Preparation method and application of polyethylene glycol-deoxycholic acid and derivatives of polyethylene glycol-deoxycholic acid

A technology of polyethylene glycol and deoxycholic acid, which is applied in the direction of drug combination and antineoplastic drugs, can solve the problems of chemotherapy failure and other problems, and achieve good biocompatibility, good anti-multidrug resistance, good The effect of applying the foreground

Active Publication Date: 2018-04-24
NANJING LAKESEN BIOPHARM TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Chemotherapy is the most common means of treating cancer, but the

Method used

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  • Preparation method and application of polyethylene glycol-deoxycholic acid and derivatives of polyethylene glycol-deoxycholic acid
  • Preparation method and application of polyethylene glycol-deoxycholic acid and derivatives of polyethylene glycol-deoxycholic acid
  • Preparation method and application of polyethylene glycol-deoxycholic acid and derivatives of polyethylene glycol-deoxycholic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]

[0033] Weigh 1mmol of deoxycholic acid and 1.5mmol of DMAP in a 100mL eggplant-shaped bottle, then add 40mL of anhydrous dichloromethane (CH 2 C l2 ) stirred at room temperature for 30min, rotating speed 600r / min, then weighed 1.1mmol polyethylene glycol and dissolved it in 5mL of dichloromethane, then added it dropwise in the reaction flask, then added 1.6mmol of DCC (dicyclohexyl Carbodiimide), stirred at room temperature for 24h, after the reaction was completed, suction filtered, extracted once with 0.5mol / L hydrochloric acid, then extracted twice with saturated brine, and the organic layer was washed with anhydrous magnesium sulfate (MgSO 4 ) drying, suction filtration, rotary evaporation to concentrate the solvent, anhydrous ether for precipitation, standing overnight, suction filtration, and vacuum drying at 37°C to obtain polyethylene glycol-deoxycholic acid (PEG-DCA).

[0034] The infrared and 1H NMR images of the resulting polyethylene glycol-deoxycholic...

Embodiment 2

[0037]

[0038] 1. Synthesis of 3,3'-dithiodipropionic anhydride

[0039] Weigh 5g of 3,3'-dithiodipropionic acid and place it in a vacuum drying oven to dry at 30°C, and then take another 50mL of acetyl chloride and re-distill it at 75°C. Add the freshly distilled acetyl chloride to the dried 3,3'-dithiodipropionic acid, and reflux at 70°C for 2 hours. After the reflux is completed, the excess acetyl chloride is evaporated under reduced pressure, and the residue is precipitated by adding excess ice anhydrous ether. Place in the lower layer of the refrigerator to freeze overnight at -20°C, filter with suction the next day, and dry the precipitate in a vacuum oven at 45°C for 10 hours. A light yellow to grayish yellow flaky solid was obtained with a yield of about 60%.

[0040] 2. Weigh 1.07g (5.6mmol) of the above-mentioned synthesized 3,3'-dithiodipropionic anhydride, place in a 100mL round-bottomed three-necked flask, add 40mL of anhydrous DMF, and 2 After protecting an...

Embodiment 3

[0047]

[0048] 1. Synthesis of PEG-DCA-DTPA

[0049] Weigh 0.5mmol of dithiodipropionic anhydride and place it in a three-neck flask filled with 25mL of dichloromethane, stir under nitrogen protection until all dithiodipropionic anhydride is dissolved, weigh 0.1mmol PEG-DCA, 0.5mmol DMAP In 8 mL of dichloromethane, the mixture was added dropwise into a three-necked flask, and then 4 drops of triethylamine were added, and reacted at 35° C. for 24 h. The reaction solution was precipitated with ether, and the precipitate was dissolved in saturated sodium bicarbonate to generate a large number of bubbles, then extracted twice with dichloromethane, the organic phase was discarded, and the pH was adjusted to about 2 with 0.1mol / L hydrochloric acid, and then Extracted twice with dichloromethane, combined the organic phases, dried over anhydrous magnesium sulfate, concentrated the solvent, precipitated with diethyl ether, filtered with suction, and dried under vacuum at 37°C to ob...

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Abstract

The invention belongs to the technical field of pharmacy, and particularly relates to a preparation method and application of polyethylene glycol-deoxycholic acid and derivatives of polyethylene glycol-deoxycholic acid. A parent nucleus of the polyethylene glycol-deoxycholic acid derivative is polyethylene glycol-deoxycholic acid, a joint key is an oxidation and reduction sensitive key, a pH sensitive key or an enzymatic hydrolytic key, and a ligand is a hydrophobic amino acid compound, a bio-compatible polymer or an insoluble anticancer drug. The preparation method of the polyethylene glycol-deoxycholic acid comprises the following steps: dissolving deoxycholic acid and 4-dimethylaminopyridine in anhydrous dichloromethane to obtain a deoxycholic acid solution, then dissolving polyethyleneglycol in dichloromethane to obtain a polyethylene glycol solution, then gradually dropwise adding the deoxycholic acid solution and the polyethylene glycol solution into a reaction bottle, adding acatalyst, and obtaining polyethylene glycol-deoxycholic acid by virtue of reaction. The polyethylene glycol-deoxycholic acid and derivatives of polyethylene glycol-deoxycholic acid prepared by the invention have good anti-multidrug resistance and a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and specifically relates to a preparation method and application of polyethylene glycol-deoxycholic acid and derivatives thereof. Background technique [0002] Chemotherapy is the most common means of treating cancer, but the effect of chemotherapy will fail due to the drug resistance of tumor cells. Multidrug resistance (MDR) refers to the cross-resistance of tumor cells to drugs with different structures and mechanisms of action. The cross-resistance of tumor cells to multiple chemotherapeutic drugs is an obstacle to the success of chemotherapy. According to incomplete statistics, more than 90% of patients died due to multidrug resistance. There are many reasons for the production of MDR. In 1976, Juliano used Chinese hamster ovary cells to make it resistant to colchicine. It first revealed that MDR was related to the decrease of intracellular drug concentration, and confirmed the existence o...

Claims

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Application Information

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IPC IPC(8): C08G65/332A61P35/00
CPCC08G65/3324
Inventor 蒲晓辉宗兰兰尹丽王海彦李蒙蒙李建业徐天宏
Owner NANJING LAKESEN BIOPHARM TECH CO LTD
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