CN101220068B - 一组格尔德霉素衍生物及其制备方法 - Google Patents
一组格尔德霉素衍生物及其制备方法 Download PDFInfo
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- CN101220068B CN101220068B CN2008100011706A CN200810001170A CN101220068B CN 101220068 B CN101220068 B CN 101220068B CN 2008100011706 A CN2008100011706 A CN 2008100011706A CN 200810001170 A CN200810001170 A CN 200810001170A CN 101220068 B CN101220068 B CN 101220068B
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- ethylamino
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- 230000007246 mechanism Effects 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical class COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- YNOGYQAEJGADFJ-UHFFFAOYSA-N oxolan-2-ylmethanamine Chemical group NCC1CCCO1 YNOGYQAEJGADFJ-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000002512 suppressor factor Substances 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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Abstract
本发明提供了一组新的格尔德霉素衍生物及其制备方法;本发明还提供了以所述化合物为活性成分的药物组合物;实验研究结果证明,所说衍生物具有广谱抗病毒活性,对艾滋病毒(HIV-1)和乙肝病毒(HBV)的抑制作用较强,并对疱疹病毒也有较好的抑制活性;由于其对热休克蛋白90(Hsp90)具有抑制作用,本发明化合物同时具有抗病毒和抗肿瘤功效。
Description
技术领域:
本发明涉及一组格尔德霉素结构改造衍生物;本发明又涉及所述化合物的制备方法及其在抗病毒和抗肿瘤方面的应用;本发明还涉及所说化合物的药物组合物。
背景技术:
格尔德霉素为吸湿链霉菌发酵产生的苯醌安莎类抗生素,由一个苯醌结构与一个平面性大环安莎桥构成。格尔德霉素的作用靶点是热休克蛋白90(Hsp90),它特异性地使Hsp90失活而抑制肿瘤生长或抑制病毒的复制。格尔德霉素通过干扰Hsp90的正常功能,阻止Hsp90底物蛋白活化,诱导细胞周期阻断而抑制病毒复制,从而起到抗病毒或抗肿瘤的作用。独特的作用机理,使得格尔德霉素具有抗病毒/抗肿瘤广谱、与其它药物没有交叉耐药和本身难以产生耐药的特性。格尔德霉素是以细胞因子为靶点的新型抗病毒或抗肿瘤药物合成与筛选的优异先导化合物。
中国医学科学院医药生物技术研究所以Hsp90抑制剂筛选研究为主要目的,对格尔德霉素进行了系列研究,并拥有格尔德霉素抗病毒感染治疗药物用途的专利(ZL97100523),对格尔德霉素的抗病毒活性、作用机理和开发应用等作了深入研究(Li Yuhuan,Tao Peizheng et al:Antimicrobial Agents andChemotherapy,48(3):867-872;2004)。本发明人在合成和研究格尔德霉素17位核苷衍生物(CN1817866A)抗病毒作用的基础上,又合成了一组新型格尔德霉素17位结构改造物及17,19位同时改造的衍生物,并测定了化合物的抗病毒活性。所说格尔德霉素结构改造衍生物及其抗病毒活性,迄今为止,尚未见有国内外的相关报道。
本发明的主要目的在于:通过在格尔德霉素分子的17位或19位引入不同的取代基团,保留或增强格尔德霉素原有抗病毒活性的同时,改善其毒性等,以期获得具有较小毒性和较高疗效的新型Hsp90抑制剂类化合物,为以Hsp90为靶点的抗病毒或抗肿瘤药物的进一步研究开发奠定基础。
发明内容:
本发明提供了一组格尔德霉素的结构改造衍生物,其结构如式(I)所示:
其中:
R1为通过含有3-20个碳的直链或支链、饱和或不饱和、不含或含有醚键或酯键或酰胺键的联结部分,另一端联有脂肪环状或芳香环状结构的基团;环状结构部分可带有烃基、卤素、羟基、羧基、腈基、氨基、磺酸基、磷酸基,或者是其酯或盐;
R2为H、与R1相同或不同的取代基;
X为H、NH、O、S。
式(I)化合物的制备可由以下通用方法实现。合成制得或商业购买得到的带有R1取代基的胺,在卤代烷烃类溶剂、醇性溶剂或极性非质子性溶剂(N,N-二甲基甲酰胺、二甲亚砜、乙酸乙酯、乙腈、丙酮)中,碱性条件(三乙胺、吡啶、N,N-二甲基吡啶、碳酸钾、碳酸钠、氢氧化钙)下,与格尔德霉素反应,得到17-位单取代化合物(I,X-R2为H)。17,19双取代化合物的制备以17-位单取代化合物为原料,在相似条件下,与R2XH反应,得到17和19位双取代目标化合物(I,R1、X-R2都不为H)。
当R1另一端联有3,4-二羟基甲基化咖啡酸结构时,式(I)的制备方法按照如下路线进行:咖啡酸在碱性条件下与甲基化试剂(硫酸二甲酯、甲烷磺酸甲酯、碘甲烷、碳酸二甲酯)反应,得到3,4-二羟基甲基化咖啡酸。然后,将3,4-二羟基甲基化咖啡酸与酰氯化试剂反应得到的酰氯,与单N-叔丁氧羰基乙二胺
反应,得到(2-叔丁氧酰胺基)乙基-3,4-二羟基甲基化咖啡酰胺。脱叔丁基保护基,得到(2-氨基)乙基-3,4-二羟基甲基化咖啡酰胺。(2-氨基)乙基-3,4-二羟基甲基化咖啡酰胺与格尔德霉素反应,按照前述类似方法制得化合物17-位含有二羟基甲基化咖啡酰胺基结构的格尔德霉素衍生物。
当R1另一端联有胞嘧啶核苷结构时,式(I)的制备方法按照如下路线进行:胞苷在酸催化下与2,2-二甲氧基丙烷反应,得到2’,3’-异丙叉胞苷。在脱水剂(DCC、TBU)作用下,与γ-叔丁氧酰胺基丁酸缩合,得到2’,3’-异丙叉胞苷与γ-叔丁氧酰胺基丁酸的酯化产物。酸催化下醇解脱保护基,得到γ-氨基丁酸胞苷酯盐酸盐。最后,γ-氨基丁酸胞苷酯盐酸盐与格尔德霉素反应,按照前述类似方法,制得17-位含有胞嘧啶核苷结构的格尔德霉素衍生物。
当R1另一端联有烟酰胺基结构时,式(I)的制备方法按照如下路线进行:烟酸在酰氯化试剂(二氯亚砜)作用下,得到的烟酰氯与2-(N-叔丁氧羰基)乙二胺反应,得到化合物2-(叔丁氧酰胺基)乙基烟酰胺。酸催化下脱保护基,得到(2-氨基)乙基烟酰胺。最后,(2-氨基)乙基烟酰胺与格尔德霉素反应,按照前述类似方法,制得17-位含有烟酰胺基结构的格尔德霉素衍生物。
当R1另一端联有磷酸基结构时,式(I)的制备方法按照如下路线进行:将对甲苯磺酰氧烷基磷酸二乙酯在极性非质子性溶剂中,与邻苯二甲酰亚胺钾盐反应,制得N-烃基磷酸二乙酯-邻苯二甲酰亚胺,再与水合肼反应,得到亚甲氨基磷酸二乙酯,最后,按照前述类似方法与格尔德霉素反应,制得17-位含有磷酸基结构的格尔德霉素衍生物。
按照上述路线和方法,制备得到了本发明所述一组化合物(表1)。
本发明检测了式(I)化合物的抗乙肝病毒(HBV)、抗艾滋病毒(HIV)、抗疱疹病毒(HSV)作用。基于格尔德霉素作用于热休克蛋白90的机理,格尔德霉素同时还具有抗肿瘤活性。
本发明还提供了所述化合物的药物组合物,其以含治疗有效量的上述化合物为活性成分,并含有一种或多种药学上可接受的载体。
本发明的化合物和药物组合物可用于制备抗病毒或抗肿瘤药物。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备,例如使活性成分与一种或多种载体混合,然后将其制成所需的剂型。
本发明的药物组合物优选含有重量比为0.1%-99.5%的活性成分,最优选含有重量比为0.5%-99.5%的活性成分。
发明效果:
按照以上所述路线和方法,能够稳定、可重复地合成得到本发明的一组格尔德霉素新衍生物。生物活性及药理实验结果证明,所述衍生物具有广谱抗病毒活性,对艾滋病毒(HIV-1)和乙肝病毒(HBV)的抑制作用较强。此外,本发明化合物对疱疹病毒也有较强抑制活性。各化合物的结构及活性测定结果如表1所示。
表1:发明化合物的结构及抗病毒活性
具体实施方案:
以下实施例可以使本领域技术人员更全面地理解本发明,但不以任何方式限制本发明。
<实施例1>:17-(2’-(1”,4”-氧氮杂环己基-1”-)乙胺基)-17-去甲氧基格尔德霉素GM-APML)的制备:
取格尔德霉素50mg(89.29μmo1),加入5mL CHCl3,甲醇0.5ml,搅拌至格尔德霉素溶解,反应液呈橙黄色。加入4-(2-氨基乙基)-1,4-氧氮杂环己烷21mg(164μmol),室温反应进行4天,蒸干溶剂,得暗紫色固体,将固体残留物溶于10mL乙酸乙酯,依次用去离子水,饱和NaHCO3,1mol/LHCl溶液,饱和食盐水洗。有机相中加入无水Na2SO4干燥过夜。滤除干燥剂,有机相减压浓缩。用硅胶柱进行层析分离,得化合物GM-APML 46.2mg(61.2%)。
1H-NMR(400MHz,CDCl3)δ(ppm):0.9~1.0(m,6H,C10-CH3,C14-CH3),1.28-1.38(m,2H,C13-H2),1.5(m,1H,C14-H),1.64(m,2H,C15-H2),1.78(s,3H,C8-CH3),2.03(s,3H,C2-CH3),2.5(br,4H,C17-NH-CH2-CH2-N-),2.6~2.7(br,4H,C17-N-CH2-CH2-O),2.7~2.8(m,1H,C10-H),3.23(s,3H,C12-OCH3),3.36(s,3H,C6-OCH3),3.44(d,1H,J=9.2Hz,C12-H),3.5(br,1H,C17-NH),3.58(d,1H,J=9.2Hz,C11-H),3.64~3.8(m,4H,C170-(CH2-CH2)-N-),4.31(d,1H,J=10.0Hz,C6-H),4.4(br,1H,C11-OH),4.84(br,2H,-NH2),5.19(s,1H,C7-H),5.83(t,1H,J=10.4,C5-H)5.86(d,1H,J=9.6,C9-H),6.58(t,1H,J=11.2Hz,C4-H),6.96(d,1H,J=11.6Hz,C3-H),7.15(br,1H,C20-NH-CO),9.19(s,1H,C19-H)
<实施例2>:17-(2’-(1”-氮杂环己基-1”-)乙胺基)-17-去甲氧基格尔德霉素(GM-AEPD)的制备:
当侧链反应物为2-(1’-氮杂环己基)乙胺时,按实施例1类似方法合成得到化合物GM-AEPD。
1H-NMR(400MHz,CDCl3)δ(ppm):0.82(1H,m,C14-H),0.94~1.0(m,6H,C10-CH3,C14-CH3),1.24-1.3(m,4H,C13-H2,C15-H2),1.4~1.5(m,2H,C17-N(CH2-CH2)2 CH2)),1.6(br,4H,C17-N(CH2-CH2)2CH2),1.76(br,1H,C10-H),1.78(s,3H,C8-CH3),2.03(s,3H,C2-CH3),2.3~2.4(br,4H,C17-N-(CH2-CH2)2CH2),2.6~2.8(m,4H,C17-NH-CH2-CH2-N),3.24(s,3H,C12-OCH3),3.38(s,3H,C6-OCH3),3.44(d,1H,J=9.2Hz,C12-H),3.58(d,1H,J=9.2Hz,C11-H),3.7(br,1H,C17-NH-),4.31(d,1H,J=10.0Hz,C6-H),4.5(br,1H,C11-OH),4.80(br,2H,-CO-NH2),5.20(s,1H,C7-H),5.83(t,1H,J=10.4,C5-H)5.94(d,1H,J=9.6,C9-H),6.59(t,1H,J=11.6Hz,C4-H),6.96(d,1H,J=11.6Hz,C3-H),7.22(br,1H,C20-NH-CO),9.19(s,1H,C19-H)
<实施例3>:1 7-(4’-苄基-4’-氮杂环己胺基)-17-去甲氧基格尔德霉素(GM-ABPD)的制备:
当侧链反应物为4-苄基-4-氮杂环己胺时,按实施例1类似方法合成得到化合物GM-ABPD。
1H-NMR(400MHz,CDCl3)δ(ppm):0.94~1.0(dd,6H,C10-CH3,C14-CH3),1.5~1.6(m,4H,C17-NH-CH(CH2-CH2)2N-),1.64(d,2H,C15-H2),1.7(m,2H,C13-H2),1.8(s,3H,C8-CH3),1.9(s,2H,C17-NH-CH-(CH2-CH2)2-N-CH2-Ph),2.03(s,3H,C2-CH3),2.1-2.2(m,2H,C17-NH-CH-(CH2-CH2)2-N-CH2-Ph),2.7~2.8(m,3H,C14-CH,C17-NH-CH-(CH2-CH2)2-N-CH2-Ph),2.87(br,1H,C17-NH-CH(CH2-CH2)2N-),3.26(s,3H,C12-OCH3),3.38(s,3H,C6-OCH3),3.4(d,1H,J=9.2Hz,C12-H),3.58(d,1H,J=9.2Hz,C11-H),3.6(s,1H,C10-H),3.9(br,1H,C17-NH-),4.2(br,1H,C11-OH),4.3(d,1H,J=10.0Hz,C6-H),4.78(br,2H,-CO-NH2),5.17(s,1H,C7-H),5.8-5.9(m,2H,C5-H,C9-H),6.27(br,1H,C20-NH-CO),6.5(t,1H,J=11.2Hz,C4-H),6.9(d,1H,J=11.6Hz,C3-H),7.34(br,5H,C17-Ph),9.13(s,1H,C19-H)
<实施例4>:17-(四氢哌嗪-4’-基-甲胺基)-17-去甲氧基格尔德霉素(GM-AMPP)的制备:
当侧链反应物为四氢哌嗪-4’-基-甲胺时,按实施例1类似方法合成得到化合物GM-AMPP。
1H-NMR(400MHz,DMSO)δ(ppm):0.6(d,3H,C10-CH3),0.8(m,3H,C14-CH3),0.82-1.08(m,5H,C17-N-(CH2-CH2)2-CH-CH2-NH2),1.24(m,2H,C13-H2),1.5(m,1H,C14-H),1.58(s,3H,C8-CH3),1.60(d,2H,C15-H2),1.8(s,3H,C2-CH3),2.3(br,2H,C17-N-(CH2-CH2)2-CH-CH2-NH2),2.4~2.5(br,4H,C17-N-(CH2-CH2)2-),2.8(m,1H,C10-H),3.18(br,6H,C6-OCH3,C12-OCH),3.28(d,1H,J=8.8Hz,C12-H),3.38(d,1H,J=8.8Hz,C11-H),4.36(t,1H,C11-OH)4.82(d,1H,J=6.8Hz,C6-H),,4.82(br,2H,-NH2),5.2(s,1H,C7-H),5.22(d,1H,J=10.0,C9-H),5.4(t,1H,J=10.4,C5-H),6.4(br,2H,C17-CH2-NH2),6.55(t,1H,J=11.2Hz,C4-H),6.99(br,1H,C20-NH-CO),7.1(s,1H,C19-H),7.12(d,1H,J=11.0Hz,C3-H),7.4,7.7(s,s,2H,-CO-NH2)
<实施例5>:17-(桃金娘烷胺基)-17-去甲氧基格尔德霉素(GM-MTA)的制备:
当侧链反应物为桃金娘烷胺时,按实施例1类似方法合成得到化合物GM-MTA。
1H-NMR(400MHz,CDCl3)δ(ppm):0.87(d,3H,C14-CH3),0.95(d,3H,C10-CH3),1.02(s,3H,MTA-9’CH3),1.24(s,3H,MTA-10’CH3),1.5-1.6(m,3H,MTA-5’CH2,2’-CH),1.72(m,1H,C14-CH),1.80(s,3H,C8-CH3),1.8-2.0(m,6H,MTA-3’CH2,7’CH2,C15-CH2),2.02(s,3H,C2-CH3),2.32(m,1H,C17-6’CH),2.42(m,2H,C13-CH2),2.65(d,1H,C10-CH),2.74(m,1H,C17-4’CH),3.374(s,3H,C12-OCH3),3.370(s,3H,C6-OCH3),3.6-3.4(m,4H,C11-H,C12-H,C17-NH-CH2-),4.3(d,2H,J=10Hz,C6-H),4.37(br,1H,C11-OH),4.76(br,2H,C1-CO-NH2),5.20(s,1H,C7-H),5.857(t,1H,J=11.2Hz,C5-H),5.904(d,1H,J=10Hz,C9-H),6.38(br,1H,C20-NH-CO),6.58(t,1H,J=11.4Hz,C4-H),6.97(d,1H,J=11.6Hz,C3-H),9.19(s,1H,C19-H)
<实施例6>:17-((二乙酯磷)甲胺基)-17-去甲氧基格尔德霉素(GM-AP)的制备:
将对甲苯磺酸亚甲基磷酸二乙酯1.1g(3.4mmol)溶于DMF15ml中,加入邻苯二甲酰亚胺钾盐0.9g(4.8mmol)混合搅拌,逐渐升温至90℃,反应2小时后原料消失,恢复至室温后减压蒸干溶剂,残余物用硅胶柱分离得到黄色固体产物N-亚甲基磷酸二乙酯-邻苯二甲酰亚胺500mg。
前步所得产物200mg(0.7mmol)溶于15ml乙醇中,加入0.1ml(2mmol)水合肼,室温反应4小时后,减压蒸干反应液,向残余物中加入乙酸乙酯,混匀后过滤除去固体,滤液用硅胶柱分离得到无色油状产物亚甲氨基磷酸二乙酯80mg.
然后,以亚甲氨基磷酸二乙酯为反应物与格尔德霉素反应,按实施例1类似方法合成得到化合物GM-AP。
1H-NMR(300MHz,CDCl3)δ(ppm):0.94~1.04(dd,6H,C10-CH3,C14-CH3),1.36(dt,6H,-PO(OCH2CH3)2),1.6-1.8(br,1H,C17-NH-CH2-),1.8(d,6H,C8-CH3,C2-CH3),2.03(br,3H,C13-H2,C14-H),2.18(s,C10-H-),2.35(m,1H,C9-H),2.7(m,2H,C15-CH2),3.28(s,3H,C12-OCH3),3.36(s,3H,C6-OCH3),3.43(d,1H,J=9.2Hz,C12-H),3.58(d,1H,J=9.2Hz,C11-H),3.9-4.0(dd,2H,C17-NH-CH2-P),4.15-4.2(five,4H,-PO(OCH2CH3)2),4.3(d,1H,J=10.0Hz,C6-H),4.78(br,2H,-CO-NH2),5.27(s,1H,C7-H),5.8(d,1H,C5-H),5.9(d,1H,C9-H),6.3(br,1H,C20-NH-CO),6.6(t,1H,J=11.2Hz,C4-H),6.9(d,1H,J=11.6Hz,C3-H),9.07(s,1H,C19-H)
<实施例7>:17-(3’-(1”-咪唑基)丙胺基)-17-去甲氧基格尔德霉素(ZJH061129)的制备:
当侧链反应物为N-(3-氨基丙基)咪唑时,按实施例1类似方法合成得到化合物ZJH061129。
1H-NMR(400M,CDCl3)δ(ppm):0.87(d,3H,J=6.5Hz,CH3);0.99(d,3H,J=7.0Hz,CH3);1.64~1.72(m,3H,CH,CH2);1.79(s,3H,CH3);2.02(s,3H,CH3);2.11~2.22(m,3H,咪唑NCHa,CH2);2.62~2.65(m,1H,OCH);2.72~2.75(m,1H,CH);3.27(s,3H,OCH3);3.35(s,3H,OCH3);3.42~3.43(m,1H,OCH);3.48~3.54(m,3H,咪唑NCHb,NCH2);4.04~4.14(m,2H,CH2);4.28~4.31(m,1H,OCH);5.18(s,1H,OCH);5.84~5.88(m,2H,2×=CH);6.19~6.21(m,1H,Ar-H);6.55~6.60(m,1H,=CH);6.92~6.95(m,1H,=CH);7.11(s,1H,Ar-H);7.51(s,1H,Ar-H);9.12(s,1H,Ar-H)。
MS(ESI):m/z=654(M+1)。
<实施例8>:17-(4”-氨基磺酰基)苯乙胺基-17-去甲氧基格尔德霉素(ZJH061208)的制备:
当侧链反应物为4-氨基乙基-苯磺酰胺时,按实施例1类似方法合成得到化合物ZJH061208。
1H-NMR(400M,CDCl3)δ(ppm):0.94(d,3H,C14-CH3);1.00(d,3H,C10-CH3);1.24-1.31(m,2H,C13-H2);1.79(s,3H,C8-CH3);2.02(s,3H,C2-CH3);2.31-2.37(m,1H,C10-H);2.66-2.69(m,1H,C11-H);2.72-2.75(m,1H,C14-CH);3.03-3.06(m,2H,C24-CH2);3.27(s,3H,C12-OCH3);3.36(s,3H,C6-OCH3);3.43-3.58(m,2H,C15-CH2);3.76-3.86(m,2H,C25-CH2);4.11-4.13(m,1H,C12-CH);4.31(d,1H,C6-CH);5.19(s,1H,C7-CH);5.84-5.89(m,2H,C5-CH,C9-CH);6.55-6.61(m,1H,C4-CH);6.95(d,1H,C3-CH);7.38(d,2H,C27-CH,C31-CH);7.91(d,2H,C28-CH,C30-CH);9.14(s,1H,C19-CH)。
MS(ESI):m/z=767.0(M+K),751.0(M+Na)。
<实施例9>:17-(3’,4’-亚甲二氧苯甲氨基)-17-去甲氧基格尔德霉素(ZJH061217)的制备:
当侧链反应物为3’,4’-亚甲二氧苯甲氨(胡椒甲胺)时,按实施例1类似方法合成得到化合物ZJH061217。
1H-NMR(400M,CDCl3)δ(ppm):0.99-1.03(m,6H,2CH3);1.80(s,3H,CH3);2.03(s,3H,CH3);2.41-2.47(m,1H);2.68(d,1H);2.73-2.77(m,1H);2.88(br,1H);2.95(br,1H);3.27(s,3H,OCH3);3.37(s,3H,OCH3);3.44-3.60(m,2H,CH2);4.18(br,1H,OH);4.31(d,1H,J=10Hz);4.48-4.68(m,2H,CH2);4.79(br,2H,NH2);5.19(s,1H);5.84-5.93(m,2H,2CH);5.99(d,2H);6.36(br,1H);6.58(t,1H,J=11.5Hz);6.73-6.82(m,3H,3CH);6.96(d,1H,J=12Hz);7.30(s,1H);8.02(br,1H);9.16(s,1H)。
MS(ESI):m/z=7 1 8.2(M+K),702.2(M+Na),679.2(M+)。
<实施例10>:17-(2’-噻吩乙胺基)-17-去甲氧基格尔德霉素(ZJH061221)的制备:当侧链反应物为2-噻吩乙胺时,按实施例1类似方法合成得到化合物ZJH061221。
1H-NMR(400M,CDCl3)δ(ppm):0.95-1.00(m,6H,2CH3);1.79(s,3H,CH3);2.02(s,3H,CH3);2.35-2.41(m,1H);2.68-2.76(m,2H,2CH);2.95(s,2H);3.16-3.20(t,2H,CH2);3.26(s,3H,OCH3);3.36(s,3H,OCH3);3.43-3.58(m,2H,CH2);3.76-3.84(m,2H,CH2);4.30(d,1H,J=10Hz);4.84(br,2H,NH2);5.18(s,1H);5.83-5.90(m,2H,2CH);6.36(br,1H,NH);6.57(t,1H,J=11.5Hz);6.90-6.98(m,3H,3CH);7.21(d,1H,J=Hz);7.61(d,1H,J=15.5Hz);8.01(br,1H,OH);9.14(s,1H)。
MS(ESI):m/z=678.2(M+Na),656.2(M+H),624.2(M-33,-OCH3)。
<实施例11>:17-(反-4’-羟基环己胺基)-17-去甲氧基格尔德霉素(ZJH061223)的制备:
当侧链反应物为反-4-氨基环己醇时,按实施例1类似方法合成得到ZJH061223。
1H-NMR(400M,CDCl3)δ(ppm):0.97-1.01(m,6H,2CH3);1.38-1.57(m,2H,2CH);1.77(m,1H,CH);1.80(s,5H,CH3+2CH);2.00(m,2H,2CH);2.03(s,3H,CH3);2.09-2.11(d,2H,2CH);2.16-2.22(m,1H);2.72-2.77(m,2H,2CH);3.27(s,3H,OCH3);3.38(s,3H,OCH3);3.45-3.60(m,2H,CH2);3.72(m,2H,CH2);3.88(m,1H);4.31(d,1H,J=10Hz);4.74(br,2H,NH2);5.19(s,1H);5.84-5.92(m,2H,2CH);6.25(br,1H,NH);6.58(t,1H,J=11.5Hz);6.94-7.00(m,1H);7.28(s,1H);9.17(s,1H)。
MS(ESI):m/z=667.3(M+Na),644.3(M+)。
<实施例12>:17-(3’-(2”-吡咯烷酮基)丙胺基)-17-去甲氧基格尔德霉素(ZJH061226)的制备:
当侧链反应物为N-(3’-氨基丙基)-2-吡咯烷酮时,按实施例1类似方法合成得到化合物ZJH061226。
1H-NMR(400M,CDCl3)δ(ppm):0.98-1.00(m,6H,2CH3);1.25(s,1H);1.80(s,3H,CH3);1.83-1.88(m,2H,CH2); 2.02(s,3H,CH3);2.07(t,2H,CH2,J=Hz);2.31-2.38(m,1H);2.42(t,2H,CH2,J=Hz);2.66(d,1H);2.72-2.76(m,1H);3.26(s,3H,OCH3);3.36(s,3H,OCH3);3.37-3.46(m,5H,2CH2+CH);3.54-3.58(m,3H,CH2+CH);4.30(d,1H,J=Hz);4.80(br,2H,NH2);5.18(s,1H);5.83-5.92(m,2H,2CH);6.55-6.61(t,1H,J=Hz);6.72(br,1H,NH);6.95(d,1H,J=Hz);7.24(s,1H);7.26(s,1H);9.15(s,1H);
<实施例13>:17-(2”-(N-乙基吡咯烷基)-甲胺基)-17-去甲氧基格尔德霉素(ZJH061228)的制备:
当侧链反应物为2-氨甲基-1-乙基吡咯时,按实施例1类似方法合成得到化合物ZJH061228。
1H-NMR(400M,CDCl3)δ(ppm):0.96~1.01(m,3H,CH3);1.09~1.14(s,3H,CH3);1.54(s,3H,CH3);1.50~1.52(m,2H,CH2);1.70~1.82(m,2H,CH2);1.81(s,3H,CH3);1.90~2.00(m,1H,CH);2.03(s,3H,CH3);2.21~2.29(m,2H,CH2);2.35-2.46(m,1H,CH);2.65-2.80(m,3H,NCH2,NCH);3.27(s,3H,OCH3);3.37(s,3H,OCH3);3.41~3.76(m,4H,2×NCH2);4.32(d,1H,J=10Hz,OCH);4.5 1~4.20(m,1H,OCH);4.20~4.35(br);5.19(s,1H,OCH);5.83~5.94(m,2H,Ar-CH2);6.59(t,1H,J=11.2Hz,=CH);6.96(d,1H,J=11.2Hz,=CH);7.16~7.21(m,1H,=CH);7.26~7.32(m,1H,=CH);9.21~9.22(s,s,1H,Ar-H)。
MS(ESI):m/z=657(M+1)。
<实施例14>:17-(2”S-2”-(N-乙基吡咯烷基)-甲胺基)-17-去甲氧基格尔德霉素(ZJH071206S)的制备:
当侧链反应物为(S)-2-氨甲基-1-乙基吡咯时,按实施例1类似方法合成得到化合物ZJH071206S。
1H-NMR(400M,CDCl3)δ(ppm):0.82-0.89(m,3H,CH3);0.95-1.00(m,3H,CH3);1.08-1.14(m,3H,CH3);1.25-1.30(m,H,);1.80(s,3H,CH3);2.02(s,3H,CH3);2.35-2.41(m,1H);2.68-2.76(m,2H,2CH);2.95(s,2H);3.16-3.20(t,2H,CH2);3.26(s,3H,OCH3);3.36(s,3H,OCH3);3.43-3.58(m,2H,CH2);3.76-3.84(m,2H,CH2);4.30(d,1H,J=10Hz);4.84(br,2H,NH2);5.18(s,1H);5.83-5.90(m,2H,2CH);6.36(br,1H,NH);6.57(t,1H,J=11.5Hz);6.90-6.98(m,3H,3CH);7.21(d,1H,J=Hz);7.61(d,1H,J=15.5Hz);8.01(br,1H,OH);9.14(s,1H)。
MS(ESI):m/z=678.2(M+Na),656.2(M+H),624.2(M-33,-OCH3)。
<实施例15>:17-(2”R-2”-(N-乙基吡咯烷基)-甲胺基)-17-去甲氧基格尔德霉素(ZJH071210R)的制备:
当侧链反应物为(R)-2-氨甲基-1-乙基吡咯时,按实施例1类似方法合成得到化合物ZJH071210R。
1H-NMR(600M,CDCl3)δ(ppm):0.83-0.89(m,6H,2CH3);1.00()1.80(s,3H,CH3);2.02(s,3H,CH3);2.35-2.41(m,1H);2.68-2.76(m,2H,2CH);2.95(s,2H);3.16-3.20(t,2H,CH2);3.26(s,3H,OCH3);3.36(s,3H,OCH3);3.43-3.58(m,2H,CH2);3.76-3.84(m,2H,CH2);4.30(d,1H,J=10Hz);4.84(br,2H,NH2);5.18(s,1H);5.83-5.90(m,2H,2CH);6.36(br,1H,NH);6.57(t,1H,J=11.5Hz);6.90-6.98(m,3H,3CH);7.21(d,1H,J=Hz);7.61(d,1H,J=15.5Hz);8.01(br,1H,OH);9.14(s,1H)。
MS(ESI):m/z=678.2(M+Na),656.2(M+H),624.2(M-33,-OCH3)。
<实施例16>:17-(2’-(3”,4”-二甲基咖啡酰胺基)乙胺基)-17-去甲氧基格尔德霉素(ZJH070413)的制备:
取咖啡酸1.8g(0.01mol),加入15mL纯化水,以30%NaOH调节pH至13,咖啡酸全部溶解。加入硫酸二甲酯6g(0.05mol),室温搅拌反应,不时调节pH>10。反应进行10小时,以2N的HCl溶液调节pH至3,过滤,固体以水洗至pH 6-7,干燥,得到3,4-二甲基咖啡酸。
取5.25g乙二胺于250mL置于三口瓶中,加入1,4-二氧六环30mL,搅拌。于室温氮气保护下滴加二碳酸二叔丁酯2.45g和1,4-二氧六环30mL的溶液。反应2小时后,减压蒸干,加入50mL纯化水,搅拌,有白色固体析出。过滤,水洗,滤液以二氯甲烷50mL提取三次。合并二氯甲烷提取液,无水硫酸钠干燥。过滤,滤液蒸干,得到无色油状液体。用硅胶柱进行层析分离,得到单N-叔丁氧羰基乙二胺。
取3,4-二甲基咖啡酸0.208g(0.001mol),加入3mL二氯亚砜,50℃下反应4小时。水泵减压蒸干后加入5mL二氯甲烷,搅拌,加入单N-叔丁氧羰基乙二胺0.160g和吡啶4mL的溶液,室温下反应3小时。将反应液过滤,滤液依次以饱和NaHCO3溶液、水洗,无水硫酸钠干燥。过滤,滤液蒸干,用硅胶柱进行层析分离,得到(2-叔丁氧酰胺基)乙基-3,4-二甲基咖啡酰胺。
取甲醇2mL于三口烧瓶中,冰浴下滴加乙酰氯1mL,滴加完毕后室温搅拌反应30分钟。然后滴加(2-叔丁氧酰胺基)乙基-3,4-二甲基咖啡酰胺0.263g(0.75mmol)的甲醇溶液,室温反应3小时至反应完全。过滤,甲醇洗。滤液减压蒸干后加入石油醚,有黄色固体析出,过滤,分别以乙酸乙酯、氯仿洗。固体烘干,得到(2-氨基)乙基-3,4-二羟基甲基化咖啡酰胺盐酸盐。
取格尔德霉素50mg(89.29μmol),加入5mL CHCl3,甲醇0.5mL,搅拌至格尔德霉素溶解,反应液呈橙黄色。加入上步操作所得N-氨乙基-3,4-二甲基-咖啡酰胺盐酸盐75mg(260μmol)和0.5mL三乙胺,室温反应进行3天,蒸干溶剂,得紫色固体,用硅胶柱进行层析分离,得到化合物17-(2’-(3”,4”-二甲基咖啡酰胺基)乙胺基)-17-去甲氧基格尔德霉素(ZJH070413)55.2mg(79.4%)。
1H-NMR(500M,CDCl3)δ(ppm):0.98(m,6H,2CH3);1.80(s,3H,CH3);2.02(s,3H,CH3);2.37-2.42(m,1H);2.65(d,1H);2.72-2.76(m,1H);3.07-3.12(m,2H,CH2);3.26(s,3H,OCH3);3.35(s,3H,OCH3);3.57-3.58(m,2H,CH2);3.71-3.85(m,2H,CH2);3.90(s,6H,2CH3);4.25(br,1H,OH);4.30(d,1H,J=10Hz);4.80(br,1H,NH);5.18(s,1H);5.84-5.90(m,2H,2CH);6.15-6.17(m,1H);6.30(d,1H,J=15.5Hz);6.57(t,1H,J=11.5Hz);6.83-6.84(m,1H);6.86(d,1H,J=8Hz);6.94(d,1H,J=12Hz);7.02(s,1H);7.08(d,1H,J=8Hz);7.24(s,1H);7.61(d,1H,J=15.5Hz);9.13(s,1H);12.00(br,4H,CONH)。
<实施例17>:17-(2’-烟酰胺基乙胺基)-17-去甲氧基格尔德霉素(ZJH070418)的制备:
单N-叔丁氧羰基乙二胺的制备方法按照实施例16中的方法合成。
取烟酸1.85g(0.015mol),加入二氯甲烷5mL,搅拌,不溶。加入二氯亚砜4.4mL(0.06mol),氮气保护下油浴50℃回流反应4小时。撤去油浴,将反应液过滤,二氯甲烷洗,得到白色针状晶体,为烟酰氯。
取单N-叔丁氧羰基乙二胺2.4g(0.015mol),加入二氯甲烷2ml和四氢呋喃2mL,搅拌,再加入5mL三乙胺。然后加入上步固体烟酰氯,室温反应3小时,反应完全。过滤,二氯甲烷洗。滤液蒸干,得到粘稠液体。用硅胶柱进行层析分离,得到化合物(2-叔丁氧酰胺基)乙基烟酰胺。
取4ml无水甲醇于三口烧瓶中,冰水浴冷却,滴加2mL乙酰氯,滴加完毕后室温反应30分钟。加入(2-叔丁氧酰胺基)乙基烟酰胺0.53g(2mmol)的甲醇液,室温30分钟反应完全。过滤,乙酸乙酯洗后的白色固体,为(2-氨基)乙基烟酰胺。
取格尔德霉素50mg(89.29μmol),加入5mLCHCl3,甲醇0.5mL,搅拌至格尔德霉素溶解,反应液呈橙黄色。加入上步所得(2-氨基)乙基烟酰胺44mg(153μmol)和0.5ml三乙胺,室温反应进行2天,蒸干溶剂,得紫色固体,用硅胶柱进行层析分离,得到化合物17-(2’-烟酰胺基乙胺基)-17-去甲氧基格尔德霉素(ZJH070418)58.3mg(94.2%)。
1H-NMR(500M,CDCl3)δ(ppm):0.98-0.99(m,6H,2CH3);1.80(s,3H,CH3);2.02(s,3H,CH3);2.42-2.46(m,1H);2.65(d,1H);2.72-2.76(m,1H);3.09-3.12(m,2H,CH2);3.27(s,3H,OCH3);3.35(s,3H,OCH3);3.42-3.57(m,2H,CH2);3.79-3.93(m,4H,2CH2);4.30(d,1H,J=10Hz);4.80(br,2H,NH2);5.17(s,1H);5.30(br,1H);5.84-5.90(m,2H,2CH);6.57(t,1H,J=11.5Hz);6.93-6.95(d,H,CH);7.21(s,1H);7.53(s,1H);8.44(d,1H,J=15.5Hz);8.76(s,1H);9.13(s,1H);9.34(s,1H);11.89(br,3H,3NH).
<实施例18>:17-(4’-((5”-(4-氨基-2-氧代嘧啶-1-(2H)-基)-3”,4”-二羟基-四氢呋喃-2”-基)甲氧基)-4’-氧代丁胺)-17-去甲氧基格尔德霉素(GM-CY)的制备:
参照文献(赵知中等,有机化学中的保护基团,科学出版社,1984:41-49),以Boc2O为原料,保护γ-氨基丁酸的伯氨基,得到γ-叔丁氧酰胺-丁酸。
取对甲苯磺酸0.476g(2.5mmol),加入10mL丙酮。溶解后加入2,2-二甲氧基丙烷1.5mL(12mmol)和胞苷0.486g(2mmol)。固体溶解后,室温搅拌反应1.5小时,有大量白色固体生产。过滤,固体烘干,得到2’,3’-异丙叉胞苷对甲苯磺酸盐,备用。
取γ-叔丁氧酰胺-丁酸0.457g(2.25mmol),加入5mL CHCl3。溶解后加入二环己基碳二亚胺(DCC)0.6g(2.91mmol),室温搅拌,出现大量白色混浊。反应进行4小时,滤除白色沉淀,含有γ-叔丁氧酰胺-丁酸酐的滤液备用。
取2’,3’-异丙叉胞苷对甲苯磺酸盐,置100mL圆底烧瓶中,加入二氯甲烷15mL和1mL三乙胺,搅拌。溶解后,将上步反应所得滤液转入反应瓶,氮气保护下室温搅拌。反应进行30小时,滤除不溶物,油泵减压浓缩得略显黄色的粘稠液体,用硅胶柱进行层析分离,得到2’,3’-异丙叉胞苷与γ-叔丁氧酰胺-丁酸的酯化产物。
取4ml无水甲醇于三口烧瓶中,冰水浴冷却,滴加2mL乙酰氯,滴加完毕后室温反应30分钟。加入上步所得2’,3’-丙叉基胞苷与γ-叔丁氧酰胺-丁酸的酯化产物50mg(0.107mmol)的甲醇液,室温30分钟反应完全。过滤,乙酸乙酯洗后得白色固体,为γ-氨基丁酸胞苷酯盐酸盐。
取格尔德霉素50mg(89.29μmol),加入5mL CHCl3,甲醇0.5ml,搅拌至格尔德霉素溶解,反应液呈橙黄色。加入γ-氨基丁酸胞苷酯盐酸盐80.2mg(200μmol),室温反应进行3天,蒸干溶剂,得暗紫色固体,将固体残留物溶于10mL乙酸乙酯,依次用去离子水,饱和NaHCO3,1mol/LHCl溶液,饱和食盐水洗。有机相中加入无水Na2SO4干燥过夜。滤除干燥剂,有机相减压浓缩。用硅胶柱进行层析分离,得化合物17-(4’-((5”-(4-氨基-2-氧代嘧啶-1-(2H)-基)-3”,4”-二羟基-四氢呋喃-2”-基)甲氧基)-4’-氧代丁胺)-17-去甲氧基格尔德霉素。
1H-NMR(400M,CDCl3)δ(ppm):0.94-1.00(m,6H,2CH3);1.24-1.30(m,2H,CH2);1.64-1.67(m,2H,CH2);1.80(s,3H,CH3);2.02(s,3H,CH3);2.38(t,2H,CH2);2.41-2.47(m,1H);2.66~2.75(m,1H);2.72-2.76(m,1H);2.98(t,2H,CH2);3.27(s,3H,OCH3);3.37(s,3H,OCH3);3.42-3.59(m,3H,CH+CH2);3.62-3.66(m,1H);3.78-3.81(m,1H);3.89-3.94(m,2H,CH2);4.08~4.11(m,1H);4.31(d,1H);4.81(br,2H,NH2);4.95(br,1H,OH);5.19(s,1H);5.26(br,1H,OH);5.69(d,1H);5.75(d,1H);5.84-5.90(m,2H,2CH);6.55-6.61(m,1H);6.93-6.95(d,1H);7.11(br,2H,NH2);7.28(s,1H);7.82(d,1H);9.14(br,1H,NH)。
MS(ESI):m/z=857.3(M+),880.3(M+Na)。
<实施例19>:2’R-17-四氢糠胺基-17-去甲氧基格尔德霉素(THFM(R)-GM)的制备:
当侧链反应物为(R)-四氢糠胺时,按实施例1类似方法合成得到化合物THFM(R)-GM。
1H-NMR(400M,CDCl3)δ(ppm):0.9~1.0(m,6H,2CH3);1.25(s,2H,CH2);1.4~1.5(m,1H);1.61~1.65(m,2H,CH2);1.70~1.74(m,2H,CH2);1.799(s,3H,CH3);1.93~1.98(m,2H,CH2);2.025(s,3H,CH3);2.36~2.39(m,1H);2.66~2.75(m,2H,CH2);3.268(s,3H,OCH3);3.362(s,3H,OCH3);3.42-3.49(m,1H);3.56~3.62(m,1H);3.79-3.95(m,2H,CH2);4.08~4.11(m,1H);4.311(d,1H);4.806(br,2H,NH2);5.190(s,1H);5.857(t,1H);5.904(d,1H);6.583(t,1H);6.955(d,1H);7.276(s,1H);9.167(br,1H,NH)。
MS(FAB):m/z=631(M+1)。
<实施例20>:2’S-17-四氢糠胺基-17-去甲氧基格尔德霉素(THFM(S)-GM)的制备:
当侧链反应物为(S)-四氢糠胺时,按实施例1类似方法合成得到化合物THFM(S)-GM。
在HPLC图谱中,THFM(S)-GM的保留时间与THFM(R)-GM只有微小差别,两者的1H-NMR也基本相同。
1H-NMR(400M,CDCl3)δ(ppm):0.94~1.00(m,6H,2CH3);1.25(s,2H,CH2);1.30~1.32(m,1H);1.61~1.64(m,2H,CH2);1.73~1.75(m,2H,CH2);1.80(s,3H,CH3);1.93~2.00(m,2H,CH2);2.03(s,3H,CH3);2.3 1~2.37(m,1H);2.67~2.75(m,2H,CH2);3.27(s,3H,OCH3);3.36(s,3H,OCH3);3.43-3.49(m,1H);3.58~3.62(m,1H);3.79-3.96(m,2H,CH2);4.08~4.11(m,1H);4.31(d,1H);4.81(b r,2H,NH2);5.19(s,1H);5.86(t,1H);5.91(d,1H);6.55-6.60(m,1H);6.95(d,1H);7.28(s,1H);9.14(br,1H,NH)。
MS(FAB):m/z=631(M+1)。
<实施例21>:17-四氢糠胺基-17-去甲氧基格尔德霉素(THFM-GM)的制备:
当侧链反应物为四氢糠胺时,按实施例1类似方法合成得到化合物THFM-GM。
1H-NMR(400M,CDCl3)δ(ppm):0.90~1.01(m,6H,C10-CH3,C14-CH3);1.25(s,2H,C13-H2);1.4~1.5(m,1H,C14-H); 1.61~1.65(m,2H,THMF-CH2-CH 2-CH2-);1.70~1.74(m,2H,C15-H2);1.79(s,3H,C8-CH3);1.93~1.98(m,2H,THMF-CH2-CH 2-CH-);2.02(s,3H,C2-CH3);2.36~2.39(m,1H,C10-H);2.66~2.75(m,2H, C17-NH-CH 2-);3.26(s,3H,C12-OCH3);3.36(s,3H,C6-OCH3);3.42~3.49(m,1H,C12-H);3.56~3.62(m,1H,C11-H);3.79~3.95(m,2H,THMF-CH2-CH 2-O); 4.08~4.11(m,1H,C17-NH-CH2-CH-);4.31(d,J=10Hz,1H,C6-H);4.80(br,OH,NH);5.19(s,1H,C7-H);5.85(t,J=11.2Hz,1H, C5-H);5.90(d,J=10Hz,1H,C9-H);6.58(t,J=11.4Hz,1H,C4-H);6.95(d,J=11.6Hz,1H,C3-H);7.27(s,1H,C19-H);9.16(s,1H,CH)。MS(FAB):m/z=654(M+Na)。
<实施例22>:17,19-二(R)-四氢糠胺基-17-去甲氧基格尔德霉素(THFM-II)的制备:
当侧链反应物为(R)-四氢糠胺时,按实施例1类似方法合成,侧链的投料量增加5倍,并反应时间延长至10小时,得到化合物THFM-II。
1H-NMR(400M,CD3COD)δ(ppm):0.73(d,3H,J=6.4Hz,CH3);1.02(d,3H,J=6.8Hz,CH3);1.46~1.65(m,2H,CH2);1.60(s,3H,CH3);1.81~2.04(m,5H,CH,2CH2);1.91(s,3H,CH3);2.28~2.46(m,2H,CH2);2.56~2.66(m,2H,CH2);3.08~3.17(m,1H,CH);3.23(s,3H,OCH3);3.29(s,3H,OCH3);3.44~3.88(m,11H,3OCH,2OCH2,2NCH2);4.00~4.09(m,2H,CH2);4.34~4.38(dd,1H,J1=10Hz,J2=7.0Hz,OCH);4.88(d,1H,J=4.8Hz,OCH);5.27(s,1H,OCH);5.29(d,1H,J=10Hz,=CH);5.49(t,1H,J=10Hz,=CH);6.57(t,1H,J=12Hz,=CH);7.27(d,1H,J=12Hz,=CH)。
MS(+Q1):m/z=753(M++Na),731(M++1)。
<实施例23>:17,19-二(S)四氢糠胺基-17-去甲氧基格尔德霉素(THFM+2)的制备:
当侧链反应物为(S)-四氢糠胺时,按实施例1类似方法合成,侧链的投料量增加5倍,并反应时间延长至10小时,得到化合物THFM+2。
1H-NMR(400M,CD3COD)δ(ppm):0.73(d,3H,J=6.4Hz,CH3);0.92(d,3H,CH3);1.45-1.59(m,2H,CH2);1.60(s,3H,CH3);1.83-2.02(m,5H,CH,2CH2);1.90(s,3H,CH3);2.29-2.46(m,2H,CH2);2.56-2.65(m,2H,CH2);3.07-3.12(m,1H,CH);3.24(s,3H,OCH3);3.29(s,3H,OCH3);3.47-3.85(m,11H,3OCH,2OCH2,2NCH2);4.00-4.08(m,2H,CH2);4.34-4.38(dd,1H,J1=10Hz,J2=7.0Hz,OCH);4.88(d,1H,J=4.8Hz,OCH);5.26(s,1H,OCH);5.29(d,1H,J=10Hz,=CH);5.47(t,1H,J=10Hz,=CH);6.58(t,1H,J=12Hz,=CH);7.24(d,1H,J=12Hz,=CH).
MS(+Q1):m/z=753(M+Na),731(M+1)。
<实施例24>:单纯疱疹病毒(VR733株)活性的检测实验
在长满VERO细胞的培养瓶内加入0.25%胰酶0.1ml,0.02%EDTA 5ml。于37℃消化20~25分钟。废弃消化液,加培养液吹打。1∶3传代,3天长满。配制成每毫升20~30万个细胞,接种到96孔细胞培养板,每孔0.1ml。于37℃,5%CO2条件下培养24小时,细胞长成单层后进行实验。
取20~30万个VERO细胞每毫升的细胞培养液接种96孔细胞培养板,每孔0.1ml。于37℃,5%CO2条件下培养24小时。弃去培养液,加入适量HSV-1病毒,吸附1小时后,弃去病毒液。加入测试药物,每浓度2孔。于37℃,5%CO2条件下培养。48小时后观察细胞病变。按下式计算药物抑制病毒的半数有效浓度:
A=log(病变<50%的药物浓度)
B=log(病变>50%的药物浓度)
C=log(稀释倍数)
测试计算结果IC50值见(表1)。
<实施例26>:抗HBV病毒活性的实验方法
采用细胞培养法,将试验细胞配制成每毫升10万个细胞接种细胞培养板,96孔板每孔100μl,37℃ 5%CO2培养24小时,细胞长成单层后进行实验。目标化合物和对照药用培养液配制成所需浓度后加入96孔细胞培养板,每浓度4孔,每4天换同浓度药液一次,同时设无药物细胞对照组。以观察细胞病变为指标,8天显微镜下观察细胞病变程度。样品抑制肝炎病毒活性试验方法为:每毫升10万个试验细胞接种96孔细胞培养板,每孔100μl,37℃ 5%CO2培养24小时,加入药物,同时设细胞对照组,4天换原浓度药液或对照培养液一次。细胞裂解后按分子克隆实验技术方法提取HBV DNA。各样品斑点杂交、放射自显影、测量各杂交点的A值后,利用标准曲线的回归方程,计算细胞对照及给药组的HBV DNA含量后,计算出半数有效浓度值,结果见(表1)。
<实施例27>:抗HIV-1活性实验方法
在96孔细胞培养中加入8个不同稀释浓度的药液和阳性对照药液,每个稀释度重复2孔,设细胞对照;再将2×105细胞/ml 100μl接种于含药96孔细胞培养板内。置37℃、5%CO2和饱和湿度培养箱内培养,每天观察细胞病变。按HIV-1P24抗原试剂盒提供的操作步骤,测定加药后第4天(96小时)细胞培养上清HIV-1 P24抗原含量,计算出药物半数有效浓度值IC50,结果见(表1)。
Claims (2)
1.一组格尔德霉素衍生物在制备抗病毒药物中的应用,所述衍生物选自:
17-(3’,4’-亚甲二氧苯甲氨基)-17-去甲氧基格尔德霉素、
17-2’-(噻吩-2”-基)乙胺基-17-去甲氧基格尔德霉素、
17-(2’-(3”,4”-二甲基咖啡酰胺基)乙胺基)-17-去甲氧基格尔德霉素、
17-(2’-烟酰胺基乙胺基)-17-去甲氧基格尔德霉素、
17-((呋喃-2’-甲酰)肼基-N’-基)-17-去甲氧基格尔德霉素、
17-(2’-(吡啶-3”-基)乙胺基)-17-去甲氧基格尔德霉素、
17-(3’-甲氧基苯乙胺基)-17-去甲氧基格尔德霉素、
17-(二乙酯磷酸)甲胺基-17-去甲氧基格尔德霉素、
17-(3’-磷酸基丙胺基)-17-去甲氧基格尔德霉素、
17-脒甲胺基-17-去甲氧基格尔德霉素、
17-(2’-(2”-羟基乙氧基)乙胺基)-17-去甲氧基格尔德霉素、
17-(2’-(2”-羟基乙胺基)乙胺基)-17-去甲氧基格尔德霉素、
17-(2’-羟基-乙胺基)-17-去甲氧基格尔德霉素、
17-(1’-羟甲基-2’-羟基乙胺基)-17-去甲氧基格尔德霉素或
17-(2’,3’-二羟基丙胺基)-17-去甲氧基格尔德霉素。
2.权利要求1所述任一化合物与一种或多种药学上可接受的载体所组成的药物组合物在制备抗病毒药物中的应用。
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EP09703551A EP2253621A1 (en) | 2008-01-18 | 2009-01-19 | A set of geldanamycin derivatives and their preparation methods |
PCT/CN2009/000074 WO2009092295A1 (zh) | 2008-01-18 | 2009-01-19 | 一组格尔德霉素衍生物及其制备方法 |
US12/812,817 US20100311694A1 (en) | 2008-01-18 | 2009-01-19 | Set of Geldanamycin Derivatives and Their Preparation Methods |
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CN101220068B (zh) * | 2008-01-18 | 2012-06-13 | 中国医学科学院医药生物技术研究所 | 一组格尔德霉素衍生物及其制备方法 |
CN102115460B (zh) * | 2010-01-05 | 2014-08-20 | 杭州华东医药集团生物工程研究所有限公司 | 格尔德霉素衍生物及其制备方法和用途 |
CN101792418B (zh) * | 2010-03-04 | 2012-02-15 | 中国医学科学院医药生物技术研究所 | 格尔德霉素生物合成类似物19-o-甘氨酰格尔德霉素 |
CN102101867B (zh) * | 2010-12-07 | 2012-07-04 | 中国医学科学院医药生物技术研究所 | 噻嗪酮格尔德霉素及其制备方法和用途 |
CN102127019A (zh) * | 2010-12-24 | 2011-07-20 | 王文怡 | 一种格尔德霉素衍生物及其制备和药物应用 |
CN102603635B (zh) * | 2011-01-21 | 2016-08-03 | 杭州华东医药集团生物工程研究所有限公司 | 格尔德霉素衍生物及其制备方法和用途 |
CN102731401B (zh) * | 2011-04-08 | 2016-03-09 | 杭州中美华东制药有限公司 | 格尔德霉素衍生物及其制备方法和用途 |
CN102391183A (zh) * | 2011-10-26 | 2012-03-28 | 中国医学科学院医药生物技术研究所 | C-19位修饰的格尔德霉素衍生物及其制备方法 |
CN103450164B (zh) * | 2012-05-31 | 2017-02-01 | 杭州华东医药集团生物工程研究所有限公司 | 格尔德霉素衍生物及其制备方法和用途 |
CN102795953B (zh) * | 2012-08-17 | 2015-05-27 | 广西大学 | 以咖啡酸与磺胺类药物为原料合成咖啡酸酰胺衍生物的方法及用途 |
CN103360312B (zh) * | 2013-07-22 | 2015-06-03 | 山东大学 | 一组格尔德霉素衍生物及其应用 |
CN103819457B (zh) * | 2014-02-12 | 2016-08-31 | 复旦大学附属上海市第五人民医院 | 一类能够抑制去势抵抗性***癌和成骨转移的格尔德霉素衍生物及其应用 |
CN103819456B (zh) * | 2014-02-12 | 2015-10-28 | 复旦大学附属上海市第五人民医院 | 一组格尔德霉素衍生物及其应用 |
CN103804296A (zh) * | 2014-03-03 | 2014-05-21 | 山东大学 | 17-(6-(取代肉桂酰氨基)己二胺)-17-去甲氧基格尔德霉素衍生物及其应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4261989A (en) * | 1979-02-19 | 1981-04-14 | Kaken Chemical Co. Ltd. | Geldanamycin derivatives and antitumor drug |
WO2005112952A2 (en) * | 2004-05-20 | 2005-12-01 | Kosan Biosciences Incorporated | Geldanamycin compounds and method of use |
CN1817866A (zh) * | 2006-03-21 | 2006-08-16 | 中国医学科学院医药生物技术研究所 | 一组连有核苷碱基的格尔德霉素衍生物 |
CN1827617A (zh) * | 2006-04-10 | 2006-09-06 | 中国医学科学院医药生物技术研究所 | 17-(四氢呋喃-2’-基)甲胺-17-去甲氧基格尔德霉素的抗病毒作用 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2003013430A2 (en) * | 2001-08-06 | 2003-02-20 | Kosan Biosciences, Inc. | Benzoquinone ansamycins |
US6872715B2 (en) * | 2001-08-06 | 2005-03-29 | Kosan Biosciences, Inc. | Benzoquinone ansamycins |
DE60327994D1 (de) * | 2002-02-08 | 2009-07-30 | Conforma Therapeutics Corp | Ansamycine mit verbesserten pharmakologischen und biologischen eigenschaften |
RU2007120473A (ru) * | 2004-11-02 | 2008-12-10 | Конформа Терапьютикс Корпорейшн (Us) | Способы лечения формы хронического лимфоцитарного лейкоза |
EP1863769A4 (en) * | 2005-03-11 | 2009-03-18 | Univ Colorado | HSP90 INHIBITORS, METHOD FOR THE PRODUCTION THEREOF AND THEIR APPLICATIONS |
CN101220068B (zh) * | 2008-01-18 | 2012-06-13 | 中国医学科学院医药生物技术研究所 | 一组格尔德霉素衍生物及其制备方法 |
CN101302199B (zh) * | 2008-06-06 | 2012-11-21 | 中国医学科学院医药生物技术研究所 | 桂德霉素及其在制备抗肿瘤药物中的应用 |
-
2008
- 2008-01-18 CN CN2008100011706A patent/CN101220068B/zh not_active Expired - Fee Related
-
2009
- 2009-01-19 US US12/812,817 patent/US20100311694A1/en not_active Abandoned
- 2009-01-19 EP EP09703551A patent/EP2253621A1/en not_active Withdrawn
- 2009-01-19 WO PCT/CN2009/000074 patent/WO2009092295A1/zh active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4261989A (en) * | 1979-02-19 | 1981-04-14 | Kaken Chemical Co. Ltd. | Geldanamycin derivatives and antitumor drug |
WO2005112952A2 (en) * | 2004-05-20 | 2005-12-01 | Kosan Biosciences Incorporated | Geldanamycin compounds and method of use |
CN1817866A (zh) * | 2006-03-21 | 2006-08-16 | 中国医学科学院医药生物技术研究所 | 一组连有核苷碱基的格尔德霉素衍生物 |
CN1827617A (zh) * | 2006-04-10 | 2006-09-06 | 中国医学科学院医药生物技术研究所 | 17-(四氢呋喃-2’-基)甲胺-17-去甲氧基格尔德霉素的抗病毒作用 |
Non-Patent Citations (2)
Title |
---|
Schnur, R. C.等.Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives.《Journal of Medicinal Chemistry》.1995,第38卷(第19期),3806-12. * |
Tian, Zong-Qiang等.Synthesis and biological activities of novel 17-aminogeldanamycin derivatives.《Bioorganic & Medicinal Chemistry》.2004,第12卷(第20期),第5317-5329页. * |
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