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Cyclobutane dicarboxylic acid platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and purpose

A technology of cyclobutane dicarboxylic acid and platinum complexes, which can be used in drug combination, preparation of sugar derivatives, pharmaceutical formulations, etc., and can solve the problems of drug resistance of toxic side effects, 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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  • Cyclobutane dicarboxylic acid platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and purpose
  • Cyclobutane dicarboxylic acid platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and purpose
  • Cyclobutane dicarboxylic acid platinum complex, intermediate thereof, preparation method thereof, pharmaceutical composition and purpose

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Example 1: Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II)[3-(1-O-D-glucoside)cyclobutane-1,1-dicarboxylic acid]

[0110]

[0111] (1) Preparation of 1,1-ethyl dicarboxylate-3-acetoxy-cyclobutane

[0112]

[0113] 60% Sodium hydride (0.8g) was dissolved in a solution of N,N-dimethylformamide (15ml) in diethylmalonate (1.6g). The mixture was stirred at room temperature for 30 minutes. Then, a N,N-dimethylformamide solution (10 ml) containing 1,3-dibromo-2-carboxypropane (1.3 g) was added to the reaction solution, and the mixture was stirred at 80°C for 6 hours. The solvent was removed by rotary evaporation, and the residue was redissolved in a mixed solution of ethyl acetate (150ml) and saturated ammonium chloride (150ml), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate: 50 / 1) to obtain a ...

Embodiment 2

[0131] Example 2: Preparation of cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II)[3-(1-O-D-mannoside)cyclobutane-1,1-dicarboxylic acid]

[0132]

[0133] (1) Preparation of ethyl 1,1-dicarboxylate-3-[2,3,4,6-O-acetyl-1-O-D-mannoside]cyclobutane

[0134]

[0135] 1,2,3,4,6-O-pentaacetyl-D-mannose (1.84g) was added to 1,1-dicarboxylate-3-hydroxycyclobutane (1.02g) at room temperature In the dichloromethane (20ml) solution, cooled to 0 ℃, the air in the flask was replaced with nitrogen, and the ether solution of boron trifluoride (98%, 1.19ml) was slowly added dropwise under the protection of nitrogen. The reaction was stirred at 0°C for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and simple purification was carried out by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain 1.39 g of crude product.

[0136] 1 H NMR (400MHz, CDCl ...

Embodiment 3

[0144] Example 3: Cis-[trans-(1R,2R)-diaminocyclohexane]platinum(II)[3-(1-O-D-galactoside)cyclobutane-1,1-dicarboxylic acid] preparation

[0145]

[0146] (1) Preparation of ethyl 1,1-dicarboxylate-3-[2,3,4,6-O-acetyl-1-O-D-galactoside]cyclobutane

[0147]

[0148] 1,2,3,4,6-O-pentaacetyl-D-galactose (1.84g) was added to 1,1-dicarboxylate-3-hydroxycyclobutane (1.02g) at room temperature In the dichloromethane (20ml) solution, cooled to 0 ℃, the air in the flask was replaced with nitrogen, and the ether solution of boron trifluoride (98%, 1.19ml) was slowly added dropwise under the protection of nitrogen. The reaction was stirred at 0°C for 15 minutes, then slowly warmed to room temperature and stirred for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the reaction product was simply purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain 1.55 g of a crude product.

[0149] 1 H NMR (400...

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Abstract

A cyclobutane dicarboxylic acid platinum complex, an intermediate thereof, a preparation method thereof, a pharmaceutical composition and a purpose are shown as a formula (I). The cyclobutane dicarboxylic acid platinum complex has good antitumor activity. The complex provided by the invention has more than several dozen times increase in water solubility compared with that of existing platinum antitumor drugs, and the high-water solubility characteristic can increase and improve excretion of drugs in kidney, alleviates high renal toxicity side effects of platinum drugs, also enables compoundsto be easy to formulate, and is more convenient for clinical application.

Description

technical field [0001] The invention relates to a water-soluble platinum complex, 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. The water solubility of cisplatin, carboplatin, and oxaliplatin are 1.0, 17.0...

Claims

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Application Information

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IPC IPC(8): C07H1/00C07H23/00C07H15/18A61K31/7135A61P35/00A61P35/02
CPCC07H1/00C07H23/00C07H15/18A61P35/00A61P35/02A61K31/7135A61K31/282C07F15/00
Inventor 高香倩韩建斌杨金娜杨柳
Owner TIANJIN GUDUI BIOLOGICAL MEDICAL TECH INC
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