Vitamin C coupled platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and application thereof

A platinum complex and vitamin technology, applied in the field of vitamin C coupled platinum complexes, can solve the problems of toxicity, side effects, drug resistance, low water solubility, etc.

Active Publication Date: 2019-09-10
TIANJIN GUDUI BIOLOGICAL MEDICAL TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The fatal disadvantage of platinum-based anticancer drugs is that they have extremely strong toxic side effects and inherent and subsequent drug resistance problems
In addition, because these drugs are metal-organic compounds, all platinum-based drugs generally have extremely low water solubility. The water solubility of cisplatin, carboplatin, and oxaliplatin are 1.0, 17.0, and 6.0 mg / ml respectively.

Method used

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  • Vitamin C coupled platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and application thereof
  • Vitamin C coupled platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and application thereof
  • Vitamin C coupled platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Preparation of diaminoplatinum(II) [3-methylene-(2-O-L-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

[0082]

[0083] (1) Preparation of 3-benzyloxymethyl-cyclobutane-1,1-di-tert-butyl dicarboxylate

[0084]

[0085] Sodium hydride (286 mg) was suspended in 5 mL of N,N-dimethylformamide, the air in the flask was replaced with nitrogen, and the flask was placed in an ice bath. Under the protection of nitrogen, slowly add di-tert-butyl malonate (1.6mL) dropwise, and after 0.5 hours of reaction, slowly add 2-benzyloxymethyl-1,3-dibromopropane (1.15g) in N,N -Dimethylformamide (5 mL) solution, the reaction solution was warmed up to 70°C and stirred for 7 hours. Monitor the end point of the reaction with TLC. After the reaction is complete, cool the reaction solution to room temperature, add 100 mL of ethyl acetate to the reaction solution, then wash with saturated aqueous ammonium chloride (1×50 mL), and extract the aqueous phase with ethyl acetate. (2 x 25 mL), ...

Embodiment 2

[0113] Preparation of diaminoplatinum(II) [3-methylene-(3-O-L-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

[0114]

[0115] (1) Preparation of 5,6-O-isopropylidene-3-O-(3-methylene-cyclobutane-1,1-di-tert-butyl dicarboxylate) L-ascorbic acid

[0116]

[0117] Dissolve 5,6-O-isopropylidene L-ascorbic acid (0.8g) in 5mL dimethyl sulfoxide at room temperature, add sodium bicarbonate (0.3g), and stir the reaction solution for 20 minutes, then add Di-tert-butyl 3-bromomethyl-cyclobutane-1,1-dicarboxylate (0.9 g) was dissolved in dimethyl sulfoxide (5 mL), the temperature of the reaction solution was raised to 60° C., and stirred overnight. Monitor the end point of the reaction with TLC. After the reaction is complete, cool the reaction solution to room temperature, add 50 mL of water to the reaction solution for dilution, neutralize with 1M dilute hydrochloric acid, then extract with 100 mL of ethyl acetate, and use distilled water (1 ×100mL), washed with saturated sod...

Embodiment 3

[0128] Preparation of diaminoplatinum(II) [3-formic acid-(6-O-L-ascorbic acid) cyclobutane-1,1-dicarboxylic acid]

[0129]

[0130] (1) Preparation of 3-formic acid-cyclobutane-1,1-di-tert-butyl dicarboxylate

[0131]

[0132] 3-Hydroxymethyl-cyclobutane-1,1-di-tert-butyl dicarboxylate (0.8 g) was dissolved in 10 mL of acetone, and Jones reagent (chromium trioxide 420 mg, concentrated sulfuric acid 371 μL , diluted with water to 1.6mL), the reaction solution was slowly warmed up to room temperature, stirred for 2 hours, and the reaction was monitored by TLC. After the reaction was completed, a few drops of isopropanol were added dropwise to remove excess oxidant. The reaction solution was filtered with suction, and the solvent was evaporated to dryness with a rotary evaporator. The obtained green oil was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solv...

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PUM

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Abstract

A vitamin C coupled platinum complex shown in formula (I), an intermediate thereof, a preparation method thereof, a pharmaceutical composition and application thereof. The vitamin C coupled platinum complex has good anti-tumor activity. Compared with the existing platinum anti-tumor drugs, the complex has the improvement of water solubility by more than tens of times, and the characteristic of high water solubility can increase and improve the excretion of drugs in the kidney, reduce the high renal toxic and side effects commonly existing in platinum drugs, make the compounds easy to be formulated, and is more convenient to apply in clinic.

Description

technical field [0001] The invention relates to a water-soluble platinum complex, in particular to a vitamin C-coupled platinum complex for tumor treatment, its intermediate, its preparation method, pharmaceutical composition and application. Background technique [0002] Platinum anticancer drugs are a representative class of drugs in the field of tumor treatment. It belongs to cell cycle non-specific drugs and has therapeutic effects on sarcoma, malignant epithelial tumors, lymphomas and germ cell tumors. At present, the representative platinum anticancer drugs widely used in clinical treatment in the world mainly include: cisplatin, carboplatin and oxaliplatin. The fatal disadvantage of platinum-based anticancer drugs is that they have extremely strong toxic and side effects, as well as inherent and subsequent drug resistance problems. In addition, because these drugs are metal-organic compounds, all platinum-based drugs generally have extremely low water solubility. Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00C07D307/62A61K31/555A61P35/00A61P35/02
CPCC07F15/0093C07D307/62A61P35/00A61P35/02A61K31/555C07F15/00C07F15/0086A61K31/282
Inventor 韩建斌高香倩杨金娜杨柳
Owner TIANJIN GUDUI BIOLOGICAL MEDICAL TECH INC
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