CN1052482C - 喜树碱衍生物及其制备方法和抗肿瘤剂 - Google Patents
喜树碱衍生物及其制备方法和抗肿瘤剂 Download PDFInfo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明涉及通式(1)新的喜树碱衍生物,其制备方法和含它们的抗肿瘤剂。在通式(1)中,R1代表氢原子或C1-C6烷基,R2代表氢或C1-C6烷氧基,R3代表氢或卤原子或C1-C6烷基、C1-C6烷氧基、羟基、C2-C6酰氧基或甲氧基乙氧基甲氧基,R4代表氢或卤原子,和R5代表C1-C6烷基,C3-C6不饱和的烃基,烷硫基烷基、烷氧基烷基、吡啶基或取代的苯基,但条件是:所述的R2、R3和R4取代基不应同时为氢原子。
Description
本发明涉及新的水溶性喜树碱衍生物、其制备方法和含该衍生物作为活性成分的抗肿瘤剂。
本发明人已研究并提供了一些具有极佳抗肿瘤活性的新的喜树碱(以下称作CPT)衍生物,发现在B环的7位带有低级烷基并在A环的9、10和11位带有各种不同的取代基和/或烷基的全合成的CPT衍生物均显示出强抗肿瘤活性(参见JP,A,H1-186892)。
本发明人还为解决使该衍生物在使用时能够水溶的问题进行了广泛的研究。尤其是,通过将7-乙基CPT用二胺打开E内酯环随后将羟基甲基基团酰化合成的CPT衍生物,与已知的E环打开的水溶性CPT衍生物(JP,A,H1-131179)相对比,显示出极佳的水溶性,而抗肿瘤活性不降低。
除需要进一步研究以获得具有更佳的抗肿瘤活性并在给药时具有有效的水溶性的其它新的CPT衍生物外,在本领域还很需要解决的问题是:要制备出能解决毒性和用法问题的新的CPT衍生物。
因此,本发明的目的是提供具有极佳的抗肿瘤活性的水溶性的新的CPT衍生物。本发明的另一个目的是提供能解决毒性和用法问题的新的CPT衍生物。为实现这些目标,我们提供由在7位带有低级烷基并且在A环的9、10和11位还带有各种不同的取代基和/或烷基的CPT衍生物出发制备新的水溶性CPT衍生物的方法:将所述起始物用二胺打开E内酯环,接着将羟基甲基基团酰化。我们进行了广泛的安全性和制剂化的研究,结果开发出新的水溶性CPT衍生物,据认为能够达到上述目标,并能提供抗肿瘤活性极佳的新的CPT衍生物。
本发明提供由通过(1)代表的新的CPT衍生物及制备新的喜树碱衍生物的方法,所述通式(1)如下:式中R1代表氢原子或C1-C6烷基,R2代表氢或C1-C6烷氧基,R3代表氢或卤原子或C1-C6烷基、C1-C6烷氧基、羟基、C2-C6酰氧基或甲氧基乙氧基甲氧基,R4代表氢或卤原子,和R5代表C1-C6烷基,C3-C6不饱和的烷基,烷硫基烷基、烷氧基烷基、吡啶基或取代的苯基,但条件是:所述的R2、R3和R4取代基不应同时为氢原子。本发明还提供含通式(1)新的CPT衍生物作活性成分的抗肿瘤剂。
本发明的新CPT衍生物由在7位带有氢原子或低级烷基并在9、10和11位还带有各种不同取代基和/或烷基的CPT衍生物出发这样来制备:将其用N,N-二甲基乙二胺在无溶剂条件下处理,接着用适当的酰化剂将17-羟基甲基基团酰化。该在7位带有氢原子或低级烷基并且在9、10和11位还带有各种不同的取代基和/或烷基的原料CPT衍生物是已知的CPT衍生物,由天然物质(9-甲氧基CPT,10-羟基CPT、10-甲氧基CPT、11-羟基CPT、11-甲氧基CPT等)制备,或者采用已知的方法半合成或全合成制备(参见JP,A,S58-39684;JP,A,S58-134095;JP,A,S59-51287;JP,A,S59-51289;JP,A,H1-279891;JP,A,H1-186892;JP,A,H4-503505;JP,A,H5-502017;WO-91/04260;WO-92/11263;USP,5122606等)。
尽管可以采用JP,A,H1-13117中所公开的反应条件将E环用N,N-二甲基乙二胺打开随后用适当的酰化剂酰化17-羟基。但我们发现,按照该方法未必能以令人满意的收率制得目标化合物。我们测试了该方法的反应条件,结果发现在用N,N-二甲基乙二胺使E内酯环开环的第一步反应中,仅使用过量的N,N-二甲基乙二胺而不用溶剂能得到E环打开的中间体,接着用适当的酰化剂将17-羟基基团酰化,能以非常好的收率制得目标化合物。
尽管用于该酰化反应的酰化剂不是特殊的试剂、但可以使用相应的酸酐,酰卤例如酰氯、酰溴和其它相当的酰化剂。用缩合剂例如二环己基碳化二亚胺处理的相应的羧酸的混合物也可用于所述酰化反应。
用作所述酰化剂的相应的羧酸的例子有例如具有2-20个碳原子的饱和脂肪酸,具有3-20个碳原子的不饱和脂肪酸,具有环烷基的脂肪酸,或具有例如卤原子或烷硫基、氨基、酰氨基、羟基、烷氧基或烷氧基羰基的脂肪酸,具有6-20个碳原子的芳香酸或具有例如卤原子或羟基、烷氧基或低级烷基的芳香酸,杂芳族酸或氨基酸。酰化剂的实例包括乙酰氯、苯甲酰氯、丙酰氯、丁酰氯、甲氧基苯甲酰氯、氟苯甲酰氯、溴苯甲酰氯、氯苯甲酰氯、硝基苯甲酰氯、三氟甲基苯甲酰氯、萘甲酰氯、环丙烷甲酰氯、噻吩甲酰氯、巴豆酰氯、肉桂酰氯、苯基乙酰氯、苯基苯甲酰氯、环己烷甲酰氯、硬脂酰氯、油酰氯、甲氧基羰基苯甲酰氯、乙基琥珀酰氯、亚油酰氯、氯丁酰氯、乙基苯甲酰氯、甲硫基丙酰氯、新戊酰氯、烟酰氯、异烟酰氯和吡啶甲酰氯。
在所述的酰化反应中,N,N-二甲氨基吡啶等可作为催化剂存在于该反应中。
此外,不仅在开环反应过程中而且在酰化反应和其它的例如粉末化,纯化和结晶化过程中,仔细维持无水条件,能够增加目标化合物的收率。
本发明的新CPT衍生物通过将其用适当的酸例如盐酸转化成其酸加成盐能显示极佳的水溶性。本发明化合物在安全性和抗肿瘤活性方面显示极佳的结果,因此可用作新抗肿瘤剂。
现用实施例对本发明进行更详细的说明。合成实施例实施例1开环化合物(B1-B13)的制备
作为原料的在7位和A环的9、10和11位具有各取代基的CPT衍生物(A1-A12,各自的取代基见表1)按上述文献来制备。在本实施例中使用了从天然物质中分离出来的9-甲氧基CPT(A13)。由于该化合物在A环上有羟基,因此使用用常法O-甲氧基乙氧基甲基化的化合物(A10′)。
向例如3.0g原料CPT衍生物(A1-A13)中加入过量的无水N,N-二甲基乙二胺(5-100eq.,例如15ml)。将反应混合物在氮气下于50℃搅拌1.5小时。反应后将反应混合物在减压下蒸发至干。将残余物溶于无水二氯甲烷(例如15ml)中,将此溶液倒入大量的无水正己烷(例如500ml)中。滤出沉淀的结晶,用无水正己烷洗涤并干燥,以几乎定量的收率得到羟基酰胺(B1-B13,E内酯环开环的化合物)。
收率和各光谱数据示于下表2中。实施例217-羟基的酰化
向上面获得的羟基酰胺(例如1.0g)在无水二氯甲烷(例如20ml)中的溶液中,在二甲氨基吡啶(DMPA,例如100mg)存在下在冰冷却下滴加酰化剂(1.2eq.)。将反应混合物于室温搅拌过夜,并用7%碳酸氢钠水溶液和饱和氯化钠水溶液洗涤,将二氯甲烷层用无水硫酸钠干燥,接着除去不溶物,并在减压下蒸发至干。对残余物进行硅胶柱层析(10%甲醇-氯仿),并用氯仿-正己烷结晶,得到与本发明有关的17-O-酰基-21-N,N-二甲氨基乙酰胺衍生物(C1-C48)。
至于O-甲氧基乙氧基甲基衍生物,将该化合物在10%三氟乙酸-二氯甲烷中的溶液搅拌过夜。搅拌后,在冰冷却下将三乙胺(等摩尔量)滴加至反应混合物中。将反应混合物减压蒸发至干。将残余物溶于二氯甲烷中,用7%碳酸氢钠水溶液和饱和氯化钠水溶液洗涤。将有机层用无水硫酸钠干燥,随后除去不溶物,并减压蒸干。对残余物进行硅胶柱层析(10%甲醇-氯仿),并用丙酮-氯仿结晶,得到与本发明有关的17-O-酰基-21-N,N-二甲氨基乙酰胺衍生物(C28,C30,C32,C34,C36,C38)。
该合成的衍生物的收率及其光谱数据示于表1和表3中。
所得到的与本发明有关的新的喜树碱衍生物的水溶解度数据示于表4中。抗肿瘤效果
对于已获得的本发明的新的喜树碱衍生物,其抗肿瘤活性、毒理学试验、用法-剂量及制剂化法叙述如下。抗肿瘤活性
对于啮齿类动物的抗肿瘤效果能够作为在温血动物中抗肿瘤效果的可信赖的结果,这已广泛被人们所接受。本发明人以小鼠作模型研究了抗肿瘤效果。对L1210的抗肿瘤活性
将5×105个小鼠白血病L1210细胞腹膜内移植至一组六只雌性CDF小鼠(7周令,体重17-19g)中。将待测化合物在第1,5和第9天经腹膜内给予受试小鼠,并观察其延命效果。
当待测化合物以酸加成盐形式使用时,该待测化合物被溶于水中。总给药量为1.56mg/kg-400mg/kg。抗肿瘤活性用值(T/C%)来表示,其中T代表给药组的平均存活天数,而C代表未给药组的平均存活天数。若等于或大于125%,则该药物被认为是有效的。治疗指数通过测定最低有效量和最大耐受量计算出。实验结果
在上述实施例中所述的化合物的抗肿瘤实验结果示于表5中。如表5中所示,本发明中的新喜树碱衍生物,与喜树碱本身相比,治疗指数增大约6倍。在最佳剂量时,在6只小鼠一组中的5只小鼠存活。结果还显示出其在较低剂量时的有效性,抗肿瘤活性显著增加且治疗范围扩大。毒性实验
用一组20只ICR雄性小鼠(4周令,体重约20g)通过腹膜内给药进行急性毒性试验。结果示于表6中。
LD50值用Richfield-Willcokson法由在观察给予待测化合物后1周内小鼠死亡情况的致死率来计算。
据以上实验结果,我们认为,所述新的喜树碱衍生物具有较好的抗肿瘤活性,可作为比其母体化合物喜树碱毒性低的低毒性药物用于治疗癌症。
本发明的抗肿瘤剂可通过注射例如静脉内注射、皮下注射和肌肉注射及口服使用。特别优选的是将该化合物以其适宜作为药物的酸加成盐形式经静脉内给药或口服使用。
在静脉内给药时,上述各化合物的剂量取决于治疗目的,成人每日在5-400mg/个体范围内,优选20-200mg/个体,在口服情况下,成人每日在50-2000mg/个体范围内,优选100-1000mg/个体。
作为本发明的抗肿瘤剂的配制方法,可根据剂型选择各种配制的惯用法。作为适宜于通过胃肠道吸收的制剂,本发明的抗肿瘤剂可以例如片剂、粉剂、颗粒剂、胶囊剂或软胶囊剂和口服液体制剂包括水性或油性悬浮液、溶液、糖浆和酏剂等形式来配剂。注射剂可贮存在安瓿或大容器中,在这些制剂中可以使用添加剂例如防腐剂或助溶剂。
液体制剂的剂型可以是悬浮液、溶液和油性或水性介质中的乳液,可以包含添加剂例如乳化剂。对于本发明的抗肿瘤剂的制剂,活性成分的含量不低于0.1%,优选为1-50%。
在下列非限制性实施例中进一步举例说明本发明的抗肿瘤剂的制剂实施例。制剂1 注射剂
将化合物C7(R1=C2H5,R2=H,R3=CH3,R4=H,R5=C2H4SCH3)溶于含等摩尔量HCl的0.1N HCl中后,将溶液过滤,并冻干,得到50mg化合物C7的HCl盐。将该盐在无菌条件下封装入安瓿中并将其贮于冷暗处。制剂2 片剂化合物C7 50mg乳糖 89mg羟丙基纤维素 2.7mg结晶纤维素 15mg滑石粉 1.6mg硬脂酸镁 1.7mg
将以上成分混合并用压片机直接压成片(160mg/片)。表1 (各化合物的收率)A1-13 → B1-13 → C1-4B起始化合物 羟基酰胺化合物 17-O-酰基化合物→ C28.30.32.34.36.38支保护化合物NO. A R1 R2 R3 R4 R5 收率(%)A→B B→CC1 A11 Me H OEt H -CH2CH2SMe 98 38C2 A12 ″ ″ H Br ″ 99 26C3 A1 Et ″ Cl H Et 94 51C4 A1 ″ ″ ″ ″ Pr ″ 50C5 A1 ″ ″ ″ ″ -CH2CH2SMe ″ 47C6 A2 ″ ″ Br ″ ″ 98 47C7 A3 ″ ″ Me ″ ″ 98 43C8 A4 ″ ″ H F Et 95 71C9 A4 ″ ″ ″ F Pr ″ 75C10 A4 ″ ″ ″ ″ -CH2CH2SMe ″ 72C11 A4 ″ ″ ″ ″ -C6H4-OMe ″ 59C12 A5 ″ ″ ″ Cl -CH2CH2SMe 92 30C13 A6 ″ ″ F F Et 98 56C14 A6 ″ ″ ″ ″ Pr ″ 58C15 A6 ″ ″ ″ ″ -CH2CH2SMe ″ 42表1(续)C16 A6 Et H F F -C6H4-OMe 98 37C17 A7 ″ ″ Cl Cl Et 92 59C18 A7 ″ ″ ″ ″ Pr ″ 60C19 A7 ″ ″ ″ ″ -CH2CH2SMe ″ 56C20 A8 ″ ″ OMe F Et 97 70C21 A8 ″ ″ ″ ″ Pr ″ 67C22 A8 ″ ″ ″ ″ -CH2CH2SMe ″ 65C23 A9 ″ ″ Me ″ Et 94 84C24 A9 ″ ″ ″ ″ Pr ″ 82C25 A9 ″ ″ ″ ″ -CH2CH2SMe ″ 80C26 A9 Et H Me F -C6H4-OMe 94 78 表1(续)C39 A3 ″ ″ Me ″ -4-吡啶基 98 89C40 A1 ″ ″ Cl ″ ″ 94 75C41 A4 ″ ″ H F ″ 95 93C42 A9 ″ ″ Me ″ ″ 94 85C43 A8 ″ ″ OMe ″ ″ 97 95C44 A13 H OMe H H -2-吡啶基 96 80.8C45 A10 Et H OH H Me -- --C46 A10 ″ ″ ″ ″ 异丙基 -- --C47 A10 ″ ″ ″ ″ -C2H4OEt -- --C48 A10 ″ ″ OAc ″ -C6H4-F(D) 83 --表1(附)表2(羟基酰胺化合物的光谱数据)B1(7-Et-10-Cl-)黄色粉末(自 正已烷-氯仿中析出)C26H31N4O4Cl,MS[M+H]+=499,IRνMAX/KBr(cm-1):1650,1590,1510.1H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.34(3H,t,J=8Hz),2.20-2.32(
1H,m),2.27(6H,s),2.39-2.61(3H,m),2.90-3.05(2H,m),3.20-3.33(1H,m),
3.60-3.75(1H,m),4.78(1H,d,J=13Hz),5.00(1H,d,J=19Hz),5.06(1H,d,J=
19Hz),5.10(1H,d,J=13Hz),7.44(1H,br-t,J=5Hz),7.50(1H,s),7.62(1H,dd,
J=2,9Hz),7.82(1H,d,J=2Hz),7.95(1H,d,J=9Hz).B2(7-Et-10-Br-)淡黄色粉末(自 正已烷-氯仿中析出)C26H31N4O4Br,MS[M+H]+=543,IRνMAX/KBr(cm-1):1645,1585,1510.1H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.35(3H,t,J=8Hz),2.20-2.33(
1H,m),2.29(6H,s),2.35-2.63(3H,m),2.99(2H,q,J=8Hz),3.20-3.35(1H,m),
3.60-3.75(1H,m),4.78(1H,d,J=13Hz),5.02(1H,d,J=19Hz),5.07(1H,d,J=
19Hz),5.10(1H,d,J=13Hz),7.43(1H,br-t,J=6Hz),7.50(1H,s),7.75(1H,dd,
J=2,9Hz),7.88(1H,d,J=9Hz),8.02(1H,d,J=2Hz).B3(7-Et-10-Me-)无色粉末(自 正已烷-氯仿中析出)C27H34N4O4,MS[M+H]+=479,IRνMAX/KBr(cm-1):1645,1580,1560,1510.1H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.32(3H,t,J=8Hz),2.20-2.33(
1H,m),2.27(6H,s),2.38-2.60(3H,m),2.57(3H,s),2.92-3.05(2H,m),3.20-
3.33(1H,m),3.61-3.75(1H,m),4.80(1H,d,J=14Hz),5.02(1H,d,J=19Hz),5.08表2(续)
(1H,d,J=19Hz),5.12(1H,d,J=14Hz),7.34(1H,br-t,J=6Hz),7.51(1H,s),7.54
(1H,dd,J=2,9Hz),7.64(1H,br-s),7.99(1H,d,J=9Hz).B4(7-Et-11-F-)淡黄色粉末(自 正已烷-氯仿中析出)C26H31N4O4F,MS[M+H]+=483,IRνMAX/KBr(cm-1):1645,1590,1510.1H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.35(3H,t,J=8Hz),2.20-2.33(
1H,m),2.28(6H,s),2.38-2.62(3H,m),2.97-3.14(2H,m),3.20-3.33(1H,m),
3.63-3.76(1H,m),4.78(1H,d,J=13Hz),5.03(1H,d,J=19Hz),5.08(1H,d,J=
19Hz),5.12(1H,d,J=13Hz),7.32(1H,ddd,J=3,8,10Hz),7.39(1H,br-t,J=6Hz),
7.51(1H,s),7.67(1H,dd,J=3,10Hz),7.93(1H,dd,J=6,9Hz).B5(7-Et-11-Cl-)淡黄色粉末(自 正已烷-氯仿中析出)C26H31N4O4Cl,MS[M+H]+=499,IRνMAX/KBr(cm-1):1645,1600,1590.1H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.36(3H,t,J=8Hz),2.20-2.33(
,1H,m),2.28(6H,s),2.39-2.62(3H,m),2.97-3.12(2H,m),3.21-3.33(1H,m),
3.62-3.78(1H,m),4.76(1H,d,J=14Hz),5.00(1H,d,J=19Hz),5.05(1H,d,J=19Hz),
5.10(1H,d,J=14Hz),7.39-7.52(3H,m),7.84(1H,d,J=9Hz),7.97(1H,d,J=2Hz).B6(7-Et-10,11-F2-)黄色粉末(自 正已烷-氯仿中析出)C26H30N4O4F2,MS[M+H]+=501,IRνMAX/KBr(cm-1):1645,1590,1515.1H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.36(3H,t,J=8Hz),2.18-2.64(
4H,m),2.29(6H,s),3.06(2H,q,J=8Hz),3.22-3.37(1H,m),3.60-3.78(1H,m),表2(续2)
4.76(1H,d,J=14Hz),5.06(1H,d,J=19Hz),5.11(1H,d,J=19Hz),5.13(1H,d,J=
14Hz),7.36-7.44(1H,br),7.51(1H,s),7.69(1H,dd,J=8,11Hz),7.81(1H,dd,
J=8,11Hz).B7(7-Et-10,11-Cl2-)黄色粉末(自 正已烷-氯仿中析出)C26H30N4O4Cl2,MS[M+H]+=533,IRνMAX/KBr(cm-1):1650,1595,1520.1H-NMR(δppm)in CDCl3:1.09(3H,t,J=7Hz),1.38(3H,t,J=8Hz),2.18-2.34(
1H,m),2.29(6H,s),2.38-2.64(3H,m),2.94-3.11(2H,m),3.23-3.38(1H,m),
3.60-3.75(1H,m),4.71(1H,d,J=14Hz),4.97(1H,d,J=19Hz),5.03(1H,d,J=
19Hz),5.06(1H,d,J=14Hz),7.43(1H,s),7.51(1H,br-t,J=5Hz),7.94(1H,s),
8.02(1H,s).B6(7-Et-10-OMe-11-F-)黄色粉末(自 正已烷-氯仿中析出)C27H33N4O5F,MS[M+H]+=513,IRνMAX/KBr(cm-1):1650,1590,1510.1H-NMR(δppm)in CDCl3:1.11(3H,t,J=7Hz),1.31(3H,t,J=8Hz),2.20-2.37(
1H,m),2.27(6H,s),2.41-2.60(3H,m),2.85-3.04(2H,m),3.21-3.33(1H,m),
3.60-3.73(1H,m),4.00(3H,s),4.73(1H,d,J=13Hz),4.86(1H,d,J=19Hz),4.94(
1H,d,J=19Hz),5.05(1H,d,J=13Hz),6.93(1H,d,J=9Hz),7.38(1H,s),7.51(1H,
br-t,J=6Hz),7.55(1H,d,J=12Hz).B9(7-Et-10-Me-11-F-)淡黄色粉末(自 正已烷-氯仿中析出)C27H33N4O4F,MS[M+H]+=497,IRνMAX/KBr(cm-1):1645,1585,1505.表2(续3)1H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.35(3H,t,J=8Hz),2.21-2.35(1H,m),2.28(6H,s),2.40-2.62(3H,m),2.48(3H,s),2.94-3.12(2H,m),3.23-3.37(1H,m),3.59-3.74(1H,m),4.76(1H,d,J=13Hz),4.95(1H,d,J=19Hz),5.01(1H,d,J=19Hz),5.09(1H,d,J=13Hz),7.46(1H,s),7.47(1H,br-t,J=6Hz),7.52(1H,d,J=11Hz),7.65(1H,d,J=8Hz).B10.(7-Et-10-OMEM-)黄色粉末(自 正已烷-氯仿中析出)C30H40N4O7,MS[M+H]+=569,IRνMAX/KBr(cm-1):1650,1625,1585,15101H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.30(3H,t,J=8Hz),2.20-2.33(
1H,m),2.26(6H,s),2.39-2.61(3H,m),2.87-3.03(2H,m),3.24-3.33(1H,m),
3.39(3H,s),3.52-3.73(3H,m),3.83-3.94(2H,m),4.80(1H,d,J=13Hz),4.98(1H,
d,J=19Hz),5.04(1H,d,J=19Hz),5.09(1H,d,J=13Hz),5.40(1H,d,J=7Hz),5.43
(1H,d,J=7Hz),7.38-7.44(2H,m),7.46(1H,s),7.48(1H,br-t,J=6Hz),7.97(1H,
d,J=9Hz).B11(7-Me-10-OEt-)淡黄色粉末(自 正已烷-氯仿中析出)C27H34N4O5,MS[M+H]+=495,IRνMAX/KBr(cm-1):1645,1620,1590,1510.1H-NMR(δppm)in CDCl3:1.11(3H,t,J=7Hz),1.54(3H,t,J=7Hz),2.23-2.33(
1H,m),2.28(6H,s),2.39(3H,s),2.43-2.59(3H,m),3.21-3.37(1H,m),3.55-
3.72(1H,m),3.97-4.17(2H,m),4.80(1H,d,J=13Hz),4.81(1H,d,J=18Hz),4.89(
1H,d,J=18Hz),5.01(1H,d,J=13Hz),6.72(1H,d,J=3Hz),7.30(1H,dd,J=3,9Hz),
7.40(1H,s),7.49(1H,br-t,J=6Hz),7.90(1H,d,J=9Hz).表2(续4)B12(7-Me-10-Br-)淡黄色粉末(自 正已烷-氯仿中析出)C25H29N4O4Br,MS[M+H]+=529,IRνMAX/KBr(cm-1):1645,1595,1515.1H-NMR(δppm)in CDCl3:1.11(3H,t,J=7Hz),2.18-2.33(1H,m),2.29(6H,s),
2.40-2.65(3H,m),2.60(3H,s),3.20-3.35(1H,m),3.60-3.75(1H,m),4.77(1H,d,
J=13Hz),4.87(1H,d,J=19Hz),4.93(1H,d,J=19Hz),5.06(1H,d,J=13Hz),7.40-
7.48(2H,m),7.51(1H,dd,J=2,9Hz),7.61(1H,d,J=9Hz),8.14(1H,d,J=2Hz).B13(9-OMe-)淡黄色粉末(自 正已烷-氯仿中析出)C25H30N4O5,MS[M+H]+=467,IRνMAX/KBr(cm-1):3360,1650,1615,1585,1515.1H-NMR(δppm)in CDCl3:1.08(3H,t,J=7Hz),2.18-2.34(1H,m),2.23(6H,s),
2.38-2.57(3H,m),3.16-3.29(1H,m),3.58-3.72(1H,m),3.96(3H,s),4.79(1H,d,
’J=13Hz),5.02(1H,d,J=19Hz),5.08(1H,d,J=13Hz),5.09(1H,d,J=19Hz),6.77(
1H,d,J=8Hz),7.38(1H,br-t,J=5Hz),7.50(1H,s),7.57(1H,dd,J=8,8Hz),
7.63(1H,d,J=8Hz),8.50(1H,s).表3(17-O-酰基-21-酰胺化合物的光谱数据)C1mp 101-106℃,淡黄色针晶(自 正已烷-氯仿中析出)C31H40N4O6S·H2O,MS[M+H]+=597,元素分析(C,H,N):实测值(计算值)60.67,6.58,8.96(60.57,6.89,9.11),IRνMAX/KBr(cm-1):1725,1650,1620,1590,1510.1H-NMR(δppm)in CDCl3:1.09(3H,t,J=7Hz),1.54(3H,t,J=7Hz),2.09(3H,
s),2.22-2.38(1H,m),2.28(6H,s),2.41-2.68(5H,m),2.57(3H,s),2.72-2.80(
2H,m),3.24-3.34(1H,m),3.42-3.53(1H,m),4.13(2H,q,J=7Hz),4.82-5.37(1H,
br),4.96(1H,d,J=19Hz),5.07(1H,d,J=19Hz),5.49(1H,d,J=12Hz),5.53(1H,
d,J=12Hz),6.88(1H,br-s),7.35(1H,dd,J=3,9Hz),7.38(1H,br-t,J=6Hz),
7.49(1H,s),7.98(1H,d,J=9Hz).C2mp 108-18℃,黄色粉末(自 正已烷-氯仿中析出)C29H35N4O5BrS·1/2H2O,MS[M+H]+=631,元素分析(C,H,N):实测值(计算值)54.08,5.76,8.48(54.37,5.66,8.75)IRνMAX/KBr(cm-1):1725,1650,1600,1515.1H-NME(δppm)in CDCl3:1.17(3H,t,J=7Hz),2.09(3H,s),2.22-2.38(1H,m),
2.29(6H,s),2.43-2.82(7H,m),2.65(3H,s),3.24-3.35(1H,m),3.44-3.57(1H,m),
4.91(1H,d,J=19Hz),5.01(1H,d,J=19Hz),5.49(2H,s),7.48(1H,dd,J=2,9Hz;
1H,s),7.53(1H,br-t,J=6Hz),7.59(1H,d,J=9Hz),8.14(1H,d,J=2Hz).C3mp 130-133℃,黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+27.5(CH3OH,c=0.2),C29H35N4O5Cl·1/2H2O,MS[M+H]+=555,元素分析(C,H,N):实测值(计算值)61.74,6.43,9.66(61.75,6.43,9.93),IRνMAX/KBr(cm-1):1730,1650,1600,1515.表3(续)1H-NMR(δppm)in CDCl3:1.11(3H,t,J=7Hz),1.12(3H,t,J=7Hz),1.34(3H,t,
J=8Hz),2.20-2.59(6H,m),2.26(6H,s),2.92-3.10(2H,m),3.21-3.35(1H,m),3.38
-3.51(1H,m),4.99(1H,d,J=19Hz),5.10(1H,d,J=19Hz),5.26-5.60(1H,br),
5.47(1H,d,J=12Hz),5.50(1H,d,J=12Hz),7.43(1H,br-t,J=5Hz),7.49(1H,s),
7.62(1H,dd,J=2,9Hz),7.73(1H,d,J=2Hz),7.92(1H,d,J=9Hz).C4mp136-138℃,黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+26.5(CH3OH,c=0.2),C30H37N4O5Cl·1/2H2O,MS[M+H]+=569,元素分析(C,H,N):实测值(计算值)62.69,6.58,9.73(62.33,6.63,9.69),IRνMAX/KBr(cm-1):1725,1650,1595,1515.1H-NMR(δppm)in CDCl3:0.92(3H,t,J=7Hz),1.12(3H,t,J=7Hz),1.33(3H,t,
J=8Hz),1.64(2H,sextet,J=7Hz),2.16-2.35(3H,m),2.25(6H,s),2.38-2.59(3H,
m),2.90-3.07(2H,m),3.21-3.32(1H,m),3.39-3.50(1H,m),4.96(1H,d,J=19Hz),
5.07(1H,d,J=19Hz),5.31-5.60(1H,br),5.45(1H,d,J=12Hz),5.50(1H,d,J=
12Hz),7.46(1H,br-t,J=5Hz),7.47(1H,s),7.60(1H,dd,J=2,9Hz),7.68(1H,d,
J=2Hz),7.89(1H,d,J=9Hz).C5mp139-144℃,黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+20.5(CH3OH,c=0.2),C30H37N4O5ClS·1/2H2O,MS[M+H]+=601,元素分析(C,H,N):实测值(计算值)59.28,6.31,9.01(59.05,6.28,9.18),IRνMAX/KBr(cm-1):1725,1650,1600,1515.1H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.34(3H,t,J=8Hz),2.09(3H,
s),2.23-2.35(1H,m),2.31(6H,s),2.44-2.68(5H,m),2.70-2.80(2H,m),2.93-
3.09(2H,m),3.24-3.35(1H,m),3.43-3.57(1H,m),5.00(1H,d,J=19Hz),5.09(1H,
d,J=19Hz),5.51(2H,s),7.51(1H,s),7.52(1H,br-t,J=5Hz),7.62(1H,dd,J=2,表3(续2)
9Hz),7.74(1H,d,J=2Hz),7.93(1H,d,J=9Hz).C6mp149-151℃,淡黄色针晶(自正已烷-氯仿中析出)[α]25/D=+18.5(CH3OH,c=0.2),C30H37N4O5BrS,MS[M+H]+=645,元素分析(C,H,N):实测值(计算值)55.95,5.70,8.50(55.81,5.78,8.68),IRνMAX/KBr(cm-1):1725,1650,1610,1515.1H-NMR(δppm)in CDCl3:1.09(3H,t,J=7Hz),1.36(3H,t,J=8Hz),2.10(3H,
s),2.22-2.35(1H,m),2.25(6H,s),2.38-2.55(3H,m),2.57-2.68(2H,m),2.71-
2.81(2H,m),2.97-3.10(2H,m),3.24-3.34(1H,m),3.38-3.50(1H,m),4.98-5.34(
1H,br),5.05(1H,d,J=19Hz),5.13(1H,d,J=19Hz),5.49(1H,d,J=12Hz),5.57(
1H,d,J=12Hz),7.40(1H,br-t,J=6Hz),7.53(1H,s),7.77(1H,dd,J=2,9Hz),
7.90(1H,d,J=9Hz),8.00(1H,d,J=2Hz).C7mp130-134℃,黄色粉末(自正 已烷-氯仿中析出)[α]25/D=+21.5(CH3OH,c=0.2),C31H40N4O5S,MS[M+H]+=581,元素分析(C,H,N):实测值(计算值)63.88,7.02,9.43(64.11,6.94,9.65),IRνMAX/KBr(cm-1):1725,1650,1600,1515.1H-NMR(δppm)in CDCl3:1.09(3H,t,J=7Hz),1.32(3H,t,J=8Hz),2.09(3H,
s),2.20-2.36(1H,m),2.26(6H,s),2.41-2.55(3H,m),2.54(3H,s),2.57-2.67(
2H,m),2.71-2.81(2H,m),2.93-3.09(2H,m),3.25-3.35(1H,m),3.41-3.52(1H,
m),4.99(1H,d,J=19Hz),5.07(1H,d,J=19Hz),5.50(1H,d,J=12Hz),5.54(1H,
d,J=12Hz),7.44(1H,br-t,J=6Hz),7.51(1H,dd,J=2,8Hz),7.52(1H,s),
7.55(1H,br-s),7.94(1H,d,J=8Hz).C8mp164-166℃淡黄色粉末(自 正已烷-氯仿中析出)表3(续3)[α]25/D=+24.0(CH3OH,c=0.2),C29H35N4O5F·2H2O,MS[M+H]+=539,元素分析(C,H,N):实测值(计算值)60.24,6.80,9.84(60.61,6.84,9.75),IRνMAX/KBr(cm-1):1725,1650,1595,1510.1H-NMR(δppm)in CDCl3:1.08(3H,t,J=7Hz),1.13(3H,t,J=7Hz),1.36(3H,
t,J=8Hz),2.24-2.63(6H,m),2.30(6H,s),3.02-3.20(2H,m),3.25-3.55(2H,m),
5.07(1H,d,J=19Hz),5.14(1H,d,J=19Hz),5.21-5.41(1H,br),5.51(2H,br-s),
7.31(1H,ddd,J=2,9,10Hz),7.41(1H,br-t,J=5Hz),7.55(1H,s),7.69(1H,dd,
J=2,10Hz),7.93(1H,dd,J=6,9Hz).C9mp134-137℃,淡黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+22.0(CH3OH,c=0.2),C30H37N4O5F·3/2H2O,MS[M+H]+=553,元素分析(C,H,N):实测值(计算值)62.06,6.85,9.70(62.16,6.96,9.67),IRνMAX/KBr(cm-1):1725,1650,1595,1510.1H-NMR(δppm)in CDCl3:0.93(3H,t,J=7Hz),1.09(3H,t,J=7Hz),1.36(3H,t,
J=8Hz),.1.65(2H,sextet,J=7Hz),2.20-2.36(3H,m),2.25(6H,s),2.39-2.53(3H,
m),3.02-3.17(2H,m),3.25-3.35(1H,m),3.38-3.49(1H,m),5.05(1H,d,J=19Hz),
5.12(1H,d,J=19Hz),5.22-5.40(1H,br),5.47(1H,d,J=12Hz),5.53(1H,d,J=
12Hz),7.30(1H,ddd,J=3,9,10Hz),7.38(1H,br-t,J=5Hz),7.53(1H,s),7.67(
1H,dd,J=3,10Hz),7.91(1H,dd,J=6,9Hz).C10mp135-138℃,淡黄色粉末(自 正已烷-氯仿中析出).[α]25/D=+16.5(CH3OH,c=0.2),C10H37N4O5FS·3/2H2O,MS[M+H]+=585元素分析(C,H,N):实测值(计算值)58.74,6.48,9.21(58.90,6.59,9.16),IRνMAX/KBr(cm-1):1730,1650,1595,1510.1H-NMR(δppm)in CDCl3:1.09(3H,t,J=7Hz),1.36(3H,t,J=8Hz),2.10(3H,表3(续)
s),2.20-2.36(1H,m),2.25(6H,s),2.40-2.54(3H,m),2.58-2.68(2H,m),2.72-
2.82(2H,m),3.04-3.18(2H,m),3.25-3.36(1H,m),3.39-3.50(1H,m),4.99-5.31(
1H,br),5.06(1H,d,J=19Hz),5.14(1H,d,J=19Hz),5.49(1H,d,J=12Hz),5.58(
1H,d,J=12Hz),7.31(1H,ddd,J=3,9,10Hz),7.39(1H,br-t,J=5Hz),7.55(1H,
s),7.68(1H,dd,J=3,10Hz),7.93(1H,dd,J=6,9Hz).C11mp180-182℃,淡黄色粉末(自 正已烷-氯仿中析出)[α]25/D=-59.5(CH3OH,c=0.2),C34H37N4O6F·H2O,MS[M+H]+=617元素分析(C,H,N):实测值(计算值)64.34,6.40,8.98(64.34,6.19,8.83),IνMAX/KBr(cm-1):1700,1650,1600,1510.1H-NMR(δppm)in CDCl3:1.12(3H,t,J=7Hz),1.34(3H,t,J=8Hz),2.18(6H,s),2.29
-2.44(3H,m),2.47-2.59(1H,m),2.99-3.22(3H,m),3.30-3.42(1H,m),5.03(1H,d,
J=19Hz),5.2(1H,d,J=19Hz),5.58-5.93(1H,br),5.73(1H,d,J=12Hz),5.81(1H,
d,J=12Hz),6.82(2H,d,J=9Hz),7.22-7.28(1H,m),7.51(1H,br-t,J=5Hz),7.57(
7H,s),7.63(1H,dd,J=3,10Hz),7.85(1H,dd,J=6,9Hz),7.96(2H,d,J=9Hz).C12mp131-133℃,淡黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+25.5(CH3OH,c=0.2),C30H37N4O5ClS·H2O,MS[M+H]+=601,元素分析(C,H,N):实测值(计算值)57.80,6.05,8.91(58.20,6.35,9.05)IRνMAX/KBr(cm-1):1730,1650,1605,1515.1H-NMR(δppm)in CDCl3:1.09(3H,t,J=7Hz),1.37(3H,t,J=8Hz),2.10(3H,
s),2.22-2.36(1H,m),2.26(6H,s),2.40-2.54(3H,m),2.56-2.68(2H,m),2.70-
2.81(2H,m),3.02-3.18(2H,m),3.25-3.35(1H,m),3.40-3.52(1H,m),4.97-5.35(
1H,br),5.05(1H,d,J=19Hz),5.13(1H,d,J=19Hz),5.49(1H,d,J=11Hz),5.57(
1H,d,J=11Hz),7.42(1H,br-t,J=6Hz),7.46(1H,dd,J=2,9Hz),7.54(1H,s),表3(续5)
7.85(1H,d,J=9Hz),8.02(1H,d,J=2Hz).C13mp168-170℃,黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+24.0(CH3OH,c=0.2),C29H34N4O5F2·H2O,MS[M+H]+=557,元素分析(C,H,N):实测值(计算值)60.91,6.22,9.75(60.62,6.31,9.75),IRνMAX/KBr(cm-1):1725,1655,1600,1515.1H-NMR(δppm)in CDCl3:1.07(3H,t,J=7Hz),1.13(3H,t,J=7Hz),1.36(3H,t,
J=8Hz),2.18-2.52(6H,m),2.24(6H,s),3.07(2H,q,J=8Hz),3.25-3.36(1H,m),
3.38-3.49(1H,m),5.06-5.38(1H,br),5.10(1H,d,J=19Hz),5.16(1H,d,J=19Hz),
5.48(1H,d,J=12Hz),5.56(1H,d,J=12Hz),7.36(1H,br-t,J=5Hz),7.55(1H,s),
7.69(1H,d,J=8,11Hz),7.86(1H,d,J=8,11Hz).C14mp160-162℃,黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+21.5(CH3OH,c=0.2),C10H36N4O5F2·1/2H2O,MS[M+H]+=571,元素分析(C,H,N):实测值(计算值)61.73,6.53,9.75(62.16,6.43,9.67),IRνMAX/KBr(cm-1):1720,1655,1600,1520.1H-NMR(δppm)in CDCl3:0.93(3H,t,J=7Hz),1.07(3H,t,J=7Hz),1.36(3H,t,J=8Hz),
1.65(2H,sextet,J=7Hz),2.16-2.36(3H,m),2.24(6H,s),2.38-2.52(3H,m),3.07(
2H,q,J=8Hz),3.25-3.36(1H,m),3.37-3.48(1H,m),5.05-5.34(1H,br),5.10(1H,d,
J=19Hz),5.16(1H,d,J=19Hz),5.47(1H,d,J=12Hz),5.57((1H,d,J=12Hz),7.35(1H,
br-t,J=5Hz),7.55(1H,s),7.70(1H,dd,J=8,11Hz),7.86(1H,dd,J=8,11Hz).C15mp119-125℃,黄色针晶(自 正已烷-氯仿中析出)[α]25/D=+22.0(CH3OH,c=0.2),C30H36N4O5F2S·H2O,MS[M+H]+=603,元素分析(C,H,N):实测值(计算值)57.83,6.03,9.08(58.05,6.17,9.03),表3(续6)IRνMAX/KBr(cm-1):1725,1650,1600,1515.1H-NMR(δppm)in CDCl3:1.08(3H,t,J=7Hz),1.36(3H,t,J=8Hz),2.10(3H,s),2.20
-2.34(1H,m),2.25(6H,s),2.40-2.54(3H,m),2.58-2.70(2H,m),2.71-2.83(2H,m),
3.07(2H,q,J=8Hz),3.26-3.37(1H,m),3.40-3.52(1H,m),5.08(1H,d,J=19Hz),
5.15(1H,d,J=19Hz),5.49(1H,d,J=12Hz),5.60((1H,d,J=12Hz),7.43(1H,br-t,
J=5Hz),7.55(1H,s),7.67(1H,dd,J=8,11Hz),7.83(1H,dd,J=8,11Hz).C16mp175-178℃,无色针晶(自 正已烷-氯仿中析出)[α]25/D=-57.0(CH3OH,c=0.2),C34H37N4O6F2·1/2H2O,MS[M+H]+=635,元素分析(C,H,N):实测值(计算值)63.74,5.79,8.93(63.44,5.79,8.70),IRνMAX/KBr(cm-1):1695,1650,1600,1510.1H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.35(3H,t,J=8Hz),2.19(6H,
s),2.26-2.55(4H,m),3.05(2H,q,J=8Hz),3.14-3.25(1H,m),3.30-3.42(1H,m),
5.08(1H,d,J=19Hz),5.15(1H,d,J=19Hz),5.55-5.90(1H,br),5.70(1H,d,J=
12Hz),5.84(1H,d,J=12Hz),6.84(2H,d,J=9Hz),7.48(1H,br-t,J=5Hz),7.57(
1H,s),7.65(1H,dd,J=8,11Hz),7.82(1H,dd,J=8,11Hz),7.97(2H,d,J=9Hz).C17,mp153-156℃,黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+34.5(CH3OH,c=0.2),C29H34N4O5Cl2·1/2H2O,MS[M+H]+=589,元素分析(C,H,N):实测值(计算值)58.12,5.74,9.35(58.20,5.89,9.36),IRνMAX/KBr(cm-1):1725,1650,1600,1515.1H-NMR(δppm)in CDCl3:1.11(3H,t,J=7Hz),1.12(3H,t,J=7Hz),1.38(3H,t,J=
8Hz),2.19-2.38(3H,m),2.27(6H,s),2.40-2.58(3H,m),2.96-3.14(2H,m),3.21-
3.32(1H,m),3.40-3.51(1H,m),4.99(1H,d,J=19Hz),5.08(1H,d,J=19Hz),5.45(
1H,d,J=12Hz),5.49(1H,d,J=12Hz),7.46(1H,s),7.49(1H,br-t,J=5Hz),表3(续7)
7.89(1H,s),8.05(1H,s).C18mp142-147℃,黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+31.5(CH3OH,c=0.2),C30H36N4O5Cl2·1/2H2O,MS[M+H]+=603,元素分析(C,H,N):实测值(计算值)58.97,5.95,9.06(58.82,6.09,9.15),IRνMAX/KBr(cm-1):1725,1650,1600,15151H-NMR(δppm)in CDCl3:0.92(3H,t,J=7Hz),1.11(3H,t,J=7Hz),1.38(3H,
t,J=8Hz),1.64(2H,sextet,J=7Hz),2.18-2.35(3H,m),2.26(6H,s),2.39-
2.56(3H,m),2.98-3.14(2H,m),3.21-3.32(1H,m),3.38-3.52(1H,m),5.00(
1H,d,J=19Hz),5.09(1H,d,J=19Hz),5.48(2H,s),7.45(1H,br-t,J=5Hz),
7.47(1H,s),7.92(1H,s),8.07(1H,s).C19mp139-142℃,黄色针晶(自 正已烷-氯仿中析出)[α]25/D=+27.5(CH3OH,c=0.2),C30H36N4O5Cl2S·1/2H2O,MS[M+H]+=635,元素分析(C,H,N):实测值(计算值)55.94,5.69,8.79(55.90,5.79,8.69),IRνMAX/KBr(cm-1):1725,1650,1600,1515.1H-NMR(δppm)in CDCl3:1.09(3H,t,J=7Hz),1.38(3H,t,J=8Hz),2.09(3H,
s),2.21-2.37(1H,m),2.29(6H,s),2.43-2.67(5H,m),2.70-2.81(2H,m),2.99-
3.16(2H,m),3.24-3.35(1H,m),3.42-3.55(1H,m),5.03(1H,d,J=19Hz),5.11(1H,
d,J=19Hz),5.49(1H,d,J=12Hz),5.54(1H,d,J=12Hz),7.49(1H,br-t,J=6Hz),
7.50(1H,s),7.96(1H,s),8.11(1H,s).C20mp112-117℃,淡黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+28.5(CH3OH,c=0.2),C30H37N4O6F·3/2H2O,MS[M+H]+=569,表3(续8)元素分析(C,H,N):实测值(计算值)60.15,6.78,9.40(60.49,6.77,9.41),IRνMAX/KBr(1-1):1725,1650,1595,1515.1H-NMR(δppm)in CDCl3:1.12(3H,t,J=7Hz),1.13(3H,t,J=7Hz),1.31(3H,
t,J=8Hz),2.21-2.63(6H,m),2.28(6H,s),2.88-3.08(2H,m),3.18-3.30(1H,m),
3.40-3.52(1H,m),4.00(3H,s),4.89(1H,d,J=19Hz),5.02(1H,d,J=19Hz),5.41(
1H,d,J=12Hz),5.50(1H,d,J=12Hz),6.89(1H,d,J=9Hz),7.40(1H,s),7.46(1H,
br-t,J=6Hz),7.57(1H,d,J=12Hz).C21mp109-113℃,淡黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+29.5(CH3OH,c=0.2),C31H39N4O6F·2H2O,MS[M+H]+=583,元素分析(C,H,N):实测值(计算值)60.09,6.99,9.29(60.18,7.01,9.06),IRνMAX/KBr(cm-1):1725,1650,1595,1510.1H-NMR(δppm)in CDCl3:0.92(3H,t,J=7Hz),1.13(3H,t,J=7Hz),1.31(3H,
t,J=8Hz),1.63(2H,sextet,J=7Hz),2.18-2.37(3H,m),2.28(6H,s),2.39-2.63(
3H,m),2.87-3.07(2H,m),3.17-3.30(1H,m),3.41-3.53(1H,m),4.00(3H,s),
4.89(1H,d,J=19Hz),5.02(1H,d,J=19Hz),5.24-5.57(1H,br),5.40(1H,d,J=
12Hz),5.49(1H,d,J=12Hz),6.89(1H,d,J=9Hz),7.40(1H,s),7.46(1H,br-t,J=
6Hz),7.57(1H,d,J=12Hz).C22mp125-129℃,淡黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+22.0(CH3OH,c=0.2),C31H39N4O6FS·3/2H2O,MS[M+H]+=615,元素分析(C,H,N):实测值(计算值)59.82,6.40,9.02(59.89,6.60,8.73),IRνMAX/KBr(cm-1):1725,1650,1600,1510.1H-NMR(δppm)in CDCl3:1.11(3H,t,J=7Hz),1.33(3H,t,J=8Hz),2.09(3H,
s),2.22-2.36(1H,m),2.26(6H,s),2.39-2.69(5H,m),2.71-2.80(2H,m),2.94-T表3(续)
3.10(2H,m),3.21-3.34(1H,m),3.39-3.51(1H,m),4.03(3H,s),4.93-5.38(1H,
br),4.97(1H,d,J=19Hz),5.07(1H,d,J=19Hz),5.50(2H,s),7.01(1H,d,J=
9Hz),7.38(1H,br-t,J=6Hz),7.44(1H,s),7.64(1H,d,J=12Hz).C23mp164-165℃淡黄色粉末(自 正 已烷-氯仿中析出)[α]25/D=+24.5(CH3OH,c=0.2),C30H37N4O5F·3/2H2O,MS[M+H]+=553,元素分析(C,H,N):实测值(计算值)61.88,6.85,9.71(62.16,6.96,9.67),IRνMAX/KBr(cm-1):1725,1650,1595,1510.1H-NMR(δppm)in CDCl3:1.09(3H,t,J=7Hz),1.13(3H,t,J=7Hz),1.36(3H,t,
J=8Hz),2.19-2.57(6H,m),2.25(6H,s),2.48(3H,s),2.99-3.16(2H,m),3.23-3.34
(1H,m),3.38-3.49(1H,m),5.02(1H,d,J=19Hz),5.10(1H,d,J=19Hz),5.49(2H,
s),7.38(1H,br-t,J=5Hz),7.49(1H,s),7.58(1H,d,J=11Hz),7.67(1H,d,J=8Hz).C24mp148-154℃,淡黄色针晶(自 正 已烷-氯仿中析出)[α]25/D=+24.0(CH3OH,c=0.2),C31H39N4O5F·1/2H2O,MS[M+H]+=567,元素分析(C,H,N):实测值(计算值)64.28,7.07,9.65(64.68,7.00,9.73),IR MAX/KBr(cm-1):1725,1650,1600,1510.1H-NMR(δppm)in CDCl3:0.93(3H,t,J=7Hz),1.09(3H,t,J=7Hz),1.36(3H,
t,J=8Hz),1.64(2H,sextet,J=7Hz),2.19-2.35(3H,m),2.24(6H,s),2.38-2.54(
3H,m),2.48(3H,s),2.99-3.16(2H,m),3.23-3.34(1H,m),3.38-3.50(1H,m),
5.02(1H,d,J=19Hz),5.10(1H,d,J=19Hz),5.21-5.42(1H,br),5.47(1H,d,J=
12Hz),5.51(1H,d,J=12Hz),7.38(1H,br-t,J=5Hz),7.49(1H,s),7.58(1H,d,
J=11Hz),7.68(1H,d,J=8Hz).C25mp107-121℃,黄色针晶(自 正 已烷-氯仿中析出)表3(续10)[α]25/D=+54.0(CH3OH,c=0.2),C31H39N4O5FS·2H2O,MS[M+H]+=599,元素分析(C,H,N):实测值(计算值)60.75,6.67,9.15(60.55,6.83,8.83),IRνMAX/KBr(cm-1):1725,1650,1595,1510.1H-NMR(δppm)in CDCl3:1.10(3H,t,J=7Hz),1.36(3H,t,J=8Hz),2.09(3H,
s),2.22-2.35(1H,m),2.28(6H,s),2.40-2.66(5H,m),2.46(3H,s),2.72-2.81(
2H,m),2.97-3.14(2H,m),3.24-3.34(1H,m),3.43-3.54(1H,m),4.98(1H,d,J=
19Hz),5.07(1H,d,J=19Hz),5.51(2H,s),7.47(1H,s),7.48(1H,br-t,J=5Hz),
7.54(1H,d,J=11Hz),7.63(1H,d,J=8Hz).C26mp189-192℃,淡黄色粉末(自 正 已烷-氯仿中析出)[α]25/D=-59.0(CH3OH,c=0.2),C35H39N4O6F·H2O,MS[M+H]+=631,元素分析(C,H,N):实测值(计算值)64.43,6.57,8.73(64.80,6.37,8.64)IRνMAX/KBr(cm-1):1700,1650,1605,1510.1H-NMR(δppm)in CDCl3:1.12(3H,t,J=7Hz),1.34(3H,t,J=8Hz),2.17(6H,
s), 2.28-2.42(3H,m),2.45(3H,s),2.48-2.60(1H,m),2.96-3.18(3H,m),3.28-
3.39(1H,m),4.98(1H,d,J=19Hz),5.09(1H,d,J=19Hz),5.52-5.98(1H,br),5.74
(1H,d,J=12Hz),5.78(1H,d,J=12Hz),6.82(2H,d,J=9Hz),7.48-7.55(3H,m),
7.60(1H,d,J=8Hz),7.95(1H,d,J=9Hz).C27mp82-87℃黄色棱晶(自 正 已烷-氯仿中析出)[α]25/D=+24.0(CH3OH,c=0.2),C33H44N4O8·H2O,MS[M+H]+=625,元素分析(C,H,N):实测值(计算值)61.85,7.12,8.81(61.67,7.21,8.72),IRνMAX/KBr(cm-1):1730,1650,1620,1585,1510.1H-NMR(δppm)in CDCl3:1.08(3H,t,J=7Hz),1.12(3H,t,J=7Hz),1.30(3H,
t,J=8Hz),2.25-2.41(3H,m),2.35(6H,s),2.43-2.66(3H,m),2.91-3.07(2H,m),表3(续11)
3.27-3.37(1H,m),3.39(3H,s),3.46-3.63(3H,m),3.83-3.93(2H,m),4.99(1H,d,
J=19Hz),5.08(1H,d,J=19Hz),5.27-5.62(1H,br),5.38(1H,d,J=7Hz),5.41(1H,
d,J=7Hz),5.46(1H,d,J=12Hz),5.50(1H,d,J=12Hz),7.34(1H,d,J=3Hz),7.39(
1H,dd,J=3,9Hz),7.44-7.55(2H,s,br-t),7.95(1H,d,J=9Hz)C28mp214-215℃淡黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+34.0(CH3OH,c=0.2),C29H36N4O6,MS[M+H]+=537,元素分析(C,H,N):实测值(计算值)64.67,6.69,10.22(64.91,6.76,10.44),IRνMAX/KBr(cm-1):1720,1645,1620,1585.1H-NMR(δppm)in DMSO-d6:0.87(3H,t,J=7Hz),1.05(3H,t,J=8Hz),1.31(3H,
t,J=8Hz),2.08-2.24(2H,m),2.27(2H,q,J=8Hz),2.74(6H,s),2.99-3.15(4H,
m),3.22-3.54(2H,m),5.25(2H,s),5.31(1H,d,J=11Hz),5.37(1H,d,J=11Hz),
6.28(1H,s),7.38-7.47(3H,m),8.02(1H,d,J=10Hz),8.30(1H,br-t,J=6Hz),
9.43-9.88(1H,br),10.36(1H,s).C29mp78-82℃,黄色针晶(自 正 已烷-氯仿中析出)[α]25/D=22.5(CH3OH,c=0.2),C34H46N4O8·3/2H2O,MS[M+H]+=639,元素分析(C,H,N):实测值(计算值)61.61,7.03,8.38(61.34,7.42,8.42),IRνMAX/KBr(cm-1):1725,1650,1620,1585,1510.1H-NMR(δppm)in CDCl3:0.93(3H,t,J=7Hz),1.08(3H,t,J=7Hz),1.30(3H,t,J=8Hz),
1.64(2H,sext,J=7Hz),2.23-2.38(3H,m),2.34(6H,s),2.43-2.64(3H,m),2.89-
3.08(2H,m),3.25-3.36(1H,m),3.39(3H,s),3.45-3.63(3H,m),3.83-3.93(2H,m
),4.98(1H,d,J=19Hz),5.08(1H,d,J=19Hz),5.30-5.58(1H,br),5.37(1H,d,J=
7Hz),5.41(1H,d,J=7Hz),5.46(1H,d,J=12Hz),5.49(1H,d,J=12Hz),7.34(1H,d,
J=3Hz),7.39(1H,dd,J=3,9Hz),7.44-7.52(2H,s,br-t),7.95(1H,d,J=9Hz).表3(续12)C30mp218-219℃,无色粉末(自 正已烷-氯仿中析出)[α]25/D=+32.5(CH3OH,c=0.2),C30H38N4O6,MS[M+H]+=551,元素分析(C,H,N):实测值(计算值)65.34,6.99,10.04(65.44,6.96,10.17),IRνMAX/KBr(cm-1):1715,1645,1620,1585.1H-NMR(δppm)in DMSO-d6:0.87(3H,t,J=7Hz),0.90(3H,t,J=7Hz),1.30(3H,
t,J=8Hz),1.55(2H,sextet,J=7Hz),2.12(6H,s),2.25-2.32(6H,m),3.02-3.25(
4H,m),5.26(2H,s),5.29(1H,d,J=11Hz),5.37(1H,d,J=11Hz),6.28(1H,s),
7.37(1H,s),7.38-7.45(2H,m),7.78(1H,br-t,J=6Hz),8.04(1H,d,J=10Hz),
10.29(1H,br-s).C31mp84-90℃,淡黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+18.0(CH3OH,c=0.2),C34H46N4O8S·H2O,MS[M+H]+=671,元素分析(C,H,N):实测值(计算值)59.33,6.77,7.96(59.28,7.02,8.13),IRνMAX/KBr(cm-1):1725,1650,1620,1585,15101H-NMR(δppm)in CDCl3:1.07(3H,t,J=7Hz),1.31(3H,t,J=8Hz),2.09(3H,
s),2.24-2.41(1H,m),2.36(6H,s),2.42-2.68(5H,m),2.71-2.80(2H,m),2.93-
3.07(2H,m),3.27-3.41(1H,m),3.39(3H,s),3.49-3.61(3H,m),3.83-3.92(2H,
m),5.00(1H,d,J=19Hz),5.10(1H,d,J=19Hz),5.22-5.60(1H,br),5.38(1H,d,
J=7Hz),5.42(1H,d,J=7Hz),5.52(2H,s),7.37(1H,d,J=3Hz),7.41(1H,dd,J=3,
9Hz),7.44-7.54(2H,br-m),7.97(1H,d,J=9Hz).C32mp172-175℃,淡黄色粉末(自 正已烷-氯仿中析出)[α]25/D=+25.0(CH3OH,c=0.2),C10H36N4O6S,MS[M+H]+=583,元素分析(C,H,N):实测值(计算值)61.62,6.52,9.44(61.84,6.57,9.61),表3(续13)IRνMAX/KBr(cm-1):1725,1645,1620,1585.1H-NMR(δppm)in DMSO-d6:0.87(3H,t,J=7Hz),1.30(3H,t,J=8Hz),2.02-2.32
(4H,m),2.07(3H,s),2.13(6H,s),2.52-2.59(2H,m),2.64-2.72(2H,m),3.00-
3.26(4H,m),5.26(2H,s),5.34(1H,d,J=11Hz),5.42(1H,d,J=11Hz),6.22(1H,s),
7.34-7.48(3H,m),7.79(1H,br-t,J=6Hz),8.04(1H,d,J=10Hz),10.30(1H,br).C13MP78-86℃,黄色针晶(自 正已烷-氯仿中析出)C34H44N4O8·1/2H2O,MS[M+H]+=637,元素分析(C,H,N):实测值(计算值)63.02,7.02,8.67(63.24,7.02,8.68),IRνMAX/KBr(cm-1):1710,1650,1620,1585,1510.1H-NMR(δppm)in CDCl3:1.08(3H,t,J=7Hz),1.31(3H,t,J=8Hz),1.83(3H,
dd,J=2,7Hz),2.25(6H,s),2.26-2.37(1H,m),2.39-2.53(3H,m),2.94-3.08(2H,
m),3.21-3.47(1H,m),3.39(3H,s),3.54-3.61(2H,m),3.84-3.91(2H,m),5.04(
1H,d,J=19Hz),5.12(1H,d,J=19Hz),5.39(1H,d,J=7Hz),5.42(1H,d,J=7Hz),
5.53(1H,d,J=12Hz),5.61(1H,d,J=12Hz),5.80-5.88(1H,m),6.98(1H,dq,J=7,
14Hz),7.32-7.55(4H,m),8.00(1H,d,J=9Hz).C34黄色粉末(自 正已烷-氯仿中析出)C30H36N4O6,MS[M+H]+=549,IRνMAX/KBr(cm-1):1705,1675,1645,1590,1510.1H-NMR(δppm)in DMSO-d6:0.88(3H,t,J=7Hz),1.31(3H,t,J=8Hz),1.84(3H,
dd,J=2,7Hz),2.08-2.26(2H,m),2.74(6H,s),2.98-3.04(4H,m),3.29-3.52(2H,
m),5.26(2H,s),5.35(1H,d,J=11Hz),5.42(1H,d,J=11Hz),5.80-5.90(1H,m),
6.30(1H,s),6.87(1H,dq,J=7,16Hz),7.38-7.48(3H,m),8.20(1H,d,J=3Hz),
9.46-9.63(1H,br),10.35(1H,s).表3(续14)C35MP102-105℃,黄色棱晶(自 正已烷-氯仿中析出)C37H43N4O8F,MS[M+H]+=691,IRνMAX/KBr(cm-1):1710,1650,1620,1600,1505.1H-NMR(δppm)in CDCl3:1.14(3H,t,J=7Hz),1.27(3H,t,J=8Hz),2.16(6H,
s),2.22-2.42(3H,m),2.49-2.62(1H,m),2.82-3.18(3H,m),3.18-3.42(1H,m),
3.39(3H,s),3.50-3.64(2H,m),3.80-3.93(2H,m),4.94(1H,d,J=19Hz),5.08(1H,
d,J=19Hz),5.35(1H,d,J=7Hz),5.40(1H,d,J=7Hz),5.55-5.77(1H,br),5.78(
2H,s),7.01(2H,dd,J=9,9Hz),7.22(1H,d,J=3Hz),7.27(1H,s),7.35(1H,dd,
J=3,9Hz),7.48(1H,br-t,J=6Hz),7.50(1H,s),7.90(1H,d,J=9Hz),8.02(2H,
dd,J=6,9Hz).C36mp231-232℃,无色粉末(自 正已烷-氯仿中析出)[α]25/D=-6.5(CH3OH,c=0.2),C33H35N4O6F,MS[M+H]+=603,IRνMAX/KBr(cm-1):1710,1645,1620,1595,1520.1H-NMR(δppm)in DMSO-d6:0.91(3H,t,J=7Hz),1.30(3H,t,J=8Hz),2.11-
2.30(2H,m),2.53(6H,s),2.62-2.90(2H,m),2.99-3.40(4H,m),5.29(2H,s),
5.57(1H,d,J=11Hz),5.62(1H,d,J=11Hz),6.36(1H,s),7.33(1H,dd,J=9,9Hz),
7.38-7.48(3H,m),7.97(2H,dd,J=6,9Hz),8.04(1H,d,J=9Hz),8.94-10.27(1H,
br),10.34(1H,s).C37mp105-109℃,黄色棱晶(自 正已烷-氯仿中析出)[α]25/D=+62.0(CHCl3,c=0.2),C37H43N4O6F,MS[M+H]+=691.IRνMAX/KBr(cm-1):1720,1650,1620,1590,1510.1H-NMR(δppm)in CDCl3:1.14(3H,t,J=7Hz),1.27(3H,t,J=8Hz),2.16(6H,表3(续15)
s),2.23-2.43(3H,m),2.50-2.66(1H,m),2.83-3.05(1H,m),3.06-3.19(1H,m),
3.27-3.44(1H,m),3.39(3H,s),3.50-3.63(2H,m),3.80-3.92(2H,m),4.95(1H,d,
19Hz),5.08(1H,d,J=19Hz),5.35(1H,d,J=7Hz),5.40(1H,d,J=7Hz),5.50-5.82(
1H,br),5.77(1H,d,J=12Hz),5.81(1H,d,J=12Hz),7.13-7.25(2H,m),7.27-7.39
(2H,m),7.48(1H,br-t,J=6Hz),7.50(1H,s),7.66-7.73(1H,m),7.80(1H,d,J=
8Hz),7.90(1H,d,J=9Hz).C38mp223-224℃,无色粉末(自 正已烷-氯仿中析出)C33H35N4O6F,MS[M+H]+=603,IRνMAX/KBr(cm-1):1710,1645,1620,1590,1520.1H-NMR(δppm)in DMSO-d6:0.91(3H,t,J=7Hz),1.30(3H,t,J=8Hz),2.08-
2.34(2H,m),2.54(6H,s),2.54-2.75(2H,m),2.95-3.43(4H,m),5.29(2H,s),
5.58(1H,d,J=11Hz),5.65(1H,d,J=11Hz),6.35(1H,s),7.34-7.68(6H,m),7.76(
1H,d,J=7Hz),8.05(1H,d,J=9Hz),8.08-8.22(1H,br),9.22-9.66(1H,br),
10:32(1H,s)C39mp162-164℃,黄色粉末(自 正已烷-氯仿中析出)C33H37N5O5·H2O,MS[M+H]+=584,元素分析(C,H,N):实测值(计算值)65.44,6.53,11.54(65.87,6.53,11.64),IRνMAX/KBr(cm-1):1720,1645,1595,15151H-NMR(δppm)in CDCl3:1.13(3H,t,J=7Hz),1.31(3H,t,J=8Hz),2.16(6H,
s),2.27-2.42(3H,m),2.51(3H,s),2.52-2.63(1H,m),2.90-3.14(3H,m),3.30-
3.41(1H,m),4.89(1H,d,19Hz),5.10(1H,d,J=19Hz),5.62-5.84(1H,br),5.81(
1H,d,J=12Hz),5.86(1H,d,J=12Hz),7.44-7.53(3H,m),7.55(1H,s),7.81(2H,
dd,J=1,5Hz),7.89(1H,d,J=9Hz),8.67(2H,dd,J=1,5Hz).表3(续16)C40mp165-167℃,黄色粉末(自 正已烷-氯仿中析出)C32H34N5O5Cl·1/2H2O,MS[M+H]+=604,元素分析(C,H,N):实测值(计算值)62.54,5.78,11.35(62.69,5.75,11.42),IRνMAX/KBr(cm-1):1720,1650,1595,1515.1H-NMR(δppm)in CDCl3:1.14(3H,t,J=7Hz),1.34(3H,t,J=8Hz),2.16(6H,
s),2.27-2.41(3H,m),2.52-2.64(1H,m),2.93-3.13(3H,m),3.30-3.40(1H,m),
5.01(1H,d,J=19Hz),5.12(1H,d,J=19Hz),5.51-5.57(1H,br),5.80(1H,d,J=
12Hz),5.86(1H,d,J=12Hz),7.49(1H,t,J=5Hz),7.53(1H,s),7.62(1H,dd,J=2,
9Hz),7.70(1H,d,J=2Hz),7.81(2H,dd,J=1,5Hz),7.90(1H,d,J=9Hz),8.68(2H,
dd,J=1,5Hz).C41mp~171℃,淡黄色粉末(自 正已烷-氯仿中析出)C30H34N4O4F,MS[M+H]+=588,IRνMAX/KBr(cm-1):1720,1650,1595,1510.1H-NMR(δppm)in CDCl3:1.15(3H,t,J=7Hz),1.35(3H,t,J=8Hz),2.16(6H,
s),2.27-2.42(3H,m),2.52-2.66(1H,m),2.98-3.18(3H,m),3.29-3.40(1H,m),
5.02(1H,d,19Hz),5.12(1H,d,J=19Hz),5.72-5.91(1H,br,D2Oex.),5.81(1H,d,
J=12Hz),5.87(1H,d,J=12Hz),7.23(1H,ddd,J=3,8,10Hz),7.52(1H,t,J=5Hz,
D2Oex.),7.55(1H,s),7.57(1H,dd,J=3,10Hz),7.80(2H,dd,J=2,4Hz),7.82(
1H,dd,J=6,9Hz),8.67(2H,dd,J=2,4Hz)C42mp~169℃,淡黄色粉末(自 正已烷-氯仿中析出)C31H36N4O4F,MS[M+H]+=602,IRνMAX/KBr(cm-1):1720,1650,1600,1505.表3(续17)1H-NMR(δppm)in CDCl3:1.13(3H,t,J=7Hz),1.36(3H,t,J=8Hz),2.17(6H,
s),2.28-2.60(4H,m),2.47(3H,m),2.98-3.17(3H,m),3.29-3.40(1H,m),5.02(
1H,d,J=19Hz),5.13(1H,d,J=19Hz),5.30-5.50(1H,br),5.81(1H,d,J=12Hz),
5.84(1H,d,J=12Hz),7.39(1H,br-t,J=5Hz,D2Oex.),7.52(1H,s),7.54(1H,d,
J=12Hz),7.64(1H,d,J=8Hz),7.81(2H,dd,J=2,5Hz),8.68(2H,dd,J=2,5Hz).C43mp159-164℃,黄色针晶(自 正已烷-氯仿中析出)C31H36N4O5F,MS[M+H]+=618,IRνMAX/KBr(cm-1):1720,1650,1595,1510.1H-NMR(δppm)in CDCl3:1.17(3H,t,J=7Hz),1.30(3H,t,J=8Hz),2.17(6H,
s),2.26-2.42(3H,m),2.54-2.68(1H,m),2.87-3.08(3H,m),3.28-3.41(1H,m),
4.00(3H,s),4.90(1H,d,J=19Hz),5.04(1H,d,J=19Hz),5.48-5.82(1H,br,
D2Oex.),5.76(1H,d,J=12Hz),5.86(1H,d,J=12Hz),6.85(1H,d,J=9Hz),7.45(
1H,s),7.52(1H,t,J=6Hz,D2Oex.),7.55(1H,d,J=12Hz),7.81(2H,dd,J=2,
5Hz),8.67(2H,dd,J=2,5Hz).C44mp147-150℃,黄色粉末(自 正已烷-氯仿中析出).C31H33N5O6·H2O,MS[M+H]+=572,元素分析(C,H,N):实测值(计算值)62.85,6.03,11.78(63.15,5.98,11.88),IRνMAX/KBr(cm-1):3390,1710,1650,1615,1590,1520.1H-NMR(δppm)in CDCl3:1.08(3H,t,J=7Hz),2.15(6H,s),2.29-2.55(4H,m),
3.22-3.41(2H,m),4.02(3H,s),5.14(1H,d,J=19Hz),5.20(1H,d,J=19Hz),5.34
(1H,br-s),5.77(1H,d,J=12Hz),5.94(1H,d,J=12Hz),6.87(1H,d,J=8Hz),7.39-
7.47(2H,m),7.60-7.68(2H,m),7.73(1H,d,J=9Hz),7.80(1H,ddd,J=2,8,8Hz),
8.13(1H,d,J=8Hz),8.65-8.70(2H,m).表3(续18)C45无色粉末(自 正已烷-氯仿中析出)C28H34N4O6,MS[M+H]+=523,C46黄色粉末(自 正已烷-氯仿中析出)C30H38N4O6,MS[M+H]+=551,C47无色粉末(自 正已烷-氯仿中析出)C31H40N4O7,MS[M+H]+=581,C48mp179-182℃,黄色粉末(自 正已烷-氯仿中析出)C35H37N4O7F,MS[M+H]+=645,表4(水溶解度)化合物序号 溶解度(mg/ml) 化合物序号 溶解度(mg/ml)C3 >64 C21 >63C2 >67 C22 >65C3 29 C23 20C4 41 C24 42C5 21 C25 >63C6 25 C26 9C7 21 C28 >56C8 20 C30 >58C9 >59 C32 >62C10 >62 C34 >59C11 8 C36 17C12 >64 C38 6C13 >59C14 >60C15 >64C16 6C17 >64C18 35C19 24C20 >60表5(喜树碱衍生物的抗肿瘤活性)化合物序号 最佳剂量和抗肿瘤活性 治疗指数
总剂量(mg/kg) T/C% 40 天存活者
(最大可耐受剂量/
最低有效剂量)
C1 6.25 252 0/6 4(6.25/1.56)
C2 25 214 0/6 8(25/3.13)
C3 6.25 275 1/6 >4(6.25/<1.56)
C4 6.25 280 1/6 >4(6.25/<1.56)
C5 6.25 295 3/6 >4(6.25/<1.56)
C6 6.25 183 1/6 >4(6.25/<1.56)
C7 100 368 5/6 32(100/3.13)
C8 12.5 364 4/6 8(12.5/1.56)
C9 12.5 293 2/6 8(12.5/1.56)
C10 12.5 240 1/6 8(12.5/1.56)
C11 50 243 0/6 8(50/6.25)
C12 25 281 1/6 16(25/6.25)
C13 1.56 214 0/6 -
C14 1.56 257 1/6 -
C15 1.56 260 0/6 -
C16 12.5 259 0/6 2(12.5/6.25)
C17 6.25 286 2/6 4(6.25/1.56)
C18 3.13 225 0/6 >2(3.13/<1.56)
C19 3.13 198 0/6 >2(3.13/<1.56)
C20 3.13 312 0/6 >2(3.13/<1.56)
C21 3.13 265 0/6 >2(3.13/<1.56)
C22 1.56 228 0/6 -
表5(续)化合物序号 最佳剂量和抗肿瘤活性
治疗指数
总剂量(mg/kg) T/C% 40天存活者 (最大可耐受剂量/
最低有效剂量)
C23 12.5 317 0/6 >8(12.5/<1.56)
C24 25 326 1/6 >16(25/<1.56)
C25 12.5 300 1/6 >8(12.5/<1.56)
C26 50 264 0/6 >4(50/12.5)
C28 200 180 0/6 16(200/12.5)
C30 200 235 0/6 32(200/6.25)
C32 200 198 0/6 32(200/6.25)
C36 200 214 0/6 16(200/12.5)
C38 200 226 0/6 16(200/12.5)
C39 50 376 3/6 16(50/3.13)
C40 12.5 266 1/6 4(6.25/1.56)
C41 25 300 2/6 >16(25/<1.56)
C42 12.5 257 2/6 >8(12.5/1.56)
C43 6.25 275 2/6 >4(6.25/1.56)
C45 400 147 0/6 4(400/100)
C46 400 189 0/6 16(400/25)
C47 400 156 0/6 4(200/50)
C48 200 188 0/6 8(200/25)
对照
CPT-Na盐 60 203 0/6 6(60/10)
表6(喜树碱衍生物的急性毒性)化合物序号 LD50 值(mg/kg) 化合物序号 LD50 值(mg/kg)
C1 164.5 C22 68.6
C2 241.1 C23 184.2
C3 185.6 C24 203.2
C4 142.4 C25 154.3
C5 167.5 C26 113.0
C6 116.3 C28 340.6
C7 234.5 C30 361.5
C8 124.5 C32 307.0
C9 152.1 C36 477.2
C10 145.8 C38 420.6
C11 146.1 C29 320.1
C12 284.5 C40 213.4
C13 67.6 C41 220.1
C14 98.3 C42 310.5
C15 85.2 C43 164.9
C16 65.6 C45 376.2
C17 112.0 C46 478.3
C18 92.3 C47 471.2
C19 94.8 C48 418.3
C20 84.5 对照
C21 124.3 CPT-Na盐 227.0
Claims (3)
2.制备权利要求1的通式(1)的喜树碱衍生物的方法,其中将通式(2)的喜树碱衍生物在无溶剂条件下与N,N-二甲基乙二胺反应以打开E内酯环,接着用相应的酰化剂将17-羟基酰化;所述通式(2)喜树碱衍生物如下:其中R1、R2、R3和R4的定义同上。
3.权利要求1的通式(1)的喜树碱衍生物在制备具有抗肿瘤活性的药物组合物中的应用。
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JP246660/94 | 1994-09-06 | ||
JP6246660A JPH0873461A (ja) | 1994-09-06 | 1994-09-06 | 新規なカンプトテシン誘導体、その製造法および抗腫瘍剤 |
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US (1) | US5843954A (zh) |
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IL (1) | IL114989A (zh) |
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JP4094710B2 (ja) | 1997-11-06 | 2008-06-04 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体 |
FR2792937B1 (fr) | 1999-04-27 | 2001-08-10 | Cemaf | NOUVEAUX DERIVES DE PYRROLO-(3,4-b) QUINOLEINE, LEUR PROCEDE DE PREPARATION ET LEUR UTILISATION A TITRE DE MEDICAMENT |
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
AR027687A1 (es) | 2000-03-22 | 2003-04-09 | Yakult Honsha Kk | Procedimiento para preparar camptotecina |
CZ299329B6 (cs) * | 2003-08-26 | 2008-06-18 | Pliva-Lachema A.S. | Zpusob výroby 7-ethyl-10-[ 4-(1-piperidino)-1-piperidino]karbonyloxykamptothecinu |
CZ299593B6 (cs) * | 2003-12-16 | 2008-09-10 | Pliva-Lachema A. S. | Zpusob výroby 7-ethyl-10-hydroxykamptothecinu |
ITMI20051348A1 (it) * | 2005-07-14 | 2007-01-15 | Indena Spa | Analoghi della camptotecina loro processo di ottenimento loro uso e formulazioni che li contengono |
CN100339377C (zh) * | 2005-09-05 | 2007-09-26 | 合肥中科大生物技术有限公司 | 喜树碱衍生物及其制备 |
CN1319971C (zh) * | 2005-09-09 | 2007-06-06 | 合肥中科大生物技术有限公司 | 喜树碱衍生物及其用途 |
CN102746314B (zh) * | 2011-04-18 | 2016-07-06 | 华东师范大学 | 含有稳定7元内酯环的喜树碱类化合物、制备方法和用途 |
US11814394B2 (en) | 2021-11-16 | 2023-11-14 | Genequantum Healthcare (Suzhou) Co., Ltd. | Exatecan derivatives, linker-payloads, and conjugates and thereof |
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EP0296612A1 (en) * | 1987-06-25 | 1988-12-28 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
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JPS5839684A (ja) * | 1981-09-04 | 1983-03-08 | Yakult Honsha Co Ltd | 10−置換カンプテシン誘導体の製造法 |
JPS5951287A (ja) * | 1982-09-17 | 1984-03-24 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体 |
US4981968A (en) * | 1987-03-31 | 1991-01-01 | Research Triangle Institute | Synthesis of camptothecin and analogs thereof |
US5049668A (en) * | 1989-09-15 | 1991-09-17 | Research Triangle Institute | 10,11-methylenedioxy-20(RS)-camptothecin analogs |
US5122606A (en) * | 1987-04-14 | 1992-06-16 | Research Triangle Institute | 10,11-methylenedioxy camptothecins |
JP2540357B2 (ja) * | 1987-06-24 | 1996-10-02 | 第一製薬株式会社 | 六環性化合物 |
JP2538792B2 (ja) | 1987-06-25 | 1996-10-02 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体 |
JPH0615547B2 (ja) * | 1988-01-20 | 1994-03-02 | 株式会社ヤクルト本社 | 新規なカンプトテシン誘導体 |
WO1991004260A2 (en) * | 1989-09-15 | 1991-04-04 | Research Triangle Institute | 10,11-methylenedioxy-20(rs)-camptothecin and 10,11-methylenedioxy-20(s)-camptothecin analogs |
US5162532A (en) * | 1990-12-20 | 1992-11-10 | North Carolina State University | Intermediates and method of making camptothecin and camptothecin analogs |
-
1994
- 1994-09-06 JP JP6246660A patent/JPH0873461A/ja not_active Ceased
-
1995
- 1995-08-12 KR KR1019950025066A patent/KR100351952B1/ko not_active IP Right Cessation
- 1995-08-17 IL IL11498995A patent/IL114989A/en not_active IP Right Cessation
- 1995-08-29 CA CA002157128A patent/CA2157128C/en not_active Expired - Fee Related
- 1995-08-30 ZA ZA957269A patent/ZA957269B/xx unknown
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- 1995-09-05 ES ES95113931T patent/ES2146275T3/es not_active Expired - Lifetime
- 1995-09-05 DK DK95113931T patent/DK0700914T3/da active
- 1995-09-05 DE DE69516605T patent/DE69516605T2/de not_active Expired - Fee Related
- 1995-09-05 AT AT95113931T patent/ATE192447T1/de not_active IP Right Cessation
- 1995-09-05 EP EP95113931A patent/EP0700914B1/en not_active Expired - Lifetime
- 1995-09-05 RU RU95115049A patent/RU2133748C1/ru not_active IP Right Cessation
- 1995-09-05 PT PT95113931T patent/PT700914E/pt unknown
- 1995-09-05 AU AU30474/95A patent/AU688547B2/en not_active Ceased
- 1995-09-06 CN CN95109535A patent/CN1052482C/zh not_active Expired - Fee Related
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1997
- 1997-11-21 US US08/976,398 patent/US5843954A/en not_active Expired - Fee Related
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2000
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0296612A1 (en) * | 1987-06-25 | 1988-12-28 | Kabushiki Kaisha Yakult Honsha | Camptothecin derivatives and process for preparing same |
Non-Patent Citations (1)
Title |
---|
CHEMICAL PHARMACEUTICAL BULLETIN,41(2) 1993.1.1 Seigo sawada,et al * |
Also Published As
Publication number | Publication date |
---|---|
US5843954A (en) | 1998-12-01 |
AU688547B2 (en) | 1998-03-12 |
ES2146275T3 (es) | 2000-08-01 |
CA2157128C (en) | 2006-04-11 |
EP0700914B1 (en) | 2000-05-03 |
DE69516605T2 (de) | 2000-10-26 |
GR3033798T3 (en) | 2000-10-31 |
IL114989A0 (en) | 1995-12-08 |
CN1126212A (zh) | 1996-07-10 |
IL114989A (en) | 1998-09-24 |
JPH0873461A (ja) | 1996-03-19 |
CA2157128A1 (en) | 1996-03-07 |
PT700914E (pt) | 2000-09-29 |
KR100351952B1 (ko) | 2002-12-28 |
NZ272904A (en) | 1996-08-27 |
RU2133748C1 (ru) | 1999-07-27 |
EP0700914A1 (en) | 1996-03-13 |
DK0700914T3 (da) | 2000-07-31 |
KR960010644A (ko) | 1996-04-20 |
ATE192447T1 (de) | 2000-05-15 |
AU3047495A (en) | 1996-03-21 |
ZA957269B (en) | 1996-03-25 |
DE69516605D1 (de) | 2000-06-08 |
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