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Prodrug based on gemcitabine structure as well as synthesizing method and application thereof

A technology of gemcitabine and synthesis method, applied in the field of nucleoside drugs

Inactive Publication Date: 2009-09-09
SANLUGEN PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Metabasis work is limited to cytosine O 5 ring phosphorylation

Method used

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  • Prodrug based on gemcitabine structure as well as synthesizing method and application thereof
  • Prodrug based on gemcitabine structure as well as synthesizing method and application thereof
  • Prodrug based on gemcitabine structure as well as synthesizing method and application thereof

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preparation example Construction

[0055] The present invention also provides the synthetic method of the prodrug based on the gemcitabine structure, comprising the following steps:

[0056] 1) The acid anhydride or acid chloride and alcohol or amine are directly mixed or dissolved in an organic solvent according to the ratio of acid anhydride or acid chloride: alcohol or amine = 1: 1 ~ 1: 1.5 molar ratio, and react at room temperature to the melting temperature of the reactant for 2 ~ 8 hours, the corresponding substituted acid is obtained;

[0057] 2) Gemcitabine hydrochloride, the substituted acid obtained in step 1), benzotriazole-1-oxyl tripyrrolidinylphosphonium hexafluorophosphate and 4-dimethylaminopyridine according to 1: (1~2):( 0.9~1.5): (1~3) molar ratio is dissolved in the organic solvent, stirred at room temperature for 12~24 hours;

[0058] 3) In step 2), the reaction solution is poured into water, extracted, and the separated organic phase is dried and purified to obtain the target product.

...

specific Embodiment approach

[0088] Hereinafter, the present invention will be described more specifically using examples, but the present invention is not limited to the following examples.

[0089] Gemcitabine hydrochloride was purchased from Ningbo Tianheng Pharmaceutical Co., Ltd.;

[0090] Benzotriazole-1-oxytripyrrolidinylphosphine hexafluorophosphate was purchased from Jill Biochemical (Shanghai) Co., Ltd.;

[0091] 4-Dimethylaminopyridine was purchased from Jill Biochemical (Shanghai) Co., Ltd.

Embodiment 1

[0093] N 4 -(2-Dodecyloxyformylbenzoyl)-2'-deoxy-2',2'-difluorocytidine (Compound NO.1)

[0094] Mix 5.0g phthalic anhydride (34mmol), 7.5g lauryl alcohol (40mmol) and 240mg 4-dimethylaminopyridine (2mmol), heat and melt, react for 4 hours, cool to room temperature, and quantitatively obtain 2-n- Lauryloxyformylbenzoic acid.

[0095] With 700mg gemcitabine hydrochloride (2.34mmol), 1.02g 2-n-dodecyloxyformylbenzoic acid (3.04mmol), 1.34g benzotriazole-1-oxyl tripyrrolidinylphosphonium hexafluorophosphate ( 2.57mmol) and 428mg of 4-dimethylaminopyridine (3.51mmol) were dissolved in N,N-dimethylformamide (10mL), and stirred overnight at room temperature. The reaction solution was poured into water, extracted three times with ethyl acetate, and the separated organic phase was dried over anhydrous sodium sulfate. After removing the solvent by evaporation under reduced pressure, the residue was purified on a silica gel column (developing solvent: dichloromethane / methanol=30 / 1) t...

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Abstract

The invention belongs to the field of nucleoside drugs, more particularly relates to a prodrug based on a gemcitabine structure shown as a formula (I) as well as a synthesizing method and the application thereof, wherein a is equal to an integer from 0 to 6; b is equal to an integer from 0 to 6; c is equal to an integer from 0 1 to 8; d is equal to an integer from 1 to 4; E is five-membered or six-membered ring alkyl, five-membered or six-membered ring naphthene base containing 1-4 hetero atoms, aryl or heteroaryl. The hetero atoms are selected from O, N or S; Z is selected from O, N or S; and V is selected from hydrogen, alkyl, alkoxyl, ester group, halogen, amido, amino or substituted amino. The invention utilizes N<4> modification to increase the solubility, the bioavailability and the organ specificity of the prodrug, and the generated prodrug compound can solve the problem of fast metabolization, thereby improving the capacities of antitumor, anticancer, anti-infection and diffusion prevention and being capable of specifically acting on liver or colon. The synthesizing method has simple procedures, easily-obtained materials, high productivity rate and low cost and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of nucleoside drugs, and relates to a gemcitabine-based prodrug, a synthesis method thereof, and applications related to the treatment of various cancers and related diseases. Background technique [0002] According to WHO statistics, in 2007, there were as many as 12 million newly diagnosed cancer patients in the world, and over the past few years, more than 7 million patients worldwide died of cancer every year. This figure is very close to the number of people who die from acute cardiovascular disease. Cancer is about to become the deadliest disease in the world. [0003] Nucleoside drugs, such as cytarabine, gemcitabine, decitabine, azacitidine, cladribine, fludarabine, clofibrate, nelarabine, 6-azauridine and thiazofurin, etc. It is widely used in the treatment of various cancers. At the same time, many nucleoside drugs are in the clinical research stage, such as 4'-thio-fluoro-ara-C, 2'-deoxy-2'fluoromethylcy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06
CPCA61K31/7068C07H19/06A61P1/00A61P1/16A61P1/18A61P11/00A61P13/00A61P35/00A61P43/00
Inventor 薛晓霞李刚孙昌俊李文保
Owner SANLUGEN PHARMATECH
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