CN1195766C - 热敏的环三磷腈-铂复合共轭物,其制备方法以及含有该共轭物的抗癌剂 - Google Patents
热敏的环三磷腈-铂复合共轭物,其制备方法以及含有该共轭物的抗癌剂 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/65812—Cyclic phosphazenes [P=N-]n, n>=3
- C07F9/65815—Cyclic phosphazenes [P=N-]n, n>=3 n = 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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Abstract
本发明提供了一种由式(1)代表的、新的热敏环三磷腈-铂复合共轭物,其中m(选自整数2,7,或12)为聚(烷氧基乙二醇)重复单元;n(选自0至3的整数)表示烷基链的长度;x表示阴离子氨基酸残基的长度,其选自整数0(氨基丙二酸衍生物)、1(天冬氨酸衍生物)和2(谷氨酸衍生物);A2为二配位螯合二胺,其选自2,2-二甲基-1,3-丙二胺(dmpda),反式(±)-1,2-二氨基环己烷(dach)和1,1-二氨基甲基环己烷(dmach)。
Description
发明领域
本发明涉及一种可以全身或局部施用且具有极好的抗癌活性的热敏环三磷腈-铂复合共轭物,其制备方法以及含有该共轭物作为活性组分的抗癌剂。更特别地,本发明的该化合物为一种在包括体温的温度范围内显示热敏性的可生物降解的环三磷腈-铂复合共轭物。
发明背景
本发明人发现通过六氯环三磷腈((NPCl2)3)的氯原子与低或高分子量的亲水性聚(烷氧基乙二醇)和疏水性氨基酸酯亲核取代得到的衍生物可显示出热敏性(韩国专利申请No.99-48800)。本发明人通过向这些三聚衍生物的水解氨基酸基团引入(二胺)铂(II)离子,成功地制备了它们的铂复合物。使我们惊奇的是这些新的三聚铂复合共轭物还在包括体温在内的宽温度范围显示出热敏性,并且显示出高的抗癌活性。这些新的热敏铂复合共轭抗癌剂所显示出的控制释放性质还从来没有报道过。由于利用它们的热敏性可实现靶药物传送,这些化合物可以全身或局部施用。因此,我们期待这些新的化合物将在治疗实体肿瘤中提供一种新的且显著改进的治疗方式。
在本发明中热敏聚合物指的是可在低温下溶于水,但在高于某一临界温度时由于它们的水溶性快速降低而沉淀的那些聚合物。当这种相变可逆时,称相转变温度为下限临界溶解温度(LCST)或浊点。低于LCST时,聚合物-水分子之间的氢键作用强于聚合物-聚合物分子之间的疏水性相互作用。然而,当温度增加时,聚合物-水分子之间的氢键作用变弱,而聚合物-聚合物分子之间的疏水性相互作用提高,导致聚合物在水溶液中沉淀下来。
这些热敏聚合物在许多领域中已被广泛研究,其中所述领域主要包括药物递送系统、医学生物材料、薄膜、生物化学反应分离过程、化妆品和光学系统。然而,大多数常规的热敏有机聚合物公知为水解不可降解的。近年来,已报道了一些可生物降解的聚合物(Jeong,B.等人,自然(Nature),388,860(1997);Song,S.-C.等人,大分子(Macromolecules),32,2188(1999);Lee,S.B.等人,大分子,32,7820(1999))。然而直至今日,没有任何热敏的抗癌药物被报道。顺铂为一种铂复合物,其于1979年通过美国FDA批准作为抗癌剂,已被用作最有效的化疗剂之一,用来治疗多种癌症,例如睾丸癌、卵巢癌、膀胱癌和头颈癌。然而由于其高毒性(LD50=13mg/Kg,M.J.Cleare,生物化学(Biochimie)60,835(1978)),使其使用受到限制。尽管第二代抗癌剂卡铂显示比顺铂低得多的毒性(LD50=180mg/Kg,M.J.Cleare,生物化学60,835(1978)),但由于它的抗癌活性低于顺铂,且价格比顺铂昂贵而未被广泛使用。因此,迫切需要开发与顺铂相比具有较高和较广泛抗癌活性和较低毒性的第三代抗癌剂。
发明概述
因此,本发明的一个目的在于开发第三代抗癌剂,其与常规使用的顺铂相比,具有较高的抗癌活性和较低的毒性。
为实现此目的,本发明人发现了一类新的环三磷腈-铂复合共轭抗癌剂,通过向可生物降解的环三磷腈中引入增溶剂和铂复合物,根据所需目的,可对其LCST进行可变地设计,并可精确地控制LCST。本发明的这些新的环三磷腈-铂复合共轭抗癌剂可以利用药物的热敏性质全身或局部施用。
更特别地,本发明的目的是提供低聚的热敏环三磷腈-铂复合共轭物,以及它们的制备方法。其中所述热敏环三磷腈-铂复合共轭物具有立体专一的化学结构和LCST(可为了所需目的而设计),是通过六氯环三磷腈中的氯原子与聚(烷氧基乙二醇)和氨基酸酯亲核取代,而后水解被取代的氨基酸酯,接下来与(二胺)铂盐反应而制备的。
本发明的另一个目的是提供以热敏环三磷腈-铂复合共轭物作为活性组分的抗癌剂。
发明详述
为实现上述目的,本发明人进行了以下实验。首先将六氯环三磷腈与具有不同分子量的亲水性聚(烷氧基乙二醇)反应,而后与各种疏水性氨基酸酯反应,得到一类具有热敏性质的新的环三磷腈衍生物。用碱水解三聚物中被取代的氨基酸酯,而后与(二胺)铂(II)盐反应,得到由氨基酸的羧基和铂(II)阳离子之间通过共价键形成的环三磷腈-铂复合共轭物。我们意外地发现这些三聚铂共轭物在宽的温度范围内显示出热敏性。此外,我们发现由于这些环三磷腈-铂复合物的LCST易于通过对不同的聚(烷氧基乙二醇),氨基酸和铂衍生物的适当选择而改变,因此为了所需的应用目的,可以设计并控制环三磷腈-铂复合共轭物的LCST。
本发明之式1所代表的新的立体专一的环三磷腈-铂复合共轭物的制备方法详述如下。
式1
其中,m选自整数2,7和12;n选自整数0,1,2和3;x选自整数0,1和2;且A2为二配位螯合二胺,其选自2,2-二甲基-1,3-丙二胺(dmpda),反式(±)-1,2-二氨基环己烷(dach)和1,1-二氨基甲基环己烷(dmach)。
在上述中,选自整数2,7,或12的m为聚(烷氧基乙二醇)重复单元,选自0至3的整数的n表示烷基链的长度,选自0至2的整数的x表示阴离子氨基酸残基的长度。
式2代表的三聚氨基酸酯衍生物是通过首先将六氯环三磷腈与亲水的聚(烷氧基乙二醇)反应,而后与一系列疏水性氨基酸酯反应而制备的。将式2的三聚衍生物与3摩尔式3的碱土金属氢氧化物或6摩尔的式4的碱金属氢氧化物在甲醇或乙醇中反应3~5小时,分别得到式5的环三磷腈-碱土金属盐或式6的环三磷腈-碱金属盐中间体。将3摩尔式7的(二胺)硫酸铂或硝酸铂与此中间体在蒸馏水中于1~5℃下反应3~7小时,而后冷冻干燥反应混合物。
式2
式3
M(OH)2
式4
M’OH
式5
式6
式7
A2PtL2
在式2-7中,m,n,x和A的定义同式1中的定义;R选自甲基,乙基或苄基;M为碱土金属离子(例如钡或钙);M’为碱金属离子(例如锂离子、钠离子或钾离子);且L2选自硫酸根离子或硝酸根离子。
式7的(二胺)铂盐的水溶液是按照文献中的方法(R.C.Harrison,无机化学学报(Inorg.Chimica Acta)46,L15(1980))通过(二胺)碘化铂与银的酸式盐反应制备的。
在搅拌下向上述冷冻干燥产物中加入醇,而后将溶液混合物离心。分离出上清液并通过减压蒸发浓缩后,向其中加入过量的醚或己烷以沉淀最终产物。使用醇/醚或己烷的溶剂对重复该沉淀过程2~3次,并将最终沉淀真空干燥。为了去除最终产品中的少量其它异构体,可根据三聚衍生物之异构体的LCST,向产物的水溶液中加入适当的降低LCST的化合物(NaCl,KCl,CF3CH2OH或CH3(CH2)3OH)以诱导较纯产物的沉淀。通过离心去除上层水相,得到纯化的沉淀。重复该纯化过程2~3次,而后冷冻干燥最终溶液,以得到式1的热敏环三磷腈-铂复合共轭物。
本发明的制备方法可由以下的反应路线1进行图解表示:
反应路线1
以下实施例将对本发明进行更详细地说明,但是本发明不局限于所给出的实施例。
本发明化合物中的碳,氢,氮的元素分析是在KIST的专门分析中心使用碳,氢和氮分析仪(Perkin Elmer)进行的,并且使用Polyscan 61E ICP进行磷和铂的分析。氢和磷核磁共振波谱是用Varian Gemini-300得到的,且LCST是通过使用Perkin-Elmer Lamda 18 UV/VIS分光光度计测定的。
实施例
实施例1
{NP[(OCH2CH2)2OCH3][L-Asp·Pt(dmpda)]3的制备
将{NP[(OCH2CH2)2OCH3][NHCH(CH2COOC2H5)COOC2H5]}3(1.00g,0.95mmol)溶于甲醇(50ml)后,用冰水浴将反应容器的温度控制在0~5℃。在搅拌下向此溶液中缓慢加入含有过量Ba(OH)2·8H2O(1.19g,3.78mmol)的甲醇溶液。30分钟后去除冰水浴,而后继续反应3小时。减压浓缩反应混合物直至仅有很少量的溶剂残余。向浓缩的反应混合物中加入过量的醚或己烷,以引起水解产物的沉淀。将如此得到的沉淀重新溶于少量甲醇,然后通过加入过量的醚或己烷再沉淀。沉淀过程重复2-3次后,真空干燥最终的沉淀,得到0.99g环三磷腈钡盐(产率,93%)。将此三聚钡盐(0.99g,0.87mmol)溶于20毫升蒸馏水,并用冰-水浴将反应容器的温度控制在1~5℃。向此溶液中于30分钟内滴加加入将(dmpda)PtSO4(0.87g,2.62mmol)溶解在蒸馏水中制备的水溶液。将反应混合物反应3小时而后冷冻干燥。向干燥的混合物中加入过量的甲醇或乙醇,然后搅拌以提取环磷腈-铂复合共轭物。为增加最终的共轭产物之纯度,可重复纯化过程2~3次,其中所述纯化过程包括将共轭产物溶于少量甲醇或乙醇中,然后通过加入过量醚或己烷而沉淀。真空干燥最终的沉淀以得到最终产物(1.25g,产率,81.0%)。
分子式:C42H87N12O21P3Pt3
元素分析(%):C,27.59;H,4.80;N,9.55;P,5.15;Pt,31.56
理论值:C,28.43;H,4.94;N,9.47;P,5.24;Pt,32.98
质子核磁共振波谱(D2O,ppm):
δ0.9-1.2(b,6H,H2NCH2C(CH3)2CH2NH2),
δ2.3-2.7(b,6H,H2NCH2C(CH3)2CH2NH2,-NHCH(CH2COO)COO),
δ3.4(s,3H,-O(CH2CH2O)2CH3),
δ3.6-3.9(b,6H,-OCH2CH2OCH2CH2OCH3),
δ4.1-4.4(b,3H,-OCH2CH2OCH2CH2OCH3,
-NHCH(CH2COO)COO),
磷核磁共振波谱(D2O,ppm):δ32-48
下限临界溶解温度:98.0℃。
实施例2
{NP[(OCH2CH2)2OCH3][L-Asp·Pt(dach)]}3的制备
使用{NP[(OCH2CH2)2OCH3][NHCH(CH2COOC2H5)COOC2H5]}3(0.73g,0.69mmol),Ba(OH)2·8H2O(0.87g,2.76mmol),环三磷腈-钡盐(0.69g,0.61mmol),和(dach)PtSO4(0.63g,1.83mmol),按照与实施例1相同的方法得到最终的共轭产物{NP[(OCH2CH2)2OCH3][L-Asp·Pt(dach)]}3(1.05g,产率95.5%)。
分子式:C45H87N12O21P3Pt3
元素分析(%):C,29.01;H,4.79;N,9.39;P,5.01;Pt,30.95
理论值:C,29.85;H,4.84;N,9.28;P,5.13;Pt,32.33
质子核磁共振波谱(D2O,ppm):
δ1.1-1.4(b,4H,
δ1.5.1.7(b,2H,
δ2.0-2.2(b,2H,
δ2.3-2.5(b,2H,
磷核磁共振波谱(D2O,ppm):δ34-44
下限临界溶解温度:92.0℃。
实施例3
{NP[(OCH2CH2)2OCH3][L-Asp·Pt(dmach)]}3的制备
使用{NP[(OCH2CH2)2OCH3][NHCH(CH2COOC2H5)COOC2H5]}3(0.82g,0.78mmol),Ba(OH)2·8H2O(0.87g,2.76mmol),环三磷腈-钡盐(0.74g,0.65mmol),和(dmach)PtSO4(0.72g,1.96mmol),按照与实施例1相同的方法得到最终的共轭产物,{NP[(OCH2CH2)2OCH3][L-Asp·Pt(dmach)]}3(0.97g,产率78.2%)。
分子式:C51H99N12O21P3Pt3
元素分析(%):C,30.22;H,5.15;N,8.80;P,4.82;Pt,29.05
理论值:C,32.33;H,5.27;N,8.87;P,4.90;Pt,30.89
质子核磁共振波谱(D2O,ppm):
δ1.3-1.6(b,10H,H2NCH2C(C5H10)CH2NH2),
δ2.4-2.8(b,6H,H2NCH2C(C5H10)CH2NH2,-NHCH(CH2COO)COO),
δ3.4(s,3H,-O(CH2CH2O)2CH3),
δ3.6-3.8(b,6H,-OCH2CH2OCH2CH2OCH3),
δ4.1-4.4(b,3H,-OCH2CH2OCH2CH2OCH3,
-NHCH(CH2COO)COO),
磷核磁共振波谱(D2O,ppm):δ34-44
下限临界溶解温度:74.5℃。
实施例4
{NP[(OCH2CH2)2OCH3][L-Glu·Pt(dach)]}3的制备
使用{NP[(OCH2CH2)2OCH3][NHCH((CH2)2COOC2H5)COOC2H5]}3(0.73g,0.69mmol),Ba(OH)2·8H2O(0.87g,2.76mmol),环三磷腈-钡盐(0.69g,0.61mmol),和(dach)PtSO4(0.63g,1.83mmol),按照与实施例1相同的方法得到最终的共轭产物,{NP[(OCH2CH2)2OCH3][L-Glu.Pt(dach)]}3(1.05g,产率95.5%)。
分子式:C48H93N12O21P3Pt3
元素分析(%):C,29.01;H,4.79;N,9.39;P,5.01;Pt,3.0.95
理论值:C,29.85;H.4.84;N,9.28;P,5.13;Pt,32.33
质子核磁共振波谱(D2O,ppm):
δ1.5-1.7(b,2H,
δ2.0-2.2(b,4H,
-NHCH(CH2CH2COO)COO),
δ2.3-2.5(b,4H,
-NHCH(CH2CH2COO)COO),
δ3.4(s,3H,-O(CH2CH2O)2CH3),
δ3.6-3.8(b,6H,-OCH2CH2OCH2CH2OCH3),
δ4.1-4.4(b,3H,-OCH2CH2OCH2CH2OCH3,-NHCH(CH2CH2COO)COO),
磷核磁共振波谱(D2O,ppm):δ34-44
下限临界溶解温度:82.0℃.
实施例5
{NP[(OCH2CH2)2OC2H5][L-Mal·Pt(dach)]}3的制备
{NP[(OCH2CH2)2OC2H5][NHCH(COOC2H5)COOC2H5]}3(0.50g,0.46mmol),Ba(OH)2·8H2O(0.58g,1.84mmol),环三磷腈-钡盐(0.41g,0.35mmol),和(dach)PtSO4(0.36g,1.56mmol),按照与实施例1相同的方法得到最终的共轭产物,{NP[(OCH2CH2)2OC2H5][L-Mal·Pt(dach)]}3(0.46g,产率73.0%)。
分子式:C45H87N12O21P3Pt3
元素分析(%):C,27.91;H,4.70;N,9.17;P,5.05;Pt,30.01
理论值:C,29.86;H,4.84;N,9.28;P,5.13;Pt,32.33
质子核磁共振波谱(D2O,ppm):
δ2.3-2.5(b,2H,
δ3.6-3.8(b,8H,-OCH2CH2OCH2CH2OCH2CH3),
δ4.1-4.4(b,3H,-OCH2CH2OCH2CH2OCH3,-NHCH(COO)COO),
磷核磁共振波谱(D2O,ppm):δ36-46
下限临界溶解温度:39.0℃.
实施例6
{NP[(OCH2CH2)2OC2H5][L-Asp·Pt(dmpda)]}3的制备
使用{NP[(OCH2CH2)2OC2H5][NHCH(CH2COOC2H5)COOC2H5]}3(0.80g,0.73mmol),Ba(OH)2·8H2O(0.69g,2.91mmol),环三磷腈-钡盐(0.64g,0.54mmol),和(dmpda)PtSO4(0.54g,1.63mmol),按照与实施例1相同的方法得到最终的共轭产物,{NP[(OCH2CH2)2OC2H5][L-Asp·Pt(dmpda)]}3(0.61g,产率64.0%)。
分子式:C45H93N12O21P3Pt3
元素分析(%):C,31.59;H,5.01;N,9.20;P,5.20;Pt,29.98
理论值:C,29.76;H,5.16;N,9.25;P,5.11;Pt,32.22
质子核磁共振波谱(D2O,ppm):
δ0.9-1.1(b,6H,H2NCH2C(CH3)2CH2NH2),
δ1.1-1.4(b,3H,-O(CH2CH2O)2CH3),
δ2.2-2.6(b,6H,H2NCH2C(CH3)2CH2NH2,-NHCH(CH2COO)COO),
δ3.5-3.9(b,8H,-OCH2CH2OCH2CH2OCH2CH3),
δ4.0-4.3(b,3H,-OCH2CH2OCH2CH2OCH3,
-NHCH(CH2COO)COO),
磷核磁共振波谱(D2O,ppm):δ34-46
下限临界溶解温度:46.5℃。
实施例7
{NP[(OCH2CH2)2OC2H5][L-Asp·Pt(dach)]}3的制备
使用{NP[(OCH2CH2)2OC2H5][NHCH(CH2COOC2H5)COOC2H5]}3(1.00g,0.91mmol),Ba(OH)2·8H2O(1.15g,3.64mmol),环三磷腈-钡盐(0.97g,0.82mmol),和(dach)PtSO4(0.85g,2.47mmol),按照与实施例1相同的方法得到最终的共轭产物,{NP[(OCH2CH2)2OC2H5][L-Asp·Pt(dach)]}3(1.25g,产率82.2%)。
分子式C48H93N12O21P3Pt3
元素分析(%):C,33.25;H,4.95;N,9.15;P,4.93;Pt,29.09
理论值:C,31.12;H,5.06;N,9.07;P,5.02;Pt,31.59
质子核磁共振波谱(D2O,ppm):
δ1.5-1.7(b.2H,
δ2.0-2.2(b,2H,
δ2.6-2.9(b,2H,-NHCH(CH2COO)COO),
δ3.6-3.9(b,8H,-OCH2CH2OCH2CH2OCH2CH3),
δ4.0-4.2(b,3H,-OCH2CH2OCH2CH2OCH3,-NHCH(CH2COO)COO),
磷核磁共振波谱(D2O):δ36-44
下限临界溶解温度:42.0℃.
实施例8
{NP[(OCH2CH2)2OC2H5][L-Asp·Pt(dmach)]}3的制备
使用{NP[(OCH2CH2)2OC2H5][NHCH(CH2COOC2H5)COOC2H5]}3(0.65)g,0.59mmol),Ba(OH)2·8H2O(0.75g,2.37mmol),环三磷腈-钡盐(0.59g,0.50mmol),和(dmach)PtSO4(0.55g,1.50mmol),按照与实施例1相同的方法得到最终的共轭产物,{NP[(OCH2CH2)2OC2H5][L-Asp·Pt(dmach)]}3(0.60g,产率62.5%。
分子式:C54H105N12O21P3Pt3
元素分析(%):C,30.01;H,5.22;N,8.58;P,4.69;Pt,28.99
理论值:C,33.49;H,5.47;N,8.68;P,4.79;Pt,30.22
质子核磁共振波谱(D2O,ppm):
δ1.2-1.3(b,3H,-OCH2CH2OCH2CH2O6CH2CH3),
δ1.3-1.6(b,10H,H2NCH2C(C5H10)CH2NH2),
δ2.5-2.9(b,6H,H2NCH2C(C5H10)CH2NH2,-NHCH(CH2COO)COO),
δ3.6-3.9(b,8H,-OCH2CH2OCH2CH2O6CH2CH3),
δ4.0-4.2(b,3H,-OCH2CH2OCH2CH2OCH2CH3,
-NHCH(CH2COO)COO),
磷核磁共振波谱(D2O,ppm):δ36-46
下限临界溶解温度:35.0℃。
实施例9
{NP[(OCH2CH2)2OC3H7][L-Asp·Pt(dach)]}3的制备
使用{NP[(OCH2CH2)2OC3H7][NHCH(CH2COOC2H5)COOC2H5]}3(0.55g,0.50mmol),Ba(OH)2·8H2O(0.63g,2.00mmol),环三磷腈-钡盐(0.45g,0.37mmol),和(dach)PtSO4(0.38g,1.12mmol),按照与实施例1相同的方法得到最终的共轭产物{NP[(OCH2CH2)2OC3H7][L-Asp·Pt(dach)]}3(0.36g,产率50.0%)。
分子式:C51H99N12O21P3Pt3
元素分析(%):C,31.01;H,5.30;N,8.89;P,4.85;Pt,28.91
理论值:C,33.49;H,5.47;N,8.68;P,4.79;Pt,30.22
质子核磁共振波谱(D2O,ppm):
δ0.9-1.1(b,3H,-O(CH2CH2O)2CH2CH2CH3),
δ2.0-2.2(b,2H,
δ3.3-3.9(b,8H,-OCH2CH2OCH2CH2OCH2CH2CH3),
δ4.0-4.3(b,3H,-OCH2CH2OCH2CH2OCH2CH2CH3,-NHCH(CH2COO)COO).
磷核磁共振波谱(D2O,ppm):δ33-46
下限临界溶解温度:22.0℃.
实施例10
{NP[(OCH2CH2)2OC4H9][L-Asp·Pt(dach)]}3的制备
使用{NP[(OCH2CH2)2OC4H9][NHCH(CH2COOC2H5)COOC2H5]}3(0.55g,0.50),Ba(OH)2·8H2O(0.63g,2.00mmol),环三磷腈-钡盐(0.45g,0.37mmol),和(dach)PtSO4(0.38g,1.12mmol),按照与实施例1相同的方法得到最终的共轭产物,{NP[(OCH2CH2)2OC4H9][L-Asp·Pt(dach)]}3(0.36g,产率50.0%)。
分子式:C54H105N12O21P3Pt3
元素分析(%):C,31.01;H,5.30;N,8.89;P,4.85;Pt,28.91
理论值:C,33.49;H,5.47;N,8.68;P,4.79;Pt,30.22
质子核磁共振波谱(D2O,ppm):
δ0.9-1.1(b,3H,-O(CH2CH2O)2CH2(CH2)2CH3),
δ1.1-1.5(b,8H,
-O(CH2CH2O)2CH2(CH2)2CH3)
δ1.5-1.7(b,2H,
δ2.0-2.2(b,2H,
δ3.3-3.9(b,8H,-OCH2CH2OCH2CH2OCH2(CH2)2CH3),
δ4.0-4.3(b,3H,-OCH2CH2OCH2CH2O(CH2)3CH3,-NHCH(CH2COO)COO),
磷核磁共振波谱(D2O,ppm):δ33-46
下限临界溶解温度:12.0℃.
实施例11
{NP[(OCH2CH2)2OCH3][L-Asp·Pt(dach)]}3的制备
使用{NP[(OCH2CH2)7OCH3][NHCH(CH2COOC2H5)COOC2H5]}3(0.72g,0.42mmol),Ba(OH)2·8H2O(0.52g,1.66mmol),环三磷腈-钡盐(0.55g,0.28mmol),和(dach)PtSO4(0.28g,0.83mmol),按照与实施例1相同的方法得到最终的共轭产物,{NP[(OCH2CH2)7OCH3][L-Asp·Pt(dach)]}3(0.60g,产率85.7%)。
分子式:C75H147N12O36P3Pt3
元素分析(%):C,33.45;H,5.75;N,6.68;P,3.65;Pt,21.25
理论值:C,36.03;H,5.93;N,6.72;P,3.72;Pt,23.41
质子核磁共振波谱(D2O,ppm):
δ2.0-2.2(b.2H,
δ2.6-2.9(b,2H,-NHCH(CH2COO)COO),
δ3.3-3.4(s,3H,-O(CH2CH2O)7CH3),
δ3.6-3.9(b,26H,-OCH2CH2O(CH2CH2O)8CH3),
磷核磁共振波谱(D2O,ppm):δ38-42
下限临界溶解温度:84.0℃.
实施例12
{NP[(OCH2CH2)12OCH3][L-Asp·Pt(dach)]}3的制备
使用{NP[(OCH2CH2)12OCH3][NHCH(CH2COOC2H5)COOC2H5]}3(0.67g,0.29mmol),Ba(OH)2·8H2O(0.36g,1.14mmol),环三磷腈-钡盐(0.68g,0.26mmol),和(dach)PtSO4(0.27g,0.79mmol),按照与实施例1相同的方法得到最终的共轭产物,{NP[(OCH2CH2)12OCH3][L-Asp·Pt(dach)]}3(0.66g,产率81.5%)。
分子式:C105H207N12O51P3Pt3
元素分析(%):C,38.75;H,6.85;N,5.35;P,2.89;Pt,19.05
理论值:C,40.68;H,6.73;N,5.42;P,2.99;Pt,18.88
质子核磁共振波谱(D2O,ppm):
δ1.1-1.5(b,4H,
δ1.5-1.7(b,2H,
δ2.0-2.2(b,2H,
δ2.6-2.9(b,2H,-NHCH(CH2COO)COO),
δ3.3-3.4(s,3H,-O(CH2CH2O)12CH3),
δ3.6-3.9(b,26H,-OCH2CH2O(CH2CH2O)11CH3),
δ4.0-4.2(b,3H,-OCH2CH2O(CH2CH2O)11CH3,-NHCH(CH2COO)COO),
磷核磁共振波谱(D2O,ppm):δ34-46
下限临界溶解温度:没有观测到(高于100℃.)
对本发明之环三磷腈-Pt共轭物的生物测定
按照本发明实施例所制备的复合物之抗癌活性是如下测定的。
1.体外活性的测定
(1)样品:实施例2,实施例6,实施例7和实施例11
(2)癌细胞系:小鼠白血病L1210细胞系
(3)实验方法:将L1210细胞于含10%FBS的RPMI 1640培养基中培养,将细胞浓度控制在1×105个细胞/毫升。向细胞中加入以对数剂量系列稀释的样品后,将细胞置于37℃、含5%CO2的培养箱中培养。
在24,48和72小时后用台盼蓝染料排斥试验测定活细胞数量。通过与对照组(其中没有进行化学处理)的细胞数量比较,计算每种化合物显示50%细胞生长抑制(ED50)的浓度。结果见表1。
2.体内(i.p.)活性的测定
(1)样品:实施例2,实施例6,实施例7和实施例11
(2)癌细胞系:小鼠白血病L1210细胞系
(3)实验方法:向BDF1小鼠(6-8周龄,每组8只小鼠)腹膜内注射来自DBA/2供体小鼠的白血病L1210细胞(1×105个细胞/0.1毫升)。根据样品的溶解性可将其溶于PBS溶液或悬浮在0.5%吐温80中。将这些样品溶液通过腹膜内注射,每天一次,连续施用5天,或在癌细胞植入后第1-5和9天时,以不同的剂量给药。每天观测小鼠,测定存活率。通过与对照组(其中没有进行化学处理)的平均存活时间比较,计算存活时间增加的平均百分率(T/C,%)以测定抗癌活性。结果见表1。
表1环三磷腈-Pt共轭物的生物测定结果
化合物 | 体外ED50(M) | 体内(i.p.) | |
剂量(mg kg-1) | T/C(%) | ||
实施例2 | 0.4 | 906030 | >511.0>293.8217.3 |
实施例6 | 6030 | 162.0146.1 | |
实施例7 | 0.4 | 806040 | >271.7226.7200.8 |
实施例11 | 0.2 | 906030 | 204.2229.2197.0 |
顺铂 | 0.7 | 4 | 163.0 |
卡铂 | 5.9 | 40 | 168.0 |
本发明的效果
根据本发明,提供了一类新的环三磷腈铂共轭物抗癌剂,其具有立体专一的化学结构和热敏性。本发明的环三磷腈-共轭物显示出热敏性,可根据所需目的而可变地设计并精确地控制其转变温度。根据本发明的热敏环三磷腈-铂共轭物抗癌剂可通过全身或局部施用治疗癌症。
Claims (9)
1.由式1所代表的环三磷腈-铂复合共轭物
式1
其中,m选自整数2,7和12;n选自整数0,1,2和3;x选自整数0,1和2;且A2为二配位螯合二胺,其选自2,2-二甲基-1,3-丙二胺,反式(±)-1,2-二氨基环己烷和1,1-二氨基甲基环己烷。
2.制备根据权利要求1的、由式1代表的环三磷腈-铂复合共轭物的方法,其包含以下步骤:
(1)通过式2的三聚氨基酸酯衍生物与式3的碱土金属氢氧化物或式4的碱金属氢氧化物的水解反应,分别得到式5的环三磷腈-碱土金属盐或式6的环三磷腈-碱金属盐中间体;
(2)将式5或6的环三磷腈金属盐中间体与式7的(二胺)铂(II)盐以摩尔比1∶3反应,得到权利要求1所述的式1的环三磷腈-铂复合共轭物,
式2
式3
M(OH)2
式4
M’OH
式5
式6
式7
A2PtL2
其中,m选自整数2,7和12;n选自整数0,1,2和3;x选自整数0,1和2;且A2为二配位螯合二胺,其选自2,2-二甲基-1,3-丙二胺,反式(±)-1,2-二氨基环己烷和1,1-二氨基甲基环己烷;R选自甲基,乙基和苄基;M为碱土金属离子;M’为碱金属离子;且L2为硫酸根或硝酸根阴离子。
3.根据权利要求2的方法,其中式3的碱土金属为钡或钙,式4的碱金属为锂、钠或钾,且式7的铂盐为(二胺)铂(II)硫酸盐或(二胺)铂(II)硝酸盐。
4.根据权利要求2或3的方法,其中不可溶副产物硫酸钡可通过离心或过滤除去,该副产物是由式5的环三磷腈-钡盐与式7的(二胺)铂(II)硫酸盐在水溶液中反应而产生的。
5.根据权利要求2或3的方法,其中副产物硫酸钠可通过透析除去,该副产物是由式6的环三磷腈-钠盐与式7的(二胺)铂(II)硫酸盐在水溶液中反应而产生。
6.根据权利要求2或3的方法,其中式5或6的环三磷腈-金属盐中间体是通过加入过量的乙醚或己烷而沉淀的,所述环三磷腈-金属盐中间体是通过将式2的环三磷腈衍生物与式3的碱土金属氢氧化物或式4的碱金属氢氧化物分别于甲醇中水解而产生的。
7.根据权利要求2或3的方法,其中在式5或6的环三磷腈-金属盐与式7的(二胺)铂(II)硫酸盐在水溶液中于1~5℃反应5~10小时并冷冻干燥后,以甲醇或乙醇作溶剂提取式1的环三磷腈-铂复合共轭物。
8.获得式1之纯的最终产物的方法,其为通过向权利要求7中得到的产物之甲醇或乙醇溶液中加入过量的乙醚或己烷进行的沉淀过程。
9.抗癌组合物,其包含权利要求1的环三磷腈-铂复合共轭物作为活性组分。
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2000
- 2000-08-21 KR KR1020000048360A patent/KR100363394B1/ko not_active IP Right Cessation
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2001
- 2001-01-10 JP JP2002521473A patent/JP3677269B2/ja not_active Expired - Fee Related
- 2001-01-10 WO PCT/KR2001/000033 patent/WO2002016376A1/en active IP Right Grant
- 2001-01-10 AU AU27130/01A patent/AU781233B2/en not_active Ceased
- 2001-01-10 CA CA002388334A patent/CA2388334C/en not_active Expired - Fee Related
- 2001-01-10 CN CNB018024688A patent/CN1195766C/zh not_active Expired - Fee Related
- 2001-01-10 EP EP01901579A patent/EP1311519A4/en not_active Withdrawn
- 2001-01-30 US US09/771,716 patent/US6333422B1/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
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CA2388334C (en) | 2006-06-20 |
CA2388334A1 (en) | 2002-02-28 |
JP3677269B2 (ja) | 2005-07-27 |
KR100363394B1 (ko) | 2002-12-05 |
EP1311519A1 (en) | 2003-05-21 |
AU2713001A (en) | 2002-03-04 |
JP2004506739A (ja) | 2004-03-04 |
WO2002016376A1 (en) | 2002-02-28 |
CN1388808A (zh) | 2003-01-01 |
KR20020015180A (ko) | 2002-02-27 |
AU781233B2 (en) | 2005-05-12 |
EP1311519A4 (en) | 2005-02-16 |
US6333422B1 (en) | 2001-12-25 |
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