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Fluorine-containing water-soluble platinum complex and its preparation method and use

A platinum complex and water-soluble technology, which is applied in the field of fluorine-containing water-soluble platinum complexes and its preparation, can solve the problems of tumor targeting and anti-tumor effects to be improved, and achieve poor stability of preparations, improve targeting, The effect of high water solubility

Active Publication Date: 2017-05-03
TIANJIN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] Chinese patent 201210205475.5 discloses "a fluorine-containing water-soluble platinum complex for tumor therapy and its preparation method". This compound has solved the problem of water solubility, but its tumor targeting and anti-tumor effects still need to be improved

Method used

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  • Fluorine-containing water-soluble platinum complex and its preparation method and use
  • Fluorine-containing water-soluble platinum complex and its preparation method and use
  • Fluorine-containing water-soluble platinum complex and its preparation method and use

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preparation example Construction

[0083] The preparation method shown in method C is to condense halohydrin with acetylated deoxyglucose in the presence of Lewis acid, then carry out substitution reaction with malonate derivatives, and finally obtain compound (III) after deprotection reaction route. The acetylation of deoxyglucose involved in the above preparation route can be carried out according to the methods reported in the literature, for example, using acetic anhydride in pyridine as the acetylation reagent and heating at room temperature or 60° C. for 1-24 hours can be completed. The condition of the glycoside synthesis reaction in the presence of Lewis acid is to use 0.1-50 equivalents of fluorine-containing malonate derivatives for deoxyglucose compounds, or conversely use 0.1-50 equivalents of deoxyglucose raw materials for fluorine-containing malonate derivatives. The Lewis acid used can be BF 3 , SnCl 4 , FeCl3 , AlCl 3 , hydrochloric acid, p-toluenesulfonic acid, camphorsulfonic acid, etc., th...

Embodiment 1

[0087] (1) Preparation of 1-O-(3,4,6-triacetyl-D-2-deoxyglucoside)-2-bromo-ethane (V-1):

[0088]

[0089] At room temperature, 1.6 g of D-2-deoxyglucose was dissolved in pyridine and acetic anhydride (7 ml: 7 ml), stirred overnight, and the end point of the reaction was monitored by TLC. After the reaction was completed, 100 ml of ethyl acetate was added, washed with 5% aqueous hydrochloric acid (2×25 ml), the aqueous phase was extracted with ethyl acetate (2×25 ml), and the organic phases were combined. The organic phase was washed successively with saturated aqueous ammonium chloride solution (1×100ml), distilled water (1×100ml), saturated aqueous sodium bicarbonate solution (1×100ml), saturated aqueous sodium chloride solution (1×100ml), and washed with anhydrous sulfuric acid Sodium dry. The solvent was evaporated to dryness with a rotary evaporator to obtain a slightly yellow crude product of 3,4,6-triacetyl-D-2-deoxyglucose. Dissolve the obtained crude product in 2...

Embodiment 2

[0111] Preparation of diaminoplatinum (II) [1-O-(D-2-deoxyglucoside)-propane-3-fluoro-3,3-dicarboxylate] (I-2):

[0112]

[0113] 1) Dissolve 110 mg of crude product 1-O-(D-2-deoxyglucoside)-propane-3-fluoro-3,3-dicarboxylic acid (III-1) in 5 ml of deionized water, add hydrogen octahydrate Barium oxide (about 98 mg dissolved in 5 ml of water) was used to adjust the pH of the reaction solution to 8, and stirred at room temperature for 30 minutes.

[0114] 2) Dissolve platinum diaminosulfate (115 mg) in 2 ml of water under nitrogen protection, add to the reaction solution in 1), adjust the pH to 8 with barium hydroxide solution, and stir at room temperature overnight in the dark.

[0115] 3) After the reaction is completed, use a centrifuge to remove the precipitate, collect the supernatant, use semi-preparative HPLC to refine and separate, and use a freeze dryer to freeze-dry to obtain 100 mg of the final product as a white solid.

[0116] NMR spectrum (400MHz, D2O), ppm: 4...

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Abstract

The invention discloses a fluorine-containing water-soluble platinum complex and its preparation method and use. The fluorine-containing water-soluble platinum complex is shown in the formula (I). The fluorine-containing water-soluble platinum complex has excellent tumor-selective drug accumulation effects and prevents rejection-caused tumor resistance to drugs by targeting delivery to tumor cells. Compared with clinical drugs, the complex has high water solubility and is suitable for clinical preparation. Compared with a clinical drug oxaliplatin, the complex has superiority in cytotoxicity. The fluorine-containing water-soluble platinum complex solves the problem the existing platinum drug has poor water solubility, poor stability and clinical use inconvenience, improves drug targeting effects on tumor cells, and solves the problem that the existing clinical drugs has deficiency in tumor treatment effects, resistance to drugs and toxic or side effect.

Description

technical field [0001] The invention relates to a fluorine-containing water-soluble platinum complex and a preparation method thereof. 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. [0003] [0004] 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 following table shows the water solubility data of the above three listed clinical dru...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00C07H23/00C07H1/00A61P35/00
CPCC07F15/0093C07H1/00C07H23/00
Inventor 高清志刘冉韩建斌高香倩刘朋兴米倩
Owner TIANJIN UNIV
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