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Water solubility platinum complex containing deoxyglucose, preparation method and application

A technology of deoxyglucose and platinum complexes, which is applied in the preparation of sugar derivatives, medical preparations containing active ingredients, sugar derivatives, etc., can solve the problems of tumor targeting and selective anti-tumor effects that need to be improved, and achieve Excellent tumor selective drug accumulation, high water solubility, and improved targeting effect

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

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Problems solved by technology

[0012] Patent WO2006091790A1 discloses "Platinum Complex with Molecular Structure Containing Sugar and Its Preparation and Application Method". This compound has anti-tumor efficacy, but the tumor-targeting and selective anti-tumor effects need to be improved

Method used

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  • Water solubility platinum complex containing deoxyglucose, preparation method and application
  • Water solubility platinum complex containing deoxyglucose, preparation method and application
  • Water solubility platinum complex containing deoxyglucose, preparation method and application

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preparation example Construction

[0096] The preparation methods shown in methods E and F are to condense halohydrin with D-2-deoxyglucose or acetylated deoxyglucose in the presence of Lewis acid, and then perform a substitution reaction with a malonate derivative to finally obtain the compound (III) preparation route. The acetylation of D-2-deoxyglucose involved in the above preparation route, the condensation reaction in the presence of Lewis acid, the 2-position alkylation substitution reaction of malonate and the final deprotection reaction, its reaction conditions and implementation methods are the same as Method C and method D are the same as described.

[0097] In the above method, the malonate intermediate containing substituent A can be prepared according to known operating methods reported in the literature: Journal of Organic Chemistry, 1998, vol.63, 11 p.3677-3679; Journal of the American Chemical Society, 2004, vol. 126, 36 p. 11293–11302.

[0098] Main experimental instruments:

[0099] Nuclea...

Embodiment 1

[0101] (1) Preparation of 1-O-(3,4,6-triacetyl-D-2-deoxyglucoside)-2-bromo-ethane (V-1):

[0102]

[0103] At room temperature, 1.6 g of D-2-deoxyglucoside 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...

Embodiment 2

[0121] Preparation of diaminoplatinum (II) [1-O-(D-2-deoxyglucoside)-propane-3,3-dicarboxylate]:

[0122]

[0123] 1) Dissolve 100mg of crude 1-O-(D-2-deoxyglucoside)-propane-3,3-dicarboxylic acid in 5ml of deionized water, add octahydrate barium hydroxide (approximately 95mg is dissolved in 5ml of water ) to adjust the pH of the reaction solution to 8, and stir at room temperature for 30 minutes.

[0124] 2) Dissolve platinum diaminosulfate (110 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.

[0125] 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 115 mg of the final product as a white solid.

[0126] NMR spectrum (400MHz, D2O), ppm: 4.92(s,1H), 3.80-3.90(m,1H), 3.60-3.80(m,2H), 3.40...

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Abstract

The invention discloses a water solubility platinum complex containing deoxyglucose and a preparation method and application. The water solubility platinum complex containing the deoxyglucose is shown as the formula (1) (please see the formula in the specifications). The water solubility platinum complex containing the deoxyglucose has an excellent tumor selective drug accumulation effect, and drug resistance formed by a repulsive effect of a tumor to drugs is overcome through targeting performance transmission to tumor cells. Compared with clinical drugs, the water solubility platinum complex containing the deoxyglucose has higher water solubility and is capable of achieving clinical preparation easily. Compared with the clinical drug, namely, oxaliplatin, the water solubility platinum complex containing the deoxyglucose has superiority in the aspect of cytotoxicity. In conclusion, according to the water solubility platinum complex containing the deoxyglucose, not only is the problem of poor preparation stability and the shortcoming of inconvenient clinical using in existing platinum drugs because of lacking in water solubility solved, but also targeting performance of the drugs to tumor cells can be improved, and the deficiency of the existing clinical drugs in the aspects of the tumor therapy effect, the drug resistance and toxic and side effects is solved.

Description

technical field [0001] The invention relates to a water-soluble platinum complex containing deoxyglucose 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H23/00C07H1/00C07F15/00A61K31/7135A61P35/00A61P35/02
Inventor 高清志高香倩刘冉韩建斌米倩
Owner TIANJIN UNIV
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