CN103263675B - Poly (epsilon-caprolactone) supported anti-tumor prodrug and preparation method thereof - Google Patents

Poly (epsilon-caprolactone) supported anti-tumor prodrug and preparation method thereof Download PDF

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CN103263675B
CN103263675B CN201310179788.2A CN201310179788A CN103263675B CN 103263675 B CN103263675 B CN 103263675B CN 201310179788 A CN201310179788 A CN 201310179788A CN 103263675 B CN103263675 B CN 103263675B
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caprolactone
poly
ε
bromination
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CN103263675A (en
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张雪飞
麻戈军
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湘潭大学
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Abstract

本发明公开了一种聚ε-己内酯负载的抗肿瘤前药及其制备方法,制备方法是将α位溴代ε-己内酯通过开环聚合生成聚α位溴代ε-己内酯;再在聚α位溴代ε-己内酯的α位上发生硫代苹果酸的巯基–α位溴代酯的点击化学反应,得到含羧基侧基的聚ε-己内酯;得到的含羧基侧基的聚ε-己内酯与抗肿瘤药物分子发生取代反应后,用碱金属的强碱弱酸盐溶液中和,萃取出杂质,除杂质后的溶液经透析后,即得;本发明的抗肿瘤前药水溶解性好,可完全生物降解,载药量高,纯度高,含可进一步修饰基团;制备方法经济、高效和无毒,可以工业生产。 The present invention discloses a method for preparing prodrugs and antitumor one poly ε- caprolactone load, methods of preparation are cyclic polymerization of poly α-bromo-ε- caprolactone position the α position by the open-bromo-ε- caprolactone ester; click chemistry reaction -α-mercapto-ester bromination thiomalate recurrence at the α position poly α bromination ε- caprolactone, poly-ε- caprolactone to give a carboxyl-containing side groups; obtain poly-ε- caprolactone with antineoplastic molecule containing pendant carboxyl groups occurs after the substitution reaction, a strong base, weak acid salt with an alkali metal solution and extracted impurities, impurities other solution by dialysis, to obtain ; according to the present invention before anti-tumor medicine solubility, and can be completely biodegradable, high drug loading, high purity, containing groups may be further modified; preparation economical, efficient and non-toxic, industrial production can be.

Description

一种聚e-己内酯负载的抗肿瘤前药及其制备方法 The method of preparing a prodrug and anti-tumor load poly-caprolactone e-

技术领域 FIELD

[0001] 本发明涉及一种聚e -己内酯负载的抗肿瘤前药及其制备方法,属于抗肿瘤药物改性领域。 [0001] The present invention relates to a poly e - preparing prodrugs and antitumor caprolactone load, belonging to the field of antineoplastic modified.

背景技术 Background technique

[0002] 紫杉醇属于抗肿瘤药物,它已经被证明在乳腺癌、卵巢癌、非小细胞肺癌和前列腺癌有很好的临床效果。 [0002] Paclitaxel belongs antitumor agent, it has been demonstrated in breast, ovarian, non-small cell lung cancer and prostate cancer have a good clinical results. 紫杉醇的毒性是通过与细胞中的微管相互作用引起的,这种相互作用扰乱了癌细胞的有丝分裂从而导致癌细胞死亡。 Toxicity of paclitaxel by microtubules in cell interaction due to this interaction disrupting mitosis of the cancer cell thereby leading to cell death. 虽然紫杉醇是很好的抗癌剂,但是它们的超亲油性导致在水中的溶解性很差。 Although Taxol is a good anti-cancer agents, but their lead to super-lipophilic poorly soluble in water.

[0003] 为了克服紫杉醇在水中溶解性的问题,目前在临床上用的紫杉醇制剂是将紫杉醇溶于聚氧乙烯菌麻油与无水乙醇(50:50, v/v)的混合溶液中,浓度为7mmol/L。 [0003] In order to overcome water solubility problems of paclitaxel, paclitaxel is currently used clinically in the formulation of paclitaxel is dissolved in sesame oil, polyoxyethylene bacteria and ethanol (50:50, v / v) mixed solution, the concentration of It is 7mmol / L. 这种制剂的商标为Taxol®., This formulation is a trademark Taxol®.,

[0004] 虽然紫杉醇制剂Taxol®已得到了广泛的应用,但是仍存在不足: [0004] Although the formulation of paclitaxel Taxol® has been widely used, but there is still insufficient:

[0005] (1)聚氧乙烯蓖麻油不是惰性的,它能引起许多副反应,如过敏反应和神经毒性。 [0005] (1) polyoxyethylene castor oil are not inert, it can cause many side reactions, such as allergic reactions and neurotoxicity.

[0006] (2)注射药物前,常常需要加入皮质类固醇和抗组胺药,从而可能出现不良反应。 [0006] (2) before injection of the drug, it is often necessary to add corticosteroids and antihistamines, such adverse reactions can occur.

[0007] (3)2006年,Figg的研究表明:Taxol®中的聚氧乙烯菌麻油降低了药物的抗肿瘤疗效。 [0007] (3) In 2006, Figg studies show: polyoxyethylene bacteria in sesame oil Taxol® reduced the anti-tumor efficacy of the drug.

[0008] 为了克服Taxol®中的问题,人们提出了四种策略:⑴设计新的紫杉醇衍生物; (2)改变紫杉醇配方;(3)同其它抗肿瘤药物合用;(4)制备紫杉醇前药。 [0008] In order to overcome the problems of Taxol®, four strategies have been proposed: ⑴ design of new taxol derivatives; (2) changing the formulation of paclitaxel; (3) in combination with other antineoplastic agents; (4) Preparation of paclitaxel prodrug . 其中,前药是活性原药的生物可逆性衍生物,它常被用来克服原药的一些缺点,如低的水溶性,低的渗透性, 低的口服吸收,低的稳定性,毒性和非靶向性。 Wherein the prodrug is biologically active derivative reversible original drug, it is often used to overcome some of the disadvantages of the original drug, such as low water solubility, low permeability, low oral absorption, low stability, toxicity and non-targeted. 前药的术语也可以定义为:一种几乎没有活性的化学药品,但是它在体内吸收或分布后,能转化为原药而发挥药效。 The term prodrug may be defined as: an almost no chemical activity, but after absorption in vivo or distribution, can be converted to the original drug efficacy play.

[0009] 2001年到2002年期间,全世界得到批准的药物至少有14%是前药。 During the [0009] 2001 to 2002, the world of drugs have been approved by at least 14% is a prodrug. 这种趋势引起研究着对如药的研究,尤其是关于癌症药如药的研究,紫杉醇的衍生物是研究热点之一。 This trend is caused by the research study such as medicine, especially drugs such as research on cancer drugs, paclitaxel derivatives is one of the hotspots.

[0010] 从目前文献报道来看,紫杉醇前药主要分两类: [0010] From the current literature reports, paclitaxel prodrug two main categories:

[0011] 一类是小分子修饰的紫杉醇前药,被引入的小分子基团大部分是可电离的,包括铵盐、羧酸盐、磺酸盐和磷酸盐。 [0011] One is a modified small molecule prodrugs of paclitaxel, a small molecular group is introduced mostly ionizable, include ammonium salts, carboxylates, sulfonates and phosphates.

[0012] 另一类是水溶性聚合物紫杉醇前药,从而提高药物分子的水溶性、稳定性和生物利用度,改善药物分子的药代动力学,通过增强渗透和保留(EPR)效应被动靶向肿瘤组织。 [0012] Another class of water soluble prodrugs of paclitaxel polymer, water soluble drug molecules to improve stability and bioavailability, improved pharmacokinetics of the drug molecule, by enhancing passive target penetration and retention (EPR) effect the tumor tissue. 同时聚合物载体在药物释放以后,不会在体内长时间积累,可以排出体外或水解后被吸收。 While the polymer carrier after drug release, does not accumulate in the body for a long time, after the hydrolysis can be absorbed or excreted. 目前报道的这种水溶性聚合物有:聚乙二醇(PEG),N-(2-羟丙基)甲基丙烯酰胺,羧甲基环糊精,聚谷氨酸,树枝状聚合物。 Such water-soluble polymers currently reported are: polyethylene glycol (PEG), N- (2- hydroxypropyl) methacrylamide, carboxymethyl cyclodextrin, polyglutamate, dendrimers.

[0013] 目前对聚合物前药体系的研究成为当今新药开发的热点,由于聚合物对肿瘤组织独特的增强渗透和保留特性,设计聚合物前药能够有效地将原药输送至肿瘤部位,同时改善其水溶性,这些是以改善药物水溶性进行小分子修饰原药的方法所达不到的效果。 [0013] Current research on polymeric prodrug systems become a hot new drug development, due to the unique polymers enhance penetration and retention characteristics, design prodrugs of the polymer can be effectively delivered to the site of the original tumor drugs, while tumor tissues improve its water solubility, these are water-soluble small-molecule drugs to improve the modification of the original drug way beyond the reach of the effect. 另外, 聚合物前药相对于小分子修饰的原药来说,前者在相对低廉的价格下就可以制成前药。 Further, the polymer prodrugs modified small molecule with respect to the original drug, the former is at a relatively low price can be made prodrugs.

[0014] 聚合物修饰剂的选择是药物分子修饰的关键,脂肪族聚酯如聚乳酸(PLA),聚乳酸-羟基乙酸共聚物(PLGA)和聚e-己内酯(PCL)属于生物可降解聚合物。 [0014] The choice of polymer modifier key is modified drug molecule, aliphatic polyesters such as polylactic acid (PLA), polylactic acid - glycolic acid copolymer (PLGA) and poly-e- caprolactone (PCL) may belong to a biological degradation of the polymer. 由于其分子量可控制在相当宽的范围而受到重视。 Because of its molecular weight can be controlled in a relatively wide range and attention. 特别是在与PEG形成嵌段共聚物后,不仅具有生物可降解性,而且大大地改善了材料与人体的生物相容性,作为药物载体材料时,延长了药物在体内的循环时间,提高了药效,降低了免疫响应性,成为人们研究的热点。 Especially after the formation of the block copolymer and PEG, not only biodegradable but also greatly improving the biocompatibility of the material and the human body, as a drug carrier material, prolonged circulation time of drug in vivo, improved efficacy, reduced immune response, has become a hot research.

[0015] 中国专利CN1629150A公开的可生物降解的紫杉醇前药即聚乙二醇-脂肪族聚酯嵌段共聚物和紫杉醇键合而成。 [0015] Chinese patent CN1629150A disclosed a biodegradable paclitaxel prodrugs i.e. polyethylene glycol - aliphatic polyester block copolymer and paclitaxel bonded. 该前药具有两亲性,能够制成水基制剂,克服了现有紫杉醇制剂水溶性差和过敏反应严重等缺点。 The prodrug amphiphilic, water-based formulation can be made to overcome the conventional paclitaxel formulation of poorly water soluble and allergic reactions and serious drawbacks. 中国专利CN101543632A公开了一种以PEG为载体, 以羟基乙酸、L-乳酸或者他们的齐聚物为连接臂,与紫杉醇或多烯紫杉醇发生键合反应,得到了新型紫杉醇或多烯紫杉醇前药。 Chinese Patent CN101543632A discloses PEG as a carrier, glycolic acid, L- lactic acid or their oligomers that the connecting arm, bonding reaction occurs with paclitaxel or docetaxel, obtained new prodrugs of paclitaxel or docetaxel . 中国专利CN101618220A公开了一种基于甘油为支化单元的新型可降解树枝状大分子为载体的抗肿瘤前药及制备方法。 Chinese Patent CN101618220A discloses a novel glycerol-based biodegradable branched dendrimers as the carrier unit antitumor prodrugs and methods of preparation. 该新型可生物降解两亲性树枝状大分子是基于甘油及羟基乙酸齐聚物,乳酸齐聚物,羟基乙酸和乳酸的交替齐聚物,羟基乙酸、乳酸与氨基酸的交替齐聚物、以及它们的共聚齐聚物和PEG而构筑的。 The novel biodegradable amphiphilic dendrimers are based on glycerol and glycolic acid oligomer, oligomers of lactic acid, glycolic acid and lactic acid oligomers alternately, glycolic acid, lactic acid and oligomers alternately, and and their co-oligomers and PEG constructed. 所得树枝状聚合物在缩合剂存在下与抗肿瘤药物,进行键合反应,得到抗肿瘤药物的前药。 The resulting dendrimers in the presence of a condensing agent and anticancer drugs, a bonding reaction, to give the prodrug anticancer drugs. 中国发明专利CN1425706A和CN1711989A公开了聚乙二醇单甲醚-聚e -己内酯两亲性嵌段共聚物能够通过化学键合的方法,使一些难溶性的治疗剂如紫杉醇、阿霉素等进入到所形成的胶束中,形成胶束载药体系,进而实现对药物的控释。 Chinese invention patent CN1425706A and CN1711989A disclose a polyethylene glycol monomethyl ether - Poly e - caprolactone amphiphilic block copolymer can be chemically bonded by the process, so that some insoluble therapeutic agents such as paclitaxel, adriamycin, etc. into the formed micelles, micelle forming drug system, thus achieving controlled release of a drug. 上述修饰方法中,作为修饰剂的连接臂都是一些易于降解且对生物体无害的低分子量聚酯,但是由于PEG本身不具有生物降解性,另外只有分子量小于5000的PEG才能被细胞吞噬或是通过肾脏排出体外,并且一些聚乙二醇-脂肪族聚酯两亲性嵌段共聚物对药物分子的载药量也有限,同时也难以对其结构进行进一步修饰,限制了其应用。 In the above-described method for modification, the connecting arm as it is some of the modifying agent is susceptible to degradation and low molecular weight polyesters of the living body sound, but since the PEG itself is not biodegradable, the only other PEG molecular weight less than 5000 can be swallowed or cells It is discharged through the kidneys in vitro, and some of the polyethylene glycol - aliphatic polyester block copolymer amphiphilic drug loading of drug molecules is limited, but also it is difficult to further modify its structure, limiting its application.

[0016] 在现有的文献中,还未见环状酯单体的均聚物或共聚物作为主链,不使用PEG,而直接用小分子修饰制成水溶性聚合物前药的。 [0016] In the prior literature, no further cyclic ester monomer homopolymer or copolymer as a main chain, without using PEG, directly modified with a small molecule drug made of a water-soluble polymer precursor.

发明内容 SUMMARY

[0017] 本发明针对现有技术中抗肿瘤前药主要通过PEG- e -己内酯嵌段共聚物为载体, 存在载药性低,PEG无生物降解性,不能对分子进行进一步修饰的缺陷,目的之一是在于提供一种水溶解性好,可完全生物降解,载药量高,纯度高,含可修饰基团的聚e -己内酯负载的抗肿瘤前药。 [0017] The present invention is directed to the prior art anti-tumor drugs primarily through the front PEG- e - caprolactone block copolymer as a carrier, the carrier presence of low potency, PEG no biodegradability, can not be further modified molecular defects, one purpose is to provide a good solubility in water, can be completely biodegradable, high drug loading, high-purity, modified polyethylene-containing group e - caprolactone load antitumor prodrugs.

[0018] 本发明的另一个目的是在于还提供了一种经济、高效和无毒的制备上述聚e -己内酯负载的抗肿瘤前药的方法。 [0018] Another object of the present invention is to further provide an economical, efficient and non-toxic producing the above poly-e - Method of anti-tumor drugs caprolactone front load.

[0019] 本发明提供了一种聚e -己内酯负载的抗肿瘤前药,该抗肿瘤前药具有式1和/ 或式2结构: [0019] The present invention provides a poly-e - 2 structure antitumor prodrugs caprolactone load, before the antitumor agent having the formula 1 and / or formula:

[0020] [0020]

Figure CN103263675BD00051

[0023]式2 [0023] Formula 2

[0024] M为碱金属原子中一种或几种; [0024] M is an alkali metal atom of one or more;

[0025] D为抗肿瘤药物分子基团; [0025] D is a group antitumor agent molecules;

[0026] R选自Cp6的烷氧基中一种; [0026] R is selected from alkoxy of one Cp6;

[0027] X为1〜100, y为1〜100, z为3〜300,且z > x+y,x、y和z都为整数; [0027] X is 1~100, y is 1~100, z is 3~300, and z> x + y, x, y and z are integers;

[0028] n 为10 〜300。 [0028] n is 10 ~ 300.

[0029] 所述的抗肿瘤药物分子基团优选为紫杉醇基团、多烯紫杉醇基团、阿霉素基团或喜树碱基团中一种或几种。 [0029] The antitumor agent of the molecular group is preferably a group of paclitaxel, docetaxel group, camptothecin doxorubicin group or one or more groups.

[0030] 所述的抗肿瘤药物分子基团为抗肿瘤药物分子与聚e -己内酯上的羧基侧基发生取代反应后形成的基团。 [0030] The antitumor agent according to molecular groups with polyethylene molecule antineoplastic e - a group formed after the substitution reaction on the carboxyl side groups caprolactone.

[0031] 所述的M优选为锂原子、钠原子或者钾原子中一种或几种;特别优选为钠原子或钾原子中一种或两种。 [0031] said M is preferably a lithium atom, a sodium atom or a potassium atom of one or more; and particularly preferably a sodium atom or a potassium atom of one or both.

[0032] 所述的抗肿瘤前药,R优选为Cp6的直链烷氧基中一种。 [0032] The anti-cancer drugs before, R is preferably a straight-chain alkoxy of one Cp6.

[0033] 本发明还提供了一种如上所述的抗肿瘤前药的制备方法,该制备方法是将a位溴代e -己内酯先通过开环聚合生成聚a位溴代e -己内酯;再在聚a位溴代e -己内酯的a位上发生硫代苹果酸的巯基-a位溴代酯的点击化学反应,得到含羧基侧基的聚e _己内酯;将得到的含羧基侧基的聚e _己内酯与抗肿瘤药物分子发生取代反应后,用碱金属的强碱弱酸盐溶液中和,萃取出杂质,除杂质后的溶液经透析后,即得。 [0033] The present invention further provides a method for preparing an anti-tumor prodrugs as described above, the preparation process is a bromination e - caprolactone to ring-opening polymerization of a poly A bromination e - hexyl lactone; in yet a poly a bromination e - thiomalate occur on a bit-caprolactone -a bromination mercapto esters click chemistry reaction to obtain poly E _ polycaprolactone containing pendant carboxyl groups; the resulting polycaprolactone and poly E _ antineoplastic molecule containing pendant carboxyl groups occurs after the substitution reaction, a solution of a strong base weak acid salts of alkali metals, extracted impurities, and after dialysis, the solution in addition to impurities, that is, too.

[0034] 所述的开环聚合反应温度为80〜200° C;优选为80〜140° C。 [0034] The ring-opening polymerization temperature of 80~200 ° C; preferably 80~140 ° C.

[0035] 所述的开环聚合反应时间42〜54h。 [0035] The ring-opening polymerization time 42~54h.

[0036] 所述的开环聚合过程中使用的催化剂为无毒或低毒的辛酸亚锡、烷基锌或烷基铝;所述催化剂的用量是a位溴代e _己内酯质量的〇. 5〜2%。 [0036] The ring-opening polymerization catalyst used in the process is non-toxic or low toxic stannous octoate, zinc, or aluminum alkyl group; the amount of the bromination catalyst is a mass of caprolactone E _ billion. 5~2%.

[0037] 所述的开环聚合是在溶剂无水甲苯、四氢呋喃或二甲苯中进行。 [0037] The ring-opening polymerization in a solvent of anhydrous toluene, xylene or tetrahydrofuran, for.

[0038] 所述的开环聚合采用的引发剂为Cp6的醇类,优选为Cp6的直链醇。 [0038] The initiator used in ring-opening polymerization of Cp6 alcohols, preferably linear alcohols Cp6.

[0039] 所述聚a位溴代£ _己内酯的分子量由单体与引发剂的物质的量之比,及反应时间来决定。 [0039] The bromination £ _ a poly-caprolactone, molecular weight determined by the ratio of the amount of substance of monomer to initiator, and the reaction time.

[0040] 所述的巯基-a位溴代酯点击化学反应温度为〇〜40° C。 [0040] The mercapto -a bit bromo ester click chemistry reaction temperature 〇~40 ° C.

[0041] 所述的巯基_a位溴代酯点击化学反应时间为18〜30h。 [0041] The bromination _a mercapto ester click chemistry reaction time 18~30h.

[0042] 所述的巯基_a位溴代酯点击化学反应是在溶剂N,N-二甲基甲酰胺或二甲基亚砜中进行;采用三乙胺或脂肪族胺类为缚酸剂。 [0042] The bromination _a mercapto ester click chemistry reaction is carried out in a solvent N, N- dimethylformamide or dimethylsulfoxide; use triethylamine or aliphatic amines as acid binding agent .

[0043] 所述的抗肿瘤药物分子为紫杉醇、多烯紫杉醇、阿霉素或喜树碱一种或几种。 Molecule anticancer drugs [0043] of the paclitaxel, docetaxel, doxorubicin, or camptothecin one or several.

[0044] 所述的碱金属的强碱弱酸盐溶液为碳酸钠溶液、碳酸氢钠溶液、碳酸钾溶液或碳酸氢钾溶液中一种或几种。 [0044] strong base weak acid salt of the alkali metal solution is a solution of sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate solution one or more.

[0045] 所述的中和以pH在8〜9之间为终点。 [0045] The neutralized to a pH of between 8-9 as the end point.

[0046] 所述的取代反应反应温度为0〜40° C。 [0046] The substitution reaction temperature is 0~40 ° C.

[0047] 所述的取代反应反应时间为20〜28h。 [0047] The substitution reaction time 20~28h.

[0048] 所述的取代反应加入DMP作为酰化试剂。 [0048] The substitution reaction as acylating agent is added DMP.

[0049] 上述方法中得到的含羧基侧基的聚e -己内酯与抗肿瘤药物分子发生取代反应后,过滤除去不溶物,然后加入碱金属的强碱弱酸盐溶液中和直到PH值稳定在8〜9之间后,用有机溶剂萃取出杂质;将剩余可溶性盐溶液用蒸馏水透析,过滤,最后冷冻干燥得水溶性抗肿瘤前药;所述的萃取采用的萃取剂为三氯甲烷、二氯甲烷或乙酸乙酯;所述的碱金属的强碱弱酸盐溶液为碳酸钠溶液、碳酸氢钠溶液、碳酸钾溶液或碳酸氢钾溶液中一种或几种。 [0049] The above-described method containing pendant carboxyl groups obtained poly e - caprolactone with antineoplastic molecules after substitution reaction, insolubles were filtered off, followed by addition of a strong base weak acid salts of alkali metals in solution until the PH value and after stabilization between 8-9, extracted with an organic solvent impurities; the remaining solution was dialyzed against distilled water soluble salt, filtered and finally freeze dried to give a water-soluble anti-cancer drugs before; extraction of the extractant employed is chloroform , dichloromethane or ethyl acetate; the solution of an alkali metal salt of a weak alkali is sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate solution one or more.

[0050] 本发明的a位溴代e-己内酯的制备方法: [0050] a bit-bromo-e- caprolactone preparation of the present invention:

[0051] 将环己酮在醋酸铵催化作用下和N-溴代丁二酰亚胺在0〜100° C下发生自由基取代反应,得到a位溴代环己酮;得到的a位溴代环己酮用间氯过氧苯甲酸通过Baeyer-Villiger氧化反应后,即得a位溴代e-己内酯;其中,自由基取代反应采用的溶剂为无水乙醚、四氯化碳、三氯甲烷、二氯甲烷、四氢呋喃、乙腈或甲醇;Ba eyer-Villiger 氧化反应温度为〇〜40° C,采用的溶剂为二氯甲烷、三氯甲烷、乙腈、丙酮或四氢呋喃。 [0051] The cyclohexanone and N- bromosuccinimide occurs under catalysis of ammonium acetate at 0~100 ° C radical substitution, to give a bromination cyclohexanone; obtained a bromo-bit substituting cyclohexanone m-chloroperbenzoic acid by the Baeyer-Villiger oxidation reaction, to obtain a bromination e- caprolactone; wherein radical substitution reaction solvent employed is anhydrous diethyl ether, carbon tetrachloride, chloroform, dichloromethane, tetrahydrofuran, acetonitrile or methanol; Ba eyer-Villiger oxidation reaction temperature is 〇~40 ° C, the solvent employed is dichloromethane, chloroform, acetonitrile, acetone or tetrahydrofuran.

[0052] 本发明的聚e -己内酯负载的抗肿瘤前药合成路线如下: [0052] e present invention are poly - Scheme antitumor prodrugs load caprolactone as follows:

[0053] 以抗肿瘤药物分子,Paclitaxcl= [0053] The antitumor agent molecules, Paclitaxcl =

Figure CN103263675BD00061

碱金属的强碱弱酸盐采用NaHCO3为例: Alkali weak acid salts of alkali metals using NaHCO3 as an example:

[0054] [0054]

Figure CN103263675BD00071

Figure CN103263675BD00081

[0057] 本发明的有益效果: [0057] Advantageous effects of the invention:

[0058] 与现有脂肪族聚酯前药相比,本发明的优点在于:本发明的聚e_己内酯通过硫代苹果酸作为连接臂,每个e-己内酯结构单元上的a位碳含两个侧羧基,从而使其载药量和聚合物钠盐的水溶性都增加;如紫杉醇在负载量最高可达到66wt% ;本发明的聚e -己内酯负载的抗肿瘤前药避免了使用TOG,聚e-己内酯的生物分解性强,且侧基数目的增力口,从而克服了一些聚乙二醇-脂肪族聚酯两亲性嵌段共聚物存在对药物分子的载药量有限、难以对PEG结构进行进一步修饰和高分子量的PEG难以排出体外的缺点;本发明方法中通过中和,萃取及透析过程,达到了一个很好的纯化本发明的聚e -己内酯负载的抗肿瘤前药;本发明的制备方法成本低,产率高,安全无毒,可以广泛应用。 [0058] Compared with the conventional aliphatic polyester prodrugs, advantages of the present invention: poly caprolactone e_ the present invention by a connecting arm as thiomalate, each e- caprolactone structural units a two-position carbon containing carboxyl side, so that it and the drug loading have increased the water-soluble polymer is a sodium salt; as paclitaxel loading can reach 66wt%; e present invention poly - caprolactone antitumor load prodrugs avoids the use of the TOG, poly-e- caprolactone biodegradable strong base and the side port object booster, to overcome some of the polyethylene glycol - aliphatic polyester block copolymer is an amphiphilic drug is present molecule drug loading is limited, the structure is difficult to be further modified PEG and PEG molecular weight is difficult to discharge disadvantage in vitro; method of the present invention, by neutralization, extraction and the dialysis process, to achieve a good purification of the poly e - anti-tumor drugs caprolactone front load; production method of the present invention is low cost, high yield, safe, non-toxic, can be widely applied.

附图说明 BRIEF DESCRIPTION

[0059]【图1】为聚a位溴代e-己内酯的核磁氢谱图。 [0059] [FIG 1] is a poly-e- caprolactone bromination hydrogen NMR spectrum.

[0060] 【图2】为含羧基侧基的聚e -己内酯的核磁氢谱图。 [0060] [Figure 2] is a carboxyl group-containing pendant groups of poly e - caprolactone hydrogen NMR spectrum.

[0061]【图3】为侧链键接上紫杉醇药物分子的聚e -己内酯的核磁氢谱图。 [0061] [3] connected to the side chain of paclitaxel molecule is poly key e - caprolactone hydrogen NMR spectrum.

[0062]【图4】为本发明聚a位溴代e_己内酯负载抗肿瘤药物前后的凝胶色谱图:a为聚a位溴代e-己内酯,b为含羧基侧基的聚e-己内酯,c为侧链键接上紫杉醇药物分子的聚e-己内酯。 [0062] [4] of the present invention is a poly A site e_ gel chromatograms bromo-caprolactone antineoplastic agents before and after the load: a. A poly A bromination e- caprolactone, b is a carboxyl-containing side groups poly-e- caprolactone, c is connected to the side chain bond polyethylene e- caprolactone paclitaxel molecule.

[0063]【图5】为本发明聚a位溴代e_己内酯负载抗肿瘤药物前后的红外光谱图:a为聚a位溴代e-己内酯,b为含羧基侧基的聚e-己内酯,c为侧链键接上紫杉醇药物分子的聚e-己内酯。 [0063] [5] of the present invention, a poly-caprolactone bromination e_ IR spectra before and after the load anticancer drugs: a. A poly A bromination e- caprolactone, b is a carboxyl-containing side groups poly-e- caprolactone, c is connected to the side chain bond polyethylene e- caprolactone paclitaxel molecule.

具体实施方式 Detailed ways

[0064] 以下实施例是对本发明的进一步说明,而不是限制本发明。 [0064] The following examples further illustrate the present invention and not to limit the present invention.

[0065] 实施例1 [0065] Example 1

[0066] 1、a位溴代环己酮的制备 Preparation of [0066] 1, a bromination of cyclohexanone

[0067] 在装有磁石的500mL底烧瓶中加入20. 00g(0. 20mol)环己酮、38. 14g(0. 21mol) N-溴代丁二酰亚胺、I. 54g(0. 02mol)醋酸铵和300mL无水乙醚,夹入铁架台上,然后装上冷凝管,冷凝管上接一个氮气包,于25° C下反应0. 5h ;反应完成后,过滤,滤液用蒸馏水洗三遍;有机相用无水硫酸镁干燥,过滤,浓缩溶剂后,硅胶柱走柱分离(石油醚/乙酸乙酯=10:1),得到30. 09g (85. 0%)浅黄色油状液体。 [0067] was added 20. 00g (0. 20mol) cyclohexanone, 38 in 500mL flask equipped with a magnet in the bottom. 14g (0. 21mol) N- bromosuccinimide, I. 54g (0. 02mol ) ammonium acetate and 300mL of anhydrous ether, is sandwiched formwork table and then, a condenser, a condenser connected to a nitrogen gas bag, 0. 5h the reaction at 25 ° C; after completion of the reaction, was filtered, the filtrate was washed with distilled water three times; the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated the solvent, column separation down a silica gel column (petroleum ether / ethyl acetate = 10: 1) to give 30. 09g (85. 0%) as a pale yellow oily liquid.

[0068] 2、a位溴代e -己内酯的制备 Preparation caprolactone - [0068] 2, a bromination e

[0069] 在装有磁石的500mL单口圆底烧瓶中加入17. 70g(0. IOmol) a位溴代环己酮和20.64g(0.12mol)间氯过氧苯甲酸,再加入300mL二氯甲烷,于25° C下反应48h。 [0069] Add 500mL single-necked round-bottomed flask equipped with a magnet of 17. 70g (0. IOmol) a bromination of cyclohexanone and 20.64 g (0.12 mol) m-chloroperbenzoic acid, 300mL of dichloromethane was added , for 48h at 25 ° C. 反应完成后,过滤,滤液置入冰箱中一个晚上,然后再过滤除去间氯苯甲酸;滤液分别用饱和硫代硫酸钠洗三遍,饱和碳酸氢钠三遍,蒸馏水洗三遍;有机相用无水硫酸镁干燥,过滤,浓缩溶剂后,硅胶柱走柱分离(石油醚/二氯甲烷=10:1),得到无色油状液体a位溴代e-己内酯8. 68g(44. 9%);聚合前,a位溴代己内酯用无水乙醚和石油醚的混合溶剂于-25° C下重结晶三遍。 After completion of the reaction, filtered and the filtrate placed in the refrigerator overnight, then filtered to remove inter-chlorobenzoic acid; filtrate was washed three times with saturated sodium thiosulfate, three times with saturated sodium bicarbonate, washed three times with distilled water; the organic phase was washed with dried over anhydrous magnesium sulfate, filtered and the solvent was concentrated down on silica gel column separation column (petroleum ether / dichloromethane = 10: 1), to give a colorless oil bromination e- caprolactone 8. 68g (44. 9%); prior to polymerization, a bromination caprolactone at -25 ° C was recrystallized three times with a mixed solvent of anhydrous ether and petroleum ether.

[0070] 3、聚a位溴代e -己内酯的制备 [0070] 3 a poly A bromination e, - caprolactone prepared

[0071] 在氮气保护下将I. 00g(0. 005mol)单体a位溴代e -己内酯,I. 7mg(0. 52mmol) 引发剂无水甲醇,21mg(0. 5mmol)催化剂辛酸亚锡,5mL溶剂甲苯加入干燥的schlenk瓶中, 抽真空再充入氮气三次,氮气保护下置于110° C;油浴锅中反应48h,反应结束后,旋干甲苯,经二氯甲烷溶解,用冷冻的无水甲醇沉降三次,抽干后真空干燥一晚上,即得。 [0071] Under a blanket of nitrogen I. 00g (0 005mol.) Site monomer a brominated e -. Caprolactone, I 7mg (. 0 52mmol) in dry methanol initiator, 21mg (0 5mmol.) Octylate catalyst stannous, the solvent toluene was added 5 mL of dry schlenk flask evacuated and filled with nitrogen three times and placed under nitrogen, 110 ° C; the reaction an oil bath of 48h, after the completion of the reaction, spin dry toluene, methylene chloride was dissolved , three times with anhydrous methanol settling frozen, drained and dried under vacuum overnight, to obtain. (核磁如图1所不,分子量分布见图4a,红外见图5a)。 (FIG. 1 does NMR, the molecular weight distribution shown in Figure 4a, infrared Figure 5a).

[0072] 4、含羧基侧基的聚e -己内酯的制备 [0072] Carboxyl side groups containing 4 poly e, - caprolactone prepared

[0073] 在氮气保护下将Ig硫代苹果酸溶解于IOmLDMF中,待完全溶解后,向反应体系中慢慢滴加6mL三乙胺,然后将用DMF溶解好的0.5g聚a位溴代e-己内酯慢慢滴加到反应体系中,室温反应24h。 [0073] Ig under nitrogen to thiomalic acid is dissolved in the IOmLDMF, until complete dissolution, the reaction system was slowly added dropwise 6mL of triethylamine, and then dissolving a poly A good 0.5g bromination with DMF e- caprolactone was slowly added dropwise to the reaction system, the reaction at room temperature 24h. 反应结束后,用NaCO3水溶液将体系调至pH为8〜9,用二氯甲烷和乙酸乙酯各萃取三次,然后滴加稀盐酸将水溶剂调至pH为3〜5,体系有固体析出,倾倒出上层水溶液,然后用蒸馏水洗三次,最后冷冻干燥或真空干燥得产物(核磁如图2所示, 分子量分布见图4b,红外见图5b)。 After completion of the reaction, NaCO3 aqueous system was adjusted to pH 8-9, extracted three times each with dichloromethane and ethyl acetate, followed by dropwise addition of dilute aqueous hydrochloric acid and the solvent was adjusted to pH 3 to 5, the precipitated solid system, aqueous upper layer was decanted, then washed three times with distilled water, and finally freeze-dried or dried in vacuo to give the product (NMR shown in Figure 2, a molecular weight distribution shown in Figure 4b, infrared Figure 5b).

[0074] 5、一种e -己内酯主链的水溶性聚合物紫杉醇前药的制备 5. A e [0074] - Preparation of caprolactone water-soluble polymer backbone paclitaxel prodrugs

[0075] 将0. lg(0. 45mmol)侧羧基聚a位溴代己内酯溶解在5mLDMF中,加入0. 065g(0. 08mmol)紫杉醇,在IOmin 内将0. 024g(0. 085mmol)DCC 在DMF 中的溶液加入到25mL反应瓶中,再加入催化量的DMAP,在常温下搅拌24h;反应结束后,过滤除去不溶物;用NaHCO3水溶液将体系调至pH为8〜9,用二氯甲烷和乙酸乙酯各萃取三次,将可溶性盐溶液用蒸馏水透析,过滤,最后冷冻干燥得水溶性抗肿瘤前药〇. 15g,产率89. 1%。 [0075] A 0. lg (0. 45mmol) carboxyl side of a poly-caprolactone bromination was dissolved in 5mLDMF added 0. 065g (0. 08mmol) taxol, in the IOmin 0. 024g (0. 085mmol) DCC in DMF was added to the reaction flask 25mL, was added a catalytic amount of DMAP, stirred at room temperature for 24h; after completion of the reaction, insolubles were removed by filtration; with NaHCO3 aqueous system was adjusted to pH 8-9, with two chloride and extracted three times with ethyl acetate each, the soluble salt solution was dialyzed against distilled water, filtered and finally freeze-dried to obtain water-soluble prodrugs of antineoplastic billion. 15g, yield 89.1%.

[0076] 在所得前药中滴加稀盐酸溶液调至pH为3〜5,体系析出粘稠状物质,抽干后冷冻干燥,得到含羧基侧基的聚e _己内酯主链上键接上紫杉醇的聚合物,核磁如图3所示,分子量分布见图4c,红外见图5c),此步骤所得聚合物主要用于测试表征。 [0076] dilute hydrochloric acid was added dropwise a solution of the resultant was adjusted to pH ~ 5 as prodrugs, precipitated viscous substance system, drained after the freeze-dried, to give carboxyl-containing side groups E _ poly caprolactone primary key chain connected paclitaxel polymer, NMR shown in Figure 3, a molecular weight distribution shown in Figure 4C, infrared see FIG. 5C), this step tests to characterize the resultant polymers are used.

Claims (5)

1. 一种聚e-己内酯负载的抗肿瘤前药,其特征在于,具有式1和/或式2结构: An anti-tumor prodrug poly-e- caprolactone load, characterized by having the structure of formula 2 and / or the formula:
Figure CN103263675BC00021
式2 M为碱金属原子中一种或几种; D为抗肿瘤药物分子基团; R选自C1 ~ 6的烧氧基中一种; X为1〜100, y为1〜100, z为3〜300,且z > x+y,x、y和z都为整数; n 为10 〜300 ; 所述的抗肿瘤药物分子基团为紫杉醇基团、多烯紫杉醇基团、阿霉素基团或喜树碱基团中一种或几种。 Formula 2 M is an alkali metal atom of one or more; D is molecule antineoplastic group; R group is selected from C1 ~ 6 of burning of one; X is 1~100, y is 1~100, z is 3~300, and z> x + y, x, y and z are integers; n is 10 ~ 300; said antineoplastic is paclitaxel molecular group group group docetaxel, doxorubicin camptothecin group or one or more groups.
2. 如权利要求1所述的抗肿瘤前药,其特征在于,所述的M为锂原子、钠原子或者钾原子中一种或几种。 2. As the antitumor agent according to claim 1, wherein said M is a lithium atom, a sodium atom or a potassium atom of one or more.
3. 如权利要求1所述的抗肿瘤前药,其特征在于,R为Cp6的直链烷氧基中一种。 Before the antitumor agent according to claim 1, wherein, R is a straight-chain alkoxy of one to Cp6.
4. 一种如权利要求1〜3任一项所述的抗肿瘤前药的制备方法,其特征在于,将a位溴代e -己内酯先通过开环聚合生成聚a位溴代e -己内酯;再在聚a位溴代e -己内酯的a位上发生硫代苹果酸的巯基-a位溴代酯的点击化学反应,得到含羧基侧基的聚e _己内酯;将得到的含羧基侧基的聚e _己内酯与抗肿瘤药物分子发生取代反应后,用碱金属的强碱弱酸盐溶液中和,萃取出杂质,除杂质后的溶液经透析后,即得。 4. A method of preparing an anti-tumor before the drug according to any of claims 1 ~ 3, characterized in that a bromination e - caprolactone to a polymer that generated by ring-opening bromination e - caprolactone; e then brominated in a poly a site - mercapto -a bit bromoester thiomalate occur on a bit-caprolactone click chemistry reaction, to give a polyethylene containing pendant carboxyl groups caprolactone e _ ester; E _ the obtained poly caprolactone with antineoplastic molecule containing pendant carboxyl groups occurs after the substitution reaction, a strong base, weak acid salt with an alkali metal solution and extracted impurities, in addition to impurities by dialysis solution after, that is.
5. 如权利要求4所述的制备方法,其特征在于,所述的碱金属的强碱弱酸盐溶液为碳酸钠溶液、碳酸氢钠溶液、碳酸钾溶液或碳酸氢钾溶液中一种或几种。 5. The method as claimed in claim 4, wherein the strong base weak acid salt of the alkali metal solution is a solution of sodium carbonate, sodium bicarbonate, potassium bicarbonate or potassium carbonate or a solution of one several.
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