CN1243746C - 抑制血管生成的杂环化合物 - Google Patents
抑制血管生成的杂环化合物 Download PDFInfo
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- CN1243746C CN1243746C CNB008123578A CN00812357A CN1243746C CN 1243746 C CN1243746 C CN 1243746C CN B008123578 A CNB008123578 A CN B008123578A CN 00812357 A CN00812357 A CN 00812357A CN 1243746 C CN1243746 C CN 1243746C
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- Prior art keywords
- borrelidin
- compound
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- dried
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract
本发明涉及通式(I)的化合物,其中R表示通式-COOR1、-CONR2R3、-CONR4CONR4R5或-CH2OR6,其中R1表示C2-6烷基;取代的C1-6烷基;或C3-6环烷基;R2和R3相同或不同,并且彼此独立地表示氢原子或任选取代的C1-6烷基;5或6-元环烷基或杂芳基;和它们的互变异构体、溶剂化物、它们的混合物和所有这些化合物的酸加成盐。本发明还涉及含有通式(I)的化合物作为活性剂的药物组合物。按照本发明的血管生成抑制剂可以抑制活组织内的新血管形成,由此可以用来预防和抑制与肿瘤生长有关的血管生成,并且可以用来预防肿瘤转移灶的形成。
Description
技术领域
本发明涉及新的疏螺体素衍生物,更加具体地涉及通过转变疏螺体素的环戊烷环上的羧基制备的疏螺体素衍生物。此外,本发明涉及含有这些化合物的药物组合物和这些化合物在制备药物组合物中的应用。
背景技术
按照本发明新的化合物表现出有价值的生物功效,也就是它们具有显著的血管生成抑制效果和抗转移作用。
已知血管生成是一种现象,在这种现象中血管在生物体内形成并构成新的血管***。血管生成具有非常不同的形式,这取决于内皮细胞的生长和机能,可以被肯定它是某种级联反应。血管生成发生于正常的生理环境下,如同在胚胎、胎儿、胎盘、子宫和类似器官的情况中进化和繁殖过程的一部分。然而,它也可以是病理过程的一部分,其伴随创伤愈合、感染以及肿瘤生长,从而进一步促进肿瘤转移灶的形成。
据文献记载,临床观察很早就已知,大多数的癌性肿瘤患者死于转移瘤。近年来通过放疗和化疗已经使这种境况得到改善,但所得的结果决不可靠。
鉴于在研究恶性疾病的病理学特征时所获得的结果,最近几年发展出一种新的抗肿瘤药物研究的趋势。由于这种新的趋势,目前除了抑制肿瘤组织生长的活性剂的研究以外,新活性剂的设计甚至也针对其它负责维持恶性的病理学活动(无限增殖化、转移、细胞凋亡、血管生成)。在这些活动中特别值得注意的是新血管形成(新血管的形成),其确保生长肿瘤的连续血液供应,因为供血不足会杀死肿瘤细胞。根据肿瘤-生物学检查的结论,恶性疾病的进程可以被视作是血管生成的一种功能,其由恶化前期向发病期的转变,并且对休眠状态的肿瘤细胞群取向于增殖的诱导作用可能与血管的形成密切相关。
所以,当今抗肿瘤剂的药物研究的目标在于设计和开发出具有新攻击点的分子,通过具有新的攻击点的分子,癌症的治疗可以比以往更加有效。
在这些新分子中优先考虑一组抗血管生成药,其通过抑制新血管形成且由此抑制转移灶的形成可能在肿瘤疾病的治疗中开辟一个新时代。
已知数种化合物具有血管生成抑制作用。在这些化合物中例举下列化合物,但不穷尽:血管静止(angiostatic)甾类化合物[Folkman,J.等,科学(Science)221,719(1993)],如抑制内皮细胞功能的可的松;抑制内皮细胞产生纤溶酶原激活剂的甲羟孕酮醋酸酯[Nicosia,R.F.和Ottinetti,A.,实验研究(Lab.Invest.)63,115(1990)];抑制小管形成的烟曲霉素[Ingber,D.等,自然(Nature)348,555(1990)];一种抑制内皮细胞迁移和增殖的多糖硫酸酯(SD-4152);和导致内皮细胞分化和转化的视黄酸[TsutomuOikawa,Kekkan to Naihi 2,470(1992)]。然而,这些物质在临床实践中不是作为血管生成抑制剂起作用:这是由于它们的一些具有强有力的副作用而其它没有足够的靶向作用。
首先,临床上有效的血管生成抑制剂是α-干扰素[Bronty-Boye,D.和Zetter,B.E.,科学(Science)208,516(1980);Sidky,Y.A.和Borden,E.C.,癌症研究(Cancer Res.),47,5155(1987)]。目前,数种具有不同化学结构的血管生成抑制性化合物的临床试验正处于研究中;此类化合物譬如是烟曲霉素的衍生物,如AGM-1470[Kusaka,M.等,生物生理学研究通讯(Biophys.Res.Comm.)174,1070(1991)];3-(2,4-二甲基吡咯-5-基)-吲哚啉-2-酮(SU-5416),U.S.5,792,783;5-甲基异噁唑-4-羧基-N-[4-(三氟甲基)-苯基]-酰胺(来氟米物,SU101),US5,610,173;2(R)-异丁基-3(S)-二羟基-N-[2,2-二甲基-1(S)-(N-甲基氨基甲酰基)-丙基]-琥珀酰亚胺(marimastat);3β-[{3-[(4-氨基丁基)-氨基]-丙基}-氨基]-5α-胆甾烷-7,24-二醇-24-氢硫酸酯(角鲨胺(squalamine)),US5,192,756;ZD4190,血管内皮生长因子的抑制剂等。
最近日本作者描述了已知的疏螺体素[化学名:2’-(7-氰基-8,16-二羟基-9,11,13,15-四甲基-18-氧代-氧杂环十八碳-4,6-二烯-2-基)-环戊烷-1’-甲酸]具有血管生成抑制作用,其是一种含有18元环的大环内酯抗生素[Keller-Schierlein,W.,经验(Experientia)22,476(1966);Helvetica Chim.Acta50,731(1967);Anderson,B.F.等,澳大利亚化学杂志(Aust.J.Chem.)42,717(1989)],这归因于其诱导毛细管形成细胞的细胞凋亡的特性[Wakabayashi,T.等,抗生素杂志(J.Antibiot.)50,671(1997)]。此外,业已证实,它可以有效地对抗人结肠癌的细胞系WiDr和人***癌的细胞系PC-3(公开的日本专利申请号8-173,176和9-227,549)。
而且,已知疏螺体素表现出抗菌、抗病毒、除草和杀昆虫效果并具有中间LD50值(Glasby,J.S.,抗生素百科全书(Encyclopedia ofAntibiotics),p.145,J.Wiley(编辑),1979)。
由文献了解并且另外通过我们自己的研究都支持疏螺体素的效能涉及两种肿瘤生物学事件:一方面增殖,而另一方面内皮细胞形成毛细管,也就是血管生成。虽然在两种细胞功能的敏感性方面存在差异(在促进毛细管形成上存在约5倍的差异),但当我们在以其它细胞种类为目标考虑对细胞增殖的抑制作用时,这种选择性程度较低。
发明内容
本发明的目标在于通过修饰疏螺体素的结构来分开两种细胞生物学效应。更加具体地,本发明的目的在于通过转化位于疏螺体素分子的环戊烷环上的羧基来制备新的疏螺体素衍生物,与对细胞增殖的作用相比,该衍生物对内皮细胞的毛细管形成产生极其强有力的作用。也就是,按照我们的假设,临床实践中需要这样的血管生成抑制活性剂,其只在较高剂量下才会抑制细胞增殖。(在此值得提及已知血管生成抑制化合物的选择性事实上普遍是,它们对内皮细胞增殖的抑制作用比对机体其它细胞系的***更加明确)。
在我们的研究中,令人惊讶地观察到通式(I)的新型疏螺体素衍生物:
完全满足上述目的。
这个发现使所属领域技术人员十分惊讶,因为只有很少疏螺体素衍生物公开在文献中,即Anderson,K.和Rickards,R.W.[自然(Nature)206,269(1965)]制备出其甲酯和甲酯的二乙酸盐,Berger,J.等[生物化学丛刊(Arch.Biochem.)22,476(1949)]进一步描述了其苄酯和疏螺体素甲酯的双-O-(4-硝基苯甲酰基)衍生物,但上述作者没有提及这些化合物的任何生物学作用。另一方面,按照文献,只有那些其中位于环戊烷环上的羧基未被取代的疏螺体素衍生物才具备血管生成抑制作用。此类化合物被记载在例如公开的日本专利申请JP09227549-A(Kokai)中,其描述了腈或羧基与疏螺体素骨架的7位碳原子结合且一个氢原子或低级烷基与9位碳原子结合的化合物。
基于上述内容,本发明涉及通式(I)的化合物-其中:
R表示通式-COOR1、-CONR2R3、-CONR4CONR4R5或-CH2OR6,其中
R1表示C2-6烷基;C1-6烷基,其被羟基、氨基、二(C1-4烷基)-氨基或5-8元饱和含氮杂环基(其除氮原子以外还可以含有一个氧原子或一个或两个附加氮原子)或被5-或6-元含氮芳族杂环基(其除氮原子以外还可以含有一个氧原子或一个或两个附加氮原子)取代;或C3-6环烷基;
R2和R3相同或不同且彼此独立地表示氢原子或C1-6烷基,其可以任选地被卤素原子、羟基、氨基、C2-5烷氧基羰基、二(C1-4烷基)-氨基或5-8元饱和含氮杂环基(其除氮原子以外还可以含有一个氧原子或一个或两个附加氮原子)或5-或6-元芳族碳环基或含有一个氧和/或氮原子的芳族杂环基取代;5或6-元环烷基或杂芳基;
R4和R5相同或不同并彼此独立地表示氢原子、C1-6烷基、C3-6环烷基或任选取代的苯基;
R6表示氢原子;C1-6烷基、C3-6环烷基或C2-6脂族酰基,其可以被卤素原子、氨基、二(C1-4烷基)-氨基或任选取代的苯基任选取代;
任选取代的氨基甲酰基、任选取代的苯甲酰基或C1-4烷基磺酰基-和它们的互变异构体、溶剂化物、它们的混合物和所有这些化合物的酸加成盐。
在此值得提及,通式(I)的图示中字母(R)和(S)表示相应碳原子的绝对构型。
在通式(I)的化合物的取代基的含义列举中命名“烷基”是指直链或支链基团。此类基团例如是、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、叔戊基、1-乙基-丙基、己基和异己基。
环烷基可以是环丙基、环戊基或环己基。
卤素原子可以是氯或溴原子。
在R1、R2和R3的含义中5-8元饱和、含氮杂环基可以例如但不仅仅是1-吡咯烷基、1-哌啶基、六氢-1H-氮杂-1-基、八氢吖辛因-1-基、哌嗪基和吗啉基。
在R2和R3的含义中,C2-5烷氧基羰基可以例如但不仅仅是甲氧羰基甲基、叔丁氧基羰基甲基、甲氧羰基乙基和甲氧羰基丙基。
在R2和R3的含义中,5-或6-元芳族碳环基可以例如但不仅仅是苯基或取代的苯基。
在R1、R2和R3的含义中,命名“5-或6-元含氧和/或氮的芳族杂环基”和“杂芳基”是指例如但不仅仅是下列基团:呋喃基、吡咯基、噁唑基、异噁唑基、咪唑基、吡唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,3,4--噁二唑基、1,2,3-***基、1,2,4-***基、哒嗪基、嘧啶基、吡嗪基、1,3,5-三嗪基、2-吡啶基、3-吡啶基和4-吡啶基。
在R6的含义中命名“C2-6脂族酰基”是指例如:乙酰基、丙酰基、丁酰基、异丁酰基、仲丁酰基、叔丁酰基、正己酰基或异己酰基。术语“C1-4烷基磺酰基”是指例如甲磺酰基或乙磺酰基。另外,术语“任选取代的氨基甲酰基”是指氨基甲酰基、C1-6烷基氨基甲酰基、C3-6环烷基氨基甲酰基或被C2-6脂族酰基任选取代的氨基甲酰基,其可以被卤素原子任选取代,如氯乙酰基-氨基甲酰基。
术语与通式(I)的化合物形成的“盐”应理解为是指与生理可接受无机和有机酸形成的盐。适合形成盐的酸例如是盐酸、氢溴酸、磷酸或硫酸。例如甲酸、乙酸、马来酸、富马酸、琥珀酸、乳酸、柠檬酸或甲磺酸可以用作有机酸。
一优选组的本发明通式(I)的化合物包括通式(I)的化合物,其中R表示通式-CONR2R3,其中R2和R3表示氢原子,或R2和R3之一表示氢原子而另一个表示被5-或6-元含氮芳族杂环基取代的C1-6烷基。
为了制备通式(I)的化合物,可以采用酯化、酰氨化和还原等方法,它们一般可以由文献中获知,如从合成有机化学(SyntheticOrganic Chemistry)(Wagner,R.B.和Zook,H.D.,Wiley,New York,1956)。
可以采用上述通用方法制备通式(I)的化合物,例如采用下列方法:
a)由疏螺体素生成的酰氯与适当的醇或胺的反应,
b)疏螺体素在碳二亚胺和碱的存在下的直接酯化或酰胺化,
c)由疏螺体素生成的酯与适当醇的酯交换,
d)疏螺体素甲酯与适当胺的反应,
e)由疏螺体素与如N-羟基苯并***形成活性酯,随后与适当的醇或胺反应,
f)由疏螺体素与例如氯甲酸酯形成混合酐,随后与适当的胺反应,
g)由疏螺体素生成的混合酐用金属氢化物还原,生成醇,
h)由疏螺体素制备的醇的烷基化和酰化等。
我们发现,首选通过由疏螺体素与N-羟基苯并***在碳二亚胺的存在下所生成的活性衍生物与适当的醇反应可以制备本发明疏螺体素的新的酯衍生物。
该反应在惰性溶剂中进行,优选四氢呋喃。在该过程中,用二环己基碳二亚胺(DCC)作为碳二亚胺并用二甲基氨基吡啶(DMAP)作为碱。使用10摩尔的过量醇组分是合适的。该反应在0℃-50℃的温度内进行,优选20℃,在搅拌下反应1-8小时,优选3小时。
疏螺体素的酰胺衍生物可以非常适宜采用例如由氯甲酸酯生成的混合酐衍生物来制备。该反应可以在惰性无水溶剂如四氢呋喃、二氯甲烷、四氯化碳中进行。三乙胺、吡啶和二甲基氨基吡啶可以用作酸结合剂。根据被偶联的胺可以使用1-10摩尔。该反应通过搅拌在-20℃和+20℃的温度下、在1-8小时内进行。在我们最优选的方法中,混合酐衍生物是于无水四氢呋喃中、-20℃下、在三乙胺的存在下用氯甲酸异丁酯制成,随后该反应用5摩尔的胺进行3小时而生成的。
疏螺体素的醇衍生物可以首选由疏螺体素的混合酐衍生物通过含水复合金属氢化物(优选硼氢化钠)在四氢呋喃中-20℃下还原来制得。
疏螺体素的醇衍生物的烷基化和酰化等可以以本身已知的方法进行。
所属领域技术人员明白,当制备通式(I)的化合物,而其起始化合物中的某些取代基含有在指定反应中不希望被转化的反应性基团时,则可采取以有机化学领域中本身已知的方式将这个(这些)基团保护起来,并且在指定反应之后脱除该保护基,通过这种方式分子的其它部分不应该经受任何不期望的转化。为了保护所述基团,可以采用本身已知的常用保护基。此类保护基公开在例如书籍Greene,T.W.和Wuts,P.的“有机合成中的保护性基因”(“Protective Groupsin Organic Synthesis”)(John Wiley & Sons,New York,1991)中。
一部分的本发明通式(I)的化合物含有碱性N原子,其适宜形成盐。通式(I)的此类碱可以通过已知途径转化为优选的药学可接受的酸加成盐,譬如通过把碱溶于适当的有机溶剂中且加入适宜的酸或用适当有机溶剂制成的酸的溶液。所得的盐通过过滤或通过真空蒸发溶剂来分离,并且如果希望,可以以已知方式纯化,如通过重结晶。
如上所述,本发明通式(I)的化合物具有有价值的生物学功效,也就是它们表现出显著的血管生成抑制作用,同时伴随有非常良好的选择性。
通过测量对内皮细胞的增殖和毛细管形成的作用业已测定出本发明的化合物的血管生成抑制作用。试验方法如下所示。
细胞增殖的试验
令内皮细胞ECV304(DSMZ号ACC310)在体外单层培养物中于含有10%胎牛血清(蛋白GMK(Protein GMK),Gdll,匈牙利)的培养基RPMI1640(SIGMA,USA)中增殖。将疏螺体素及其按照本发明通式(I)的新衍生物加入到指数期的培养物中至不同的终浓度(0.1-100μg/ml)。细胞培养物的生长是在Fluoroscan Ascent FL设备中且在改变DNA的量的基础上进行,借助于Hoechst 33342染色剂测定。
实际上对由人脐带(HUVEC)制备的细胞培养物可以观察到,疏螺体素和本发明通式(I)的化合物对内皮增殖具有相似的增殖抑制作用。
内皮毛细管形成的试验
将由鼠科动物EHS瘤制备的用于诱导毛细管形成的基膜蛋白凝胶置于ECV304内皮细胞之上。用疏螺体素和本发明通式(I)的新疏螺体素衍生物按照细胞增殖试验情况中相同的方式进行处理。通过显微镜并借助于形态量度程序检验细胞参与毛细管形成的程度,由此获得的数据表示为未处理对照的百分比。
结果
两种方法显示出可以适当地证实,本发明的新疏螺体素衍生物满足了选择性抑制毛细管形成的要求。也就是,它显示出,相对于疏螺体素来说,通式(I)的新衍生物的细胞增殖抑制作用明确降低,而毛细管形成抑制作用却只有很小程度的变化或完全没有改变。通过乘以抑制50%细胞增殖并抑制毛细管形成的活化剂浓度的比例可以测定出各化合物的选择性的相对程度。(该比例由本发明新化合物的适当抑制浓度除以疏螺体素的适当抑制浓度获得)。在由此计算出的选择性指数的基础上,与疏螺体素相比而言,实施例1的化合物对毛细管形成的抑制作用比对细胞增殖的抑制作用是60倍,实施例3的化合物是37倍,实施例2的化合物是7.5倍且实施例4的化合物是6倍。
当采用“微血管形成”法[Parish等,癌症研究(Cancer Res.)59,3433(1999)]时可以证实与毛细管形成的抑制有关的试验数据。该方法使我们能够研究由人胎盘的动脉制成的组织培养物中的新血管形成。我们可以陈述,本发明的疏螺体素衍生物显著抑制内皮细胞的增殖和更加好地抑制小管形成。
基于我们的试验结果,我们可以得出结论,事实上,本发明的新的疏螺体素衍生物首先作用于细胞机制,其能够阻断内皮细胞的毛细管形成,并且只在较高浓度时才会影响到该细胞的增殖。我们认识到,在相同的内皮细胞培养物中,本发明的新疏螺体素衍生物在较低浓度下可以抑制小管形成而不是内皮细胞的增殖,这不但是崭新的,而且是令人惊讶的。所以,该选择性没有出现在不同敏感性的不同细胞中,但可以在涉及毛细管形成的细胞间连接和细胞增殖之间观察到。
转移模型体系中抗肿瘤作用的研究
1.在Lewis肺腺癌模型[Holmgren等,自然医学(NatureMedicine)1,149(1995)]中,疏螺体素以非常小的程度抑制在除去肺内原发性肿瘤后形成的转移结的增殖。另一方面,当引入中毒剂量的五分之一时,实施例15的化合物不仅经腹膜内而且经口服时也可以非常显著地抑制微转移瘤的增长。
2.在结肠38脾-肝模型[Dong,Z.等,国家癌症研究所杂志(J.NatICancer Inst.)86,913(1994);Shaheen,R.M.等,癌症研究(Cancer Research)89,5412(1999)]试验体系中,移植到脾内的小鼠结肠腺癌细胞的转移形成能力在实施例15的化合物的亚毒性给药之后明显地减弱。
本发明的化合物可以单独或优选以药物组合物的形式用于治疗目的。所述的组合物属于本发明的范围。
这些药物组合物含有一定量的通式(I)的化合物以产生预期效果,并且含有载体、填充剂、稀释剂和/或其它本身已知且制药工业中常用的药物辅料。
譬如可以用水、醇、明胶、乳糖、蔗糖、淀粉、果胶、硬脂酸镁、硬脂酸、滑石、多种动植物油以及二醇(如丙二醇或聚乙二醇)作为上面提及的载体、稀释剂和填充剂。作为药物辅料,可以使用如防腐剂、抗氧剂、多种天然或合成的乳化剂、分散剂或湿润剂、着色剂、矫味剂、缓冲剂、崩解剂和其它提高活性剂的生物利用性的材料。
本发明的药物组合物可以为常规形式,例如口服制剂,其可利用上述药物辅剂制备。这些口服组合物可以是固体药物形式,如片剂、胶囊、粉末、丸剂、糖锭剂或颗粒剂;或液体药物形式,如糖浆剂、溶液、乳液或混悬液。直肠制剂可以是栓剂。回避胃***给药的非肠道制剂可以例如是注射或输注溶液。另外,本发明的药物组合物可以是外用制剂,如软膏、霜剂、压缩水、洗眼溶液、滴眼剂等。
虽然本发明的化合物产生所需药学作用所必须的剂量特别取决于个体状态和患者的年龄,并且最终由医生决定;为了预防和/或治疗疾病,其中需要抑制与疾病有关的血管生成,可以采用约0.5mg至约100mg/1kg体重的剂量。该剂量可以每天分数次给药,视吸收的情况而定。
含有本发明通式(I)的化合物的药物组合物可以被用作外科干预和放疗的辅药,主要用于治疗和预防肿瘤的增加并且用于限制癌转移灶的形成。此外,它们可以用来治疗其它疾病和状态,其中对血管形成的抑制、控制和/或消退产生有益效果;在此我们提及例如关节炎或血管翳、多种眼科病例(例如视网膜下新血管形成(subretinalisneovascularisatio))以及牛皮癣。
基于上面内容,本发明还提供一种治疗哺乳动物中血管生成性疾病的方法;由过度不适当血管生成引起;该方法包括给需要这种治疗的哺乳动物施用有效量的通式(I)的化合物。
本发明的化合物及其制备方法进一步通过下列非限定实施例说明。
实施例1
疏螺体素-2-吗啉代乙酯[(I),R=COO(CH2)2C4H8NO]
20℃下,搅拌的同时将120mg(0.245mmol)疏螺体素溶于5ml绝对四氢呋喃,随后向该溶液中加入38mg(0.245mmol)1-羟基苯并***、30mg(0.245mmol)二甲基氨基吡啶和65mg(0.31mmol)二环己基碳二亚胺。搅拌30分钟后,加入0.3ml(0.32g,2.45mmol)4-(2-羟乙基)吗啉。在20℃下搅拌3小时,起始化合物(Rf=0.43)消失且出现产物(Rf=0.51),通过薄层层析(硅胶板,洗脱剂体系:氯仿/甲醇95∶5)证实该产物。使该反应混合物蒸发至干。把干燥的残余物溶于50ml氯仿,用2×50ml水洗涤,用硫酸钠干燥且蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的氯仿和乙酸乙酯的混合物层析。合并用65∶35洗脱混合物洗脱的含有产物的馏分且蒸发至干。所得油状产物(133mg)的结构通过光谱(PMR,CMR,TS)数据确认。
(值得提及,光谱数据中指定的1″、2″、3″、5″和6″是指吗啉环。)
特征光谱数据:
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4,93,d,t;H-4:6,20ddd;H-5:6,36,dd;H-6:6,82,d;H-8:4,10;H-16:3,84,m;-O-CH2-CH2-:4,12,m和4,30,m;-CH2-CH2-1”:~2,50;H2-2”和H2-6”:~2,50;H2-3”和H2-5”:3,68,t.
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76,4,d;C-4:138,5,d;C-5:126,9,d;C-6:143,9,d;C-7:116,0,s;7-CN:118,2,s;C-8:73,1,d;C-16:70,0,d;C-18:172,4,s;1’-CO-O:176,0,s;O-CH2-CH2:61,8,t;CH2-CH2-1”:57,0,t;C-2”,6”:53,8,t;C-3”,5”:66,9,d.
TS(EI,70eV;m/z):602,[M]+*;113,[CH2=CH-吗啉基]+*;100,[CH2=吗啉基]+*.
实施例2
疏螺体素-2-(2-吡啶基)-乙酯[(I),R=COO(CH2)2C5H4N]
向由150mg(0.306mmol)疏螺体素按照实施例1制得的1-羟基苯并***活性酯中加入0.35ml(0.38g,3.06mmol)的2-(2-羟乙基)-吡啶。20℃下搅拌3℃后,起始疏螺体素(Rf=0.43)消失且出现产物(Rf=0.58),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/甲醇95∶5)。将反应混合物蒸发至干。把干燥的残余物溶于100ml氯仿,用3×30ml水洗涤,用硫酸钠干燥且蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的氯仿和乙酸乙酯的混合物层析。合并用1∶1洗脱混合物洗脱出的含有产物的馏分并蒸发至干。所得的固化油状产物(171mg)的结构通过光谱(PMR,CMR,TS)数据确认。
(值得提及,光谱数据中指定的2″、3″、4″、5″和6″是指吡啶环)
特征光谱数据
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4,90,d,t;H-4:6,15ddd;H-5:6,36,dd;H-6:6,80,d;H-8:4,12;H-16:3,85,m;-O-CH2-CH2-:4,35-4,60,m;-CH2-CH2-2”:3,10,t;H-3”:7,17,d;H-4”:7,62,m;H-5”:7,15,m;H-6”:6,52,d.
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76,2,d;C-4:138,6,d;C-5:126,8,d;C-6:144,0,d;C-7:115,9,s;7-CN:118,2,s;C-8:73,1,d;C-16:70,1,d;C-18:172,4,s;1’-CO-O-:176,0,s;-O-CH2-CH2-:63,8,t;-CH2-CH2-2”:37,3,t;C-2”:157,9,s;C-3”:123,3,d;C-4”:136,4,d;C-5”:126,9,d;C-6”:149,4,d.
TS(EI,70eV;m/z):594,[M]+*.
实施例3
疏螺体素酰胺[(I),R=CONH2]
搅拌的同时使150mg(0.306mmol)疏螺体素溶于10ml绝对四氢呋喃中,随后在-20℃下加入47μl(0.33mmol)三乙胺和44μl(0.33mmol)氯甲酸异丁酯。-20℃下搅拌30分钟后,过滤出三乙胺.HCl盐,向该溶液中加入100μl(1.5mmol)25%氢氧化铵水溶液。搅拌反应混合物3小时后,起始疏螺体素(Rf=0.43)消失且出现产物(Rf=0.33),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/甲醇95∶5)。用1-2滴乙酸使反应混合物的pH为7,随后将反应混合物蒸发至干。把干燥残余物溶于100ml氯仿,用2×30ml水洗涤,用硫酸钠干燥且蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的氯仿和乙酸乙酯的混合物层析。合并用55∶45洗脱混合物洗脱出的含产物馏分并蒸发至干。所得的固化油性产物(109mg)的结构用光谱(PMR、CMR、TS)数据确认。
特征光谱数据:
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4,90,d,t;H-4:6,16ddd;H-5:6,30,dd;H-6:6,75,d;H-8:4,04;8-OH:2,95;H-16:3,75,m;NH2:5,55és 5,72.
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76,6,d;C-4:138,8,d;C-5:126,8,d;C-6:144,0,d;C-7:115,9,s;7-CN:118,3,s;C-8:73,0,d;C-16:69,8,d;C-18:172,4,s;1’-CONH2:178,1,s.
TS(EI,70eV;m/z):488,[M]+*;470,[M-H2O]]+*;452,[M-2H2O]]+*;435,[M-H2O-NH3]]+*”;417,[M-2H2O-NH3]]+*.TS(CI,异丁烷;m/z):489,[M+H]]+;471,[M+H-H2O]]+.
实施例4
疏螺体素2-吗啉代乙基酰胺[(I),R=CONH(CH2)2C4H8NO]
向按照实施例3由150mg(0.306mmol)疏螺体素制备的混合酐溶液内加入0.25ml(1.9mmol,0.25g)的4-(2-氨基乙基)-吗啉。搅拌3小时后,起始疏螺体素(Rf=0.43)消失且出现产物(Rf=0.22),其通过薄层层析(硅胶板,洗脱剂体系:氯仿/甲醇95∶5)验证。把反应混合物蒸发至干。将干燥残余物溶于100ml氯仿,用3×30ml水洗涤,用硫酸钠干燥并蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的氯仿和乙酸乙酯的混合物层析。合并用95∶5洗脱混合物洗脱出的含产物馏分和蒸发至干。所得固化油性产物(172mg)的结构用光谱(PMR、CMR、TS)数据确认。
(值得提及,光谱数据中指定的2″、3″、5″和6″是指吗啉环)
特征光谱数据
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:5,00,d,t;H-4:6,20ddd;H-5:6,35,dd;H-6:6,80,d;H-8:4,10;H-16:3,82,m;NH:6,15,t;NH-CH2-CH2-N:3,20-3,45,m;NH-CH2-CH2-N:2,32,m;H-2”-6”;2,45,m;H-3”-5”:3,70,m.
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76,5,d;C-4:139,1,d;C-5:126,5,d;C-6:144,1,d;C-7:115,8,s;7-CN:118,3,s;C-8:73,1,d;C-16:69,2,d;C-18:172,2,s;1’-CO-N:175,5,s;NH-CH2-CH2-N:57,1,t és36,3,t;C-2”,6”:53,3,t;C-3”,5”:66,8t.
TS(EI,70eV;m/z):601,[M]]+*;585,[M-H2O]]+*;113,[CH2=CH-吗啉基]]+*;100,[CH2=吗啉基]]+.
实施例5
疏螺体素-醇[(I),R1=CH2OH]
将由150mg(0.306mmol)疏螺体素按照实施例3制备的混合酐溶液滴加至60mg(1.5mmol)NaBH4在2ml水中的溶液内且冷却至-20℃。搅拌5小时后,起始疏螺体素(Rf=0.43)消失且出现产物(Rf=0.52),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/甲醇95∶5)。此后,把1-2滴的乙酸加入到反应混合物中用于分解过量的NaBH4,随后把反应混合物蒸发至干。将干燥残余物溶于100ml氯仿,用2×30ml水洗涤,用硫酸钠干燥和蒸发至干。干燥的残余物(185mg)在硅胶柱上用乙酸乙酯含量递增的氯仿和乙酸乙酯混合物层析。合并用3∶1洗脱混合物洗脱出的含产物馏分且蒸发至干。所得固化油性产物(117mg)的结构通过光谱(PMR、CMR、TS)数据确认。
特征光谱数据:
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4,92,d,t;H-4:6,20ddd;H-5:6,35,dd;H-6:6,80,d;H-8:4,10;H-16:3,87,m;1’-CH2-OH:3,45,m.
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76,7,d;C-4:139,1,d;C-5:126,7,d;C-6:144,1,d;C-7:115,8,s;7-CN:118,3,s;C-8:73,0,d;C-16:70,5,d;C-18:172,3,s;1’-CH2-OH:66,4,t.
TS(EI,70eV;m/z):475,[M]]+*;457,[M-H2O]]+*;439,[M-2H2O]]+*.
TS(CI,异丁烷;m/z):476,[M+H]]+;458,[M+H-H2O]]+*;440,[M+H-2H2O]]+.
实施例6
疏螺体素-N,N’-二环己基甲酰氨基酰胺[(I),R=CON(C6H11)CONHC6H11]
20℃下,搅拌的同时将98mg(0.2mmol)疏螺体素溶于2ml绝对四氢呋喃,随后向该溶液内加入124mg(0.6mmol)二环己基碳二亚胺。在相同温度下搅拌该反应混合物,反应的进程用薄层层析监测。在硅胶板上,于氯仿/甲醇95∶5洗脱体系中,起始疏螺体素(Rf=0.43)在5小时后消失且出现产物(Rf=0.74)。此后把反应混合物蒸发至干,粗产物(240mg)在硅胶柱上用乙酸乙酯含量递增的氯仿和乙酸乙酯的混合物层析。合并用8∶2洗脱混合物洗脱出的含产物馏分且蒸发至干。所得的固化油性产物(105mg)的结构由光谱(PMR、CMR、TS)数据确认。
特征光谱数据
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4,93,d,t;H-4:6,28ddd;H-5:6,36,dd;H-6:6,84,d;H-8:~4,10;H-16:3,85,m;环己烷:3,65,m,1H;4,05,m,1H;1,4-2,1,m,20H.
13C-NMR(CDCl3;δ[ppm],δTMSS=0;多重态):C-2:77,0,d;C-4:139,0,d;C-5:126,7,d;C-6:144,1,d;C-7:115,7,s;7-CN:118,2,s;C-8:73,1,d;C-16:69,1,d;C-18:172,7,s;1’-CO-N:加宽符号,不是从基线出现的;N-CO-N:153,6,s;环己基:50.1,d;40.9,d(加宽符号);32.7,t(2C);32.6,t(2C);24.7,t;25.9,t(2C);26.0,t(2C).
TS(EI,70eV;m/z):695,[M]+*;570,[M-O=C=N-C6H11]+*;552,[570-H2O]+*.
TS(CI,异丁烷;m/z):696,[M+H]+*;571,[M+H-O=C=N-C6H11]+;553,[571-H2O]+;83,[C6H11]+.
实施例7
疏螺体素-苄酰胺[(I),R=CONHCH2-C6H5]
向由200mg(0.41mmol)疏螺体素按照实施例3制备的混合酐溶液加入220μl(2mmol,2.14mg)苄胺。搅拌3小时后,起始疏螺体素(Rf=0.52)消失且出现产物(Rf=0.69),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/甲醇3∶7)。把反应混合物蒸发至干。将干燥残余物溶于100ml氯仿,用3×30ml水洗涤,用硫酸钠干燥且蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的氯仿和乙酸乙酯的混合物层析。合并用8∶2洗脱混合物洗脱出的含产物馏分且蒸发至干。所得的固化油性产物(135mg)的结构通过光谱(PMR、CMR、TS)数据确认。
特征光谱数据
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4.95,d,t;H-4:6.24,ddd;H-5:6.35,dd;H-6:6.79,d;H-8:4.10,m;H-16:3.80,m;1’-CONH-5.98,t;NH-CH2-Ph:4.26,dd,和4.44,dd;Ph:7.15-7.35,m,5H
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76.7,d;C-4:138.8,d;C-5:126.7,d;C-6:144.0,d;C-7:115.8,s;7-CN:118.3,s;C-8:73.0,d;C-16:69.8,d;C-18:172.4,s;1’-CO-NH-:175.4,s;NH-CH2-Ph:43.8,t;Ph:138.2,s;128.7,d;127.7,d;127.6,dTS(EI,70eV;m/z):578,[M]+*;560,[M-H2O]+;542,[M-2H2O]+*;
435,[M-2H2O-C6H5CH2NH2]+*;106,[C7H8N]+;91,[C7H7]+.TS(CI,异丁烷;m/z):579,[M+H]+;561,[M+H-H2O]+;106,
C7H8N]+;91,[C7H7]+.
实施例8
疏螺体素-2-吡啶甲基酰胺[(I),R=CONHCH2-C5H4N]
向由200mg(0.41mmol)疏螺体素按照实施例3制备的混合酐溶液内加入206μl(2mmol,216mg)2-吡啶甲胺。搅拌3小时后,起始疏螺体素(Rf=0.52)消失且出现产物(Rf=0.29),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/甲醇3∶7)。把反应混合物蒸发至干。将干燥残余物溶于100ml氯仿,用3×30ml水洗涤,用硫酸钠干燥和蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的氯仿和乙酸乙酯的混合物层析。合并用1∶1洗脱混合物洗脱出的含产物馏分且蒸发至干。所得的固化油性产物(188mg)的结构通过光谱(PMR、CMR、TS)数据确认。
特征光谱数据
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:5.00,dt;H-4:6.20,ddd;H-5:6.40,dd;H-6:6.80,d;H-8:4.15,m;H-16:3.82,m;1’-CONH-:7.14,t;NH-CH2-2Py:4.55,d;Py:7.20-7.36,m,2H;7.70,td,1H和8.50,d,1H
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76.7,d;C-4:139.2,d;C-5:126.5,d;C-6:144.2,d;C-7:115.7,s;7-CN:118.2,s;C-8:73.1,d;C-16:69.3,d;C-18:172.3,s;1’-CO-NH-:175.6,s;NH-CH2-2Py:44.3,t;Py:156.3,s;122.8,d;137.2,d;122.5,d;148.8,d
TS(EI,70eV;m/z):579,[M]+*;561,[M-H2O]+*;336,[C20H22N3O2]+;109,[C5H4NCH2NH3]+;107,[C6H7N2]+;92,[C6H6N]+.
TS(CI,异丁烷;m/z):580,[M+H]+.
实施例9
疏螺体素-4-吡啶甲基酰胺[(I),R=CONHCH2-C5H4N]
向由200mg(0.41mmol)疏螺体素按照实施例3制备的混合酐溶液内加入206μl(2mmol,216mg)的4-吡啶甲胺。搅拌3小时后,起始疏螺体素(Rf=0.43)消失且出现产物(Rf=0.24),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/甲醇95∶5)。把反应混合物蒸发至干。将干燥残余物溶于100ml氯仿,用3×30ml水洗涤,用硫酸钠干燥和蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的二氯甲烷和乙酸乙酯的混合物层析。合并用15∶85洗脱混合物洗脱出的含产物馏分且蒸发至干。所得的固化油性产物(201mg)的结构由光谱(PMR、CMR、TS)数据确认。
特征光谱数据
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4.98,dt;H-4:6.22,m;H-5:6.36,dd;H-6:6.78,d;H-8:4.10,m;H-16:3.78,m;1’-CONH-:6.55,t;NH-CH2-4Py:4.18,dd和4.62,dd;Py:7.15,d,2H和8.48,d,2H
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76.6,d;C-4:138.7,d;C-5:126.7,d;C-6:143.9,d;C-7:116.0,s;7-CN:118.4,s;C-8:72.9,d;C-16:69.5,d;C-18:172.2,s;1’-CO-NH-:176.0,s;NH-CH2-4Py:42.3,t;Py:149.7,d;122.2,d和147.7,s
TS(EI,70eV;m/z):579,[M]+*;561,[M-H2O]+*;336,[C20H22N3O2]+;107,[C6H7N2]+;93[C6H7N]]+*;92,C6H6N]+.
TS(CI,异丁烷;m/z):580,[M+H]+;562,[M+H-2O]+.
实施例10
疏螺体素-2-糠基酰胺[(I),R=CONHCH2-C4H3O]
向由200mg(0.41mmol)疏螺体素按照实施例3制备的混合酐溶液内加入177μl(2mmol,194mg)2-糠基胺。搅拌3小时后,起始疏螺体素(Rf=0.52)消失且出现产物(R,=0.70),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/乙酸乙酯3∶7)。反应混合物蒸发至干。将干燥残余物溶于100ml氯仿,用3×30ml水洗涤,用硫酸钠干燥和蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的二氯甲烷和乙酸乙酯的混合物层析。合并用65∶35洗脱混合物洗脱的含产物馏分并蒸发至干。所得固化油性产物(105mg)的结构通过光谱(PMR、CMR、TS)数据确认。
特征光谱数据
IR:3357;2958;2213;1723;1651cm-1
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4.88,dt;H-4:~6.15,m;H-5:6.30,dd;H-6:6.75,d;H-8:4.03,m;H-16:3.76,m;1’-CONH-:5.86,t;NH-CH2-2Fu:4.28,dd和4.48,dd;Fu:6.13,dd;6.25,d和7.27,d
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76.7,d;C-4:138.8,d;C-5:126.7,d;C-6:144.1,d;C-7:115.7,s;7-CN:118.2,s;C-8:73.1,d;C-16:69.6,d;C-18:172.5,s;1’-CO-NH-:175.2,s;NH-CH2-2Fu:36.8,t;Fu:151.0,s;110.5,d;107.5,d;142.2,d
TS(EI,70eV;m/z):568,[M]+*;550,[M-H2O]+*;96,[C5H6NO]+;81,[C5H5O]+.
TS(CI,异丁烷;m/z):569,[M+H]+;551,[M+H -H2O]+;96,C5H6NO]+;81,[C5H5O]+.
实施例11
疏螺体素-3-吡啶基酰胺[(I),R=CONH-C5H4N]
向由200mg(0.41mmol)疏螺体素按照实施例3制备的混合酐溶液内加入188mg(2mmol)3-氨基吡啶。搅拌3小时后,起始疏螺体素(Rf=0.43)消失且出现产物(Rf=0.25),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/甲醇95∶5)。把反应混合物蒸发至干。将干燥残余物溶于100ml氯仿,用3×30ml水洗涤,用硫酸钠干燥和蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的二氯甲烷和乙酸乙酯的混合物层析。合并用1∶9洗脱混合物洗脱出的含产物的馏分且蒸发至干。所得固化油性产物(144mg)的结构通过光谱(PMR、CMR、TS)数据确认。
特征光谱数据
IR:3318;2958;2212;1730;1542cm-1
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4.92,dt;H-4:6.20,m;H-5:6.35,dd;H-6:6.76,d;H-8:4.08,d;H-16:3.76,m;CO-NH-3Py:7.70,s;Py:8.53,d;8.22-8-36,m,2H和7.25,t
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76.5,d;C-4:138.5,d;C-5:126.9,d;C-6:143.9,d;C-7:115.9,s;7-CN:118.2,s;C-8:73.1,d;C-16:70.6,d;C-18:172.4,s;1’-CO-NH-:174.6,s;Py:145.1,d;126.9,s;140.6,d;123.7,d;135.1,d
TS(EI,70eV;m/z):565,[M]+*;547,[M-H2O]+*;322,[C20H22N3O2]+;121,[C6H5N2O]+;95[C5H7N2]+.
TS(CI,异丁烷;m/z):566,[M+H]+;548,[M+H-H2O]+;95[C5H7N2]+.
实施例12
疏螺体素基-甘氨酸-叔丁酯[(I),R=CONHCH2-COOC4H9]
向由200mg(0.41mmol)疏螺体素按照实施例3制备的混合酐溶液内加入280mg(1,67mmol)甘氨酸-叔丁酯盐酸盐和235μl(1.69mmol,170mg)三乙胺。搅拌3小时后,起始疏螺体素(Rf=0.52)消失且出现产物(Rf=0.73),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/乙酸乙酯3∶7)。把反应混合物蒸发至干。将干燥残余物溶于100ml氯仿,用3×30ml水洗涤,用硫酸钠干燥和蒸发至干。干燥的残余物在硅胶柱上用甲醇含量递增的氯仿和甲醇的混合物层析。合并用96∶4洗脱混合物洗脱出的含产物馏分和蒸发至干。所得固化油性产物(129mg)的结构通过光谱(PMR、CMR、TS)数据确认。
特征光谱数据
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4.92,dt;H-4:6.22,m;H-5:6.38,dd;H-6:6.82,d;H-8:4.10,dd;H-16:3.85,m;CO-NH-CH2:6.15,t;NH-CH2-CO-:3.88,dd和3.99,dd;tBu:1.48,s,3H
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76.7,d;C-4:139.0,d;C-5:126.7,d;C-6:144.2,d;C-7:115.7,s;7-CN:118.2,s;C-8:73.1,d;C-16:69.5,d;C-18:172.5,s;1’-CO-NH-:175.5,s;NH-CH2-CO:42.2,t;CH2-CO-O:169.5,s;O-C-(CH3)3:82.5,s;O-C-(CH3)3:28.0,q
TS(EI,70eV;m/z):602,[M]+*;528,[M-C4H9OH]+*;435,[M-2H2O-C5H13NO2]+*.
TS(CI,异丁烷;m/z):603,[M+H]+;547,[M+H-4H8]+;529,[M+H-C4H9OH]+
实施例13
疏螺体素-环己基酰胺[(I),R=CONH-C6H11]
向由200mg(0.41mmol)疏螺体素按照实施例3制备的混合酐溶液内加入234μl(2mmol,203mg)环己胺。搅拌3小时后,起始疏螺体素(Rf=0.52)消失且出现产物(Rf=0.68),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/乙酸乙酯3∶7)。把反应混合物蒸发至干。将干燥残余物溶于100ml氯仿,用3×30ml水洗涤,用硫酸钠干燥和蒸发至干。干燥的残余物在硅胶柱上用甲醇含量递增的氯仿和甲醇的混合物层析。合并用96∶4洗脱混合物洗脱出的含产物馏分且蒸发至干。所得的固化油性产物(205mg)的结构通过光谱(PMR、CMR、TS)数据确认。
特征光谱数据
IR:3344;2931;2213;1717;1647;1541cm-1
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4.94,dt;H-4:6.25,m;H-5:6.35,dd;H-6:6.83,d;H-8:4.10,dd;H-16:3.88,m;CO-NH-:5.35,d;环己基-CH:3.75,m,1H
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76.8,d;C-4:139.0,d;C-5:126.7,d;C-6:144.1,d;C-7:115.7,s;7-CN:118.2,s;C-8:73.2,d;C-16:69.7,d;C-18:172.5,s;1’-CO-NH-:174.3,s;环己基:50.47,d;33.3,t;33.4,t;25.3,t;24.7,t;24.8,t
TS(EI,70eV;m/z):570,[M]+*;552,[M-H2O]+*;534,[M-2H2O]+*;327,[C20H27N2O2]+;224,[C13H22NO2]+.
TS(CI,异丁烷;m/z):571,[M+H]+;553,[M+H-H2O]+.
实施例14
疏螺体素-1-乙醇酰胺[(I),R=CONH-CH2CH2OH]
向由200mg(0.41mmol)疏螺体素按照实施例3制备的混合酐溶液内加入124μl(2mmol,125mg)乙醇胺。搅拌3小时后,起始疏螺体素(Rf=0.43)消失且出现产物(Rf=0.26),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/甲醇95∶5)。反应混合物蒸发至干。将干燥残余物溶于100ml氯仿,用3×30ml水洗涤,用硫酸钠干燥和蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的氯仿和乙酸乙酯的混合物层析。合并用3∶7洗脱混合物洗脱出的含产物馏分和蒸发至干。所得固化油性产物(198mg)的结构通过光谱(PMR、CMR、TS)数据确认。
特征光谱数据:
IR:3350;2958;2212;1719;1646cm-1
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4.98,dt;H-4:6.28,m;H-5:6.38,dd;H-6:6.83,d;H-8:4.10,d;H-16:3.82,m;CO-NH-CH2:6.32,t;NH-CH2-CH2-:3.38,m;CH2-CH2-OH:3.70,m
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76.7,d;C-4:139.0,d;C-5:126.6,d;C-6:144.1,d;C-7:115.8,s;7-CN:118.4,s;C-8:73.1,d;C-16:69.4,d;C-18:172.3,s;1’-CO-NH-:176.7,s;NH-CH2-CH2:42.3,t;CH2-CH2-OH:61.7,t
TS(EI,70eV;m/z):532,[M]+*;514,[M-H2O]+*;496,[M-H2O]+*;478,[M-3H2O]+*;289,[C16H21N2O3]+;271,[C16H19N2O2]+;186,[C9H16NO3]+.
TS(CI,异丁烷;m/z):533,[M+H]+;515,[M+H-H2O]+.
实施例15
疏螺体素-3-吡啶甲基酰胺[(I),R=CONHCH2-C5H4N]向由4.0g(8.2mmol)疏螺体素按照实施例3制备的混合酐溶液加入4.2ml(41.2mmol,4.46g)3-吡啶甲胺。搅拌3小时后,起始疏螺体素(Rf=0.43)消失且出现产物(Rf=0.24),其通过薄层层析验证(硅胶板,洗脱剂体系:氯仿/甲醇95∶5)。反应混合物蒸发至干。将干燥残余物溶于500ml氯仿,用3×1500ml水洗涤,用硫酸钠干燥和蒸发至干。干燥的残余物在硅胶柱上用乙酸乙酯含量递增的氯仿和乙酸乙酯的混合物层析。合并用2∶8洗脱混合物洗脱出的含产物馏分且蒸发至干。向所得的固化油性物质(3.62g)加入4ml乙酸乙酯和20ml正己烷,研制固体物质,随后过滤。由此得到3.04g产物。Mp.:99-105℃。
元素分析C34H49N3O5(M:579.785):
计算值:C=70.43%,H=8. 52%,N=7.25%,
实测值:C=70.45%,H=8.88%,N=6.91%.
UV:λmax(EtOH)=256nm(E=29166).
产物的结构通过光谱(PMR、CMR、TS)数据确认。
特征光谱数据
IR:3325;2958;2212;1732;1651;1251cm-1
1H-NMR(CDCl3;δ[ppm],δTMS=0;多重态):H-2:4.98,dt;H-4:6.22,m;H-5:6.39,dd;H-6:6.81,d;H-8:4.10,d;H-16:3.80,m;1’-CONH-:6.50,t;NH-CH2-3Py:4.25,dd和4.60,dd;Py:7.25,dd;7.63,d和8.43-8.53,m,2H
13C-NMR(CDCl3;δ[ppm],δTMS=0;多重态):C-2:76.5,d;C-4:138.7,d;C-5:126.7,d;C-6:144.0,d;C-7:116.0,s;7-CN:118.5,s;C-8:73.0,d;C-16:69.7,d;C-18:172.2,s;1’-CO-NH-:175.8,s;NH-CH2-3Py:41.1,t;y:148.8,d;134.2,s;135.7,d;123.6,d;148.6,d
TS(EI,70eV;m/z):579,[M]+*;561,[M-H2O]+*;336,[C20H22N3O2]+;107,[C6H7N2]+;93[C6H7N]+*;92,[C6H6N]+.
TS(CI,异丁烷;m/z):580,[M+H]+.
盐酸盐的制备
将350mg(0.6mmol)上述产物溶于5ml四氢呋喃,随后在0℃和搅拌下加入70μl的37%盐酸水溶液。真空下蒸发溶剂,与苯共沸蒸馏除去水。干燥的残余物用绝对***研制。过滤固体物质且用***洗涤。由此得到330mg产物。Mp.:114-119℃。
元素分析C34H49N3O5·HCl·2H2O(M:652.246):
计算值:C=62.61%,H=8.35%,N=6.44%,Cl=5.44%,H2O=5.52%;
实测值:C=64.16%,H=8.22%,N=6.44%,Cl=5.67%,H2O=5.57%.
UV:λmax(EtOH)=256nm(ε=30170).
特征光谱数据
1H-NMR(DMSO-d6,δ[ppm],δTMS=0;多重态):H-2:4.85,dt;H-4:6.30,m;H-5:6.48,dd;H-6:6.95,d;H-8:4.08,d;H-16:3.70,m;1’-CONH-:8.60,t;NH-CH2-3Py:4.26,dd和4.54,dd;Py:7.92,dd;8.30,d和8.68-8.82,m,2H
13C-NMR(DMSO-d6,δ[ppm],δTMS=0;多重态):C-2:75.6,d;C-4:139.1,d;C-5:127.5,d;C-6:143.4,d;C-7:116.6,s;7-CN:119.4,s;C-8:70.8,d;C-16:70.0,d;C-18:171.1,s;1’-CO-NH-:175.9,s;NH-CH2-3Py:38.2,t;Py:143.4,d;141.5,d;141.3,d;139.3,s;126.6,d
Claims (11)
1.通式(I)的化合物
-其中
R表示通式-COOR1、-CONR2R3、或-CONR4CONR4R5,其中
R1表示C1-6烷基,其被羟基、氨基、二(C1-4烷基)-氨基或5-8元饱和含氮杂环基或被5-或6-元含氮芳族杂环基取代;或C3-6环烷基;其中所述5-8元饱和含氮杂环基除氮原子以外还可以含有一个氧原子或一个或两个附加氮原子,所述5-或6-元含氮芳族杂环基除氮原子以外还可以含有一个氧原子或一个或两个附加氮原子,
R2和R3相同或不同,并且彼此独立地表示氢原子或C1-6烷基,其可以任选地被卤素原子、羟基、氨基、C2-5烷氧基羰基、二(C1-4烷基)-氨基或5-8元饱和含氮杂环基或5-或6-元芳族碳环基或含有一个氧和/或氮原子的芳族杂环基取代;5或6-元环烷基或杂芳基;其中所述5-8元饱和含氮杂环基除氮原子以外还可以含有一个氧原子或一个或两个附加氮原子,
R4和R5相同或不同并彼此独立地表示氢原子、C1-6烷基、C3-6环烷基或苯基;
和它们的互变异构体、溶剂化物、它们的混合物和所有这些化合物的酸加成盐。
2.权利要求1的选自下列的化合物:
疏螺体素-3-吡啶甲基酰胺及其酸加成盐,
疏螺体素-2-吡啶甲基酰胺及其酸加成盐,
疏螺体素-酰胺,和
疏螺体素-N,N-二环己基甲酰氨基酰胺。
3.权利要求1的通式(I)的化合物,其是疏螺体素-3-吡啶甲基酰胺或其盐酸盐。
5.权利要求1中所述的化合物在制备用于治疗与血管生成有关的疾病的药物中的用途。
6.权利要求1所述的化合物的用途,用于制备治疗与血管生成有关的肿瘤的药物组合物。
7.权利要求1所述的化合物的用途,用于制备预防肿瘤转移灶形成的药物组合物。
8.权利要求1所述的化合物的用途,用于制备增补癌症疗法的药物组合物。
9.权利要求1所述的化合物的用途,用于制备治疗与血管生成有关的关节炎或血管翳的药物组合物。
10.权利要求1所述的化合物的用途,用于制备治疗与血管生成有关的牛皮癣的药物组合物。
11.权利要求1中所定义的通式(I)的化合物在制备用于治疗哺乳动物中血管生成性疾病的药物中的用途,所述的疾病是由过度的、不适当的血管生成引起。
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KR (1) | KR20020068495A (zh) |
CN (1) | CN1243746C (zh) |
AP (1) | AP1383A (zh) |
AT (1) | ATE241611T1 (zh) |
AU (1) | AU772206B2 (zh) |
BG (1) | BG106373A (zh) |
BR (1) | BR0012968A (zh) |
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DK (1) | DK1206462T3 (zh) |
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HK (1) | HK1048995B (zh) |
HR (1) | HRP20020103B1 (zh) |
HU (1) | HUP9902628A3 (zh) |
IL (1) | IL147904A (zh) |
IS (1) | IS2137B (zh) |
MX (1) | MXPA02001117A (zh) |
NO (1) | NO20020485L (zh) |
NZ (1) | NZ517422A (zh) |
OA (1) | OA12004A (zh) |
PL (1) | PL354281A1 (zh) |
PT (1) | PT1206462E (zh) |
RU (1) | RU2247723C2 (zh) |
SK (1) | SK1822002A3 (zh) |
UA (1) | UA74341C2 (zh) |
WO (1) | WO2001009113A2 (zh) |
YU (1) | YU7302A (zh) |
ZA (1) | ZA200200838B (zh) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6693099B2 (en) * | 2000-10-17 | 2004-02-17 | The Procter & Gamble Company | Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance |
SI1483251T1 (sl) | 2002-03-12 | 2010-03-31 | Bristol Myers Squibb Co | C cian epotilonski derivati |
GB0230217D0 (en) * | 2002-12-27 | 2003-02-05 | Biotica Tech Ltd | Borrelidin-producing polyketide synthase and its uses |
US8440217B1 (en) | 2005-06-15 | 2013-05-14 | Mawaheb M. EL-Naggar | Method and system with contact lens product for treating and preventing adverse eye conditions |
GB0609981D0 (en) * | 2006-05-19 | 2006-06-28 | Biotica Tech Ltd | Novel compounds |
GB0713563D0 (en) * | 2007-07-13 | 2007-08-22 | Biotica Tech Ltd | Methods of screening for anti-angiogenic compounds |
WO2009027393A2 (en) * | 2007-08-27 | 2009-03-05 | Basf Se | Pyrazole compounds for controlling invertebrate pests |
DE102008014077A1 (de) | 2008-03-13 | 2009-09-17 | Discovery Partner International Gmbh | Borrelidin-Derivate |
WO2009141786A2 (en) * | 2008-05-21 | 2009-11-26 | Piramal Life Sciences Limited | Anti-inflammatory compounds |
DK3034522T3 (en) | 2014-12-15 | 2019-04-15 | Borealis Ag | Use of a polypropylene composition |
Family Cites Families (2)
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JPH08173176A (ja) | 1994-12-22 | 1996-07-09 | Mercian Corp | 血管新生阻害剤 |
JP3786461B2 (ja) | 1996-02-22 | 2006-06-14 | メルシャン株式会社 | 新生理活性物質 |
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