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Bola type ribavirin compound, and preparation method and application thereof

A ribavirin compound and compound technology, applied in the preparation of sugar derivatives, chemical instruments and methods, drug combinations, etc., can solve problems such as poor water solubility of ribavirin compounds, drug side effects, and impact

Active Publication Date: 2017-05-31
CHONGQING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, like most nucleoside analogs, ribavirin compounds also face the problems of poor water solubility and large effective dose, which affects the possibility of entering clinical research. a puzzle to be solved
In addition, as a small molecule drug, it lacks selectivity to normal tissues and tumors in cancer treatment, and it is difficult to really act on the lesion, which is also the root cause that restricts the efficacy of this type of drug and leads to drug side effects

Method used

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  • Bola type ribavirin compound, and preparation method and application thereof
  • Bola type ribavirin compound, and preparation method and application thereof
  • Bola type ribavirin compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of reaction intermediate II-1

[0038]

[0039] Dissolve 3.3mL of II-1a (1,8-dibromooctane) in 3mL of dimethylformamide, add dropwise a xylene solution containing 1.6g of sodium acetylide, react for 24 hours, filter the reaction solution, spin to dry the solvent, Distillation under reduced pressure gave the product II-1b. Add 630mg compound II-1b and 660mg potassium thioacetate respectively in a round bottom flask, add DMF as a solvent, spin dry the solvent after reacting at room temperature for 4 hours, separate the organic layer after adding dichloromethane and water, spin dry the solvent, and Separation by column chromatography gave compound II-1c. Dissolve 100 mg of compound A3 in DMF, add 80 μL of hydrazine hydrate dropwise at room temperature, then add 100 μL of acetic acid dropwise, react for 30 minutes at room temperature, add water and ethyl acetate for extraction, dry the organic phase over anhydrous sodium sulfate, and spin the solvent to obta...

Embodiment 2

[0042] Preparation of reaction intermediate II-2

[0043]

[0044] 75 mg of compound II-1b and 9.5 mg of potassium phosphate were dissolved in 5 mL of acetonitrile, and oxygen was introduced to react at room temperature for 5 h. The solvent was spin-dried and separated by column chromatography to obtain compound II-2 with a yield of 77.8%.

[0045] II-2: 1 H NMR (400MHz, CDCl 3 ): δ2.68(t, J=8Hz, 4H), 2.18(t, J=4Hz, 4H), 1.94(s, 2H), 1.71-1.63(m, 4H), 1.56-1.50(m, 4H) ,1.39-1.31(m,16H).

Embodiment 3

[0047] Preparation of reaction intermediate II-3

[0048]

[0049] Dissolve 5.1 mL of trimethylsilylacetylene in 45 mL of tetrahydrofuran, and add 23.2 mL of butyllithium dropwise at -78°C. After 15 minutes, 28 mL of DMPU was added and stirred at -78°C for 1 hour. Subsequently, 2 mL of a tetrahydrofuran solution of 2.8 g of compound II-3a was added and reacted overnight at room temperature. The reaction solution was adjusted to pH 1-2 with 1N hydrochloric acid, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, spin-dried to dry the solvent, and separated by column chromatography to obtain compound II-3b. 1.6g of compound II-3b was dissolved in TBAF in tetrahydrofuran and reacted at room temperature for 3h. The reaction was quenched with ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was spin-dried, an...

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Abstract

The invention relates to a Bola type ribavirin compound. A structure is shown as a general formula I. Through studying the characteristics of the special structure of the Bola type amphiphilic molecules, the structure optimization is performed by aiming at 1, 2, 4-ribavirin; the water solubility and the cancer cell growth inhibition rate of the compound are improved. Further, the compound has the capability of forming nanometer scale particles through self assembly in a water solution, so that the compound can be more easily gathered into the tumor tissues to realize the targeted medication through high permeability of the solid tumor and the retention effect. Meanwhile, as a nanometer medicine carrier, the compound can also encapsulate and seal other micromolecular medicine to reach the combined medication effect. In the general formula, n, R1, R2, R3 and R4 are defined as the patent claim. The formula I is shown as the accompanying drawing.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and relates to a Bola-type ribavirin compound, as well as its preparation method and application. Background technique [0002] Nucleoside analogs are an important class of antiviral and anticancer drugs. They have a structure similar to natural nucleosides, and can mimic natural nucleosides, participate in DNA / RNA synthesis of viruses and cancer cells, or interact with certain enzymes in viruses and cancer cells, thereby inhibiting virus replication and cancer cell growth the goal of. Various nucleoside drugs with antiviral and anticancer activities have been obtained by modifying the ribose part or base part of nucleosides, such as ribavirin, lamivudine, gemcitabine ( gemcitabine), 5-fluorouridine (floxuridine) and cytarabine (cytarabine), etc. Among them, ribavirin, as an outstanding representative of nucleoside drugs, has broad-spectrum antiviral properties, and has a good inhibitory effe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08C07D249/10C07D249/12C07H19/056C07H1/00A61P35/00A61K9/14
CPCA61K9/14C07D249/08C07D249/10C07D249/12C07H1/00C07H19/056
Inventor 夏熠林伟张燕华陈迷谜李梦垚
Owner CHONGQING UNIV
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