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Antiviral agent cidofovir derivatives

A technology of derivatives and drugs, applied in the field of new derivatives of cidofovir, which can solve the problems of not enough to cause biological effects, difficult compatibility of lipophilicity, poor ability, etc.

Inactive Publication Date: 2005-11-02
横店集团成都分子实验室有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because the high polarity of the phosphate moiety is incompatible with the lipophilicity of the cell membrane, phosphorylated acyclovir has almost no antiviral activity
The reason may be that since all the above-mentioned compounds produce only limited (if any) cellular activity against viral cell lines, it is estimated that their ability to penetrate the cell membrane is poor enough to cause biological effects

Method used

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  • Antiviral agent cidofovir derivatives
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  • Antiviral agent cidofovir derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Preparation of intermediate (R)-2,3-isopropylidene glycerol methanesulfonyl ester (5)

[0048] 1. Preparation of 1,2-5,6-bis(dioxyisopropylidene)mannitol (2)

[0049] Add 37.5g (0.206mol) of mannitol (1) to 40g (0.293mol) of zinc chloride and 250mL of acetone, stir at room temperature for 20-24h, dissolve 45g (0.325mol) of potassium carbonate in 45mL of hot water, and add dropwise to the reaction flask , stir for 15-20 minutes, filter, wash with 50ml×3 water, add about 15mL concentrated ammonia water to the filtrate, concentrate to obtain a white solid, add a small amount of water, extract 3 times with dichloromethane, dry with anhydrous sodium sulfate, and use it directly in the next step reaction. For example, the dichloromethane layer can be evaporated to dryness to obtain 51.75 g of white paste-like solid, the yield is 97-98% (the yield in the literature is 87%).

[0050] 1 H NMR (CDCl 3 ): δ 3.68 (dd, H-1, H-6), 3.27 (m, 4H, H-2, H-3, H-4, H-5)

[00...

Embodiment 2

[0060] Example 2 Preparation of intermediate benzoylcytosine (6)

[0061] 3g (0.027mol) cytosine was added to 300ml of pyridine, then 37.5mL of benzoyl chloride was added dropwise, stirred at room temperature for about half an hour, the dropping was completed, stirred for 45 minutes, added dropwise 2N hydrochloric acid, stirred at room temperature for 2h, suction filtered, the solid was 5% sodium hydroxide was dissolved, then 2N hydrochloric acid was added dropwise, the refrigerator was placed overnight, suction filtration, and vacuum drying to obtain 5.8 g of white solid, mp>300 ° C (document mp> 300 ° C), yield 95% (document yield is 89%).

[0062] 1 H NMR (d 6 -DMSO): δ 11.17 (s, 1H, NH), 11.27 (s, 1H, NH), 8.18 (d, J=7Hz, 1H, H-6), 7.96 (d, J=7Hz, 2H, 2 ×BzH), 7.85(d, J=6Hz, 1H, H-5), 7.76-7.46(m, 3H, 3×BzH)

Embodiment 3

[0063] Example 3 Intermediate (S)-N 1 Preparation of -[(3-Trityloxy-2-ethylphosphorylmethoxy)glycerol]-cytosine (11)

[0064] 1. (S)-N 1 -[2,3-O-Isopropylidene-2,3-(dihydroxy)glycerol]-N 4 - Preparation of Benzoylcytosine (7)

[0065] Method 1: finely ground benzoylcytosine (6) 6g (0.0276mol) and 5.4g (0.0390mol) finely ground potassium carbonate, add anhydrous N,N-dimethylformamide (DMF) 120mL, oil The bath was heated to 90°C, and 5.2g (0.0267mol) of (R)-2,3-isopropylidene glyceryl methanesulfonyl ester (5) dissolved in 50mL of DMF was slowly added dropwise. After about 1h, the reaction was complete. Suction filtration, wash the precipitate with DMF, concentrate the filtrate under reduced pressure, add 300 mL of dichloromethane to the obtained solid, stir for about 2 h, filter, wash the precipitate with dichloromethane, and concentrate the filtrate under reduced pressure to obtain a pale yellow oil, which is separated by column chromatography to obtain The white solid was...

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Abstract

The invention discloses a new derivant for antiviral cidofovir, as well as the method for making such derivant, which is taking key intermediate (S)-N1-[(3-trity methoxy-2-ethphosphoric acid methoxy) glycerol alcohol]-cytosine as raw material, to condensation react with Boc-amino acid with the help of condensating agent to get intermediate compound, and then stripping protecting group Boc and trityl, and hydrolyzing phosphate, after deacidizing it, reacting with chlorpivalmethylactone to get new derivant.

Description

technical field [0001] The present invention relates to the field of antiviral drugs, more specifically to new cidofovir derivatives. Background technique [0002] Viruses are tiny organisms that can infect all biological cells. They can use the metabolic system of host cells to parasitize and proliferate, and produce cytotoxicity or cause various diseases in animals or humans. Viral diseases are currently the most widely spread infectious diseases with the highest incidence. According to incomplete statistics in Western countries, the incidence of viral diseases has reached more than 60% of the entire disease, far exceeding the 16% of bacterial infections. Moreover, in some of these viral diseases, once infected, the virus can exist in the body for several years or for life, and some have the possibility of inducing cancer. Therefore, the research and development of new antiviral drugs is the goal of many drug workers. [0003] Cytomegalovirus (Cytomegalovirus, CMV) is a ...

Claims

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Application Information

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IPC IPC(8): C07F9/6512
CPCY02P20/55
Inventor 杨勤胡键徐鸣夏
Owner 横店集团成都分子实验室有限公司
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