CN1067430A - 制备膦基-烃基ⅷ族金属络合物及含有这些络合物的抗肿瘤组合物方法 - Google Patents
制备膦基-烃基ⅷ族金属络合物及含有这些络合物的抗肿瘤组合物方法 Download PDFInfo
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- CN1067430A CN1067430A CN92104058A CN92104058A CN1067430A CN 1067430 A CN1067430 A CN 1067430A CN 92104058 A CN92104058 A CN 92104058A CN 92104058 A CN92104058 A CN 92104058A CN 1067430 A CN1067430 A CN 1067430A
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- Prior art keywords
- ethane
- iii
- perchlorate
- weight
- compound
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- 239000002184 metal Substances 0.000 title description 8
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- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 25
- 238000009835 boiling Methods 0.000 claims description 15
- 239000010948 rhodium Substances 0.000 claims description 8
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 claims description 8
- 150000002500 ions Chemical class 0.000 claims description 6
- IXGNPUSUVRTQGW-UHFFFAOYSA-M sodium;perchlorate;hydrate Chemical compound O.[Na+].[O-]Cl(=O)(=O)=O IXGNPUSUVRTQGW-UHFFFAOYSA-M 0.000 claims description 3
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- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
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- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- IAOPZNCIMMSICI-UHFFFAOYSA-L dichloroiron(1+) Chemical compound Cl[Fe+]Cl IAOPZNCIMMSICI-UHFFFAOYSA-L 0.000 description 1
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- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 125000001905 inorganic group Chemical group 0.000 description 1
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- 238000012417 linear regression Methods 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
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- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 description 1
- HNNUTDROYPGBMR-UHFFFAOYSA-L palladium(ii) iodide Chemical compound [Pd+2].[I-].[I-] HNNUTDROYPGBMR-UHFFFAOYSA-L 0.000 description 1
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- 239000002831 pharmacologic agent Substances 0.000 description 1
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- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- PZSJYEAHAINDJI-UHFFFAOYSA-N rhodium(3+) Chemical compound [Rh+3] PZSJYEAHAINDJI-UHFFFAOYSA-N 0.000 description 1
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- 238000001228 spectrum Methods 0.000 description 1
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- 229910052723 transition metal Inorganic materials 0.000 description 1
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Abstract
本发明涉及制备下式化合物的方法,式中各基团
定义及该方法详细描述见说明书。
Description
本发明是关于新的双〔双〔二苯基膦基)烃基〕和双〔二苯基膦基-二苯肿基)烃基〕Ⅷ族金属化合物。这些金属化合物具有抑制肿瘤细胞生长活性,含有抑制肿瘤生长数量的这些化合物的新的药物组合物和通过给染有肿瘤细胞的一群动物服用抗肿瘤细胞生长量的这些化合物来寻求肿瘤细胞对这些化合物敏感的方法。
八族过渡金属络合物,特别是二氯化二氨铂及它用于治疗几种类型癌症,也就是睾丸和卵巢癌的用处在下面书中描述:
-M.J.Clare and P.C Hydes,Metal Ions in Biological Systems,Vol.11
-H.Sigel Edit,Marcel Dckker,New York(1980),1-62 and -S.Haghighi and C.A.Mc Auliffe,Rev.Inorg.Chem,3,291-351(1981)。
己对顺二氯化二氮铂有关的金属氨络合物做了进一步研究。上面提到的组合物在老鼠上几个抗肿瘤试验系统中没显示出活性或与活性铂化合物相比显示出较低活性。
不含氮配位基系统的金属络合物很少研究,除了后面提到的膦基-烃基IB族金属络合物外,这一族中的金属络合物没有显出明显的抗肿瘤活性〔S,Haghighi and C.A.Mc Auliffe,Rev.Inorg,Chem.,3,219-351(1981)。
目前仍然非常需要治疗癌症的化学治疗方法。
上述类型的化学治疗法应对抗某些肿瘤显示出高活性或对抗广谱的肿瘤显出活性。更重要的是这样的化合物对于存在的抗肿瘤化学疗法有阻断抗药性存在的能力。
现在已发现式1的药物活性化合物,其中:D1=D2=膦或D2=砷,D1=磷
A=(CH2)2,(CH2)3或顺-CH=CH;
X1=X2(如果二者都存在的话)=囟基或硝酸基或
X1+X2=过氧化基。
Y(如存在)=囟化物,硝酸盐,高氯酸盐,triflate或四囟代高铁酸盐(Ⅲ)
n=0,1或2;
M=Fe(Ⅱ),Fe(Ⅲ),Co(Ⅱ),Rh(Ⅰ),Rh(Ⅲ),Ir(Ⅰ),Ir(Ⅲ),Ni(Ⅱ)和Pd(Ⅱ)。
所说的氮原子游离的金属络合物显示了重要抗肿瘤活性。它们对P388淋巴细胞白血病和B16黑素瘤显示出非常好作用。特别对B16黑素瘤的高活性是明显的。
发现的活性特别奇怪,因为大多数化合物是阳离子发生物和相应的阳离子发生物氨-铂络合物。而这些络合物已知是没抗肿瘤活性。
有关的文献参考。Nelson etal.,J.Chem.Soc.,Dalton trans.,1778(1975),介绍双〔顺-1,2-双(二苯基-膦基乙烯〕二氯铁(Ⅱ)和双〔顺1,2-双(二苯基-膦基)乙烯〕二氯铁(Ⅲ)四氯代高铁酸盐(Ⅲ)。Sacconi et al.,Inorg.Chem.,20,3423(1981),介绍了上面提到的铁(Ⅱ)络合物的X-射线结晶结构。Chatt et al.,J.Chem.Soc.,5504(1961),披露双(1,2-双(二苯基-膦基)乙烷〕溴钴(Ⅱ)溴化物。Sacco et al.Gazz.Chim.Ital.,93,687(1963),披露几个双〔1,2-双(二苯基-膦基)乙烷〕钴(Ⅱ)络合物(其它之中的,溴化物,碘化物,高氯酸盐,硝酸盐)和双〔1,2-双(二苯基膦基)-乙烷〕镍(Ⅱ)二高氯酸盐。Schmid et al.,Z.Naturforsch.,20b 1008(1965),披露了双〔1,2-双(二苯基膦基)乙烷〕氯钴(Ⅱ)氯化物。Sacco et al.,J.Chem.Soc.,3274(1964),披露了双〔1,2-双(二苯基膦基)乙烷〕铑(Ⅰ)氯化物和它的高氯酸盐和四苯硼酸盐相似物。Arnold et al.,Chem,Phys,Lett.,19,546(1973),披露了双〔1,2-双(二苯基膦基)乙烷〕二氯铑(Ⅲ)氯化物。Hieber et al.,Chem.Ber.,99,2607(1966),披露了双〔1,2-双(二苯基膦基)乙烷〕铱(Ⅰ)氯化物,Sacco et al,J.Chem.Soc.Chem.Comm.,589(1966),披露了几个双〔1,2-双(二苯基膦基乙烷)〕铱(Ⅰ)络合物(氯化物,溴化物,碘化物,高氯酸盐)和双〔1,2-双(二苯基膦基)乙烷〕过氧化铱(Ⅲ)高氯酸盐。上面这个化合物由G.Rouschias et al;J,Chem.Soc.,Dalton Trans.,2531(1974)做了更详细介绍。Chatt et al;J.Chem.Soc.,2537(1962),披露了双〔1,2-双(二苯基膦基)乙烷〕镍(Ⅱ)二硝酸盐和双〔1,2-双(二苯基膦基)乙烷〕钯(Ⅱ)二溴化物。Feltham et al.,J.Chem.Soc.,4587(1964)披露了双〔1,2-双(二苯基膦基)乙烷〕钯(Ⅱ)二高氯酸盐。Westland,J.Chem Soc.A.,3060(1965)中披露了几个双〔1,2-双(二苯基膦基)乙烷〕钯(Ⅱ)络合物(氯化物,溴化物,碘化物,高氯酸盐)。struck et al,J.Med.Chem.,9,414(1966)披露了1,2-双〔二苯基膦基〕乙烷的细胞毒素活性,此化合物通常用做起始物质来制备大多数药物组合物的活性成份和主题发明的治疗方法。
前面提到的参考资料没有一个披露或建议为药物组合物或目前发明的治疗方法。
在欧洲专利申请0151046(申请日期31.01.1985)Hill,Johoson和Mirabelli披露了应用〔a-未位-双(二取代膦基)-烃〕二金(Ⅰ),二金(Ⅲ),二银(Ⅰ)和二铜(Ⅰ)的衍生物来治疗肿瘤的抗肿瘤药物组合物和化合物。
在欧洲专利申请0164970(申请日期31.05.1985)中Berners-Price,Mirabelli,Johoson和Sadler进一步披露了药物组合物,这些组合物是含有〔双〔双(二苯基膦基)烃〕一,〔双〔双(二乙基膦基)烃〕一和双〔(二苯基膦基-二乙基膦基)烃〕,金(Ⅰ),银(Ⅰ)和铜(Ⅰ)络合物或三-〔双(二苯基膦基)乙烷〕二铜(Ⅰ)络合物。
可是,在这些参考资料中一些Ⅷ族金属络合物没有介绍或提出,它们会显示出细胞毒素或任何其它的药物活性。
不是所有组合物落在通式1中都是可以的。例如化合物〔Ni Cl(diphos)2〕+Cl-就不能合成。(见R.Morassi和A.Dei,Inorg.Chim.Acta,6,314(1972)〕。
进一步观察,由于对熟悉配位化学的人们众所周知的原因,一些结合物是不能存在的,例如当金属是钯(Ⅱ)并且阴离子是Cl-时,有一个4-配位并且X1和X2不能存在。当阴离子是Br-时,1X和1Y能存在(5-配位),当阴离子是I时,2X存在并Y不能存在(6-配位),当阴离子是Cl O- 4时X不能存在并且可有两个Y(4-配位)。然而,对于在这个技术领域熟悉的人来说可能性是明显的。
说明书
本发明尤其提供了式1化合物,其中
D1=D2=磷或D1=磷并且D2=胂;
A=(CH2)2或顺-CH=CH或(CH2)3;
X1=X2(如二者都存在的话)=囟基或硝酸基或X1+X2=过氧化基;
Y(如存在)=囟代物,硝酸盐,高氯酸盐,triflate或四囟代高铁酸盐(Ⅲ);
n=0,1或2,
M=Fe(Ⅱ),Fe(Ⅲ),Co(Ⅱ),Rh(Ⅰ),Rh(Ⅲ),Ir(Ⅰ),Ir(Ⅲ),Ni(Ⅱ)或Pd(Ⅱ);规定当M=Fe(Ⅱ)时,D1=D2=磷,A=顺-CH=CH,X1=X2=囟基并且n=0;进一步规定当M=Fe(Ⅲ)时,D1=D2=磷,A=顺-CH=CH,X1=X2=囟基并且Y=四囟代高铁酸盐(Ⅲ);进一步规定当M=Co(Ⅱ)时,D1=D2=磷或D1=磷并且D2=砷,A=(CH2)2或顺-CH=CH,X1=囟基或硝酸基,n=1并且Y=囟代物,硝酸盐,高氯酸盐或triflate或n=2并且Y=高氯酸盐或triflate;进一步规定当M=Rh(Ⅰ)或Ir(Ⅰ),D1=D2=磷,A=(CH2)2或顺-CH=CH,n=1且Y=氯化物,硝酸盐,高氯酸盐或triflate或X=溴或碘且n=0;进一步规定当M=Rh(Ⅲ)或Ir(Ⅲ)时,D1=D2=磷或D1=磷且D2=砷,A=(CH2)2或顺-CH=CH,X1=X2=囟基或X1+X2=过氧化基,n=1且Y=囟代物,硝酸盐,高氯酸盐或triflate;进一步规定当M=Ni(Ⅱ)时,D1=D2=磷或D1=磷且D2=砷,A=(CH2)2或顺-CH=CH,X1=溴基或碘基,n=1且Y=溴化物,碘化物,硝酸盐或triflate或n=2且Y=硝酸盐,高氯酸盐或triflatc;进一步规定当M=Pd(Ⅱ)时,D1=D2=磷或D1=磷且D2=砷,A=(CH2)2或顺-CH=CH,X1=X2=碘基且n=0,或X1=溴基,n=1且Y=溴化物,硝酸盐,高氯酸盐或triflate,n=2,Y=氯化物,硝酸盐,高氯酸盐,triflate。上面提到形式的活性化合物既是已知的也是对于熟悉这个领域的人来讲能通过容易实现的方法制备的。除非规定其它的,制备这些化合物必需的起始物的工业来源是易得的。1,2-双(二苯基膦基)乙烷定义为diphos,1-二苯膦基-2-二苯胂基乙烷为arphos且顺-1,2-双(二苯膦基)乙烯为dppen。制备铁(Ⅱ)络合物,2摩尔当量dppen和1摩尔当量左右铁(Ⅱ)囟代物在乙醇中将温度升到回流温度反应。铁(Ⅲ)络合物可通过将1摩尔当量deppn和1摩尔当量铁(Ⅲ)囟化物在乙醇和丙酮的混合物中在70℃下反应制备。
制取钴(Ⅱ)络合物,2摩尔当量的合适配合体和1摩尔当量的合适钴(Ⅱ)盐反应,选择提供期望的共价键合的无机基团X和阴离子(Y);反应在乙醇中回流温度下(X=Y=囟代物)或在丙酮中室温下(例如X=Y=硝酸盐且Y=二高氯酸盐)进行。
制备铑(Ⅰ)络合物,对于熟悉这个领域的人有几个方法可实现,例子通过首先从(顺,顺-1,5-环辛二烯)氯化铑(Ⅰ)二聚物,乙酰丙酮和氢氧化钾在乙醚中在-70℃至室温合成起始物(顺,顺-1,5-环辛二烯)铑(Ⅰ)乙酰醋酸盐;然后1摩尔当量此产物在四氢呋喃中沸腾温度下和1摩尔当量的70%高氯酸和2摩尔当量的合适的配位基(diphos或dppen)反应获得带有Y=高氯酸盐的络合物。带有Y=triflate的铑(Ⅰ)络合物通过1摩尔当量的(顺,顺-1,5-环辛二烯)氯化铑(Ⅰ)二聚物和2摩尔当量的银triflate在丙酮中,形成的氯化银除去后,再和2摩尔当量的合适配位基(diphos或dppen)反应制备。
获取铑(Ⅲ)和铱(Ⅲ)络合物,1摩尔当量的铑(Ⅲ)或铱(Ⅲ)囟代物在乙醇中回流温度下和2摩尔当量的合适配位基反应,这个反应提供了带有X1=X2=Y=囟代物的化合物,这些化合物可转变成带有X1=X2=囟基且Y=高氯酸盐的络合物是通过溶解它们在乙醇和水的混合物中,紧接用过量高氯酸钠处理。
铱(Ⅰ)络合物可通过熟悉这个领域的人们熟知的方法制备。例如在苯中回流温度下4摩尔当量的合适配位基(diphos或dppen)和1摩尔当量的(顺,顺-1,5-环辛二烯)氯化铱(Ⅰ)二聚物混合;这样获得带有Y=氯化物的化合物能转变成相似物,例如通过溶解它们在甲醇中然后用过量高氯酸钠沉淀能得到Y=高氯酸盐的化合物。
铱(Ⅰ)和铑(Ⅰ)络合物都可通过和空气一氧气在室温下二氯甲烷中反应转变成带有X1+X2=过氧化基的金属(Ⅲ)相似物。
制备镍(Ⅱ)络合物,2摩尔当量的适宜配位基和1摩尔当量适宜的镍(Ⅱ)盐反应;反应在乙醇和水的混合物中沸腾温度下(X=Y=囟基,而不是氯基或Y=二硝酸盐)或在丙酮中室温下(Y=二高氯酸盐)进行。
带有Y=二氯化物的钯(Ⅱ)络合物通过双-(乙腈)二氯化钯(Ⅱ)和1摩尔当量的合适配位基在苯中回流温度下反应,然后通过和类似当量的配位基在二甲基甲酰胺80℃下反应来制备。这个化合物能转变成相似物。例如通过溶解它在乙醇和水的混合物中,然后用过量稀高氯酸沉淀得到带有Y=高氯酸盐的化合物,还可通过溶解它在乙醇和水的混合物中,然后在室温下将此溶液加到水中含过量碘化钠的溶液中,得到带有X1+X2=碘化物的相似物。
此发明也涉及到药物组合物,其特征在于有效抑制肿瘤细胞生长量的活性成份和惰性剂,药物可接受的载体或稀释剂,其中所说的组合物通常用于抑制对活性成份敏感的动物肿瘤细胞生长,其中活性成份是上面提到形式的化合物。
体外细胞毒性
金属络合物细胞毒的活性是在体外用于B16-F10鼠黑色素瘤细胞和HCT-116人体结肠癌细胞来评价的。B16-F10细胞株是保持在含有Earle盐(Gibco)的Eagle最低必需培养基(MEM)里。培养基中有2毫摩尔L-谷氨酰胺,2.06毫摩尔丙酮酸钠,胰岛素(0.26单位/毫升),青霉素/链霉素(分别为100单位/毫升和100μg/毫升,MEM非必需氨基酸(0.6% Gibco)和10%胎牛血清(Hyclone)。Hc T-116细胞在Mc Co Y′s5 A培养基中生长(改进型,Gibco),培养基中有2毫摩尔L-谷氨酰胺,0.12毫摩尔L-丝氨酸,0.17毫摩尔天门冬酰胺,1.5毫摩尔丙酮酸钠,MEM必需氨基酸(0.625%,Gibco),MEM非必需氨基酸(0.67%,Gibco),含维生素MEM(0.6%,Gibco)胎牛血清(10%,Hyclone)和青霉素/链霉素(分别为100单位/毫升和100μg/毫升。两种细胞株都在37℃含5%CO2高湿度恒温箱中孵育。
对数增长的细胞通过适度的胰酶消化获取,每4000个细胞加到一个96个孔微量滴度板的每一个孔槽中。此板在37℃5% CO2孵箱中过夜,允许细胞附着到板上。然后细胞用金属络合物或氯氨铂处理并孵育72小时。将板颠倒并摇动移走培养基,药物和分离的细胞。加入10%福尔马林磷酸盐缓冲液,固定细胞10分钟。将固着剂移走,培养皿空气干燥,用0.0075%结晶紫染色15分钟,洗涤两次然后空气干燥,染料用0.2ml/摩尔浓度AcoH/EtoH(1∶1)溶解与光密度测定用一种Dynatech M R600微量滴度盘读数器。IC50根据吸收数据的线性回归分析计算。
几种化合物在体外细胞毒性的试验结果见表1。
抗鼠白血病活性
所有金属络合物都做了对P388鼠白血病的抗肿瘤活性试验。选择的化合物也做了L1210鼠白血病抗肿瘤活性试验和L1210鼠白血病细胞亚株对二氯二氨络铂(L1210∶DDP)的抗药性试验。20克重的CDF1小鼠腹膜内接种106个P388白血病细胞,L1210白血病或L1210∶DPP白血病的腹水细胞,此试验根据已用的试验系统。在整个试验方法中给药开始日是紧接着移植肿瘤。络合物以各种不同剂量腹膜内注射。
每一剂量组用4到6只小鼠,这些鼠当天用络合物仅治疗一次。每一实验均包括一组10只用盐水治疗的对照鼠。在每一实验中包括用二氯二氨铂治疗的阳性对照组。鼠在治疗前称重,然后5或6天再称重,它们平均重量的变化用于测量毒性。每天观察动物的死亡率30天为一实验周期。
抗肿瘤活性根据%T/C测定,T/C%是药物治疗组存活时间与盐水治疗组存活时间比乘100。带有P388白血病细胞用盐水治疗的小鼠存活时间中位数通常为9天。带有L1210和L1210/DDP白血病细胞存活时间为7天。一种络合物如果能产生≥125的T/C百分率,被认为具有活性。
表Ⅱ和Ⅱa最广泛概括了对鼠白血病抗肿瘤活性化合物的评价。对每一化合物列出的是获得的最大T/C%和产生这种效应的剂量。
抗B16黑素瘤活性
几种金属络合物对B16黑素瘤的抗肿瘤活性的附加评价。BOF小鼠,每组10只,腹膜内接种0.5ml 10%(W∶V)B16黑素瘤的桨糊。移植后一天开始用金属络合物腹膜内治疗,每天进行共持续九天。每一化合物试验4到5个剂量。每次实验包括盐水治疗对照组和二氯二氨铂治疗组。每天观察鼠的存活数,60天为一实验周期。盐水治疗对照组显示小鼠存活时间的中位数为20~26天。
药物治疗小鼠的存活时间中位数与对照相比较(%T/C)用作抗肿瘤活性的一种测量。如果一个络合物产生≥125%T/C,那么就认为它具有活性。
金属络合物的实验结果概括在表Ⅲ中,表Ⅲ列举的每一络合物取得的最大%T/C和产生此效应的剂量。
药物制备
为了体外细胞毒性的研究,药物依靠它们的溶解度溶解或悬浮在0.9%氯化钠溶液里。偶尔用5%葡萄糖水溶液或10%DMSO0.9%氯化钠溶液。制备用于体内治疗的化合物通过加少量Tween80,将化合物溶解或悬浮在水里。
实例
下面的实例描述了组合物中化合物的化学制备和本发明的方法且并不限制在极小的范围。所有的反应都是在干燥氮气中进行。1,2-双(二苯基膦基)乙烷定义为diphos,1-二苯膦基-2-二苯胂乙烷定义为arphos且顺1,2-双(二苯磷基)乙烯定义为dppen。
实例1
具有式8的双[顺-1,2-双(二苯膦基)乙烯]二氯化铁(Ⅱ)。
将30ml乙醇中热过滤(70℃)的无水氯化铁Ⅱ(0.2536g,2mmol)溶液加到在60ml乙醇里沸腾的dppen(1.584g,4mmol)溶液中,反应的悬浮液在沸腾温度搅拌1小时,冷却到室温后,产物滤出,用乙醇和乙醚洗涤,然后在50℃真空干燥。
产量:1.74g黄色固体(95.1%重量)
溶点:275°~278℃
分析(重量%):
理论值:C67.92 H4.79 Cl7.72
试验值:C68.00 H4.99 Cl7.71
实例2
具有式20的双[顺-1,2-双(二苯膦基)乙烯]二氯化铁(Ⅲ)四氯代高铁酸盐(Ⅲ)。
15ml氯化铁(Ⅲ)(0.4866g,3mmol)甲醇溶液在70℃加到含dppen(1.485g,3.75mmol)的15ml丙酮和15ml甲醇的混合物中。得到的绿色悬浮液在70℃搅拌1小时然后冷却到室温。放置过夜后,滤出产物,产物用甲醇、苯、乙醚洗涤,然后在50℃真空干燥。
产量:1.56g绿色固体(93.4%按重量计)
溶点:200°~202℃
分析(%按重量计):
理论值:C55.89 H3.94 Cl19.05
试验值:C56.79 H4.23 Cl18.85
实例3
具有式14的双[1,2-双(二苯膦基)乙烷]溴钴(Ⅱ)溴化物。
含溴化钴(Ⅱ)六水合物(1.2g,3.673mmol)的10ml甲醇溶液加到含diphos(3g,7.5376mmol)的50ml甲醇悬浮液中。得到黑棕绿色悬浮液在室温搅拌1小时,然后在沸腾温度下搅拌0.5小时。过滤几乎清澈的溶液然后蒸发。残渣用水合乙醇(1∶3)重结晶然后在60℃真空干燥。
产量:2.65g黑绿色固体(按重量计,71.6%)
溶点:120°~125℃
分析(按重量计%):
理论值(+2乙醇):C60.72 H5.42 Cl14.44
实验值:C60.89 H5.29 Cl14.17
实例4
具有式4的双[1,2-双(二苯膦基)乙烷]硝酸钴(Ⅱ)。
硝酸钴(Ⅱ)盐六水合物(0.518g,2mmol)的20ml丙酮溶液伴随搅拌滴加到含diphos(1.99g,5mmol)的40ml丙酮悬浮液中,费时15分钟。得到清亮的棕色溶液在室温搅拌1小时然后浓缩到20ml。加入大约100ml乙醚,过滤形成的棕色沉淀,然后用乙醚洗涤。产物用丙酮重结晶然后在60℃真空干燥。
产量:1.21g黑棕色固体(62.1%按重量计)
熔点:138°~140℃。
分析(按重量计%)
理论值:C63.16 H4.96 N2.83 O10.53
实验值:C63.42 H5.46 N2.56 O10.65
实例5
具有式16的双[1,2-双(二苯膦基)乙烷]钴(Ⅱ)二高氯酸盐。
钴(Ⅱ)高氯酸盐六水合物(1.5g,4.1mmol)的40ml丙酮溶液伴随搅拌滴加到含diphos(4.1g,10.3mmol)的80ml丙酮悬浮液中,费时15分钟。得到的黄色悬浮液在室温搅拌1.5小时。然后产物滤出,用丙酮洗涤产物然后在100℃真空干燥产物。
产量:4.25g黄色固体(按重量计98.4%)
熔点:235°~240℃。
分析(按重量计%)
理论值:C59.21 H4.56 Cl6.73
实验值:C59.31 H4.67 Cl6.56
实例6
具有式21的双-[1-二苯膦基-2-二苯砷乙烷]钴(Ⅱ)二高氯酸盐。
此名称产物的制备和例5命名的产物在方式上相似,原料为钴(Ⅱ)高氯酸盐六水合物(0.732g,2mmol)和arphos(1.77g,4mmol)。
产量:0.53g黄色固体(23.2%按重量计)
熔点:±225℃(分解)
分析(按重量计%)
理论值(+0.5水):C54.23 H4.29 Cl6.16
实验值:C54.19 H4.26 Cl6.13
实例7
具有式9的双[1,2-双(二苯膦基)乙烷]铑(Ⅰ)triflate。
15ml银(Ⅰ)triflate(1.02g,3.97mmol)的丙酮溶液伴随着搅拌滴加到(顺,顺-1,5-环辛二烯)氯化铑(Ⅰ)二聚物(0.9856g,2mmol)的10ml丙酮悬浮液中,费时10分钟,在暗处搅拌2小时后,滤出形成的氯化银(Ⅰ)然后用丙酮洗涤。然后diphos(3.58g,9mmol)的15ml丙酮液加到滤液中,然后在室温搅拌1小时,然后体积浓缩到15ml。滴加60ml乙醚,然后得到的悬浮液在+3℃贮存过夜。产物滤出,用乙醚洗涤,然后在真空干燥。
产量:3.96g黄色固体(95%按重量计)
熔点:225°~230℃
分析(按重量计%)
理论值:C60.69 H4.58 S3.06 F5.44 P11.83
实验值:C60.49 H4.73 S2.93 F5.31 P10.99
实例8
具有式10的双-[1,2-双(二苯膦基)乙烷]铑(Ⅰ)高氯酸盐。
3.35ml乙酰丙酮(3.255g,32.55mmol)加到(顺,顺-1,5-环辛二烯)氯化铑(Ⅰ)二聚物(8.2g,16.27mmol)的90ml乙醚悬浮液中,然后悬浮液冷却到-80℃,然后用30分钟伴随搅拌滴加19ml氢氧化钾(5.478g,97.65mmol)水溶液。不加冷却继续搅拌直到到达室温,接着在室温搅拌4小时。然后加入25ml水和200ml苯。得到的有机层产生8.4g黄色固体(83.3%,按重量计)=(顺,顺-1,5-环辛二烯)乙酰丙酮铑(Ⅰ)。
将上面制备(顺,顺-1,5-环辛二烯)乙酰丙酮铑(Ⅰ)(0.62g,2.02mmol)溶液和在15ml四氢呋喃中70%的高氯酸(0.287g,2mmol)加到含drphos(1.67g,4.2mmol)的10ml四氢呋喃中。得到的悬浮液在室温搅拌0.5小时然后在沸腾温度搅拌2小时。冷却后体积减少到10ml,在-20℃贮存过夜,然后产物滤出,用乙醚洗涤,用二氯甲烷/四氢呋喃重结晶然后在50℃真空干燥。
产量:1.68g桔黄色固体(84%按重量计)
熔点:282℃
分析(按重量计%)
理论值:C62.51 H4.81 Cl3.55 O6.41
实验值:C62.43 H4.83 Cl3.57 O6.22
实例9
具有式17的双-[1,2-双(二苯膦基)乙烷]二氯化铑(Ⅲ)。
将Diphos(3.016g,7.5756mmol)伴随搅拌分批加到氯化铑(Ⅲ)三水化合物(0.8g,3.0388mmol)的65ml乙醇沸腾溶液中。得到的棕色悬浮液在沸腾温度下搅拌3小时。然后几乎清亮的溶液用活性炭处理,然后热过滤;溶液体积减少到15ml,然后慢慢加入乙醚,然后冷却到+3℃得到产物。产物滤出,用乙醚洗涤,然后产物在真空中干燥。
产量:1.37g黄色固体(44.9%按重量计)
熔点:265°~270℃
分析(按重量计%)
理论值:(+3乙醇):C60.88 H5.77 Cl9.30 O4.20
实验值:C60.64 H5.68 Cl9.06 O3.68
实例10
具有式15的双-[1,2-双(二苯膦基)乙烷]二氯化铑(Ⅲ)高氯酸盐。
高氯酸钠-水合物(1.07g,7.597mmol)溶在5ml水中伴随搅拌滴加到例9命名产物(1.527g,1.519mmol)的沸腾溶液中,费时10分钟,例9命名的产物溶在50ml乙醇和25ml水的混合物中。得到的悬浮液在+5℃过夜保存;然后产物滤出,用乙醇和水洗涤,用二氯甲烷/四氢呋喃重结晶,在90℃真空中干燥。
产量:1.0g黄色固体(61.7%按重量计)
理论值:C58.36 H4.49 Cl9.95
实验值:C58.15 H5.13 Cl9.75
实例11
具有式23的双[1-二苯膦基-2-二苯胂]二氯化铑(Ⅲ)。
此命名的产物与例9中命名的产物制备方法相似,只是必需在沸腾温度搅拌15小时。原料为arphos(3.32g,7.5mmol)和氯化铑(Ⅲ)triflate(0.79g,3.0mmol)。
产率:2.7g黄色固体(82.3%按重量计算)
熔点:265°~270℃(分解)
分析(按重量计%)
理论值:(+1.5水):C55.71 H4.59 Cl9.49
实验值:C55.67 H4.54 Cl9.04
实例12
具有式18的双-[1-二苯膦基-2-二苯胂乙烷]二氯化铑(Ⅲ)高氯酸盐。
溶在5ml水中的高氯酸钠-水合物(0.7g,5mmol)伴随搅拌滴加到实例11命名产物(1.0g,0.914mmol)的沸腾溶液中,费时10分钟,例11的命名产物溶在100ml乙醇中。得到的悬浮液在+5℃保存过夜;然后滤出产物,用水完全洗涤,然后用乙醇和乙醚洗,然后在真空干燥。
产量:0.72g暗黄色固体(67.9%按重量计)
熔点:>310℃(分解)
分析(按重量计%)
理论值(+1水):C53.11 H4.29 Cl9.04 O6.80
实验值:C52.90 H4.42 Cl8.57 O6.42
实例13
具有式13的双-[1,2-双(二苯膦基)乙烷]高氯酸铱(Ⅰ)。
Diphos(1.26g,3.16mmol)加到溶在10ml苯中的(顺,顺-1,5-环辛二烯)氯化铱(Ⅰ)二聚物(0.506g,0.754mmol)的溶液中。得到的悬浮液在沸腾温度搅拌3小时。冷却到室温后,悬浮液在+60℃保存过夜。然后滤出桔色固体,用苯洗涤,然后溶解在30ml乙醇中。加入高氯酸钠,水合物(0.96g,6.838mmol),得到的悬浮液在室温搅拌3小时然后在-20℃保存过夜。滤出产物,用乙醇和水洗涤,用二氯甲烷/乙醚重结晶,然后在100℃真空干燥。
产量:1.12g桔色固体(68.7%按重量计)
熔点:215°~220℃
分析(按重量计%)
理论值:C57.37 H4.41 Cl3.26 O5.88
实验值:C57.50 H4.73 Cl3.28 O6.09
实例14
具有式22的双-[1,2-双(二苯膦基)乙烷]过氧化基高氯酸铱(Ⅲ)。
溶在25ml二氯甲烷中例13命名的产物溶液(2.44g,2.2468mmol)在空气中巨烈搅拌1小时,然后加入75ml乙醇,然后得到的溶液缓慢蒸发到10ml,滤出沉淀的产物,用乙醇洗涤,在80℃真空干燥。
产量:1.9g浅-桔色固体(75.7%按重量计)
熔点:230°~235℃(分解)
分析(按重量计%)
理论值:C55.73 H4.29 Cl3.17 O8.57 P11.83
实验值:C55.79 H4.26 Cl3.16 O8.84 P10.97
实例15
具有式5的双[1,2-双(二苯膦基)乙烷]镍(Ⅱ)二硝酸盐。
将Diphos(4.0g,10.05mmol)加到硝酸镍(Ⅱ)六水合物(1.45g,4.99mmol)溶液中,硝酸镍(Ⅱ)六水合物溶在50ml乙醇中。得到的悬浮液在室温搅拌1小时,接着在沸腾温度搅拌0.5小时。然后将水加到沸腾的悬浮液直到大多数固体溶解,然后溶液热过滤,再后冷却到-20℃。滤出沉淀的产物,然后用乙醚洗涤,用水合乙醇重结晶两次,在90℃真空干燥。
产量:1.0g桔色固体(20.5%按重量计)
熔点:217°~230℃
分析(按重量计%)
理论值:C63.76 H4.91 N2.91
实验值:C63.33 H5.03 N2.79
实例16
具有式19的双-[1,2-双(二苯膦基)乙烷]高氯酸镍(Ⅱ)。
将溶在20ml丙酮中的高氯酸镍(Ⅱ)六水合物(0.731g,2mmol)溶液伴随搅拌滴加到溶在40ml丙酮中的diphos(1.633g,4.1mmol)悬浮液中,费时30分钟。得到的悬浮液在室温搅拌3.5小时。然后滤出产物,用丙酮洗涤产物,然后在真空干燥产物。
产量:1.87g黄色固体(88.6%按重量计)
熔点:248℃
分析结果(重量百分比)
理论值:C59.23 H4.59 Cl6.73
实验值:C59.22 H4.74 Cl6.47
实例17
具有式2的双[1,2-双(二苯膦基)乙烷]二氯化钯(Ⅱ)。
溶在25ml苯中的diphos(1.83g,4.6mmol)和双(乙腈)二氯化钯(Ⅱ)(1.17g,4.51mmol)的悬浮液在沸腾温度搅拌3小时。冷却后,蒸发悬浮液,然后残渣用二甲基甲酰胺;乙醚重结晶。然后将重结晶产物在80℃溶在二甲基甲酰胺。然后加入diphos(1.63g,4.095mmol)。将此混合物在室温搅拌1小时后,加入乙醚,然后滤出沉淀,用乙醚洗涤,然后用二甲基甲酰胺重结晶。
产量:2.06g白色固体(47%重量百分比)
熔点:283°~300℃
分析结果(重量百分比)
理论值:C64.06 H4.96 Cl7.27
实验值:C63.7 H5.0 Cl6.91
实例18
具有式11的双[1,2-双(二苯膦基)乙烷]二碘化钯(Ⅱ)。
溶在25ml乙醇和5ml水混合物中的例17中命名的产物(1.46g,1.5mmol)溶液伴随搅拌滴加到溶在20ml水中的碘化钠(7.495g,50mmol)溶液中,费时10分钟。得到悬浮液在室温搅拌1小时,然后滤出产物,用水洗涤,然后在300ml水∶乙醇(1∶1)中沸腾0.5小时;冷却后,悬浮液在+3℃保存过夜;滤出产物,用水、乙醇和乙醚洗涤,在100℃真空干燥。
产量:1.22g浅黄色固体(70.5%按重量计)
熔点:281.5°~284.5℃
分析结果(重量%)
理论值:C53.97 H4.15 I21.95
实验值:C53.32 H4.21 I21.29
实例19
具有式12的双[1,2-双(二苯膦基)乙烷]二高氯酸钯(Ⅱ)。
将溶在25ml水中的高氯酸(1.44g,10mmol)溶液伴随搅拌滴加到溶在20ml乙醇和5ml水混合物中例17中命名的产物(0.97g,1mmol)溶液中,费时10分钟。得到的悬浮液在室温搅拌2小时。然后滤出产物,用水洗涤,在100℃真空干燥。
产量:0.83g白黄色固体(75重量%)
熔点:328°~333℃(分解)
分析结果(重量%)
理论值(+1水):C55.75 H4.47 Cl6.33
实验值:C55.5 H4.7 Cl6.3
实例20
具有式3的双[1,2-双(二苯膦基)乙烷]二硝酸钯(Ⅱ)。
溶在5ml水中的硝酸钾(1.26g,2.59mmol)溶液伴随搅拌滴加到溶在50ml温水中例17命名产物的(1.26g,2.59mmol)的溶液中,时间大约2分钟。得到的悬浮液在室温搅拌2小时。然后滤出产物,用水洗涤,在100℃真空干燥。
产量:0.75g白色固体(59.5重量%)
熔点:270°~280℃(分解)
分析结果(重量%)
理论值:C60.80 H4.68 N2.73 O9.35
实验值:C60.56 H4.57 N2.47 O9.11
实例21
具有式7的双[1,2-双(二苯膦基)乙烷]溴化钯(Ⅱ)。
Diphos(2.0g,5.025mmol)和溶在50ml乙醇的氯化钯(Ⅱ)(0.455g,2.566mmol)在回流下沸腾10分钟。然后得到的溶液冷却,然后用15分钟伴随搅拌滴加过量水合的溴化钠。得到的悬浮液在室温搅拌1小时,然后滤出产物,用水洗涤产物,然后用水合乙醇重结晶,在真空干燥产物。
产量:1.30g非常浅黄色固体(48.2重量%)
熔点:大约240℃(分解)
分析结果(重量%)
理论值:C58.26 H4.61 Br14.91
实验值:C58.32 H4.75 Br14.61
实例22
具有式6的双[顺-1,2-双[二苯膦基)乙烷]二氯化钯(Ⅱ)。
Dppen(1.584g,4mmol)和溶在50ml乙醇的氯化钯(Ⅱ)(0.3546g,2mmol)在回流下沸腾0.5小时,得到的几乎清亮的溶液过夜,然后将溶液体积减少到15ml。此溶液在-20℃保存过夜,然后滤出结晶的产物,用乙醇和乙醚洗涤产物,在90℃真空干燥产物。
产量:0.65g奶油色固体(33.7重量%)
熔点:>320℃(分解)
分析结果(重量%)
理论值(+2水):C62.07 H4.78 Cl7.05
实验值:C62.43 H4.73 Cl7.05
实例23
进行体外细胞毒性研究的化合物根据它们的溶解度溶解或悬浮在0.9%氯化钠溶液中。有时用5%葡萄糖水溶液或10%DMSO0.9%氯化钠溶液。用于体内治疗的化合物通过加入少量Tween80溶解或悬浮在水中制备。
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NL8502929 | 1985-10-25 | ||
NL8502929A NL8502929A (nl) | 1985-10-25 | 1985-10-25 | Groep viii-overgangsmetaal-complexen, werkwijze voor het bereiden daarvan, werkwijze voor het bereiden van een geneesmiddel met toepassing van een dergelijke groep viii-overgangsmetaal-complex voor de behandeling van kanker, alsmede aldus verkregen gevormd geneesmiddel. |
CN198686107219A CN86107219A (zh) | 1985-10-25 | 1986-10-25 | 药物活性的膦基-烃基ⅷ族金属络合物,含有这些络合物的抗肿瘤组合物和制备这些络合物或抗肿瘤组合物的方法 |
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CN91101598A Pending CN1057962A (zh) | 1985-10-25 | 1991-03-16 | 制备含膦基-烃基viii族金属络合物的抗肿瘤组合物的方法 |
CN92104058A Pending CN1067430A (zh) | 1985-10-25 | 1992-05-28 | 制备膦基-烃基ⅷ族金属络合物及含有这些络合物的抗肿瘤组合物方法 |
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CN91101598A Pending CN1057962A (zh) | 1985-10-25 | 1991-03-16 | 制备含膦基-烃基viii族金属络合物的抗肿瘤组合物的方法 |
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Also Published As
Publication number | Publication date |
---|---|
EP0227127B1 (en) | 1991-05-02 |
EP0227127A3 (en) | 1988-09-07 |
ZA868162B (en) | 1987-06-24 |
AU601954B2 (en) | 1990-09-27 |
ES2039199T3 (es) | 1993-09-16 |
JPS62161795A (ja) | 1987-07-17 |
PT83612B (pt) | 1989-05-31 |
CN1057962A (zh) | 1992-01-22 |
ATE63122T1 (de) | 1991-05-15 |
NO172585B (no) | 1993-05-03 |
US4831170A (en) | 1989-05-16 |
FI85861B (fi) | 1992-02-28 |
NZ218072A (en) | 1990-12-21 |
EP0227127A2 (en) | 1987-07-01 |
NL8502929A (nl) | 1987-05-18 |
KR870003787A (ko) | 1987-05-04 |
NO864270L (no) | 1987-04-27 |
FI864327A0 (fi) | 1986-10-24 |
IL80416A0 (en) | 1987-01-30 |
FI864327A (fi) | 1987-04-26 |
CA1269395A (en) | 1990-05-22 |
YU45802B (sh) | 1992-07-20 |
YU181786A (en) | 1988-02-29 |
HUT44263A (en) | 1988-02-29 |
HU203557B (en) | 1991-08-28 |
HU903471D0 (en) | 1990-12-28 |
DE3679045D1 (de) | 1991-06-06 |
HU200609B (en) | 1990-07-28 |
DK511786D0 (da) | 1986-10-24 |
GR3001910T3 (en) | 1992-11-23 |
DK511786A (da) | 1987-04-26 |
AU6441386A (en) | 1987-05-21 |
FI85861C (fi) | 1992-06-10 |
PT83612A (en) | 1986-11-01 |
NO864270D0 (no) | 1986-10-24 |
CN86107219A (zh) | 1987-05-27 |
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