CN1041281C - 聚合物键合的紫杉醇衍生物 - Google Patents
聚合物键合的紫杉醇衍生物 Download PDFInfo
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Abstract
本发明涉及具有抗肿瘤活性的聚合物键合的紫杉醇,其衍生物,及它们的制备方法,并涉及含这类物质的药物组合物,其中90-99.9mol%由下式代表的单元构成:
Description
本发明涉及具有抗肿瘤活性的聚合物键合的紫杉醇与聚合物键合的紫杉醇衍生物及它们的制备方法,并涉及含这类物质的药物组合物。
紫杉醇是二萜类紫杉烷(taxane)族中的一员,可从短叶紫杉树皮的提取物中分离并鉴定,紫杉醇的其它类似物也是已知的,可由浆果紫杉的针状体中提取的10-脱乙酰基紫杉亭III为原料经半合成方法制备,(见Wain等,JACS,93,2325,(1971)和Lovelle等,Proc.Am.Assoc.Cancer Res.,31 P.417,(1990)。)这些化合物已显示出强效的抗肿瘤活性,但它们在水中溶解极微并在以Cre-mophor EL(商品名)为载体经注射或静脉滴注给药时会产生某些毒副作用。
本发明提供一种主要含有下述组成的式I聚合物轭合物,其中90-99.9mol%由下式代表的单元构成:0.1-5mol%由下式代表的单元构成:其中R1和R2之一是下式共聚物残基另一个是氢原子;0-9.9mol%由下式所代表的单元构成:其中R是苯基或叔丁氧基,R3是氢或乙酰基,A和A1可以是相同的或不相同的,它们代表化学单键、氨基酸残基或肽间隔基团,该肽间隔基团可选自
β Ala,Gly,Phe-Gly,Phe-Phe-,Leu-Gly,Val-Ala,Phe-Ala,Leu-Phe,Leu-Ala,Phe-Leu-Gly,Phe-Phe-Leu,Leu-Leu-Gly,Phe-Tyr-Ala,Phe-Gly-Phe,Phe-Phe-Gly,Phe-Leu-Gly-Phe,Gly-Phe-Leu-Gly-Phe,Gly-βAla,Phe-Gly-βAla,Phe-Phe-βAla,Leu-Gly-βAla,Val-Ala-βAla,Phe-Ala-βAla,Leu-Phe-βAla,Leu-Gly-βAla,Phe-Leu-Gly-βAla,Phe-Phe-Leu-βAla,Leu-Leu-Gly-βAla,Phe-Tyr-Ala-βAla,Phe-Gly-Phe-βAla,Phe-Phe-Gly-βAla,Phe-Leu-Gly-Phe-βAla或Gly-Phe-Leu-Gly-Phe-βAla.
更为特别的是本发明提供的紫杉醇及紫杉醇衍生物的聚合物轭合物具有较好的水溶性和降低的毒性。
含紫杉醇和紫杉醇衍生物单元的mol%优选为0.5-2%,在聚合物中紫杉醇的更优选含量为2-10%(w/w),最优选的化合物的特征在于含4-7%(w/w)。波浪线表示连接在紫杉醇结构的7位上的氧可以是两种构型即β型(天然的)或α型。
优选的R代表苯基,R3是乙酰基,A是苯丙氨酸-亮氨酸-甘氨酸或苯丙氨酸-亮氨酸-甘氨酸-β丙氨酸的残基。所有氨基酸残基都具有天然的L构型。根据优选的具体化实施例,聚合物轭合物是一种由1-甲基丙烯酰基氨基-2-羟基丙烷,(甲基丙烯酰甘氨酰-苯丙氨酰-亮氨酰甘氨酰基)3-氨基-2-羟基丙烷和2′-(甲基丙烯酰甘氨酰苯丙氨酰亮氨酰甘氨酰-β丙氨酰基)紫杉醇组成的共聚物。
w/w百分含量是经酶水解后用HPLC法测定的,该方法与Cancer Treatment Rep.71(1),(1987)P.53-59中所述相类似。酶水解作用
向1ml小鼠或人的血浆中加入不同浓度的聚合物键合紫杉醇并在适当的时间(24、48、72、96小时)收集100μl,贮藏在-70℃的环境中直到作进一步的处理。萃取方法
向试样加入75μl 0.5M磷酸四丁基铵(TBAP),1250μlCH3CN和150μl 5M NaCl并在4℃下强烈振荡20分钟进行样品抽提。然后将试样在离心机15000×g下离心10分钟,收集上清液并高真空蒸发。加入500μl MeOH∶H2O(75∶25v/v)回收样品,注入HPLC中测定总的紫杉醇的百分含量。HPLC系统
色谱柱:Nova Pak C18(Waters)3.9×300mm
流速:1.5ml/m
检测器:UV231nm
注样量:20μl
流动相:57.5%pH为2的水,42.5%CH3CN
本发明还提供一种供制备聚合物轭合物的方法,该法包括式II化合物与一种活化的聚合物的反应其中A2和A3中之一是化学键,另一个是A,且A、R和R3如前所限定的,该活化的聚合物主要由90-99.9mol%由下式所代表的单元构成:10-0.1mol%由下式所代表的单元所组成,其中A1如前所规定的。然后用2-羟基丙胺处理生成的聚合物轭合物。式II化合物与活化的聚合物之间的反应优选是在无水的极性有机溶剂(如二甲亚砜或二甲基甲酰胺)中并任选的在有机碱或无机碱(如碱金属碳酸盐、二甲基氨基吡啶或三乙胺)存在下进行。通常,反应完成需1-24小时。
反应通常在15-40℃下进行,优选在室温下进行。碱性碳酸盐例如是碱金属碳酸盐或碱土金属碳酸盐。
某些式II原料化合物是已知的一些化合物,即紫杉醇或紫杉醇的类似物或是由已知化合物制备的。例如7-表衍生物可以在碱存在下(Na2CO3或二氮杂双环十一碳烯)在甲苯中回流紫杉醇或它的类似物的方法制备。
式II的另外一些化合物是新的,特别是那些A3是β丙氨酸残基及那些A2或A3代表如上述对A所规定的二、三或四肽间隔基团也是本发明的范围。
式II化合物(其中A2不是化学单键)可通过由紫杉醇或紫杉醇类似物在缩合剂存在下并在有或没有外加催化剂的条件下与经保护了的氨基酸或肽反应来制备,优选在室温下反应,然后用已知的方法除去保护基团。
也可用活化了的酯(如肽或氨基酸的对硝基苯基酯)进行缩合反应。适宜的缩合剂包括碳化二亚胺如二环己基碳二亚胺(DCC)。
适宜的催化剂包括4-二甲基氨基吡啶(DMAP)、吡啶或三乙胺。
各种已知的保护氨基的基团可被采用,市售的已保护的氨基酸或肽可作为原料。用t-BOC、三苯甲游基、FMOC或苄氧羰基(CBZ)保护的氨基酸或肽可被采用。用t-BOC、三苯甲游基或FMOC基团保护的氨基酸或肽是优选的。
式II化合物(其中A3不是化学单键)可通过下述方法制备,先保护或封闭2′位羟基,接着酯化7位羟基,然后除去2′位的保护或封闭基团。
更优选的是,式II化合物(其中A3是甘氨酸或β丙氨酸残基)可通过紫杉醇与2-3当量的N-保护的氨基酸反应生成2′,7二取代紫杉醇,将2′位氨基酸裂解然后将7位氨基酸脱保护。
紫杉醇与经保护的氨基酸的反应,如上所述的是在有缩合剂及催化剂存在下进行的。
2′-氨基酸的裂解是通过调节2′-7-(氨基酸)紫杉醇溶液的pH至7-7.4来实现的,例如2′-7-二(氨基酸)紫杉醇与pH为7-7.4的磷酸盐缓冲液混合或用稍过量的NaHCO3调节pH。
氨基酸的脱保护作用是以已知的氨基酸脱保护方法进行的,例如用温合的酸(如乙酸)处理或用还原法。
因此,例如,紫杉醇能与2-3摩尔等当量的N-保护的氨基酸(用t-BOC、CBZ或FMOC保护的)在二氯甲烷中有DCC和催化量的4-二甲氨基吡啶存在下反应。在此方法中,经保护的氨基酸被引入到2′及7位置上。紫杉醇的2′、7-双氨基酸衍生物可在NaHCO3存在下于H2O/MeOH中放置2-5小时,从而在2′位置上发生选择性脱保护并生成紫杉醇的7位取代衍生物。可用适当的脱保护剂(如酸、弱碱或氢解)除去保护基团。
如US-A-4062831和US-A-4097470中所描述的活化的聚合物是一种合成的、水溶性聚合物,它是由N′-(2-羟丙基)甲基丙烯酰胺与N-甲基丙烯酰基寡肽的对硝基苯基酯共聚而制备的。
式I与式II新的紫杉醇衍生物的聚合物轭合物具有良好的水溶性,生物兼容性,并能在血浆中释放紫杉醇或紫杉醇衍生物,或者通过寡肽间隔基团的裂解内在化后将紫杉醇或紫杉醇的衍生物释放到细胞中。
生物活性
微管聚集和解聚试验
小牛微腦管蛋白用聚集一解聚双循环法
(Shelanski M.L.,Gaskin F.and Cantor C.R.Proc,Natl,Acad Sci.U.S.A.70,765-768,1973)制备,并于MAB中(0.1M MES.2.5mM EGTA,0.5mM MgSO4、0.1mM ED-TA、0.1mM DTT pH6.4)保存于液氮中。
所有实验用的蛋白质的贮存期少于4周。
每次实验前,微管蛋白在4℃下保持30分钟。
聚集是用Gaskin等提出的方法测定(Gaskin F.Cantor C.R.Shelanski M.L,J.Molec.Biol 89,737-758,(1974)。含微管蛋白(1mg/ml)和1mM GTP的样品池(光径长1cm)调整至37℃,并在配置有自动记录仪和恒温控制样品室装置的Perkin-Elmer557双波长双光束分光光度计上连续测定在340nm处的浊度。
30分钟后加入4mM CaCl2并以10分钟浊度的降低来量度其解聚作用。每隔15分钟加入所试验化合物的分级剂量并测定其浊度的变化。所得数据用由于加入所试化合物引起的再聚合百分率来表示,结果列于表1。
离体的药物敏感性试验
将指数增殖的B16-F10小鼠黑色素瘤细胞(2×104/ml)接种在添加有10%热失活胎牛血清和2mM谷氨酰胺的RPMI1640培养基中置于24个井形培养板中(Costar)。接种后立即加入分级浓度的所试验化合物,72小时温育后用Coulter计数器计数细胞来评价化合物对细胞生长的抑制作用。对每一浓度的受试化合物进行三次重复培养。所试化合物的抗增殖活性由剂量-效应曲线来计算和以IC50(受处理的培养物相对于未处理对照组,使50%细胞增长受到抑制的剂量)来表示,结果列于表1。
表1
在实施例中制备的化合物 | 微管蛋白聚集%0.5μM 5μM | IC50(μM) |
实施例 1 | 0 15 | 19 |
实施例 9 | 79 145 | 47 |
实施例 3 | 46 86 | 23 |
实施例 4 | 0 10 | 11 |
实施例 6 | 0 10 | 51 |
参比化合物:紫杉醇 | 41 96 | 39 |
以实施例6制备的共聚物-紫杉醇与紫杉醇比较对B16-F10小鼠黑色素瘤的在体试验小鼠
C57B16雌性小鼠来自意大利Charles River。
开始实验时动物为8-10周龄。药物
由于有限的水溶解性,将紫杉醇溶解于由50%聚氧乙烯蓖麻油(Cremophor El)和50%乙醇组成的载体中,然后用5%葡萄糖溶液稀释至所需浓度。溶液稍有混浊,短时间后可观察到沉淀形成。实施例6的化合物易溶于5%葡萄糖溶液中,所得溶液能长时间(超过2小时)保持澄明。最终浓度是指化合物的紫杉醇含量(总量的4%)。肿瘤
采用B16-F10小鼠黑色素瘤,105个肿瘤细胞悬浮液0.2ml皮下注入鼠的肋腹内。
用测经器测量肿瘤的大小,以下式计算肿瘤的重量: 给药
由于紫杉醇不良的溶解性和载体的毒性,紫杉醇是以腹腔给药。
实施例6化合物是以静脉注入的。在接种肿瘤后于1、5、9天分别给两种化合物。
列于表2的数据显示本发明的化合物比紫杉醇有更大的活性。
聚合物-轭合物的剂量是以紫杉醇的含量计。
表2
化合物 | 剂量(mg/Kg) | 肿瘤抑制率(%) | 毒 性 |
对 照 | - | - | - |
紫杉醇 | 14.6 | 53 | 0/10 |
22 | 38 | 0/10 | |
33 | 92 | 1/7 | |
实施例6化合物 | 14.6 | 77 | 0/9 |
22 | 79 | 0/10 |
毒性:死于毒性的小鼠数。
毒性是以与对照组比较小鼠死亡数或观察到体重显著降低和/或脾和/或肝体积缩小来量度的。
由上述数据可以看到本发明聚合物轭合物显示出良好的抗肿瘤活性。因此,这些化合物与紫杉醇或紫杉醇衍生物相比较由于其较低的毒性和较好的水溶解性是有效的抗肿瘤剂。能治疗的肿瘤的实例,如肉瘤、癌、淋巴瘤、成神经细胞瘤、黑色素瘤、骨髓瘤、Wilms肿瘤、白血病以及腺癌。
本发明的聚合物轭合物由于其溶解性的提高和毒性的降低,意味着适宜于静脉注射或滴注,剂量决定于病人的年龄、体重和身体状况,可从1mg/kg体重到1g/kg体重,优选4-800mg/kg体重。有代表性的配方中聚合物键合紫杉醇或聚合物键合紫杉醇衍生物的含量相当于0.5、1.5、10、20、25或50mg活性紫杉醇或紫杉醇衍生物。
聚合物轭合物可与药用载体或稀释剂配制成药物组合物,任何适宜的载体或稀释剂都可采用。供静脉注射或输注的溶液可含有的载体或稀释剂,例如灭菌水或优选的可以是无菌的、含水的或等渗的盐溶液。
以下述实施例说明本发明。实施例1
1-甲基丙烯酰氨基-2-羟基丙烷、1-(甲基丙烯酰-甘氨酰-苯丙氨酰-亮氨酰-甘氨酰)氨基-2-羟基丙烷与2′(甲基丙烯酰-甘氨酰-苯丙氨酰-亮氨酰-甘氨酰)紫杉醇的共聚物。
向根据J.Kopecek等在Makromol Clem177,P2833,(1976)提出的方法制备的1.4g 1-甲基丙烯酰氨基-2-羟基丙烷与N-(亚甲基羰基-苯丙氨酸-亮氨酸-甘氨酸4-硝基苯氧基)甲基丙烯酰胺的共聚物在15ml无水二甲基甲酰胺溶液中加入100mg紫杉醇及15mg二甲基氨基吡啶。
在无水、室温条件下搅拌该黄色溶液8小时,然后将2-羟基丙胺(0.2ml)滴入反应瓶中并搅拌反应物30分钟。
向反应溶液中加入0.3ml冰乙酸以使反应中止,在真空下浓缩至较小的体积,然后将其倾入200ml丙酮中。
混和30分钟后,滤集沉淀并用丙酮洗涤沉淀,得到1.25g标题化合物。
紫杉醇含量为4.5%(用酶水解法及HPLC分析法测算的)。
未反应的紫杉醇从丙酮溶液中回收。实施例2
2′(N-三苯甲游基-苯丙氨酰-亮氨酰-甘氨酰)紫杉醇。
向170mg紫杉醇在16ml乙腈的溶液中加入24mg二甲氨基吡啶和150mg N-三苯甲游基-苯丙氨酰-亮氨酰-甘氨酸4-硝基苯酯。在室温下搅拌该黄色溶液20小时然后在真空下蒸发至干。残留物用硅胶进行色层分离以35∶25的乙酸乙酯-己烷作为洗脱液,得到380mg标题化合物。
1H-NMR(400MHz,CDCl3):δ
0.82(d,J=6.4Hz,3H,δ-Leu)
0.85(d,J=6.7Hz,3H,δ-Leu)
1.15(s,3H,16)
1.26(s,3H,17)
1.2-1.6(m.3H,β+β+γ-Leu)
1.69(s,3H,19)
1.85(s,1H,OH-1)
1.89(m,1H,6β)
1.96(d,J=1.2Hz,3H,18)
2.14(dd,J=5.9Hz,J=13.5Hz,1H,β-Phe)
2.24(s,3H,CH3CO-10)
2.2-2.7(m,5H,CH2-14+OH-7+6α+βPhe+NH-Phe)
2.47(s,3H,CH3CO-4)
3.50(m,1H,α-Phe)
3.74(dd,J=4.7Hz,J=18.2Hz,1H,α-Gly)
3.80(m,1H,α-Leu)
3.83(d,J=7.0Hz,1H,3)
4.17(dd,J=7.0Hz,J=18.2Hz,1H,α′-Gly)
4.22,4.33(two-d,J=8.5Hz,2H,CH2-20)
4.46(m,1H,7)
4.97(dd,J=2.2Hz,J=9.9Hz,1H,5)
5.44(d,J=2.3Hz,1H,2′)
5.71(d,J=7.0Hz,1H,2)
5.97(dd,J=4.7Hz,J=7.0Hz,1H,NH-Gly)
6.07(dd,J=2.3Hz,J=9.4Hz,1H,3′)
6.2-6.3(m.2H,13+10)
6.8-9.2(m,30H,6-Ph)
6.95(d,J=6.7Hz,1H,NH-Leu)
8.00(d,J=9.4Hz,1H,NH-4′)实施例3
2′(苯丙氨酰-亮氨酰-甘氨酰)紫杉醇。
将250mg 2′(N-三甲苯游基-苯丙氨酸-亮氨酸-甘氨酸)紫杉醇溶解在冰乙酸(22ml)与水(6ml)的混合物中,在室温下搅拌1小时。
在真空下蒸去溶剂至干,残留物于1∶1乙醚-己烷中搅拌30分钟,过滤,得到160mg标题化合物。FAB-MS:m/z 1171,
;1112,M-CH3COOH+2H;1051,1024,911,603,569,509.1H-NMR(400MHz,CDCl3):δ0.88(d,J=6.4Hz,3H,δLeu)0.92(d,J=6.4Hz,3H,δ′Leu)1.13(s,3H,16)1.16(s,3H,17)1.4-2.0(m,4H,β+β′+γLeu+6β)1.69(s,3H,19)1.91(d,J=1.2Hz,3H,18)2.16(dd,J=6.0Hz,J=13.8Hz,1H,14)2.23(s,3H,COCH3-10)2.4-2.6(m,3H,6α+14+βPhe)2.53(s,3H,COCH3-4)2.90(dd,J=4.1Hz,J=13.5Hz,1H,β′-Phe)3.49(dd,J=4.1Hz,J=9.1Hz,1H,αPhe)3.82(d,J=7.3Hz,1H,3)3.9-4.1(m,2H,α+α′Gly)4.22,4.33(two-d,J=8.7Hz,2H,CH2-20)4.27(m,1H,α-Leu)4.44(dd,J=6.4Hz,J=10.8Hz,7)
4.98(dd,J=2.4Hz,J=9.7Hz,5)
5.61(d,J=3.2Hz,1H,2′)
5.70(d,J=7.3Hz,1H,2)
6.12(dd,J=3.2Hz,J=9.4Hz,1H,3′)
6.21(m,1H,13)
6.28(s,1H,10)
6.8-8.2(m,21H,4-Ph+NHLeu)
7.87(d,J=9.4Hz,1H,NH-4′)实施例4
1-甲基丙烯酰氨基-2-羟丙烷、1-(甲基丙烯酰-甘氨酰)氨基-2-羟丙烷与2′-(甲基丙烯酰-甘氨酰-苯丙氨酰-亮氨酰-甘氨酰)紫杉醇的共聚物。
向根据P.Rejmanova等,Makromol.Chem.178,P2159-2168所提出的方法制备的1g 1-甲基丙烯酰氨基-2-羟基丙烷与N-(亚甲基羰基-4-硝基-苯氧基)甲基丙烯酰胺共聚物在10ml无水二甲基甲酰胺的溶液中加入100mg 2′苯丙氨酸-亮氨酸-甘氨酸-紫杉醇和10mg二甲基氨基吡啶。在无水、室温条件下搅拌该黄色溶液2小时。然后将2-羟基丙胺(0.15ml)加入反应溶液中并搅拌30分钟。向反应溶液加入0.2ml冰乙酸使反应中止,在真空条件下浓缩溶液至较小的体积,然后将其倾入200ml丙酮中。
搅拌混合物1小时,滤集沉淀并用丙酮洗涤沉淀,得到960mg标题化合物。
紫杉醇含量为6%(用酶水解法和HPLC分析法测算的)。实施例5
1-甲基丙烯酰氨基-2-羟基丙烷、1(甲基丙烯酰-甘氨酰)氨基-2-羟基丙烷与2′(甲基丙烯酰-甘氨酰)紫杉醇共聚物。
向1.6g 1-甲基丙烯酰氨基-2-羟基丙烷和N-(亚甲基羰基-4-硝基苯氧基)甲基丙烯酰胺共聚物在16ml无水二甲基甲酰胺的溶液中加入100mg紫杉醇及20mg二甲基氨基吡啶。在室温下搅拌该黄色溶液20小时,然后加入2-羟基丙胺(0.2ml)搅拌30分钟。加入0.3ml冰乙酸中止反应,在真空条件下浓缩溶液至较小的体积,然后将其倾入200ml丙酮中。搅拌混合物1小时,滤集沉淀并用丙酮洗涤沉淀,得到1440mg标题化合物。
紫杉醇含量为2.75%(w/w)。实施例6
1-甲基丙烯酰氨基-2-羟基丙烷、1-(甲基丙烯酰-甘氨酰-苯丙氨酰-亮氨酰-甘氨酰)氨基-2-羟基丙烷与2′-(甲基丙烯酰-甘氨酰-苯丙氨酰-亮氨酰-甘氨酰-β丙氨酰)紫杉醇共聚物。
向根据N.F.Magri等,在J Nat.Products,51,298-306,(1988)提出的方法制备的620mg 1-甲基丙烯酰氨基-2-羟基丙烷与N-(亚甲基羰基-苯丙氨酸-亮氨酸-甘氨酸-4-硝基-苯氧基)甲基丙烯酰胺共聚物在6ml无水二甲基甲酰胺的溶液中加入62mg 2′-(β丙氨酰)紫杉醇和10mg二甲氨基吡啶。在室温及无水条件下搅拌该黄色溶液5小时。
然后加入2-羟基丙胺(0.1ml),搅拌30分钟。
加入0.15ml冰乙酸中止反应,在真空条件下浓缩溶液至较小的体积并将其倾入150ml丙酮中。搅拌混合物1小时,滤集沉淀并用丙酮洗涤沉淀,得到5.85mg标题化合物。
紫杉醇含量为4%(w/w)。实施例7
2′,7-二(苄氧羰基-β-丙氨酰)紫杉醇。
向200mg紫杉醇在15ml乙腈的溶液中加入400mg N,N′-二环己基碳二亚胺、200mg苄氧羰基-β-丙氨酸及60mg二甲基氨基吡啶。搅拌该反应混合物20小时,滤集沉淀,在真空下将溶剂蒸干。
残留物用硅胶作色层分离,用1∶1乙酸乙酯-己烷作为洗脱液,得到300mg标题化合物。
7-(苄氧羰基-β丙氨酰)紫杉醇
向171mg 2′7-二(苄氧羰基-β丙氨酰)紫杉醇在60ml甲醇溶液中加入30mg碳酸氢钠和7ml水,在室温下搅拌3小时。蒸去甲醇,用乙酸乙酯提取产物。
在真空下将溶剂蒸干,得到134mg标题化合物。实施例9
7-(β丙氨酰)紫杉醇
向135mg 7-(苄氧羰基-β丙氨酰)紫杉醇20ml甲醇和13ml甲酸溶液中加入200mg 5%Pd/C。在室温下搅拌反应混合物6小时,滤去催化剂并用甲醇洗涤,在真空下蒸发溶剂至干,残留物溶解于8ml甲醇中,用150ml乙醚沉淀,得到85mg标题化合物。FAB-MS:M/z 925,
;947,
1H NMR(400MHz,CDCl3):δ1.14(s,3H,CH3-16)1.20(s,3H,CH3-17)1.79(s,3H,CH3-19)1.85(s,3H,CH3-18)2.17(s,3H,CH3CO-10)2.2-2.6(m,6H,CH2-14+CH2-6+OCOCH2CH2NH2)2.42(s,3H,CH3CO-4)3.0-3.2(m,2H,OCOCH2CH2NH2)3.90(d,J=6.8Hz,1H,3)4.18,4.31(two d,J=8.2Hz,2H,CH2-20)4.80(d,J=3.2Hz,1H,2′)4.91(d,J=8.5Hz,1H,5)5.62(dd,J=10.2Hz,J=7.0Hz,1H,7)5.66(d,J=6.8Hz,1H,2)5.81(dd,J=2.9Hz,J=9.1Hz,1H,3′)6.17(m,1H,13)6.19(s,1H,10)7.3-8.2(m,16H,NH-4′+3-Ph)实施例10
1-甲基丙烯酰氨基-2-羟基丙烷、1-(甲基丙烯酰-甘氨酰-苯丙氨酰-亮氨酰-甘氨酰)氨基-2-羟基丙烷与7-(甲基丙烯酰-甘氨酰-苯丙氨酰-亮氨酰-甘氨酰-β丙氨酰)紫杉醇共聚物。
向1500mg 1-甲基丙烯酰氨基-2-羟基丙烷与N-(亚甲基羰基-苯丙氨酸-亮氨酸-甘氨酸-4硝基苯氧基)甲基丙烯酰胺共聚物在13ml无水二甲基甲酰胺的溶液中加入135mg 7-(β丙氨酰)紫杉醇和20mg二甲基氨基吡啶。
在室温、无水条件下搅拌该黄色溶液5小时。
加入2-羟基丙胺(0.2ml)并搅拌30分钟。
用0.3ml冰乙酸使溶液中止反应,真空浓缩至较小的体积并倾入250ml丙酮中。搅拌混合物1小时,滤集沉淀并用丙酮洗涤沉淀,得到1520mg标题化合物。
紫杉醇含量为7.8%(w/w)。
Claims (10)
1.一种聚合物轭合物,含有:90-99.9mol%由下式所代表的单元0.1-5mol%由下式所代表的单元其中R1和R2之一是下式的共聚物残基另一个是氢原子;和0-9.9mol%由下式所代表的单元其中R是苯基或叔丁氧基,R3是氢或乙酰基,A和A1可以是相同的或不相同的,它们代表化学单键、氨基酸残基或肽间隔基团,该肽间隔基团可选自
β Ala,Gly,Phe-Gly,Phe-Phe,Leu-Gly,Val-Ala,Phe-Ala,Leu-Phe,Leu-Ala,Phe-Leu-Gly,Phe-Phe-Leu,Leu-Leu-Gly,Phe-Tyr-Ala,Phe-Gly-Phe,Phe-Phe-Gly,Phe-Leu-Gly-Phe,Gly-Phe-Leu-Gly-Phe,Gly-βAla,Phe-Gly-βAla,Phe-Phe-βAla,Leu-Gly-βAla,Val-Ala-βAla,Phe-Ala-βAla,Leu-Phe-βAla,Leu-Gly-βAla,Phe-Leu-Gly-βAla,Phe-Phe-Leu-βAla,Leu-Leu-Gly-βAla,Phe-Tyr-Ala-βAla,Phe-Gly-Phe-βAla,Phe-Phe-Gly βAla,Phe-Leu-Gly-Phe-βAla和Gly-Phe-Leu-Gly-Phe-βAla.
2.根据权利要求1的聚合物轭合物,其特征是,R代表苯基
R3是乙酰基及A是Phe-Leu-Gly或Phe-Leu-Gly-βAla残基。
3.根据权利要求1或2的聚合物轭合物,其特征是,1-甲基丙烯酰氨基-2-羟基丙烷、1-(甲基丙烯酰-甘氨酰-苯丙氨酰-亮氨酰-甘氨酰)3-氨基-2-羟基丙烷与2′-(甲基丙烯酰-甘氨酰-苯丙氨酰-亮氨酰-甘氨酰-β丙氨酰)紫杉醇的共聚物。
4.制备权利要求1的聚合物轭合物的方法,其特征是,式II化合物其中A2和A3之一是化学键,另一个是A,且A、R和R3如权利要求1所限定的,与活化的聚合物反应,该活化的聚合物,由90-99.9mol%由下式代表的单元及
10-0.1mol%由下式代表的单元所组成,其中A1如权利要求1所限定,然后用2-羟基丙胺处理所生成的聚合物轭合物。
5.根据权利要求4的方法,其特征是,反应是在有机碱或无机碱存在下,在无水极性溶剂中进行的,反应温度为15-40℃,反应时间为1-24小时。
6.根据权利要求4的方法,其特征是,A2如同权利要求1所限定的A,代表二、三或四肽间隔基团。
7.根据权利要求6的方法,其特征是,紫杉醇或紫杉醇类似物与经保护的氨基酸或肽在缩合剂存在下或采用活化了的酯以及在有或没有外加催化剂存在下进行反应,然后除去保护基团。
8.根据权利要求4的方法,其特征是,A3如权利要求1所限定的A,代表β丙氨酸或二、三或四肽间隔基团。
9.根据权利要求8的方法,其特征是,包括或者(i)保护或封闭紫杉醇的2′羟基,酯化7位羟基然后除去2′位保护或封闭基团,或者(ii)使紫杉醇与所需要的N-保护的氨基酸反应生成2′,7二取代紫杉醇,裂解2′位氨基酸,然后脱去7位氨基酸的保护基团。
10.一种药物组合物,包括作为活性成分由权利要求1所限定的聚合物轭合物以及药用稀释剂或载体。
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