[Dichloro-1,2-cyclohexanediamine]platinum complex and preparation method thereof

A technology of cyclohexanediamine and platinum complexes is applied in the directions of pharmaceutical formulations, active ingredients of heavy metal compounds, and medical preparations of non-active ingredients, etc. Biocompatibility, the effect of enhancing the therapeutic effect

Active Publication Date: 2013-11-20
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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Problems solved by technology

However, the obtained micelles are formed by cross-linking between the side chains of linear polyamino acids, and the ...

Method used

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  • [Dichloro-1,2-cyclohexanediamine]platinum complex and preparation method thereof
  • [Dichloro-1,2-cyclohexanediamine]platinum complex and preparation method thereof
  • [Dichloro-1,2-cyclohexanediamine]platinum complex and preparation method thereof

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[0055] The embodiment of the present invention also discloses a preparation method of a dichloro-1,2-cyclohexanediamine platinum complex, comprising the following steps: dichloro-1,2-cyclohexanediamine platinum and a compound having the formula (I ) structure of the polymer undergoes a coordination reaction in an aqueous medium to form a dichloro-1,2-cyclohexanediamine platinum complex;

[0056]

[0057] In formula (I), R 1 Independently selected from C2~C10 straight chain alkyl, C3~C10 branched chain alkyl, phenyl or R'-CO-, R' independently selected from C2~C10 straight chain alkyl, C3~C10 branched alkyl or phenyl, R 1 Preferably C3-C8 straight-chain alkyl, C4-C8 branched-chain alkyl, phenyl, more preferably C6 alkyl;

[0058] R 2 Independently selected from H atom, C1~C20 alkyl or substituted C1~C20 alkyl, preferably H atom, C1~C10 alkyl or substituted C1~C10 alkyl, the substituted alkyl The substituents are selected from one or more of ketal, aldol, hydroxyl, aldehy...

Embodiment 1

[0087] 10g of γ-benzyl-L-glutamic acid was added to 100ml of anhydrous tetrahydrofuran under the condition of dry inert gas, fully reacted under the action of 6.5g of triphosgene, then petroleum ether was added to settle to obtain a solid, weighing After crystallization and drying, 7.85g of γ-benzyl-L-glutamic acid-N-carboxylic acid anhydride (BLG-NCA) monomer was finally obtained; under the condition of inert gas, the dimethylformamide (DMF) solution of n-hexylamine Add to the DMF solution of BLG-NCA, the ratio of n-hexylamine to γ-benzyl-L-glutamic acid-N-carboxylic acid anhydride (BLG-NCA) is 1:140, after the reaction, add ether to settle, and filter to obtain Solid, after drying, a glutamic acid copolymer with a benzyl protecting group with a degree of polymerization of 140 is obtained; after deprotection, a glutamic acid copolymer with a structure of formula (II) with a degree of polymerization of 140 is obtained, denoted as PLG 140 .

[0088] Add 1.010g of PLG prepared ...

Embodiment 2

[0091] The P(Glu) prepared by 54.0mg embodiment 1 140 -g-(mPEG 5k ) 7 Dissolve in 25mL double-distilled water, adjust the pH value to about 8.0, add 24.6mg dichloro-1,2-cyclohexanediamine platinum, react in the dark at 37°C for 72h, dialyze in pure water for 24h, change the water 6 times to remove free Dichloro-1,2-cyclohexanediamine platinum, to obtain micelles of dichloro-1,2-cyclohexanediamine platinum complex; the dichloro-1,2-cyclohexanediamine platinum The micelles of the complex were quickly frozen under aseptic conditions, and freeze-dried to obtain the freeze-dried powder of dichloro-1,2-cyclohexanediamine platinum complex, and the conversion rate was 85%.

[0092] Determination of the hydrodynamic radius of micelles, the results are shown in figure 1 , figure 1 The hydrodynamic radius distribution diagram of the dichloro-1,2-cyclohexanediamine platinum complex prepared in Example 2 of the present invention, the results show that the dichloro-1,2-cyclohexanediamin...

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Abstract

The invention provides a [dichloro-1,2-cyclohexanediamine]platinum complex, and the complex is obtained from the complex reactions between dichloro-1,2-cyclohexanediamine and a polymer which has the structure of the formula (I). The [Dichloro-1,2-cyclohexanediamine]platinum has a cyclohexanediamine structure, a stable inner-core structure is formed because of the accumulation and hydrophobic effect after the [Dichloro-1,2-cyclohexanediamine]platinum cooperate with a polymer, and the stability of the [Dichloro-1,2-cyclohexanediamine]platinum is good under physiology conditions. The complex can effectively avoid the problems of sudden release and non-specific interaction of [Dichloro-1,2-cyclohexanediamine]platinum after [Dichloro-1,2-cyclohexanediamine]platinum enters the blood circulation system through intravenous route. The complex can be assembled to form a micelle structure; accumulation of the complex on the tumor locations can be achieved through strengthening osmotic and retention effects, and thus the goals of reducing toxic and by effects and improving curative effects are achieved. Furthermore, the adopted complex has a good biological compatibility, is capable of degrading in human bodies, and thus the prepared [Dichloro-1,2-cyclohexanediamine]platinum has a good solubility.

Description

technical field [0001] The invention relates to the field of polymer medicine, in particular to a dichloro-1,2-cyclohexanediamine platinum complex and a preparation method thereof. Background technique [0002] Oxaliplatin (oxalate-1,2-cyclohexanediamine-platinum) is an anticancer drug with cytotoxicity. Due to its broad therapeutic spectrum and no cross-resistance with cisplatin, it has become the third A representative of platinum-substituting drugs, it was approved for clinical use by the US Food and Drug Administration in 2002. [0003] After oxaliplatin enters the body, it needs to undergo hydrolysis to produce dichloro-1,2-cyclohexanediamine platinum or hydrated 1,2-cyclohexanediamine platinum, and then combine with DNA or RNA to play an anti-tumor effect (B .Desoize, et al.Critical Reviews in Oncology / Hematology, 42(2002) 317-325), so dichloro-1,2-cyclohexanediamine platinum (DACHPt) can be regarded as a prodrug of oxaliplatin. As a homologue of oxaliplatin, dichlor...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/282A61P35/00A61K47/59
Inventor 汤朝晖宋万通于海洋李明强陈学思
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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