Platinum complex, its preparation and therapeutic application

A platinum complex and complex technology, applied in the direction of platinum group organic compounds, platinum group organic compounds, heavy metal compounds, etc., can solve the problem of being unsuitable for oral administration, and achieve broad-spectrum anti-tumor activity and strong efficacy. Effect

Inactive Publication Date: 2001-07-11
PLIVA LACHEMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the two compounds mentioned are only for parenteral administration, neither of them are suitable for oral administration

Method used

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  • Platinum complex, its preparation and therapeutic application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Synthesis of af-bis(acetate ion)-b-(l-adamantine)-c-ammine-de-dichloroplatinum(IV) complex (hereinafter referred to as "LA-12")

[0020] Stir 6.25 g (13.3 mmol) of b-(1-adamantine)-c-ammine-de-dichloro-af-dihydroxyplatinum(IV) complex with excess acetic anhydride (50.2 ml, 532 mmol) at room temperature . During this time, solids continued to precipitate from the original solution. After the precipitation had ceased, the solid was filtered and washed with a small amount of acetic anhydride and ether. After drying in a vacuum desiccator, 4.28 g (58.2%) of the title product were obtained.

[0021] The identity of the obtained product was confirmed by 1H and 13C NMR spectroscopy and far infrared spectroscopy, and its purity was confirmed by high performance liquid chromatography.

[0022] Product C 14 h 26 Cl 2 N 2 o 4 Elemental analysis of Pt:

[0023] C(%) H(%) N(%) Cl(%)

[0024] Measured value 30.24 4.75 4.99 12.81

[0025] Calculated value 30.44 4....

Embodiment 2

[0027] af-bis(acetate ion)-b-(l-amino-3,5-dimethyladamantane)-c-ammine-de-dichloroplatinum (IV) complex (hereinafter referred to as "LA-15" )Synthesis

[0028] Stir 0.96 g (1.93 mmol) of b-(1-amino-3,5-dimethyladamantane)-c-ammine-de-dichloro-af with excess acetic anhydride (8 ml, 84.7 mmol) at room temperature - Dihydroxyplatinum(IV) complexes. After dissolution, 10 ml of ether was added to the reaction mixture. Stirring was continued until precipitation ceased. The precipitated solid was filtered, rinsed with ether and dried in a vacuum desiccator to yield 0.72 g (64.3%) of the title product.

[0029] The identity of the obtained product was confirmed by 1H and 13C NMR spectroscopy and far infrared spectroscopy, and its purity was confirmed by high performance liquid chromatography.

[0030] Product C 16 h 30 Cl 2 N 2 o 4 Elemental analysis of Pt:

[0031] C(%) H(%) N(%) Cl(%)

[0032] Measured value 32.88 5.21 4.75 12.31

[0033] Calculated 33.11 5.21 ...

Embodiment 2a

[0035] Synthesis of b-(1-adamantine)-c-ammonia-de-dichloro-af-dihydroxyplatinum (Ⅳ) complex (hereinafter referred to as LA-11)

[0036] 8.01 g (18.44 mmol) of cis-(1-adamantine)-ammonia-dichloroplatinum(II) complex were suspended in 120 ml of water at room temperature. A stoichiometric excess (20 ml) of 30% (w / w) hydrogen peroxide in water was added to the suspension and the reaction mixture was heated at 80°C for 1 hour and then cooled to room temperature. The solid was isolated by filtration, rinsed with water and partially dried. The product was extracted and rinsed with a total of 150 ml of dimethylformamide. Rinse with ether to remove remaining dimethylformamide. After drying in a vacuum desiccator, the yield was 6.45 g, ie 74.6% of theory (relative to the starting platinum(II) complex).

[0037] The identity of the product was determined by far-infrared spectroscopy and its purity was determined by high-performance liquid chromatography.

[0038] The resulting produc...

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Abstract

Disclosed is a platinum complex formula (I) wherein X represents a halogen atom, B represents, independently to each other, a halogen atom, a hydroxyl group or a carboxylate group containing 1 to 6 carbon atoms, and A represents a primary tricyclic amine containing 10 to 14 carbon atoms which may be optionally substituted on the tricyclic ring by one or two alkyl group(s) each containing 1 to 4 carbon atoms, and, furthermore, an inclusion complex of the above platinum complex with beta- or gamma-cyclodextrin which may be optionally substituted by hydroxyalkyl groups containing 1 to 6 carbon atoms. There is also disclosed a process for the manufacture of the complex of formula (I) based on oxidation of a complex of divalent platinum of formula (II) with hydrogen peroxide and on optional substitution of hydroxyl groups in the obtained product with carboxylate groups by action of an acylating agent. The disclosed complexes may be used as such or as a part of pharmaceutical composition in a therapy of oncologic diseases.

Description

field of invention [0001] The present invention relates to a novel platinum complex for treating tumor diseases in medical practice. The invention also discloses a method for preparing the complex, the application of the complex as medicine, and a pharmaceutical composition containing the platinum complex as an active substance. Background of the invention [0002] In the late 1970s, platinum complexes as effective cytostatic agents were introduced into medical practice. The first generation of platinum complexes was cisplatin (cis-diamminedichloroplatinum(II)). During the further development of the above complexes, ten platinum complexes were synthesized and tested; among them, carboplatin became one of the most important substances for the treatment of tumors. However, said two compounds can only be administered parenterally, neither of them are suitable for oral administration. As far as oral administration is concerned, some of the tetravalent platinum complexes discl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/28A61K31/282C07C211/38A61P35/00C07F15/00C08B37/16
CPCC07F15/0093A61P35/00
Inventor 弗兰特塞克·扎克阿道夫·米斯特尔安娜·波洛瓦米兰·梅尔卡雅罗斯拉夫·图拉奈克达纳·扎卢斯卡
Owner PLIVA LACHEMA
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