CN1021912C - 铂-(iv)二胺复合物的制备方法 - Google Patents
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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
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Abstract
本发明是关于铂-(IV)-二胺复合物(式3),制备该化合物的方法,以及含有该化合物的具有抗肿瘤作用的制剂。此外,本发明还包括含有该化合物的具有抗肿瘤作用的制剂。
Description
本发明是关于铂-(Ⅳ)-二胺复合物、制备该类化合物的方法、含有该类型化合物的具有抗肿瘤作用的制剂,以及具有抗肿瘤作用的成形制剂。
大约20年以前,美国生物化学家B。Rosenberg等发现,顺式-二胺-二氯铂(顺式-铂)具有很强的抗肿瘤活性(B.Rosenberg,L.Van Camp,J.Trosko和V.H.Mansour,Nature 222,1969,385-386页)。同时发现,在肿瘤治疗中,尤其在卵巢瘤和睾丸瘤的治疗中,该化合物与其他抗肿瘤剂并用具有重要的用途。但是顺式-铂有许多十分不良的付作用。它可引起患者严重的恶心,并伴有呕吐。此外,它还有肾、骨髓和神经毒性,并可损害听力。将D.Th.Sleijfer,S.Meijer和M.H.Mulder的文章Cis-Platin:a review of clinical applications and renal toxicity(Pharm.Weekbl.〔Sci.〕1985,7:237~244页)收编在本申请中作为参考。从1970年以来,对于顺式-铂作用的机制,具有较高抗肿瘤活性和/或迄今抗肿瘤活性不敏感的类似物、降低毒付作用的类似物和/或改进物理和药学性质的类似物进行了广泛的研究。
许多铂-二胺类复合物可以从文献中查到。但是仍然十分需要已改进其特性的新的抗肿瘤剂,具体来说,十分需要对于顺式-铂有抗
性的或有严重抗性的肿瘤具有活性的化合物。将两篇近期的综述、论文收编在本申请中作为参考,例如E.W.Stern:The Search for New Platinum Antitumor Agents:Progress,Problems and Prospects,in Platinum and other Metal Coordination Compounds in Cancer Chemotherapy,由Marino Nicolini编辑,由Martinus Nijhoff出版,波士顿,Dordrecht,兰开斯特,ISBN 0-89838-358-7,1988,519-526页;H.A.Meinema,Platinaverbindingen ter bestrijding van van kanker:synthese,eigenschappen en structuur-activiteitsrelaties(治疗癌的铂类化合物:合成、性质及其结构-活性关系),Pharm.Weekbl.123(1988),549~552页。
二胺-铂复合物在德国专利申请79.04740中已有叙述,其特征在于,结构式1
中R1和R2相互独立地代表氢原子,或者代表取代或未取代的烷基、环烷基、芳基或芳烷基,同时R1和R2与它们所连接的碳原子一起可以是取代或未取代的环烷基,R3和R4相互独立地代表氢原子,或者代表取代或未取代的烷基、芳基或芳烷基,并且X代表阴离子基团。
二胺-铂复合物在德国专利申请8204067中已有叙述,其特征在于,结构式图式1中R1和R2均代表乙基,或者R1和R2与它们所连接的碳原子一起可以是苯基(这里需要指出的是,实例表明它不是苯基而是环烷基),R3和R4均代表氢原子,并且各个X代表氯代乙酸酯基或硝酸酯基,或者两个基团X一起代表丙二酸酯基,乙基丙二酸酯基、羟基丙二酸酯基、羧基邻苯二甲酸酯基、环丁烷-1,1-二羧酸酯基或草酸酯基,或者上述基团的之一为钠盐。
国家癌症研究所(National Cancer Institute,贝塞斯达,USA)和癌症治疗研究的欧州组织(European Organization for Research on the Treatment of Cancer,布鲁塞尔,比利时,)进行的广泛研究表明,上述化合物对癌具有显著的治疗活性。与实际应用的治疗癌的其他已知铂复合物相比,上述复合物有较低的肾毒性。
德国专利申请80,00032(现在专利号181.434)叙述了具有抗肿瘤作用的铂复合物式2,
其中R1和R2相互独立地代表氢原子,或者代表取代或未取代的烷基、环烷基、芳基或芳烷基,同时R1和R2与它们所连接的碳原子一起可以是取代或未取代的环烷基,R3和R4相互独立地代表氢原子,或者代表取代或未取代的烷基或芳烷基,并且X和Y代表相同或不同的阴
离子基团。上述化合物对许多类型的癌具有作用,并且有减低的肾毒性。
现已发现,结构式图中式3化合物(TNO-40)对于顺式-二胺-二氯-铂(顺式-铂)已产生抗性的肿瘤细胞具有非常好的作用。
式3化合物对于不同类型的肿瘤具有显著的作用。从带有肿瘤的小白鼠的试验结果表明,与未处理的对照组(C)相比,处理组(T)的存活时间明显延长。T/C×100%(T/C%)值大于或等于125,表明具有显著的治疗活性。
抗L1210白血病的最大T/C(%)为193(4mg/Kg),而对照组试验顺式-铂的最大T/C(%)为138(6mg/Kg);抗B黑素瘤的最大T/C(%)为163(0.8mg/Kg),而顺式-铂的最大T/C(%)为171(1.6mg/Kg),抗皮下注射移植的M5076肉瘤,静脉注射治疗最大的T/C(%)为126(3mg/Kg),而顺式-铂最大的T/C(%)为135(4mg/Kg)。
尤其使人感兴趣的是该化合物(TNO-40)对于顺式-铂已产生抗性的人卵巢癌A2780的细胞系(A2780/124和2780/DDP)具有抗肿瘤作用。这里判断标准是抑制细胞生长的浓度IC50A2780/124或IC50A2780/DDP与IC50A2780的比值≤4.0。对于TNO-40,比值分别为
3.3和3.6。对于顺式-铂,相应的比值分别为10和12.6。
按照实质上已知的方法,将得到的有效化合物制成药用制剂。其中可应用常用的添加剂。
本发明的有效化合物可以按照实质上已知的方法制备。以下述实例详细叙述制备方法。
实例Ⅰa
顺式-二氯-1,1-双(氨甲基)环戊烷-铂-(Ⅱ)
35.5g(0.086mol)氯亚铂酸钾(K2PtCl4)和17.2g1,1-双(氨甲基)-环戊烷二盐酸盐溶于200ml蒸馏水中。
将溶液温热至90°-95℃。
以一定的速度加入6.9gNaOH在70ml蒸馏水中的溶液,以致于使PH≤7(最终PH=7.5)。
生成的固体物质用抽滤法滤出,并用蒸馏水(50ml)和丙酮(25ml)漂洗。经干燥的固体物质溶于600~800ml液态氨中。滤去不溶部分。蒸发氨以后,产物用2NHCl(50ml)和蒸馏水(100ml)洗涤,并于干燥器中用氢氧化钾干燥。干重为23g(68%)。
元素分析:
计算值(%,按重量计)C:21.33 H:4.09 N:7.11
实测值(%,按重量计)C:21.25 H:4.13 N:7.27
′H-NMR谱(溶剂为DMSO-d6,VARIAN T-60)
(相对于TMS的化学位移,以ppm表示)
CH2(环):1.46
CH2(NH2):2.18
NH2:4.90(卫星信号4.30和5.55)
实例Ⅰb
四氯-1,1-双(氨甲基)环戊烷-铂-(Ⅳ)
3g(0.008mol)顺式-二氯-1,1-双(氨甲基)环戊烷-铂-(Ⅱ)悬浮于40ml蒸馏水中。
将悬浮液温热至70℃,随后边搅拌边通入氯气1小时。
向反应混合物中通入空气,以除去多余的氯气(温度=70℃)。
使反应混合物冷却,用抽滤法滤出固体物质,用蒸馏水洗涤,在减压下用氢氧化钾干燥,得到2.6g(73%)黄色固体物质。
元素分析:
计算值(%,按重量计)C:18:08 H:3.47 N:6.02
实测值(%,按重量计)C:18.06 H:3.46 N:6.14
′H-NMR谱(溶剂为DMSO-d6,VARIAN T-60)
(相对于TMS的化学位移,以ppm表示)
CH2(环):1.50
CH2(NH2):2.23
NH2:6.80(卫星信号6.33和7.20)
实例Ⅰc
顺式-硫酸根合-反式-二氯-1,1-双(氨甲基)环戊烷-铂-(Ⅳ)
将3.5g(0.0075mol)四氯-1,1-双(氨甲基)-环戊烷-铂-(Ⅳ)悬浮于110ml蒸馏水中。向该悬浮液中加入2.21g(0.007mol)硫酸银,混合物在避光下搅拌24小
时。
滤出生成的氯化银,用蒸馏水(20ml)漂洗。
清晰的黄色滤液于减压下蒸发,得到3.0g(81%)黄色固体物质。
元素分析:
计算值(%,按重量计),含二个结晶水:
C:15.98 H:3.83 N:5.32 pt:37.07
Cl:13.47 O:18.24 S:6.09
实测值(%,按重量计)
C:16.05 H:3.94 N:5.35 pt:36.99 Cl:13.65
O:18.08 S:6.09
′H-NMR谱(溶剂为D2O,VARIAN T-60)
(相对于三甲基甲硅烷基丙烷磺酸钠盐的化学位移,以ppm表示)
CH2(环):1.63
CH2(NH2):2-2.6
H2O/D2O:4.73
测定以上制备的化合物的生物效果。
体外细胞毒性
评价铂复合物在体外对下述细胞系的细胞毒性作用:B16-F10鼠黑素瘤、HCT-116人结肠癌、A2780人卵巢癌以及对顺式-铂有抗性的A2780的两个亚系。将B16-F10细胞系保存在由Earle氏盐(Gibco)、2mmolL-谷氨酰胺、2.06mmol丙酮酸钠、胰岛素(0.26单位/ml)、青霉素/链霉素(分别为10单位/ml和10mcg/ml)、MEM非必需氨基酸
(0.6%,按重量计,Gibco)和小牛血清(10%,按重量计,Hyclone)组成的伊格尔最低必需培养液(MEM)中。将HCT-116细胞培养在补充有2mmolL-谷氨酰胺、0.12mmolL-丝氨酸、0.17mmol天冬酰胺、1.5mmol丙酮酸钠、MEM必需氨基酸(0.625%,按重量计,Gibco)、MEM非必需氨基酸(0.67%,按重量计,Gibco)、MEM维生素(0.6%,Gibco)、小牛血清(10%,按重量计,Hyclone)和青霉素/链霉素(分别为10单位/ml和10mcg/ml)的McCoy氏5A改良培养液(Gibco)中。将A2780细胞系培养在补充有小牛血清(10%,按重量计,Hyclone)、2mmolL-谷氨酰胺和青霉素/链霉素的RPMI培养液1640(Gibco实验室)中。将所有的细胞系置于含5%(按体积计)CO2和高大气湿度的恒温箱中,于37℃保温。
呈对数生长的细胞通过温和的胰蛋白酶消化作用收集,并将4000个细胞加到96孔微量滴定板(Costar)中。将微量滴定板置于含5%(按体积计)CO2的恒温箱中,于37℃保温一夜,使细胞粘附在微量滴定板上。然后用铂复合物或顺式-铂处理细胞,并保温72小时。将微量滴定板翻转过来并摇动,以除去培养基、有药理学活性的化合物以及与滴定板粘附不牢的细胞。加入甲醛水溶液(10%)的磷酸盐缓冲液-生理盐水溶液,固定细胞10分钟。除去固定物,在空气中干燥微量滴定板,用0.0075%(按重量计)的结晶紫染色15分钟,洗涤两次,在空气中干燥。色斑用0.2ml0.1M乙酸/乙醇(1∶1)溶解,用Dynatech MR 600型微量滴定板读数计测定光密度。借助吸光度值的线性回归分析,计算半数抑制浓度,
即IC50值(引起50%细胞生长抑制的浓度,以mcg/ml表示)。
在体外细胞毒性试验的结果列于表A。所研究的化合物对5种细胞系均有细胞毒作用。但是最重要的事实是对顺式-铂有抗性的A2780人卵巢癌的二个亚系细胞(A2780/124和A2780/DDP)对本发明化合物敏感,这可以由IC50比值等于或小于4.0证明。
对L1210鼠白血病的作用
研究铂复合物对L1210鼠白血病的抗肿瘤作用。将L1210白血病的106腹水细胞通过腹膜内注射接种到体重为20g的CDF1小白鼠体内。在通过腹膜内接种肿瘤细胞的当天开始给予该活性复合物。通过腹膜内注射给予不同剂量的复合物。每个剂量用6只小白鼠为一组,给药当天以单次剂量给予复合物。试验中10只对照组小白鼠给予生理盐水溶液。用顺式-二胺-二氯-铂(顺式-铂)处理的小白鼠作为阳性对照。处理前将小白鼠称重,处理后第5天或第6天再次称重,各组动物体重的平均变化作为评价毒性大小的指标。每天检查动物的死亡率,在30天后结束试验。根据T/C%确定抗肿瘤的活性,T/C%是用有效复合物处理组平均存活时间与用生理盐水溶液处理的对照组平均存活时间的比值再乘以100而得到。用生理盐水溶液处理的小白鼠平均存活时间一般为7天。当T/C≥125%时,受试化合物被认为是有效的。
表B总结了该复合物对L1210鼠白血病的抗肿瘤效果。表B还列出了各个试验剂量测得的T/C%值。在本试验观察的各个剂量下,所研究的化合物TNO-40是有效的,在4mg/Kg剂量下最大的T/C为193%。
抗B16黑素瘤的作用
评价有效化合物(TNO-40)对B16黑素瘤的抗肿瘤作用。每组10只BDF1小白鼠经腹膜内注射接种0.5ml10%(重量/体积)B16黑素瘤的均匀组织匀浆悬液。在移入肿瘤细胞后1天开始经腹膜内注入该有效化合物,每天给药一次,连续9天。在每次试验中,对照组给予生理盐水溶液,用顺式-铂处理组作为阳性对照。每天统计存活的小白鼠数,60天后停止试验。用该有效化合物处理的小白鼠与对照组小白鼠的平均存活时间的比值(T/C%)作为抗肿瘤作用的指标。当T/C(%)为125时,受试化合物被认为是有效的。
表C总结了这些金属复合物的试验结果,表中还列出了各个剂量下测得的T/C(%)。每次注射量为0.4、0.8和1.6mg/Kg时,本发明化合物是有效的,每次注射0.8mg/Kg剂量时,最大T/C(%)为163。
抗M5076网状细胞肉瘤的作用
还评价了本发明的复合物对经皮下注射移植的M5076肉瘤的抗肿瘤作用。每组8只BDF1小白鼠,经皮下注射接种M5076肿瘤。在移植肿瘤之后第5天开始经静脉给小白鼠复合物,并且在第9、13和17天再各给1次。因此总共给予4次复合物。试验了复合物的4个剂量。本试验还包括用生理盐水溶液处理组和用顺式-铂处理组作为对照。每天统计小白鼠存活数,试验在75~80天之后结束。根据a)和b)确定化合物的抗肿瘤作用,a)是用有效化合物处理的小白鼠与对照组小白鼠平均存活时间的比值(T/C%),b)是用有效化合物处理的小白鼠经皮下移植的肿瘤长至重1g所需要的平均
时间与对照组小白鼠经皮下移植的肿瘤达到重1g所需要的平均时间的差值(T-C)。如果T/C≥125%,或T-C≥13天,那么该复合物被认为是有效的。
用铂复合物试验的结果总结在表D中,表中给出了各个剂量下的T/C和T-C。每次注射量为3、4mg/Kg时,研究的化合物是有效的,其T/C%值分别为126%和125%,T-C值分别为16.8天和20.3天。
表B
对L1210鼠白血病的抑制作用
化合物 剂量*%T/C
顺式-铂 4 131
6 138
8 131
10 138
TNO-40 2.5 179
4 193
6 186
8 180
*腹膜内注射,剂量为mg/kg,1天1次。
表C
对B16黑素瘤的抑制作用
化合物 剂量*%T/C
顺式-铂 0.4 117
0.8 137
1.6 171
2.4 146
TNO-40 0.2 127
0.4 137
0.8 163
1.6 139
2.4 83
*腹膜内注射,每次注射的剂量为mg/kg,第1-9天给药。
表D
对M5076肉瘤的抑制作用
化合物 给药途径 剂量*%T/C T-C
(天)
顺式-铂 静脉注射 3 134 18.3
4 135 16.3
5 131 20.5
6 121 20
TNO-40 静脉注射 3 126 16.8
4 125 20.3
5 toxic
6 toxic
*静脉注射,剂量为mg/kg,第5、9、13和17天给药。
说明书所提到的化合物的分子式如下:
Claims (1)
Applications Claiming Priority (2)
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NL8802149 | 1988-08-31 | ||
NL8802149A NL8802149A (nl) | 1988-08-31 | 1988-08-31 | Platina-(iv)diaminecomplex, werkwijze voor het bereiden van deze verbinding, preparaat met anti-tumor werking, dat ten minste een platinaverbinding bevat, alsmede gevormde preparaten met anti-tumor werking. |
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CN1021912C true CN1021912C (zh) | 1993-08-25 |
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EP (1) | EP0357108A3 (zh) |
JP (1) | JPH02108693A (zh) |
KR (1) | KR900003187A (zh) |
CN (1) | CN1021912C (zh) |
AU (1) | AU619881B2 (zh) |
DK (1) | DK427689A (zh) |
FI (1) | FI893877A (zh) |
HU (1) | HU203246B (zh) |
IL (1) | IL91087A0 (zh) |
NL (1) | NL8802149A (zh) |
NO (1) | NO893483L (zh) |
NZ (1) | NZ230127A (zh) |
OA (1) | OA09128A (zh) |
PT (1) | PT91568A (zh) |
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ZA (1) | ZA895865B (zh) |
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WO1990012018A1 (en) * | 1989-04-04 | 1990-10-18 | Daikin Industries, Ltd. | New fluorocarbon platinum complexes |
US5196555A (en) * | 1989-10-17 | 1993-03-23 | Bristol-Myers Squibb Company | Water and solvent soluble axial hydroxy and mono- and di- carboxylic acid derivatives having high tumor activity |
US5238955A (en) * | 1990-04-10 | 1993-08-24 | Asta Pharma Ag | Ethylene-substituted phenylalkylethylenediamine-platinum (II or IV) derivatives and phenylalkylethylenediamines |
NZ237443A (en) * | 1990-04-10 | 1993-11-25 | Asta Medica Ag | Phenalkylethylenediamine and aminomethyltetra hydroisoquinoline derivatives, platinum (ii) and (iv) complexes, methods of preparation and pharmaceutical compositions |
GB9020129D0 (en) * | 1990-09-14 | 1990-10-24 | Johnson Matthey Plc | Improvements in refining |
JP4664424B2 (ja) * | 2008-09-03 | 2011-04-06 | ユニーテック株式会社 | 白金錯体及びそれを含む医薬組成物 |
CN101492539B (zh) * | 2008-10-09 | 2011-11-16 | 北京联合大学 | 二氯聚天冬氨酸铂 |
JP4621285B2 (ja) * | 2009-01-19 | 2011-01-26 | ユニーテック株式会社 | 金錯体及びそれを含む医薬組成物 |
JP5179628B2 (ja) * | 2011-07-15 | 2013-04-10 | ユニーテック株式会社 | 4価白金錯体及びそれを含む医薬組成物 |
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NL8204067A (nl) * | 1982-10-21 | 1984-05-16 | Tno | Platina-diaminecomplexen, werkwijze voor het bereiden daarvan, werkwijze voor het bereiden van een geneesmiddel met toepassing van een dergelijk platinadiaminecomplex voor de behandeling van kanker, alsmede aldus verkregen gevormd geneesmiddel. |
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-
1988
- 1988-08-31 NL NL8802149A patent/NL8802149A/nl not_active Application Discontinuation
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1989
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- 1989-07-28 NZ NZ230127A patent/NZ230127A/en unknown
- 1989-07-31 US US07/386,881 patent/US5028727A/en not_active Expired - Fee Related
- 1989-08-10 ZA ZA895865A patent/ZA895865B/xx unknown
- 1989-08-15 AU AU39928/89A patent/AU619881B2/en not_active Ceased
- 1989-08-17 FI FI893877A patent/FI893877A/fi not_active Application Discontinuation
- 1989-08-18 OA OA59628A patent/OA09128A/xx unknown
- 1989-08-21 YU YU01625/89A patent/YU162589A/xx unknown
- 1989-08-29 PT PT91568A patent/PT91568A/pt unknown
- 1989-08-30 DK DK427689A patent/DK427689A/da not_active Application Discontinuation
- 1989-08-30 HU HU894503A patent/HU203246B/hu not_active IP Right Cessation
- 1989-08-30 CN CN89106648A patent/CN1021912C/zh not_active Expired - Fee Related
- 1989-08-30 JP JP1221854A patent/JPH02108693A/ja active Pending
- 1989-08-30 NO NO89893483A patent/NO893483L/no unknown
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DK427689D0 (da) | 1989-08-30 |
US5028727A (en) | 1991-07-02 |
AU619881B2 (en) | 1992-02-06 |
NO893483D0 (no) | 1989-08-30 |
CN1040591A (zh) | 1990-03-21 |
FI893877A (fi) | 1990-03-01 |
HU203246B (en) | 1991-06-28 |
NZ230127A (en) | 1991-06-25 |
ZA895865B (en) | 1990-05-30 |
YU162589A (en) | 1991-02-28 |
KR900003187A (ko) | 1990-03-26 |
IL91087A0 (en) | 1990-03-19 |
AU3992889A (en) | 1990-03-08 |
EP0357108A2 (en) | 1990-03-07 |
HUT53113A (en) | 1990-09-28 |
NL8802149A (nl) | 1990-03-16 |
PT91568A (pt) | 1990-03-30 |
NO893483L (no) | 1990-03-01 |
FI893877A0 (fi) | 1989-08-17 |
DK427689A (da) | 1990-03-01 |
EP0357108A3 (en) | 1990-12-27 |
OA09128A (en) | 1991-10-31 |
JPH02108693A (ja) | 1990-04-20 |
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