。
经检测得化合物3,1H NMR(DMSO-d6,400MHz):δ11.68(s,1H),9.16(s,1H),7.11(d,J=2.24,1H),7.07(d,1H),7.02(d,J=1.36,1H),7.00(d,J=8.88,1H),6.88(dd,J=8.12,1.64,1H),6.81(d,J=8.08,1H),6.35(d,J=2.08,1H),6.31(d,J=2.32,1H),5.96(d,J=6.32,1H),5.23(d,J=11.60,1H),4.97(t,J=1.00,1H),4.92(d,J=7.92,1H),4.79-4.73(m,1H),4.20-4.16(m,1H),3.78(s,3H),3.52-3.55(m,1H),3.35-3.33(m,1H),3.31-3.26(q,J=6.76,4H),1.17(t,J=6.92,3H),1.12(t,J=6.92,3H).13C NMR(DMSO-d6,126MHz)δ199.8,162.3,162.1,159.5,152.3,148.0,147.4,144.2,143.7,130.2,127.8,121.9,120.9,117.1,116.8,115.7,112.0,104.6,102.8,101.6,83.1,78.5,76.3,72.2,60.6,56.0,42.3,42.1,14.6,13.6.MS(ESI+)m/z calcd for C30H31NO11Na 604.18,found604.40(M+Na)+.
实施例4
化合物4的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和四氢呋喃(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将N,N-二异丙基乙胺(193.8mg,1.50mmol,3.0eq)和4-二甲氨基吡啶(18.3mg,0.15mmol,0.3eq)加入反应瓶中,氩气置换6次,将1-哌啶酰氯(147.6mg,1.00mmol,2.0eq)加入反应瓶中,氩气置换6次,将体系控温0-5℃搅拌反应14小时。TLC检测反应完毕后,向体系中加入20mL水和20mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入20mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入30mL水洗涤,分离有机相,加入30mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到400.0mg浅黄色固体,加入4.0mL二氯甲烷及0.8mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到138.0mg白色固体,mp 146-147℃。
经检测得化合物4,1H NMR(DMSO-d6,400MHz):δ11.68(s,1H),9.16(s,1H),7.11(d,J=2.00,1H),7.04(d,1H),7.02(s,1H),6.99(d,J=8.72,1H),6.88(dd,J=8.12,1.44,1H),6.81(d,J=8.04,1H),6.35(d,J=2.08,1H),6.32(d,J=2.44,1H),5.96(d,J=6.36,1H),5.23(d,J=11.56,1H),4.98(t,J=5.44,1H),4.92(d,J=7.96,1H),4.79-4.73(m,1H),4.19-4.16(m,1H),3.78(s,3H),3.56-3.51(m,1H),3.49(br,2H),3.39(br,2H),3.37-3.31(m,1H),1.58-1.53(m,6H).13C NMR(DMSO-d6,126MHz)δ199.9,162.3,162.1,159.5,151.8,148.0,147.4,144.2,143.7,130.2,127.8,121.7,120.9,117.0,116.8,115.7,111.9,104.6,102.9,101.7,83.1,78.5,76.3,72.1,60.6,56.0,45.7,45.1,25.8,25.4,24.0.MS(ESI+)m/z calcd for C31H31NO11Na 616.18,found 616.30(M+Na)+.
实施例5
化合物5的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和四氢呋喃(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将N,N-二异丙基乙胺(129.2mg,1.0mmol,2.0eq)和4-二甲氨基吡啶(12.2mg,0.10mmol,0.2eq)加入反应瓶中,氩气置换6次,将1-吡咯烷羰酰氯(70.1mg,0.53mmol,1.05eq)加入反应瓶中,氩气置换6次,将体系控温0-5℃搅拌反应15小时。TLC检测反应完毕后,向体系中加入20mL水和20mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入20mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入30mL水洗涤,分离有机相,加入30mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到320mg淡黄色固体,加入4.0mL二氯甲烷及0.8mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开1次,吹干后再放入事先配好二氯甲烷/甲醇=10/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到75.6mg白色固体,mp 142-145℃。
经检测得化合物5,1H NMR(DMSO-d6,400MHz):δ11.68(s,1H),9.16(s,1H),7.11(d,J=2.16 1H),7.06(d,1H),7.02(d,J=1.52,1H),6.99(d,J=8.92,1H),6.88(dd,J=8.16,1.24,1H),6.81(d,J=8.08,1H),6.37(d,J=2.08,1H),6.33(d,J=2.52,1H),5.96(d,J=6.36,1H),5.23(d,J=11.56,1H),4.98(t,J=5.44,1H),4.92(d,J=7.96,1H),4.79-4.73(m,1H),4.19-4.17(m,1H),3.78(s,3H),3.56-3.51(m,1H),3.46-3.43(t,J=6.32,2H),3.37-3.33(m,1H),3.32(t,J=6.12,2H),1.89-1.82(m,4H).13C NMR(DMSO-d6,126MHz)δ199.9,162.3,162.1,159.3,151.2,148.0,147.4,144.2,143.7,130.2,127.8,121.9,120.9,117.1,116.8,115.7,112.0,104.6,102.9,101.7,83.1,78.5,76.3,72.1,60.6,56.0,46.7,46.6,25.6,24.8.MS(ESI+)m/z calcd for C30H29NO11Na 602.16,found 602.30(M+Na)+.
实施例6
化合物6的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和四氢呋喃(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将N,N-二异丙基乙胺(129.2mg,1.0mmol,2.0eq)和4-二甲氨基吡啶(12.2mg,0.10mmol,0.2eq)加入反应瓶中,氩气置换6次,将二甲氨基甲酰氯(56.5mg,0.53mmol,1.05eq)加入反应瓶中,氩气置换6次,将体系控温0-5℃搅拌反应48小时。TLC检测反应完毕后,向体系中加入20mL水和20mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入20mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入30mL水洗涤,分离有机相,加入30mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到315.5mg淡黄色固体,加入4.0mL二氯甲烷及0.8mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开1次,吹干后再放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到126.1mg白色固体,mp 138-141℃。
经检测得化合物6,1H NMR(DMSO-d6,400MHz):δ11.68(s,1H),9.16(s,1H),7.11(t,J=1.96,1H),7.04(d,1H),7.02(s,1H),6.99(d,J=8.20,1H),6.88(dd,J=8.08,1.16,1H),6.81(d,J=8.08,1H),6.36(d,J=2.08,1H),6.32(d,J=2.44,1H),5.96(d,J=6.40,1H),5.23(d,J=11.60,1H),4.98(t,J=5.40,1H),4.92(d,J=7.92,1H),4.79-4.73(m,1H),4.19-4.16(m,1H),3.78(s,3H),3.56-3.51(m,1H),3.37-3.31(m,1H),3.00(s,3H),2.90(s,3H).13C NMR(DMSO-d6,126MHz)δ199.8,162.3,162.1,159.4,153.0,148.0,147.4,144.2,143.7,130.2,127.8,121.9,120.9,117.1,116.8,115.7,112.0,104.6,103.0,101.8,83.1,78.5,76.3,72.1,60.6,56.0,36.8,36.6.MS(ESI-)m/z calcd for C28H26NO11552.15,found 552.30(M-H)-.
实施例7
化合物7的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(120.6mg,0.25mmol,1.0eq)和四氢呋喃(1.8mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将N,N-二异丙基乙胺(64.6mg,0.50mmol,2.0eq)和4-二甲氨基吡啶(6.2mg,0.20mmol,0.2eq)加入反应瓶中,氩气置换6次,将4-吗啉碳酰氯(39.3mg,0.26mmol,1.05eq)加入反应瓶中,氩气置换6次,将体系控温0-5℃搅拌反应3小时。TLC检测反应完毕后,向体系中加入10mL水和10mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入10mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入30mL水洗涤,分离有机相,加入30mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到151.2mg类白色固体,加入1.5mL二氯甲烷及0.3mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=14/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到78.6mg白色固体,mp 148-151℃。
经检测得化合物7,1H NMR(DMSO-d6,400MHz):δ11.69(s,1H),9.16(s,1H),7.12(d,J=2.08,1H),7.05(dd,J=9.96,1.52,1H),7.03(d,J=1.52,1H),7.00(d,J=8.28,1H),6.88(dd,J=8.23,1.52,1H),6.81(d,J=8.08,1H),6.40(d,J=2.08,1H),6.35(d,J=2.32,1H),5.97(d,J=6.28,1H),5.24(d,J=11.56,1H),4.97(br,1H),4.93(d,J=7.92,1H),4.80-4.74(m,1H),4.20-4.17(m,1H),3.78(s,3H),3.64-3.62(t,J=5.04Hz,4H),3.53(br,3H),3.41(br,2H),3.34(m,1H);13C NMR(DMSO-d6,126MHz)δ199.9,162.3,162.1,159.2,152.0,148.0,147.4,144.2,143.7,130.1,127.8,121.8,120.9,117.1,116.8,115.7,112.0,104.7,103.0,101.8,83.1,78.5,76.3,72.1,66.1,60.6,56.0,45.1,44.3;MS(ESI-)m/z calcd for C30H28NO12 594.16,found 594.3(M-H)-.
实施例8
化合物8的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和N,N-二甲基甲酰胺(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将N,N-二异丙基乙胺(129.2mg,1.0mmol,2.0eq)和4-二甲氨基吡啶(12.2mg,0.10mmol,0.2eq)加入反应瓶中,氩气置换6次,将4-甲基哌嗪-1-甲酰氯(85.4mg,0.53mmol,1.05eq)加入反应瓶中,氩气置换6次,将体系控温0-5℃搅拌反应8小时。TLC检测反应完毕后,向体系中加入20mL水和20mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入20mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入30mL水洗涤,分离有机相,加入30mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到260.0mg黄色固体,加入4.0mL二氯甲烷及0.8mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=10/1展开剂的展缸中进行展开1次,吹干后再放入事先配好二氯甲烷/甲醇=20/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到53.0mg黄色固体,mp 137-140℃.
经检测得化合物8,1H NMR(DMSO-d6,400MHz):δ11.68(s,1H),9.16(s,1H),7.11(d,J=2.16,1H),7.04(d,1H),7.02(s,1H),6.99(d,J=8.72,1H),6.88(dd,J=8.23,1.52,1H),6.81(d,J=8.08,1H),6.37(d,J=2.08,1H),6.33(d,J=2.44,1H),5.96(d,J=6.40,1H),5.23(d,J=11.52,1H),4.98(t,J=5.56,1H),4.92(d,J=7.96,1H),4.79-4.73(m,1H),4.20-4.16(m,1H),3.78(s,3H),3.53(br,3H),3.41(br,2H),3.35(m,1H),2.35(br,4H),2.21(s,3H).13C NMR(DMSO-d6,126MHz)δ199.8,162.3,162.1,159.3,151.9,148.0,147.4,144.2,143.7,130.2,127.9,121.7,120.9,117.1,116.8,115.7,112.0,104.7,102.9,101.7,83.1,78.5,76.3,72.5,60.6,56.1,54.5,54.3,46.0,44.6,44.0.MS(ESI+)m/z calcd for C31H33N2O11 609.21,found 609.40(M+H)+.
实施例9
化合物9的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和四氢呋喃(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将N,N-二异丙基乙胺(129.2mg,1.00mmol,2.0eq)和4-二甲氨基吡啶(12.2mg,0.10mmol,0.2eq)加入反应瓶中,氩气置换6次,将N-甲氧基-N-甲基氨基甲酰氯(74.1mg,0.60mmol,1.2eq)加入反应瓶中,氩气置换6次,将体系控温0-5℃搅拌反应24小时。TLC检测反应完毕后,向体系中加入20mL水和20mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入20mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入30mL水洗涤,分离有机相,加入30mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到316.0mg浅黄色固体,加入4.0mL二氯甲烷及0.8mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=20/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到86.0mg白色固体,mp178-181℃。
经检测得化合物9,1H NMR(DMSO-d6,400MHz):δ11.69(s,1H),9.16(s,1H),7.12(d,J=1.92,1H),7.07-7.02(m,2H),7.00(d,J=8.64,1H),6.88(dd,J=8.32,1.16,1H),6.81(d,J=8.08,1H),6.43(d,J=2.08,1H),6.39(d,J=2.32,1H),5.98(d,J=6.36,1H),5.25(d,J=11.64,1H),4.98(t,J=5.44,1H),4.92(d,J=7.96,1H),4.81-4.76(m,1H),4.19-4.17(m,1H),3.78(s,3H),3.71(s,3H),3.56-3.52(m,1H),3.37-3.31(m,1H),3.21(s,3H).13C NMR(DMSO-d6,126MHz)δ199.9,162.3,162.2,158.6,153.0,148.0,147.4,144.2,143.7,130.1,127.9,121.7,120.9,117.1,116.8,115.7,112.0,105.0,103.0,101.9,83.1,78.5,76.3,72.1,61.6,60.5,56.1,35.5.MS(ESI-)m/z calcd for C28H26NO12 568.15,found 568.30(M-H)-.
实施例10
化合物10的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和N,N-二甲基甲酰胺(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(193.5mg,1.40mmol,2.8eq)加入反应瓶中,氩气置换6次,将[1,4']联哌啶-1'-甲酰氯盐酸盐(213.8mg,0.80mmol,1.6eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应14小时。TLC检测反应完毕后,向体系中加入12mL水,大量黄色固体析出,抽滤,得到251.1mg黄色固体,加入3.0mL二氯甲烷及0.3mL甲醇溶解,,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=8/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到102.1mg黄色固体,mp 144-147℃。
经检测得化合物10,1H NMR(DMSO-d6,400MHz):δ12.45(s,1H),9.90(s,1H),9.19(s,1H),7.84-7.82(m,2H),7.15(d,J=8.32,1H),7.08(d,J=1.88,1H),7.05(d,J=1.80,1H),6.90(dd,J=8.20,1.80,1H),6.82(d,J=8.04,1H),6.61(d,J=1.96,1H),5.03(t,J=5.20,1H),4.99(d,J=7.92,1H),4.31-4.27(m,1H),4.17(br,1H),4.06(br,1H),3.79(s,3H),3.59-3.56(m,1H),3.38-3.36(m,3H),3.05(t,J=13.00,1H),2.90(t,J=12.80,1H),2.49(br,3H),1.79-1.77(m,2H),1.50-1.40(m,8H).13C NMR(DMSO-d6,126MHz)δ176.9,160.3,156.8,155.2,152.0,148.0,147.5,147.4,145.8,143.9,137.5,127.6,123.9,122.0,121.0,117.3,116.8,115.7,112.0,107.2,104.3,101.5,79.0,76.3,61.7,60.5,56.1,50.0,44.4,43.9,27.9,27.5,26.3,24.7.MS(ESI+)m/z calcd for C36H39N2O11675.26,found 675.50(M+H)+.
实施例11
化合物11的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和N,N-二甲基甲酰胺(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(82.9mg,0.60mmol,1.2eq)加入反应瓶中,氩气置换6次,将二异丙基甲胺酰氯(130.9mg,0.8mmol,1.6eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应24小时。TLC检测反应完毕后,向体系中加入20mL水,大量黄色固体析出,抽滤,得到184.5mg黄色固体,加入3.0mL二氯甲烷及0.3mL甲醇溶解,,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到34.1mg黄色固体,mp 125-128℃。
经检测得化合物11,1H NMR(DMSO-d6,400MHz)δ12.44(s,1H),9.89(s,1H),9.18(s,1H),7.88-7.85(m,2H),7.15(dd,J=6.32,2.84,1H),7.07(d,J=2.04,1H),7.05(d,J=1.76,1H),6.90(dd,J=8.12,1.72,1H),6.82(d,J=8.08,1H),6.57(d,J=2.04,1H),5.02(t,J=5.48,1H),4.98(d,J=7.92,1H),4.31-4.28(m,1H),3.99(br,2H),3.79(s,3H),3.60-3.55(m,1H),3.40-3.33(m,1H),1.25(br,12H).13C NMR(DMSO-d6,126MHz)δ176.9,160.3,156.8,155.3,152.1,148.1,147.5,147.4,145.8,143.9,137.4,127.6,123.9,122.1,121.0,117.3,116.9,115.7,112.0,107.1,104.0,101.2,79.0,76.3,60.5,56.1,47.0,46.4,21.7,20.4.MS(ESI+)m/z calcd for C32H34NO11 608.21,found 608.30(M+H)+.
实施例12
化合物12的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和N,N-二甲基甲酰胺(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(69.1mg,0.50mmol,1.0eq)加入反应瓶中,氩气置换6次,将二乙氨基甲酰氯(71.2mg,0.53mmol,1.05eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应24小时。TLC检测反应完毕后,向体系中加入12mL水,大量黄色固体析出,抽滤,得到152.0mg黄色固体,加入1.2mL二氯甲烷及0.3mL甲醇溶解,,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=12/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到53.2mg黄色固体,mp 224-227℃。
经检测得化合物12,1H NMR(DMSO-d6,400MHz)δ12.44(s,1H),9.89(s,1H),9.18(s,1H),7.86-7.83(m,2H),7.15(d,J=9.16,1H),7.09(d,J=2.04,1H),7.05(d,J=1.76,1H),6.90(dd,J=8.16,1.76,1H),6.82(d,J=8.08,1H),6.60(d,J=2.04,1H),5.03(t,J=5.36,1H),4.99(d,J=7.92,1H),4.31-4.27(m,1H),3.79(s,3H),3.60-3.55(m,1H),3.42-3.35(m,3H),3.33-3.28(m,2H),1.21(t,J=7.04,3H),1.15(t,J=7.00,3H).13C NMR(DMSO-d6,126MHz)δ176.9,160.3,156.8,155.3,152.6,148.0,147.4,147.4,145.8,143.9,137.5,127.6,123.9,122.0,121.0,117.3,116.9,115.7,112.0,107.2,104.2,101.5,79.0,76.3,60.5,56.0,42.3,42.1,14.6,13.6.MS(ESI+)m/z calcd for C30H30NO11 580.18,found580.30(M+H)+.
实施例13
化合物13的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和N,N-二甲基甲酰胺(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(82.9mg,0.60mmol,1.2eq)加入反应瓶中,氩气置换6次,将1-哌啶酰氯(118.1mg,0.80mmol,1.6eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应12小时。TLC检测反应完毕后,向体系中加入20mL水,大量黄色固体析出,抽滤,得到208.1mg黄色固体,加入3.0mL二氯甲烷及0.3mL甲醇溶解,,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到67.8mg黄色固体,mp 132-135℃。
经检测得化合物13,1H NMR(DMSO-d6,400MHz)δ12.44(s,1H),9.89(s,1H),9.18(s,1H),7.85-7.82(m,2H),7.15(d,J=8.28,1H),7.08(d,J=1.16,1H),7.05(d,J=1.64,1H),6.90(dd,J=8.16,1.72,1H),6.82(d,J=8.04,1H),6.60(d,J=1.72,1H),5.03(t,J=5.40,1H),4.99(d,J=7.92,1H),4.31-4.27(m,1H),3.79(s,3H),3.60-3.55(m,3H),3.42-3.35(m,3H),1.56(br,6H).13C NMR(DMSO-d6,126MHz)δ176.9,160.3,156.9,155.3,152.1,148.0,147.4,147.4,145.8,143.9,137.5,127.6,123.9,122.0,121.0,117.3,116.9,115.7,112.0,107.2,104.3,101.5,79.0,76.3,60.5,56.0,45.7,45.1,25.9,25.5,24.1.MS(ESI+)m/z calcd for C31H30NO11 592.18,found 592.40(M+H)+.
实施例14
化合物14的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和N,N-二甲基甲酰胺(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(69.1mg,0.50mmol,1.0eq)加入反应瓶中,氩气置换6次,将1-吡咯烷羰酰氯(70.1mg,0.53mmol,1.05eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应24小时。TLC检测反应完毕后,向体系中加入25mL水,大量黄色固体析出,抽滤,得到150.5mg黄色固体,加入1.2mL二氯甲烷及0.3mL甲醇溶解,,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到52.6mg黄色固体,mp 133-136℃。
经检测得化合物14,1H NMR(DMSO-d6,400MHz)δ12.44(s,1H),9.88(s,1H),9.18(s,1H),7.84-7.81(m,2H),7.15(d,J=9.16,1H),7.08(d,J=2.00,1H),7.05(d,J=1.72,1H),6.90(dd,J=8.16,1.76,1H),6.82(d,J=8.04,1H),6.61(d,J=2.04,1H),5.03(t,J=5.44,1H),4.99(d,J=7.92,1H),4.31-4.27(m,1H),3.79(s,3H),3.60-3.55(m,1H),3.52(t,J=6.52,2H),3.39-3.36(m,3H),1.92-1.85(m,4H).13C NMR(DMSO-d6,126MHz)δ176.9,160.3,156.7,155.3,151.4,148.0,147.5,147.4,145.8,143.9,137.5,127.6,123.9,122.0,121.0,117.3,116.9,115.7,112.0,107.2,104.2,101.4,79.0,76.3,60.5,56.1,46.8,46.6,25.7,24.9.MS(ESI+)m/z calcd for C30H28NO11 578.17,found 578.40(M+H)+.
实施例15
化合物15的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和N,N-二甲基甲酰胺(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(69.1mg,0.50mmol,1.0eq)加入反应瓶中,氩气置换6次,将二甲氨基甲酰氯(56.5mg,0.53mmol,1.05eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应12小时。TLC检测反应完毕后,向体系中加入25mL水,大量黄色固体析出,抽滤,得到202.6mg黄色固体,加入1.2mL二氯甲烷及0.3mL甲醇溶解,,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开1次,吹干后再放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开1次,展开完毕后发现紫外灯下制备板上一共有2条明显的色带,将下面的吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入2mL二氯甲烷溶清,过微孔滤膜,再向滤液中加入8mL石油醚,大量固体析出,抽滤,得到109.9mg白色固体,mp 134-137℃。
经检测得化合物15,1H NMR(DMSO-d6,400MHz)δ12.45(s,1H),9.88(s,1H),9.18(s,1H),7.84-7.81(m,2H),7.16(d,J=8.44,1H),7.07(d,J=2.04,1H),7.05(d,J=1.72,1H),6.90(dd,J=8.16,1.80,1H),6.82(d,J=8.08,1H),6.60(d,J=2.04,1H),5.03(t,J=5.48,1H),4.99(d,J=7.92,1H),4.31-4.27(m,1H),3.79(s,3H),3.60-3.55(m,1H),3.40-3.33(m,1H),3.05(s,3H),2.93(s,3H).13C NMR(DMSO-d6,126MHz)δ176.9,160.3,156.8,155.2,153.3,148.0,147.4,147.4,145.8,143.9,137.5,127.6,123.9,122.0,121.0,117.3,116.9,115.7,112.0,107.2,104.3,101.4,79.0,76.3,60.5,56.0,36.8,36.6.MS(ESI+)m/z calcd for C28H26NO11 552.15,found 552.40(M+H)+.
实施例16
化合物16的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(120.6mg,0.25mmol,1.0eq)和N,N-二甲基甲酰胺(1.8mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(34.6mg,0.25mmol,1.0eq)加入反应瓶中,氩气置换6次,将4-吗啉碳酰氯(39.3mg,0.26mmol,1.05eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应3小时。TLC检测反应完毕后,向体系中加入10mL水和10mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入10mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入30mL水洗涤,分离有机相,加入30mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到156.3mg黄色固体,加入3mL二氯甲烷及0.5mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=12/1展开剂的展缸中进行展开1次,吹干后再放入事先配好二氯甲烷/甲醇=10/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到45.8mg黄色固体。产品不合格(HPLC:80%),需要二次结晶:加入2mL二氯甲烷溶解,加入15mL甲醇,浓缩至2-3mL,加入5mL甲醇,大量固体析出,抽滤,得到25.2mg黄色固体,mp 284-286℃。
经检测得化合物16,1H NMR(DMSO-d6,400MHz)δ12.46(s,1H),9.90(s,1H),9.18(s,1H),7.85(dd,J=10.68,2.16,1H),7.84(s,1H),7.16(d,J=8.40,1H),7.11(d,J=2.00,1H),7.06(d,J=1.76,1H),6.91(dd,J=8.20,1.76,1H),6.83(d,J=8.04,1H),6.64(d,J=2.04,1H),5.03(t,J=5.44,1H),4.99(d,J=7.92,1H),4.31-4.28(m,1H),3.79(s,3H),3.67(t,J=5.04,4H),3.59-3.56(m,3H),3.44(br,2H),3.40-3.36(m,1H).13C NMR(DMSO-d6,126MHz)δ176.9,160.3,156.6,155.2,152.3,148.0,147.5,147.4,145.8,143.9,137.5,127.6,123.9,122.0,121.0,117.3,116.9,115.7,112.0,107.3,104.3,101.5,79.0,76.3,66.1,60.5,56.1,45.1,44.3.MS(ESI+)m/z calcd for C30H28NO12 594.16,found 594.4(M+H)+.
实施例17
化合物17的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和N,N-二甲基甲酰胺(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(172.8mg,1.25mmol,2.5eq)加入反应瓶中,氩气置换6次,将4-甲基哌嗪-1-甲酰氯盐酸盐(149.3mg,0.75mmol,1.5eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应6-8小时。TLC检测反应完毕后,向体系中加入8mL水,大量黄色固体析出,抽滤,得到145.6mg黄色固体,加入5.0mL二氯甲烷及15.0mL甲醇溶解,浓缩至约5.0mL,加入5.0mL甲醇,大量固体析出,抽滤,得到108.8mg黄色固体。产品不合格,需要二次结晶:向粗品汇总加入10mL无水乙醇和10mL二氯甲烷,升温至70℃,基本溶清,微孔滤膜滤除不溶物,滤液浓缩至1-2mL,加入10mL甲醇,大量固体析出,抽滤,得到63.0mg黄色固体,mp 198-201℃。
经检测得化合物17,1H NMR(DMSO-d6,400MHz)δ12.45(s,1H),9.90(s,1H),9.18(s,1H),7.84-7.82(m,2H),7.15(d,J=8.48,1H),7.09(d,J=2.04,1H),7.05(d,J=1.68,1H),6.90(dd,J=8.12,1.72,1H),6.82(d,J=8.08,1H),6.61(d,J=2.04,1H),5.03(t,J=5.36,1H),4.99(d,J=7.88,1H),4.31-4.27(m,1H),3.79(s,3H),3.58(br,3H),3.44(br,2H),3.40-3.35(m,1H),2.38(br,4H),2.23(s,3H).13C NMR(DMSO-d6,126MHz)δ176.9,160.3,156.7,155.2,152.2,148.1,147.5,147.4,145.8,143.9,137.5,127.6,123.9,122.0,121.0,117.3,116.9,115.7,112.0,107.3,104.2,101.5,79.0,76.3,60.5,56.1,54.6,54.4,46.1,44.7,44.0.MS(ESI+)m/z calcd for C31H31N2O11 607.19,found 607.30(M+H)+.
实施例18
化合物18的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(585.8mg,1.21mmol,1.0eq)和N,N-二甲基甲酰胺(8.7mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(167.8mg,1.21mmol,1.0eq)加入反应瓶中,氩气置换6次,将N-甲氧基-N-甲基氨基甲酰氯(180.0mg,1.46mmol,1.2eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应14小时。TLC检测反应完毕后,向体系中加入70mL水,大量黄色固体析出,抽滤,得到280.0mg黄色固体,加入3.0mL二氯甲烷及0.3mL甲醇溶解,,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到90.0mg黄色固体,mp 114-117℃。
经检测得化合物18,1H NMR(DMSO-d6,400MHz)δ12.49(s,1H),9.94(s,1H),9.22(s,1H),7.84-7.81(m,2H),7.15(d,J=5.12,1H),7.14(d,J=5.08,1H),7.06(d,J=1.48,1H),6.91(dd,J=8.12,1.52,1H),6.83(d,J=8.04,1H),6.67(d,J=1.96,1H),5.06(t,J=5.16,1H),4.98(d,J=7.92,1H),4.31-4.27(m,1H),3.80(s,3H),3.75(s,3H),3.59-3.56(m,1H),3.38-3.34(m,1H),3.25(s,3H).13C NMR(DMSO-d6,126MHz)δ176.9,160.4,156.0,155.2,153.3,148.0,147.5,147.5,145.8,143.9,137.6,127.6,123.8,122.0,121.0,117.3,116.9,115.7,112.0,107.6,104.3,101.6,79.0,76.3,61.7,60.5,56.1,35.6.MS(ESI+)m/z calcd for C28H26NO12 568.15,found 568.30(M+H)+.
实施例19
化合物19的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(120.6mg,0.25mmol,1.0eq)和N,N-二甲基甲酰胺(1.8mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(69.2mg,0.50mmol,2.0eq)加入反应瓶中,氩气置换6次,将4-吗啉碳酰氯(76.7mg,0.52mmol,2.05eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应3小时。TLC检测反应完毕后,向体系中加入10mL水和10mL乙酸乙酯,搅拌10min,静置10min,分离有机相暂存,向水相中加入10mL乙酸乙酯,搅拌10min,静置10min,分离合并所有有机相,加入30mL水洗涤,分离有机相,加入30mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得到150.3mg黄色固体,加入2.0mL二氯甲烷及0.2mL甲醇溶解,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=14/1展开剂的展缸中进行展开1次,吹干后再放入事先配好二氯甲烷/甲醇=14/1展开剂的展缸中进行展开1次,展开完毕后将吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入15mL二氯甲烷溶清,过微孔滤膜,母液浓缩至2-3mL,向滤液中加入15mL石油醚,大量固体析出,抽滤,得到19.6mg白色固体,mp 143-146℃。
经检测得化合物19,1H NMR(DMSO-d6,400 MHz)δ12.18(s,1H),9.20(s,1H),7.55(s,1H),7.53(dd,J=8.58,1.96,1H),7.21(d,J=8.56,1H),7.17(d,J=2.04,1H),7.06(d,J=1.76,1H),6.90(dd,J=8.20,1.76,1H),6.83(d,J=8.08,1H),6.75(d,J=2.04,1H),5.05(t,J=5.40,1H),5.01(d,J=7.92,1H),4.35-4.31(m,1H),3.79(s,3H),3.68(t,J=4.32,8H),3.60-3.57(m,5H),3.44-3.36(m,5H).13C NMR(DMSO-d6,126 MHz)δ176.7,160.6,157.3,157.0,155.8,152.1,148.1,147.5,147.2,144.2,131.4,127.4,122.4,121.8,121.0,117.8,117.3,115.7,112.0,108.0,105.6,102.0,79.0,76.3,66.4,66.1,60.4,56.0,45.4,45.2,44.7,44.3.MS(ESI+)m/z calcd for C35H35N2O14 707.67,found 707.40(M+H)+.
实施例20
化合物20的合成
室温条件下,向5mL三口圆底瓶中加入水飞蓟宾(241.2mg,0.50mmol,1.0eq)和N,N-二甲基甲酰胺(3.6mL,15.0vol),氩气置换6次,开启搅拌,将体系降温至0-5℃,将碳酸钾(138.2mg,1.00mmol,2.0eq)加入反应瓶中,氩气置换6次,将二甲氨基甲酰氯(110.3mg,1.03mmol,2.05eq)加入反应瓶中,氩气置换6次,将体系自然回温至室温搅拌反应12小时。TLC检测反应完毕后,向体系中加入25mL水,大量黄色固体析出,抽滤,得到234.2mg黄色固体,加入2.2mL二氯甲烷及0.6mL甲醇溶解,,以毛细管吸取粗品溶液点在制备板上,上样结束后吹干,放入事先配好二氯甲烷/甲醇=15/1展开剂的展缸中进行展开,将上面的吸附产品的硅胶刮下,以100mL展开剂洗涤,抽滤,缩干母液,加入2mL二氯甲烷溶清,过微孔滤膜,再向滤液中加入8mL石油醚,大量固体析出,抽滤,得到37.4mg白色固体,mp 135-138℃。
经检测得化合物20,1H NMR(DMSO-d6,400 MHz)δ12.17(s,1H),9.20(s,1H),7.55(d,J=8.58,1H),7.52(dd,J=8.56,2.12,1H),7.19(d,J=8.56,1H),7.12(d,J=2.00,1H),7.06(d,J=1.72,1H),6.90(dd,J=8.20,1.76,1H),6.82(d,J=8.00,1H),6.70(d,J=2.04,1H),5.04(t,J=5.44,1H),5.01(d,J=7.96,1H),4.35-4.31(m,1H),3.78(s,3H),3.60-3.56(m,1H),3.42-3.35(m,1H),3.10(s,3H),3.05(s,3H),2.93(s,3H),2.91(s,3H),13C NMR(DMSO-d6,126MHz)δ176.8,160.5,157.5,156.7,155.8,153.1,152.9,148.1,147.5,147.1,144.2,131.8,127.4,122.5,121.9,121.0,117.8,117.3,115.7,112.1,107.8,105.5,101.9,79.0,76.3,60.4,56.1,37.0,36.8,36.8,36.6.MS(ESI+)m/z calcd forC31H31N2O12 623.59,found 623.40(M+H)+.
实施例21
另外,参考上述实施例合成方法,只要适当选择起始原材料,还可以合成出更加广泛的各种各样的衍生物,例如表2所列的化合物就是其中的一些典型的示例化合物。
表2通式Ⅰ中的比较典型的化合物
实验例肿瘤细胞抑制活性GI50值的测定
细胞活性测试采用CCK-8测试目标化合物的活性。其原理为:Cell Counting Kit-8(简称CCK-8)是一种基于WST-8的广泛应用于细胞增殖和细胞毒性的快速高灵敏度检测试剂。WST-8,是一种类似于MTT的化合物,它在电子载体(1-Methoxy PMS)存在的情况下,被线粒体中的脱氢酶还原为具有高度水溶性的橙黄色甲瓒产物(formazan)。细胞增殖越多越快,颜色越深;细胞毒性越大,则颜色越浅,对于同样的细胞,颜色的深浅与活细胞的数量成正比,因此可利用这一特性直接进行细胞增殖和毒性分析。
化合物对人甲状腺导管癌细胞与人结肠癌细胞活性测定:
以下方法用于测定化合物对MCF-7、NCI-H 1299、HepG2和HT29肿瘤细胞增殖的影响通过采用CCK-8来进行测定。
(一)具体实验操作方法与流程:
1、细胞复苏:从液氮保存罐中将冻存的细胞,立即放入37℃恒温水浴中震荡2min,至细胞冻存液完全融化后,将细胞悬液移入15mL离心管,缓慢加入4mL培养液,离心(1000r/min,5min),弃上清,吸干原液,加5mL上述培养基,轻轻吹打至单细胞悬液,将其转移至培养瓶中,放入培养箱中培养。
2、细胞铺板:将细胞浓度调整至适当中板浓度的细胞液,在96孔培养板(Corning,3599)中每孔加入90μL细胞悬液,并设置空白对照孔和溶媒对照孔。在空白对照孔加入含细胞的培养液,在溶媒对照孔中加入不含细胞的培养液。随后将培养板放入37℃,5%CO2,及100%相对湿度的培养箱中培养过夜。
3、化合物配制:称取化合物用DMSO配制成10mM的储存液,将待测化合物储备液在配药板(Beaver,Suzhou)上用无血清培养基稀释至终浓度为100μM的10×化合物工作液(包括对照品)。按3倍浓度梯度用无血清培养基稀释,得到9个浓度梯度的10×化合物工作液,化合物浓度分别为100、33.33、11.11、3.70、1.23、0.411、0.137、0.046、0.015μM
4、细胞给药:将不同浓度梯度的10×化合物工作液加入至96孔的细胞培养板中,10μL/孔,在溶媒对照孔和空白对照孔中加入10μL DMSO-细胞培养液混合液,DMSO终浓度为0.1%,每个浓度设置5个复孔。将96孔细胞板放回37℃,5%二氧化碳培养箱中培养48小时。
5、向每孔加入10μL的CCK-8溶液,将培养板置于培养箱内孵育1-4小时。
6、用酶标仪测定在450nm处的吸光度,计算抑制率。
抑制率=[(Ac-As)/(Ac-Ab)]×100%
As:实验孔吸光度(含细胞、培养基、CCK-8溶液和药物溶液);
Ac:对照孔吸光度(含细胞、培养基、CCK-8溶液,不含药物);
Ab:空白孔吸光度(含培养基、CCK-8溶液,不含细胞、药物)。
(二)结果
检测结果见表4。
表4所得化合物肿瘤细胞生长抑制活性检测结果
实验结论:与阳性药相比,化合物1-20对测试的肿瘤细胞系表现出显着增强的抗肿瘤活性,大多数化合物在低微摩尔浓度下显示出较强的抗肿瘤活性。尤其是化合物1、化合物2、化合物4、化合物10、化合物11、化合物14、化合物19、化合物20具有更好的抗肿瘤活性。
Claims (10)
1.一种含氨基甲酸结构的水飞蓟宾衍生物及其药学上可接受的盐,结构如通式Ⅰ所示:
R1和R2各自独立地选自:氢原子、氨基、酰基、烷基、烷氧基、烯基、炔基、同位素、卤代烯基、杂烷基、芳基、杂芳基;在以上基团中,各自可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、同位素、=O、-CF3、烷基、链烯基、链炔基、羧基、羟基、羟烷基、烷氧基、烷氧烷基、≡N;
R3、R4和R5各自独立地选自:氢原子、烷基、杂烷基、烯基、炔基、芳基烷基、环烷基、芳基、杂芳基、杂芳基烷基、杂环烷基、烷基氨基羰基、环烷基氨基羰基、杂芳基氨基羰基、杂芳基氨基羰基;
上述基团中的任一基团各自独立地可不被取代或被一个或多个取代基取代,这些取代基包括:卤素、同位素、氨基、羧基、苯基、苄基、苯基氧基、=O、CF3、卤代烷基、烷基、烯基、炔基、羟基、羟烷基、烷氧基、烷氧基烷基、杂烷基、芳基烷基、环烷基、芳基、杂芳基、杂芳基烷基、杂环烷基、杂环烯基、烷氧基烷基、烯氧基、炔氧基、烷基氨基、氨基烷基、烷基氨基羰基、磺酰基、烷基磺酰基、烷基亚磺酰基、或氨基磺酰基。
2.根据权利要求1所述的含氨基甲酸结构的水飞蓟宾衍生物及其药学上可接受的盐,其特征在于:
R1和R2各自独立地选自:相连氮原子一起构成的3-8元杂环基或5-10元杂芳基。
6.根据权利要求1-5所述的含氨基甲酸结构的水飞蓟宾衍生物及其药学上可接受的盐在制备治疗增生性疾病药物中的用途。
7.根据权利要求6所述的含氨基甲酸结构的水飞蓟宾衍生物及其药学上可接受的盐在制备抗肿瘤药物中的用途。
8.根据权利要求7所述用途,其特征在于:所述肿瘤为人甲状腺导管癌细胞或人结肠癌。
9.根据权利要求1-5所述的含氨基甲酸结构的水飞蓟宾衍生物及其药学上可接受的盐在制备抑制激酶药物中的用途。
10.根据权利要求9所述的用途,其特征在于:所述抑制激酶的活性是值抑制Hsp90,BCL-2,ERK,Akt,COX-2,MMP-9,CDK或者EGFR的活性。
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