CN114478498B - 一种水飞蓟宾衍生物或其药学上可接受的盐及其应用 - Google Patents
一种水飞蓟宾衍生物或其药学上可接受的盐及其应用 Download PDFInfo
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- CN114478498B CN114478498B CN202210154781.4A CN202210154781A CN114478498B CN 114478498 B CN114478498 B CN 114478498B CN 202210154781 A CN202210154781 A CN 202210154781A CN 114478498 B CN114478498 B CN 114478498B
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- silybin
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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 43
- 150000003839 salts Chemical class 0.000 title claims abstract description 16
- 229940043175 silybin Drugs 0.000 claims abstract description 55
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 claims abstract description 31
- 235000014899 silybin Nutrition 0.000 claims abstract description 29
- FDQAOULAVFHKBX-UHFFFAOYSA-N Isosilybin A Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC(=CC=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-UHFFFAOYSA-N 0.000 claims abstract description 25
- VLGROHBNWZUINI-UHFFFAOYSA-N Silybin Natural products COc1cc(ccc1O)C2OC3C=C(C=CC3OC2CO)C4Oc5cc(O)cc(O)c5C(=O)C4O VLGROHBNWZUINI-UHFFFAOYSA-N 0.000 claims abstract description 25
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 19
- LXFQSRIDYRFTJW-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonic acid Chemical compound CC1=CC(C)=C(S(O)(=O)=O)C(C)=C1 LXFQSRIDYRFTJW-UHFFFAOYSA-N 0.000 claims description 15
- HSHFRAOPRGGMDV-UHFFFAOYSA-N 4-(trifluoromethoxy)benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(OC(F)(F)F)C=C1 HSHFRAOPRGGMDV-UHFFFAOYSA-N 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 5
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- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
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- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 21
- 108010087230 Sincalide Proteins 0.000 description 20
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 20
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
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- CPHXLFKIUVVIOQ-UHFFFAOYSA-N 2-(trifluoromethoxy)benzaldehyde Chemical group FC(F)(F)OC1=CC=CC=C1C=O CPHXLFKIUVVIOQ-UHFFFAOYSA-N 0.000 description 2
- UHCDBMIOLNKDHG-UHFFFAOYSA-N 4-(trifluoromethoxy)benzenesulfonyl chloride Chemical compound FC(F)(F)OC1=CC=C(S(Cl)(=O)=O)C=C1 UHCDBMIOLNKDHG-UHFFFAOYSA-N 0.000 description 2
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- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
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Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,一种水飞蓟宾衍生物或其药学上可接受的盐及其应用,结构如通式Ⅰ和Ⅱ所示;其中,R1、R2、R3分别独立的选自氢或不同的磺酰基,R4独立的选自不同的磺酰基。该水飞蓟宾衍生物或其药学上可接受的盐具有抗肿瘤活性,可以用于制备抗肿瘤药物。相比于水飞蓟宾,本发明的化合物具有更好的药效。
Description
【技术领域】
本发明涉及医药技术领域,具体涉及一种水飞蓟宾衍生物或其药学上可接受的盐及其应 用。
【背景技术】
水飞蓟素是从水飞蓟属的菊科药用植物水飞蓟的小果实和种子中提取的混合物(Biedermann,D.etc Nat.Prod.Rep.2014,31(9),1138-1157;Kim,N.C.etc Org.Biomol.Chem.2003,1(10),1684-1689)。水飞蓟宾作为两种非对映异构体(水飞蓟宾A和水飞蓟 宾B)的混合物存在于这些提取物中,约占总成分的50-70%,是最重要的活性成分(Loguercio,C.etc World J.Gastroenterol.2011,17(18),2288-2301;Crocenzi,F.A.etc Curr.Med.Chem.2006,13(9),1055-1074)。水飞蓟宾在欧洲和亚洲被用作典型的肝脏保护剂和膳食补充剂(Strader,D.B.etc Am.J.Gastroenterol.2002,97(9),2391-2397;Schadewaldt,H.Med.Welt 1969,20(15),902-914),除此之外它还具有多种生物活性, 如抗氧化、抗病毒和抗炎作用(Federico,A.etc Molecules 2017,22(2),191;Ferenci,P.etc Gastroenterology 2008,135(5),1561-1567;Sekine,S.etc Biophys.Acta 2015,1850(2),274-280)。
水飞蓟宾具有抗肿瘤作用。体外和体内研究表明,水飞蓟宾能显着抑制人肝癌细胞和前 列腺癌细胞的增殖(Vue,B.etc Eur.J.Med.Chem.2016,109,36-46.;Sy-Cordero,A.A. etc Med.Chem.2013,21(3),742-747),其抗肿瘤作用可能与一系列分子生物学过程有关,包括细胞周期阻滞和减少转移侵袭。但水飞蓟宾的抗肿瘤活性有待进一步提高,生物利 用度有待进一步改善。
【发明内容】
本发明旨在提供水飞蓟宾衍生物或其药学上可接受的盐及其应用,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:
一种水飞蓟宾衍生物或其药学上可接受的盐,结构如通式Ⅰ和Ⅱ所示:
其中,R1、R2、R3分别独立的选自氢或不同的磺酰基,R4独立的选自不同的磺酰基。
进一步说明,所述的水飞蓟宾衍生物或其药学上可接受的盐,包括以下化合物:
7-(2,4,6-三甲基苯磺酸)-水飞蓟宾酯;
7-(4-三氟甲氧基苯磺酸)-水飞蓟宾酯;
7-(4-甲基苯磺酸)-水飞蓟宾酯;
5,7-双(4-甲基苯磺酸)-水飞蓟宾酯;
5,7,20-三(4-甲基苯磺酸)-水飞蓟宾酯;
7-(2,4,6-三甲基苯磺酸)-2,3-脱氢水飞蓟宾酯;
7-(4-三氟甲氧基苯磺酸)-2,3-脱氢水飞蓟宾酯;
7-(4-甲基苯磺酸)-2,3-脱氢水飞蓟宾酯。
本申请还公开了一种水飞蓟宾衍生物或其药学上可接受的盐的制备方法,具体步骤为: 以水飞蓟宾为原料,在碱的催化下与不同的磺酰氯反应制备得到。
进一步说明,所述的碱为氢氧化钠、氢氧化钾、氢氧化钡、氢氧化钙、碳酸钠、碳酸钾、 碳酸钙、碳酸铯、碳酸氢钠、三乙胺、4-二甲氨基吡啶、N,N-二异丙基乙胺、氢化钠中的至少一种。
进一步说明,所述不同的磺酰氯为2,4,6-三甲基苯磺酰氯、三氟甲氧基苯磺酰氯或4-甲 基苯磺酰氯。
本申请还公开了一种水飞蓟宾衍生物或其药学上可接受的盐的制备方法,具体步骤为:
(1)在室温的条件下,将水飞蓟宾溶于N,N-二甲基甲酰胺或四氢呋喃,氮气保护,开 启搅拌,加入碱,然后再加入不同的磺酰氯,在0-5℃或25℃下,搅拌反应一定时间;
(2)然后加入水,用乙酸乙酯萃取两次,合并有机相,然后用盐水洗涤,加入干燥剂干 燥,抽滤,旋干溶剂后得粗产物,经分离纯化后得到产物。
本发明的目的之二是:所述的水飞蓟宾衍生物或其药学上可接受的盐在制备抗肿瘤药物 中的应用。
本发明中,进一步说明,所述肿瘤选自非小细胞肺癌、乳腺癌、肝癌、结肠癌。
综上所述,由于采用了上述技术方案,本发明的有益效果是:
本发明的水飞蓟宾衍生物或其药学上可接受的盐,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。
本发明中式Ⅰ和Ⅱ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】
本说明书中公开的所有特征,或公开的所有方法或过程中的步骤,除了互相排斥的特征 和/或步骤以外,均可以以任何方式组合。
本说明书(包括任何附加权利要求、摘要)中公开的任一特征,除非特别叙述,每个特 征只是一系列等效或类似特征中的一个例子而已。
实施例1
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1:7-(2,4,6-三甲基苯磺酸)-水飞蓟宾酯的制备
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),氮气置换6次,开启搅拌,将体系降温至0~5℃,将氢化钠(22.0mg,0.55mmol,2.2eq,质量分数为60%)加入反应瓶中,氮气置换6次,将2,4,6-三甲基苯磺酰氯(109.4mg,0.50mmol,2.0eq)加入反应瓶中,氮气置换6次,将体系控温0~5℃搅拌反应2小时。TLC监测反应完毕后,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10mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得 到200.1mg棕色油状物,加入1mL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=20/1的展缸中进行展开,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37.8mg白色 固体,经过检测百色固体为7-(2,4,6-三甲基苯磺酸)-水飞蓟宾酯;mp 179-182℃.1H NMR(DMSO-d6,400MHz):δ11.62(s,1H),9.17(s,1H),7.19(s,2H),7.08(s,1H),7.02(s,1H),6.99-6.96(m,2H), 6.88-6.86(d,J=9.6Hz,1H),6.82-6.80(d,J=8.0Hz,1H),6.22-6.20(d,J=2.2Hz,1H),6.18-6.17(d,J=2.1Hz, 1H),5.99-5.98(br,1H),5.25-5.22(d,J=11.6Hz,1H),4.97(br,1H),4.92-4.90(d,J=7.9Hz,1H),4.79-4.76(m,1H),4.20-4.16(m,1H),3.78(s,3H),3.55-3.53(m,1H),3.36-3.32(m,1H),2.54(s,6H),2.31(s,3H).13C NMR(DMSO-d6,126MHz):δ199.66,162.43,162.30,155.94,148.07,147.46,145.18,144.30,143.77,140.10,132.52, 130.18,129.85,129.80,127.88,121.95,121.78,120.98,117.12,116.88,115.73,112.06,106.05,102.27,101.32,83.23,78.58,76.32,72.09,60.60,56.10,22.56,21.08.HRMS(ESI)calcd for C34H33O12S[M+H]+665.1687; found665.1691.
实施例2:7-(4-三氟甲氧基苯磺酸)-水飞蓟宾酯的制备
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),氮气置换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,氮气置换6次,将对三氟甲氧基苯磺酰氯(136.8mg,0.525mmol,1.05eq)加入反应瓶中,氮气置换6次,将体系控温0~5℃搅拌反应2小时。TLC监测反应完毕后,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20mL盐水洗涤,分离有机相, 硫酸钠干燥,抽滤,母液缩干,得到398.8mg黄色固体,加入4mL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=22/1 展开剂的展缸中进行展开,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194.6mg白色固体,经过检测白色固体为7-(4-三氟甲氧基苯磺酸)-水飞蓟宾酯;mp 141-144℃.1H NMR(DMSO-d6,400MHz):δ11.65(s,1H),9.19(s,1H).8.13-8.11(d,J=8.7Hz,2H), 7.70-7.68(d,J=8.8Hz,2H),7.09(s,1H),7.02(s,1H),6.99-6.97(m,2H),6.88-6.86(dd,J=8.2,1.4Hz,1H), 6.82-6.80(d,J=8.1Hz,1H),6.32-6.31(d,J=2.2Hz,1H),6.26-6.25(d,J=0.7Hz,1H),6.01(br,1H),5.25-5.22(d,J=11.8Hz,1H),4.99(br,1H),4.93-4.91(d,J=7.9Hz,1H),4.81-4.77(d,J=4.8Hz,1H), 4.21-4.16(m,1H),3.78(s,3H),3.57-3.54(m,1H),3.36-3.33(m,1H).13C NMR(DMSO-d6,126MHz):δ199.79,162.47,162.30,155.55,153.18,148.06,147.44,144.31,144.29,143.76,133.25,131.66,129.87,127.88,122.33,121.91,120.97,117.14,116.87,115.72,112.04,106.36,103.03,102.03,83.23,78.56,76.31,72.14,60.60,56.08. HRMS(ESI)calcd for C32H26F3O13S[M+H]+707.1041;found 707.1046.
实施例3:7-(4-甲基苯磺酸)-水飞蓟宾酯的制备
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),氮气置换6次,开启搅拌,将体系降温至0~5℃,将氢化钠(12.0mg,0.30mmol,1.2eq,质量分数为60%)加入反应瓶中,氮气置换6次,将4-甲基苯磺酰氯(47.7mg,0.25mmol,1.0eq)加入反应瓶中,氮气置换6次,将体系控温0~5℃搅拌反应2小时。TLC监测反应完毕后,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10mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得 到173.5mg发泡状固体,加入2mL乙酸乙酯、1mL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=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37.8mg 白色固体,经过检测白色固体为7-(4-甲基苯磺酸)-水飞蓟宾酯,mp 144-146℃.1H NMR(DMSO-d6,400MHz):δ11.63(s,1H),9.17(s,1H),7.85-7.83(d,J=8.1Hz,2H),7.52-7.50(d,J=8.0Hz,2H),7.09(s,1H), 7.02(s,1H),7.00-6.97(m,2H),6.89-6.86(dd,J=8.2,1.4Hz,1H),6.82-6.80(d,J=8.0Hz,1H),6.27-6.25(d,J =2.2Hz,1H),6.23-6.22(d,J=1.7Hz,1H),5.99-5.97(d,J=6.4Hz,1H),5.25-5.22(d,J=11.7Hz,1H),4.99(br,1H),4.93-4.91(d,J=7.9Hz,1H),4.79-4.77(m,1H),4.20-4.17(m,1H),3.79(s,3H),3.56-3.53(m,1H),3.34-3.33(m,1H),2.43(s,3H).13C NMR(DMSO-d6,126MHz):δ179.55,162.40,162.27,155.95,148.09, 147.47,146.72,144.31,143.78,131.79,130.90,129.88,128.67,127.90,121.94,120.98,117.15,116.88,115.76,112.06,106.17,102.89,101.79,83.25,78.58,76.32,72.12,60.62,56.13,21.67.HRMS(ESI)calcd for C32H29O12S[M+H]+637.1374;found 637.1380.
实施例4:5,7-双(4-甲基苯磺酸)-水飞蓟宾酯及5,7,20-三(4-甲基苯磺酸)-水飞蓟宾酯的制备
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),氮气置换6次,开启搅拌,将体系降温至0~5℃,将氢化钠(22.0mg,0.30mmol,2.2eq,质量分数为60%)加入反应瓶中,氮气置换6次,将4-甲基苯磺酰氯(95.4mg,0.50mmol,2.0eq)加入反应瓶中,氮气置换6次,将体系控温0~5℃搅拌反应2小时。TLC监测反应完毕后,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10mL盐水洗涤,分离有机相,硫酸钠干燥,抽滤,母液缩干,得 到272.4mg发泡状固体,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=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96.7mg白色固体,经过检测白色固体 为5,7-双(4-甲基苯磺酸)-水飞蓟宾酯,mp 133-135℃.1H NMR(DMSO-d6,400MHz):δ9.17(s,1H), 7.80-7.78(d,J=8.0Hz,2H),7.73-7.71(d,J=7.8Hz,2H),7.53-7.51(d,J=8.7Hz,2H),7.51-7.48(d,J=9.3 Hz,2H),7.06(s,1H),7.02(s,1H),6.97(br,2H),6.88-6.86(dd,J=8.2,1.6Hz,1H),6.84-6.83(dd,J=4.0,2.3 Hz,1H),6.82-6.80(d,J=8.1Hz,1H),6.41-6.40(d,J=2.2Hz,1H),5.82-5.80(d,J=5.2Hz,1H),5.19-5.16(d,J=11.6Hz,1H),4.97(br,1H),4.92-4.90(d,J=7.88Hz,1H),4.53-4.47(m,1H),4.20-4.16(m,1H),3.78(s,3H),3.56-3.53(m,1H),3.32-3.36(m,1H),2.45(s,3H),2.44(s,3H).13C NMR(DMSO-d6,126MHz):δ191.08,162.63,153.19,148.14,148.09,147.48,147.04,146.64,144.33,143.77,131.88,131.23,130.98,130.61,129.56, 128.75,128.69,127.89,121.83,120.99,117.14,116.88,115.75,112.94,112.07,110.79,109.95,83.32,78.58,76.31,72.83,60.61,56.13,21.69.HRMS(ESI)calcd for C39H38NO14S2[M+NH4]+808.1728;found808.1741.
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36.8mg 白色固体,经过检测白色固体为5,7,20-三(4-甲基苯磺酸)-水飞蓟宾酯,mp 148-150℃.1HNMR (DMSO-d6,400MHz):δ7.80-7.78(d,J=7.8Hz,2H),7.73-7.71(d,J=7.8Hz,4H),7.53-7.51(d,J=8.6Hz, 3H),7.48-7.46(m,3H),7.17(s,1H),7.17-7.14(d,J=8.6Hz,1H),7.09(s,1H),7.07-7.05(d,J=8.4Hz,1H), 6.98(br,2H),6.84-6.83(dd,J=3.9,2.2Hz,1H),6.41-6.40(d,J=2.2Hz,1H),5.82-5.81(d,J=4.0Hz,1H),5.20-5.17(d,J=11.6Hz,1H),5.05(br,1H),5.05-5.03(d,J=7.6Hz,1H),4.53-4.48(m,1H),4.21-4.17(m,1H), 3.57-3.54(m,1H),3.53(s,3H),3.34-3.29(m,1H),2.46(s,3H),2.43(s,6H).13C NMR(DMSO-d6,126MHz):δ 191.05,162.61,153.21,151.84,148.16,147.03,146.63,146.05,144.20,143.36,138.14,137.52,132.64,131.91,131.26,130.97,130.60,130.28,129.80,129.76,128.74,128.68,123.91,122.07,121.89,120.43,117.15,116.96, 113.13,112.94,110.77,109.99,83.27,78.27,75.81,72.87,60.36,56.17,21.68,21.63.HRMS(ESI)calcdforC46H41O16S3[M+H]+945.1551;found 945.1552.
实施例5:7-(2,4,6-三甲基苯磺酸)-2,3-脱氢水飞蓟宾酯的制备
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),氮气置换6次,开启搅拌,将碳酸钾(69.1mg,0.50mmol,1.0eq)加入反应瓶中,氮气置换6次,将2,4,6-三甲基苯磺酰氯(109.4mg,0.50mmol,1.0eq)加入反应瓶中,氮气置换6次,将体系控温至25℃,搅拌反应12小时。TLC监测反应完毕 后,将反应混合物用水(20mL)稀释并用EtOAc(20mL)萃取两次。合并的有机层用盐水 (20mL)洗涤,经硫酸钠干燥并过滤。浓缩滤液,得到142.0mg黄色固体,将固体以2mL 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=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75.6mg黄色固体,经过检测黄色固 体为7-(2,4,6-三甲基苯磺酸)-2,3-脱氢水飞蓟宾酯,mp 123-126℃.1H NMR(DMSO-d6,400 MHz):δ12.52(s,1H),10.01(s,1H),9.19(s,1H),7.84(s,1H),7.84-7.82(dd,1H),7.19(s,2H),7.15-7.13(d,J=9.5Hz,1H),7.05(s,2H),6.90-6.88(dd,J=8.2,1.7Hz,1H),6.83-6.81(d,J=8.1Hz,1H),6.36(s,1H),5.03-5.00(t,J=5.4Hz,1H),4.98-4.96(d,J=8.0Hz,1H),4.32-4.28(m,1H),3.79(s,3H),3.61-3.56(m,1H),3.39-3.36(m,1H),2.55(s,6H),2.31(s,3H).13CNMR (DMSO-d6,126MHz):δ176.79,160.65,155.14,153.36,148.10,147.87,147.52,146.00,145.18, 143.92,140.31,137.85,132.48,129.83,127.58,123.66,122.22,121.05,117.36,116.98,115.75,112.05,108.62,103.51,101.92,79.04,76.35,60.51,56.11,22.64,21.07.HRMS(ESI)calcd for C34H31O12S[M+H]+663.1531;found 663.1537.
实施例6:7-(4-三氟甲氧基苯磺酸)-2,3-脱氢水飞蓟宾酯的制备
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),氮气置换6次,开启搅拌,将碳酸钾(69.1mg,0.50mmol,1.0eq)加入反应瓶中,氮气置换6次,将对三氟甲氧基苯磺酰氯(136.8mg,0.525mmol,1.05eq) 加入反应瓶中,氮气置换6次,将体系控温至25℃,搅拌反应12小时。TLC监测反应完毕 后,将反应混合物用水(20mL)稀释并用EtOAc(20mL)萃取两次。合并的有机层用盐水(20mL)洗涤,经硫酸钠干燥并过滤。浓缩滤液,得到150.0mg黄色固体,将固体以2mL 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=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91.6mg黄色固体,经过检测黄色固 体为7-(4-三氟甲氧基苯磺酸)-2,3-脱氢水飞蓟宾酯,mp 119-122℃.1H NMR(DMSO-d6,400 MHz):δ12.56(s,1H),10.05(s,1H),9.21(s,1H),8.13-8.05(d,J=8.9Hz,2H),7.83-7.81(m,2H), 7.69-7.68(d,J=7.8Hz,2H),7.15-7.12(d,J=9.0Hz,1H),7.09-7.08(d,J=2.2Hz,1H), 7.05-7.04(d,J=1.9Hz,1H),6.91-6.88(dd,J=8.2,1.9Hz,1H),6.83-6.81(d,J=8.1Hz,1H),6.47-6.46(d,J=2.1Hz,1H),5.05-5.02(t,J=5.3Hz,1H),4.98-4.96(d,J=7.96Hz,1H),4.32-4.28(m,1H),3.80(s,3H),3.60-3.56(m,1H),3.40-3.39(m,1H).13C NMR(DMSO-d6,126MHz):δ176.84,160.80,155.15,153.18,148.09,147.96,147.52,146.04,143.94,137.90,133.01,131.78,127.58,123.64,122.34,122.21,121.49,121.04,118.90,117.37,116.98,115.74,112.05, 108.90,104.12,102.25,79.04,76.34,60.51,56.10.HRMS(ESI)calcdfor C32H24F3O13S[M+H]+705.0884;found 705.0888.
实施例7:7-(4-甲基苯磺酸)-2,3-脱氢水飞蓟宾酯的制备
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),氮气置换6次,开启搅拌,将碳酸钾(69.1mg,0.50mmol,1.0eq)加入反应瓶中,氮气置换6次,将4-甲基苯磺酰氯(95.3mg,0.50mmol,1.0eq)加入反应瓶中,氮气置换6次,将体系控温至25℃,搅拌反应12小时。TLC监测反应完毕后,将 反应混合物用水(20mL)稀释并用EtOAc(20mL)萃取两次。合并的有机层用盐水(20mL) 洗涤,经硫酸钠干燥并过滤。浓缩滤液,得到166.0mg黄色固体,将固体以2mL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=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71.6mg黄色固体,经过检测黄色固体为7-(4-甲 基苯磺酸)-2,3-脱氢水飞蓟宾酯,mp 234-237℃.1H NMR(DMSO-d6,400MHz):δ12.53(s,1H), 10.01(s,1H),9.19(s,1H),7.85-7.82(m,4H),7.51-7.49(d,J=8.0Hz,2H),7.15-7.13(d,J=8.4 Hz,1H),7.09-7.08(d,J=1.9Hz,1H),7.05-7.04(d,J=1.7Hz,1H),6.91-6.88(dd,J=8.2,1.8Hz,1H),6.83-6.81(d,J=8.0Hz,1H),6.41-6.40(d,J=2.1Hz,1H),5.03-5.01(t,J=5.4Hz,1H), 4.98-4.96(d,J=7.9Hz,1H),4.32-4.28(m,1H),3.79(s,3H),3.60-3.55(m,1H),3.40-3.35(m,1H),2.42(s,3H).13C NMR(DMSO-d6,126MHz):δ176.84,160.67,155.16,153.52,148.10, 147.94,147.52,146.74,146.02,143.93,137.85,131.49,130.88,128.80,127.59,123.67,122.24,121.05,117.39,117.02,115.75,112.07,108.72,103.97,102.11,79.04,76.35,60.51,56.12,21.67.HRMS(ESI)calcd for C32H27O12S[M+H]+635.1218;found 635.1220.
实施例8
化合物抗肿瘤活性测试
一、乳腺癌
1.细胞培养条件:10%胎牛血清的MEM完全培养基(含0.01mg/mL胰岛素),37℃、5% CO2的培养环境。
2.细胞给药:胰酶消化对数期MCF-7细胞,制成细胞悬液。根据细胞增长速率以每孔100 μL体积设置好细胞密度,接种96孔板,同时设置调零孔(培养基),对照孔(细胞、相同浓度的药物溶解介质、培养液、CCK-8)。待细胞贴壁后加药,每孔100μL,设5个复孔, 培养48h。
3.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。
4.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)。
表1本发明实施例1-3所示化合物和在不同浓度下对人类乳腺癌MCF-7细胞株的抑制率
实验结论:如表1所示,7-(2,4,6-三甲基苯磺酸)-水飞蓟宾酯、7-(4-三氟甲氧基苯磺酸) -水飞蓟宾酯、7-(4-甲基苯磺酸)-水飞蓟宾酯、7-(2,4,6-三甲基苯磺酸)-2,3-脱氢水飞蓟宾酯、 7-(4-三氟甲氧基苯磺酸)-2,3-脱氢水飞蓟宾酯和7-(4-甲基苯磺酸)-2,3-脱氢水飞蓟宾酯的抗 人类乳腺癌MCF-7增殖活性明显优于水飞蓟宾。此外,5,7-双(4-甲基苯磺酸)-水飞蓟宾酯和 5,7,20-三(4-甲基苯磺酸)-水飞蓟宾酯也具有一定的抗人类乳腺癌MCF-7增殖活性。
二、非小细胞肺癌
实验方法
1.细胞培养条件:10%胎牛血清的RPMI-1640完全培养基,37℃、5%CO2的培养环境。
2.细胞给药:胰酶消化对数期NCI-H1299细胞,制成细胞悬液。根据细胞增长速率以每 孔100μL体积设置好细胞密度,接种96孔板,同时设置调零孔(培养基),对照孔(细胞、相同浓度的药物溶解介质、培养液、CCK-8)。待细胞贴壁后加药,每孔100μL,设5个复 孔,培养48h。
3.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。
4.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)。
表2本发明实施例1-3所示化合物和在不同浓度下对人类非小细胞肺癌NCI-H1299细胞 株的抑制率
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实验结论:如表1所示,7-(2,4,6-三甲基苯磺酸)-水飞蓟宾酯、7-(4-三氟甲氧基苯磺酸) -水飞蓟宾酯、7-(4-甲基苯磺酸)-水飞蓟宾酯、5,7-双(4-甲基苯磺酸)-水飞蓟宾酯、7-(2,4,6- 三甲基苯磺酸)-2,3-脱氢水飞蓟宾酯、7-(4-三氟甲氧基苯磺酸)-2,3-脱氢水飞蓟宾酯和7-(4- 甲基苯磺酸)-2,3-脱氢水飞蓟宾酯的抗人非小细胞肺癌NCI-H1299增殖活性明显优于水飞蓟宾。此外,5,7,20-三(4-甲基苯磺酸)-水飞蓟宾酯也具有一定的抗人非小细胞肺癌NCI-H1299 增殖活性。
三、肝癌
1.细胞培养条件:10%胎牛血清的MEM完全培养基,37℃、5%CO2的培养环境。
2.细胞给药:胰酶消化对数期HepG2细胞,制成细胞悬液。根据细胞增长速率以每孔100 μL体积设置好细胞密度,接种96孔板,同时设置调零孔(培养基),对照孔(细胞、相同浓度的药物溶解介质、培养液、CCK-8)。待细胞贴壁后加药,每孔100μL,设5个复孔, 培养48h。
3.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。
4.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)。
表3本发明实施例1-3所示化合物和在不同浓度下对人类肝细胞癌HepG2细胞株的抑制 率
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实验结论:如表3所示,7-(2,4,6-三甲基苯磺酸)-水飞蓟宾酯、7-(4-三氟甲氧基苯磺酸) -水飞蓟宾酯、7-(4-甲基苯磺酸)-水飞蓟宾酯、5,7-双(4-甲基苯磺酸)-水飞蓟宾酯、7-(2,4,6- 三甲基苯磺酸)-2,3-脱氢水飞蓟宾酯、7-(4-三氟甲氧基苯磺酸)-2,3-脱氢水飞蓟宾酯和7-(4- 甲基苯磺酸)-2,3-脱氢水飞蓟宾酯的抗人肝细胞癌HepG2增殖活性明显优于水飞蓟宾。此外, 5,7,20-三(4-甲基苯磺酸)-水飞蓟宾酯也具有一定的抗人肝细胞癌HepG2增殖活性。
四、结肠癌
实验方法
1.细胞培养条件:10%胎牛血清的McCOY's 5A完全培养基,37℃、5%CO2的培养环境。
2.细胞给药:胰酶消化对数期HT-29细胞,制成细胞悬液。根据细胞增长速率以每孔100 μL体积设置好细胞密度,接种96孔板,同时设置调零孔(培养基),对照孔(细胞、相同浓度的药物溶解介质、培养液、CCK-8)。待细胞贴壁后加药,每孔100μL,设5个复孔, 培养48h。
3.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。
4.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)。
表4本发明实施例1-3所示化合物和在不同浓度下对人类结肠癌HT-29细胞株的抑制率
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实验结论:如表4所示,7-(4-三氟甲氧基苯磺酸)-水飞蓟宾酯、7-(4-甲基苯磺酸)-水 飞蓟宾酯、7-(2,4,6-三甲基苯磺酸)-2,3-脱氢水飞蓟宾酯和7-(4-甲基苯磺酸)-2,3-脱氢水飞蓟 宾酯的抗人结肠癌HT-29增殖活性明显优于水飞蓟宾。此外,7-(2,4,6-三甲基苯磺酸)-水飞 蓟宾酯、5,7-双(4-甲基苯磺酸)-水飞蓟宾酯、5,7,20-三(4-甲基苯磺酸)-水飞蓟宾酯和7-(4- 三氟甲氧基苯磺酸)-2,3-脱氢水飞蓟宾酯也具有一定的人结肠癌HT-29增殖活性。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明 基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不 偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (4)
1.一种水飞蓟宾衍生物或其药学上可接受的盐,选自以下化合物:
7-(2,4,6-三甲基苯磺酸)-水飞蓟宾酯;
7-(4-三氟甲氧基苯磺酸)-水飞蓟宾酯;
7-(4-甲基苯磺酸)-水飞蓟宾酯;
5,7-双(4-甲基苯磺酸)-水飞蓟宾酯;
7-(2,4,6-三甲基苯磺酸)-2,3-脱氢水飞蓟宾酯;
7-(4-三氟甲氧基苯磺酸)-2,3-脱氢水飞蓟宾酯;
7-(4-甲基苯磺酸)-2,3-脱氢水飞蓟宾酯。
2.如权利要求1所述的水飞蓟宾衍生物或其药学上 可接受的盐的制备方法,其特征在于,具体步骤为:以水飞蓟宾为原料,在碱的催化下与不同的磺酰氯反应制备得到;所述不同的磺酰氯为2,4,6-三甲基苯磺酰氯、三氟甲氧基苯磺酰氯或4-甲基苯磺酰氯。
3.根据权利要求2所述的制备方法,其特征在于:所述的碱为氢氧化钠、氢氧化钾、氢氧化钡、氢氧化钙、碳酸钠、碳酸钾、碳酸钙、碳酸铯、碳酸氢钠、三乙胺、4-二甲氨基吡啶、N,N-二异丙基乙胺、氢化钠中的至少一种。
4.如权利要求1所述的水飞蓟宾衍生物或其药学上可接受的盐在制备抗肿瘤药物中的应用;所述肿瘤选自乳腺癌、非小细胞肺癌、肝癌、结肠癌。
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