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Liver specific delivery-based antiviral prodrug nucleoside cyclophosphate compound and use thereof

A compound and hydrate technology, applied in the field of pharmaceutically acceptable salts and pharmaceutical compositions, solvates, and optical isomers, can solve the problem of low toxicity and side effects, and achieve the effect of low toxicity and high curative effect

Active Publication Date: 2018-01-05
ZHEJIANG PALOALTO PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, there is still a lack of virus-inhibiting compounds with high activity, strong liver-specific delivery, and low toxic and side effects. Virus Inhibitory Compounds

Method used

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  • Liver specific delivery-based antiviral prodrug nucleoside cyclophosphate compound and use thereof
  • Liver specific delivery-based antiviral prodrug nucleoside cyclophosphate compound and use thereof
  • Liver specific delivery-based antiviral prodrug nucleoside cyclophosphate compound and use thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0124] The preparation method of the compound (take the compound of formula III as an example):

[0125] In N,N-dimethylformamide and pyridine (5:1) solution, add monophosphoric acid derivative Va, 1,3-propanediol derivative Vd and dicyclohexylcarbodiimide, heat up to about 80 ℃, After the reaction was completed for 16 h, the reaction solution was rotary evaporated under reduced pressure to remove the organic solvent. The crude product was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and subjected to silica gel column chromatography to obtain Compounds of general formula II.

[0126]

[0127] Wherein, each reactant can be purchased through commercially available channels, and can also be prepared by conventional methods in the art using commercially available raw materials.

[0128] In a preferred embodiment of the present invention, the 1,3-propanediol derivative Vd (...

Embodiment 1

[0163] Example 1(2R)-9-{2-[(4S)-4-(3-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphacyclohexane Preparation of -2-yl]methoxypropyl}adenine

[0164] (R)-9-[2-(phosphonomethoxy)propyl]-adenine (84 mg, 0.294 mmol) was dissolved in N,N-dimethylformamide (15 mL) and pyridine (3 mL), respectively Dicyclohexylcarbodiimide (182 mg, 0.882 mmol) and (S)-3-(3-chloro-2-fluorophenyl)-1,3-propanediol (60 mg, 0.294 mmol) were added and the reaction mixture was heated to 80 After the reaction was completed, the reaction solution was rotary evaporated under reduced pressure to remove the organic solvent. The crude product was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and a silica gel column layer was formed. precipitation (dichloromethane:methanol=20:1 to 10:1) to obtain a white solid, yield: 41%, R f =0.4 (dichloromethane:methanol=10:1), 1 H NMR (400MHz, DMSO-d 6 )δ: 8.071-8.227(m,...

Embodiment 2

[0165] Example 2(2R)-9-{2-[(4S)-4-(3-chloro-5-fluorophenyl)-2-oxo-1,3,2-dioxaphosphacyclohexane Preparation of -2-yl]methoxypropyl}adenine

[0166] Prepared in a similar manner to Example 1, (R)-9-[2-(phosphonomethoxy)propyl]-adenine (84 mg, 0.294 mmol), dicyclohexylcarbodiimide (182 mg, 0.882mmol) and (S)-3-(3-chloro-5-fluorophenyl)-1,3-propanediol (60mg, 0.294mmol) were reacted to obtain 35mg white solid, yield: 26%, R f =0.4 (dichloromethane:methanol=10:1), 1 H NMR (400MHz, DMSO-d 6 ):δ:8.045-8.163(m,2H),7.173-7.455(m,5H),5.621-5.681(m,1H),4.228-4.271(m,1H),4.001-4.059(m,6H),1.952 -2.109(m,2H),1.097-1.196(m,3H)ppm.

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Abstract

The invention provides a liver specific delivery (LSD)-based antiviral prodrug nucleoside cyclophosphate compound and a use thereof and concretely, provides a compound shown in the formula II, its isomer, pharmaceutically acceptable salt, hydrate and solvate, and a corresponding pharmaceutical composition. The invention also provides a use of the compound or a composition of the compound and otherantiviral drugs in resistance to hepatitis B viruses (HBV), hepatitis D viruses (HDV) and human immunodeficiency viruses (HIV) and treatment on diseases caused by the above viruses.

Description

technical field [0001] The present invention relates to antiviral prodrugs based on liver specific delivery technology (Liver Specific Delivery (LSD)), preparation and application of nucleoside cyclic phosphate compounds, or optical isomers, hydrates and solvents thereof Compounds, pharmaceutically acceptable salts, and pharmaceutical compositions. Background technique [0002] Viruses such as hepatitis B virus (HBV), hepatitis D virus (HDV), and human immunodeficiency virus (HIV) are a serious threat to human health. Taking hepatitis B virus as an example, hepatitis B virus (hepatitis B) is a disease caused by hepatitis B virus, mainly inflammatory lesions of the liver, and can cause multiple organ damage. According to the World Health Organization (WTO) survey results, an estimated 240 million people worldwide are chronically infected with hepatitis B, and an estimated 780,000 people die of hepatitis B infection each year, of which 650,000 die from chronic hepatitis B. L...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6571A61K31/675A61P1/16A61P31/20A61P31/18
CPCA61K31/662A61P31/20A61P31/14A61P31/18C07F9/657181A61K31/675C07F9/657163C07B2200/13
Inventor 席志坚徐华强陆春平伍中山孙锋张振伟
Owner ZHEJIANG PALOALTO PHARMA TECH CO LTD
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