CN1653082A - 具有抗肿瘤活性的铂络合物 - Google Patents
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 21
- 229910052697 platinum Inorganic materials 0.000 abstract description 13
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- 206010028980 Neoplasm Diseases 0.000 description 8
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 4
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- 239000004332 silver Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
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- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010033109 Ototoxicity Diseases 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- -1 Platinum Metals Chemical class 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 0.000 description 1
- BKXCRQIRUZQLQP-UHFFFAOYSA-N [Pt].P(O)(O)(O)=O Chemical compound [Pt].P(O)(O)(O)=O BKXCRQIRUZQLQP-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
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- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
Abstract
本发明涉及其中金属的配体为脱氢胆酸和膦的具有抗肿瘤活性的铂络合物。
Description
发明领域
本发明涉及具有抗肿瘤活性的铂(II)络合物，特别是其中金属被膦和脱氢胆酸配位的络合物。
技术背景
自从发现顺铂的抗肿瘤性质[B.Rosenberg等，Nature 205，698，1965；222，385(1972)]以来，许多研究均集中于开发毒性更低且对肿瘤细胞选择性更高的铂络合物。事实上，尽管顺铂产生中毒性肾损害和耳毒性，但当在治疗睾丸、卵巢、头和颈的肿瘤的组合化疗中使用时其特别有效。
对其中两个配位位置被氨基配体占据而两个其它配位位置被类固醇衍生物的官能团占据的铂络合物已有描述。
发明详述
本发明涉及其中金属被脱氢胆酸和膦配位的具有抗肿瘤活性的铂(II)络合物，特别是式(1)的络合物顺式-[二(三苯基膦)-脱氢胆酸铂(II)]：
化合物(1)根据以下方案获得：使脱氢胆酸银(2)与顺式-[PtCl2(PPh3)2]反应，而(2)通过使脱氢胆酸(3)与氧化银反应获得：
通常，脱氢胆酸与氧化银之间的反应在水中进行，于回流下加热直至氧化银黑色残渣消失。
银盐(2)与顺式-[PtCl2(PPh3)2]络合物之间的反应优选如下进行：将顺式-[PtCl2(PPh3)2]络合物溶解在二氯甲烷中并将银盐混悬直至Ag2O完全沉淀，通过离心、过滤以及任选地通过用活性炭处理将其从反应混合物中除去。或者，反应可在盐(2)和顺式-[PtCl2(PPh3)2]络合物均不溶于其中的溶剂、优选丙酮和乙酸乙酯中和化合物(1)溶于其中的溶剂中进行。
根据Mc Dermott J.X.，White J.F.，Whitesides M.J.Am.Chem.Soc.1976，98，5621所述通过使顺式-[PtCl2(1，5-环辛二烯)]与三苯基膦在二氯甲烷中反应或者根据Bailar John C.Jr，Ilatani H.Inorganic Chemistry，第4卷，第11期，1965所述通过使K2PtCl4与三苯基膦在乙醇中反应获得顺式-[PtCl2(PPh3)2]络合物。
当施用于患有可用顺铂治疗或对顺铂具有抗性的肿瘤的人或动物时，化合物(1)能够诱导所述肿瘤消退。
化合物(1)可用于治疗那些使用顺铂的病症，特别是用于治疗肿瘤[Douple等，“顺铂现状和发展”，编辑A.W.Prestayk等，Academic Press，125(1980)；Douple等，Platinum Metals Res.，29；118(1985)]。
因此，本发明还涉及含有与常规载体和赋形剂混合的治疗有效量的化合物(1)的药物组合物。
化合物(1)的有效剂量将由熟练的内科医生根据常规方法确定。Freirech等，在小鼠、大鼠、仓鼠、狗、猴和人中抗癌药毒性的定量比较。Cancer Chemother.Rep，50，第4期，219-244(1986)描述了用于各种种类和大小的动物的剂量与用于人的剂量(基于mg/m2身体面积)之间的关系。患者接受的络合物剂量为0.1至200mg/kg体重，剂量方案将根据熟练临床医生公知的多种因素而改变，并且治疗方案将根据待治疗的肿瘤类型以及患者的状况而改变。
化合物(1)可通过口服、胃肠外、局部或肿瘤内途径施用。
用于胃肠外施用的药物组合物包括盐水无菌溶液或混悬液或用于临时制备溶液或混悬液的无菌粉末。用于胃肠外施用的药物组合物还包括用于肌内或腹腔内施用的油性制剂。
用于口服施用的药物组合物包括例如糖浆剂或类似的液体形式以及固体形式如片剂、胶囊剂等。
本发明的药物组合物根据常规方法制备，如Remington′sPharmaceutical Sciences Handbook，第XVII版，Mack Pub.，纽约，美国中所报道的那些方法。
如在GB 2,174,905和在US 4,871,528中所公开的那样，化合物(1)可以与一种或多种增强其抗肿瘤活性或减轻伴随铂络合物治疗的副作用的物质一起施用，例如与还原型谷胱甘肽一起施用。
络合物(1)也可以有利地与具有抗肿瘤活性的其它铂络合物一起施用，因此本发明的另一目的是含有与具有抗肿瘤活性的铂络合物组合的化合物(1)的药物组合物。
本发明还涉及化合物(1)在制备药物组合物中的用途，所述药物组合物用于治疗患有可用顺铂治疗或对顺铂具有抗性的肿瘤的哺乳动物。
通过以下实施例更详细地举例说明本发明。
实施例
材料和方法
在300MHz频率下用Varian Gemini分光计300MHz记录1H-NMR谱。化学位移以ppm表示。
在75.1MHz频率下用Varian Gemini分光计300MHz记录三元酸(11a)的13C-NMR谱。化学位移以ppm表示。
用NICOLET510P傅里叶变换分光光度计在KBr中记录红外光谱。
制备1：顺式-[PtCl2(PPh)3]的合成
方法1
a)顺式-[PtCl2(1，5-环辛二烯)]
将5g K2PtCl4(12毫摩尔)溶解在80ml水和80ml冰醋酸中。向得到的红色溶液中加入6ml(48摩尔)1，5-环辛二烯并回流70-80分钟，在此期间形成白色胶质固体在浅黄色液体中的溶液。将该溶液在减压下浓缩至小体积并通过多孔隔膜过滤。将产物在滤器上用水洗涤，然后干燥至恒重，然后再用正己烷洗涤以除去环辛二烯残余物。得到4.1g(10.95毫摩尔)产物，为白色固体(产率：91％)。
b)顺式-[PtCl2(PPh3)2]
向2.6g(7毫摩尔)顺式-[PtCl2(1，5-环辛二烯)]在80ml CH2Cl2中的溶液中逐滴加入3.7g(14毫摩尔)PPh3在100ml CH2Cl2中的溶液。
加入结束后10分钟，在减压下蒸除溶剂，将残余物用正己烷洗涤并通过多孔隔膜过滤。
得到5g(6.3毫摩尔)产物，为白色固体(产率：90％)。
方法2
将5g(19.3毫摩尔)PPh3在60ml热乙醇中的溶液回流。向其中滴加4g(9.64毫摩尔)K2PtCl4在50ml水中的溶液，并将混合物在搅拌下于60℃保持2小时。
将沉淀出的络合物通过多孔隔膜趁热过滤、用水、热乙醇洗涤，并在P2O5上干燥。
得到6.85g(8.66毫摩尔)白色固体(产率：90％)。
制备2
在搅拌下，向避光的5g(29.4毫摩尔)AgNO3在约30ml水中的溶液中缓慢加入1.9g(33.8毫摩尔)KOH在20ml水中的溶液。立即沉淀出黑色片状固体形式的Ag2O。搅拌若干分钟后，将混合物在真空下通过多孔隔膜过滤。将沉淀反复用水和甲醇洗涤，然后干燥至恒重。
产率：3.2g(13.8毫摩尔)，94％。
制备3：脱氢胆酸银的合成
将3.2g(13.8毫摩尔)Ag2O和12.75g(31.7毫摩尔)脱氢胆酸(比例1∶2.3)在约250ml水中的混悬液在剧烈搅拌下回流直至Ag2O黑色残渣消失(有效搅拌下5-6小时)。将混合物在冰浴上冷却并过滤，将沉淀反复用水和丙酮洗涤，干燥至恒重，并任选地用CHCl3洗涤以除去任何过量的脱氢胆酸。
得到13.8g(27.1毫摩尔)脱氢胆酸银，为米白色固体。
产率：86％。
制备4：顺式-[(PPh3)2Pt(RCOO)2]脱氢磷酸铂
将6.4g(12.6毫摩尔)脱氢胆酸银混悬于5g(6.3毫摩尔)顺式-[PtCl2(PPh3)2]在400ml CH2Cl2中的溶液中，并将混合物避光搅拌过夜。
将沉淀出的AgCl通过离心除去并通过在多孔隔膜上的硅藻土反复过滤以获得澄明溶液(如果过滤不足以获得澄明溶液，则用活性炭脱色)。在减压下蒸除溶剂，得到产物，为白色固体。
产率：50-70％。
31P-NMR(CDCl3)：6.6(1JPPt3813)
1H-NMR(CDCl3)：0.68(6H，d，21-CH3)；0.95(6H，s，CH3)；1.36(6H，s，CH3)；1.43-2.35(48H，m，脂族CH，CH2)；2.8(6H，m，邻近CO的CH)，7-7.6(60H，m，芳族CH)。
FT-IR(cm-1)1771(s，v CO)；1629(m)；1435(m)；1332(m)；1098(m)；693(s)；529(s)。
元素分析(对C84H96O10P2Pt的计算)
计算值：C 66.2％，H 6.3％
实测值：C 62.8％，H 5.9％
Claims (3)
1.式(1)化合物：
2.式(1)化合物在制备药物组合物中的用途。
3.含有与适宜的赋形剂和/或载体混合的式(1)化合物的药物组合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2002MI000993A ITMI20020993A1 (it) | 2002-05-10 | 2002-05-10 | Complessi di platino ad attivita' antitumorale |
| ITMI2002A000993 | 2002-05-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1653082A true CN1653082A (zh) | 2005-08-10 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA038105314A Pending CN1653082A (zh) | 2002-05-10 | 2003-05-08 | 具有抗肿瘤活性的铂络合物 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US7205287B2 (zh) |
| EP (1) | EP1504019B1 (zh) |
| JP (1) | JP2005533763A (zh) |
| CN (1) | CN1653082A (zh) |
| AT (1) | ATE302791T1 (zh) |
| AU (1) | AU2003236633B2 (zh) |
| CA (1) | CA2485431A1 (zh) |
| DE (1) | DE60301404T2 (zh) |
| DK (1) | DK1504019T3 (zh) |
| EA (1) | EA200401316A1 (zh) |
| ES (1) | ES2247544T3 (zh) |
| HR (1) | HRP20041016A2 (zh) |
| IL (1) | IL165123A (zh) |
| IS (1) | IS7522A (zh) |
| IT (1) | ITMI20020993A1 (zh) |
| MX (1) | MXPA04011056A (zh) |
| NO (1) | NO20044876L (zh) |
| NZ (1) | NZ536457A (zh) |
| PL (1) | PL372553A1 (zh) |
| PT (1) | PT1504019E (zh) |
| WO (1) | WO2003095470A1 (zh) |
| ZA (1) | ZA200409061B (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030784A (zh) * | 2010-11-26 | 2011-04-27 | 金川集团有限公司 | 一种顺-二(三苯基膦)二氯化铂(ii)的制备方法 |
| WO2012116644A1 (zh) * | 2011-03-02 | 2012-09-07 | Chen Jianhua | 一种靶向性抗肿瘤的化合物及其制备方法和用途 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2008331439B9 (en) * | 2007-12-07 | 2014-04-10 | Prana Biotechnology Ltd | Compounds for therapy and diagnosis |
| RU2667128C2 (ru) | 2016-12-29 | 2018-09-14 | Герман Петрович Беккер | Композиция для приготовления противоопухолевого средства и способ приготовления противоопухолевого средства на ее основе |
-
2002
- 2002-05-10 IT IT2002MI000993A patent/ITMI20020993A1/it unknown
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2003
- 2003-05-08 NZ NZ536457A patent/NZ536457A/en unknown
- 2003-05-08 WO PCT/EP2003/004828 patent/WO2003095470A1/en active IP Right Grant
- 2003-05-08 AT AT03735368T patent/ATE302791T1/de not_active IP Right Cessation
- 2003-05-08 JP JP2004503484A patent/JP2005533763A/ja active Pending
- 2003-05-08 ES ES03735368T patent/ES2247544T3/es not_active Expired - Lifetime
- 2003-05-08 DK DK03735368T patent/DK1504019T3/da active
- 2003-05-08 CA CA002485431A patent/CA2485431A1/en not_active Abandoned
- 2003-05-08 PT PT03735368T patent/PT1504019E/pt unknown
- 2003-05-08 EA EA200401316A patent/EA200401316A1/ru unknown
- 2003-05-08 MX MXPA04011056A patent/MXPA04011056A/es active IP Right Grant
- 2003-05-08 ZA ZA200409061A patent/ZA200409061B/en unknown
- 2003-05-08 CN CNA038105314A patent/CN1653082A/zh active Pending
- 2003-05-08 AU AU2003236633A patent/AU2003236633B2/en not_active Ceased
- 2003-05-08 EP EP03735368A patent/EP1504019B1/en not_active Expired - Lifetime
- 2003-05-08 PL PL03372553A patent/PL372553A1/xx unknown
- 2003-05-08 DE DE60301404T patent/DE60301404T2/de not_active Expired - Fee Related
-
2004
- 2004-10-22 US US10/971,900 patent/US7205287B2/en not_active Expired - Fee Related
- 2004-10-29 HR HR20041016A patent/HRP20041016A2/hr not_active Application Discontinuation
- 2004-11-09 IS IS7522A patent/IS7522A/is unknown
- 2004-11-09 IL IL165123A patent/IL165123A/en not_active IP Right Cessation
- 2004-11-09 NO NO20044876A patent/NO20044876L/no not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030784A (zh) * | 2010-11-26 | 2011-04-27 | 金川集团有限公司 | 一种顺-二(三苯基膦)二氯化铂(ii)的制备方法 |
| WO2012116644A1 (zh) * | 2011-03-02 | 2012-09-07 | Chen Jianhua | 一种靶向性抗肿瘤的化合物及其制备方法和用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| PL372553A1 (en) | 2005-07-25 |
| DE60301404T2 (de) | 2006-03-09 |
| EP1504019A1 (en) | 2005-02-09 |
| DK1504019T3 (da) | 2005-12-19 |
| CA2485431A1 (en) | 2003-11-20 |
| ITMI20020993A1 (it) | 2003-11-10 |
| DE60301404D1 (de) | 2005-09-29 |
| EP1504019B1 (en) | 2005-08-24 |
| IS7522A (is) | 2004-11-09 |
| NO20044876L (no) | 2004-11-09 |
| WO2003095470A1 (en) | 2003-11-20 |
| IL165123A (en) | 2009-09-01 |
| US20050107337A1 (en) | 2005-05-19 |
| MXPA04011056A (es) | 2005-02-14 |
| AU2003236633A1 (en) | 2003-11-11 |
| ES2247544T3 (es) | 2006-03-01 |
| HRP20041016A2 (en) | 2005-02-28 |
| EA200401316A1 (ru) | 2005-04-28 |
| ZA200409061B (en) | 2005-11-10 |
| JP2005533763A (ja) | 2005-11-10 |
| AU2003236633B2 (en) | 2008-02-28 |
| ATE302791T1 (de) | 2005-09-15 |
| PT1504019E (pt) | 2005-10-31 |
| US7205287B2 (en) | 2007-04-17 |
| IL165123A0 (en) | 2005-12-18 |
| NZ536457A (en) | 2006-07-28 |
| ITMI20020993A0 (it) | 2002-05-10 |
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