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Antiviral agent cidofovir derivatives and intermediates thereof

A technology of derivatives and drugs, applied in the field of new derivatives and intermediates of cidofovir, can solve problems such as insufficient biological effect, incompatibility with lipophilicity, and poor ability

Inactive Publication Date: 2009-06-03
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 and intermediates thereof
  • Antiviral agent cidofovir derivatives and intermediates thereof
  • Antiviral agent cidofovir derivatives and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Example 1 Preparation of intermediate (R)-2,3-glycidyl methanesulfonyl ester (5)

[0039] 1. Preparation of 1,2-5,6-bis(dioxyisopropylidene)mannitol (2)

[0040]Add 37.5g (0.206mol) 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 , stirred for 15-20 minutes, filtered, washed with 50ml×3 water, added about 15mL concentrated ammonia water to the filtrate, concentrated to a white solid, added a small amount of water, extracted 3 times with dichloromethane, dried over anhydrous sodium sulfate, and used directly in the next step reaction. If the dichloromethane layer is evaporated to dryness, 51.75 g of white paste solid can be obtained, with a yield of 97-98% (the literature yield is 87%).

[0041] 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)

[0042] 2. Preparation of (S)-2,3-...

Embodiment 2

[0051] Embodiment 2 Preparation of intermediate benzoylcytosine (6)

[0052] Add 3g (0.027mol) of cytosine to 300ml of pyridine, then dropwise add 37.5mL of benzoyl chloride, stir at room temperature, drop it in about half an hour, and stir for 45 minutes, add 2N hydrochloric acid dropwise, stir at room temperature for 2 hours, filter with suction, use for solid 5% sodium hydroxide was dissolved, then dripped into 2N hydrochloric acid, placed overnight in the refrigerator, suction filtered, and vacuum-dried to obtain 5.8g white solid, mp>300°C (document mp>300°C), yield 95% (documentation yield is 89%).

[0053] 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

[0054] Example 3 Preparation of intermediate (S)-N1-[(3-trityloxy-2-ethylphosphorylmethoxy)glycerol]-cytosine (11)

[0055] 1. (S)-N 1 -[2,3-O-isopropylidene-2,3-(dihydroxy)glycerol]-N 4 - Preparation of Benzoylcytosine (7)

[0056] Method 1: Add 6 g (0.0276 mol) of finely ground benzoylcytosine (6) and 5.4 g (0.0390 mol) of finely ground potassium carbonate, add 120 mL of anhydrous N,N-dimethylformamide (DMF), oil Heat the bath to 90°C, slowly add dropwise a solution of 5.2g (0.0267mol) (R)-2,3-isopropylidene glycerol methanesulfonyl ester (5) dissolved in 50mL of DMF, drop it for about 1 hour, and the reaction is complete. Suction filtration, washing the precipitate with DMF, concentrating the filtrate under reduced pressure, adding 300 mL of dichloromethane to the obtained solid, stirring for about 2 hours, filtering, washing the precipitate with dichloromethane, concentrating the filtrate under reduced pressure to obtain a light yellow oil, which was separated by column ...

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Abstract

The invention discloses a new derivant and intermediate 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 to get new derivant.

Description

technical field [0001] The invention relates to the field of antiviral drugs, more specifically to new cidofovir derivatives and intermediates. 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, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6512A61K31/675A61P31/12A61P31/22
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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