Nucleotide analogs and use thereof, and medicament composition containing nucleotide analogs

A compound and medicinal salt technology, which is applied in the field of pharmaceutical compositions containing such compounds, can solve problems such as DNA chain interruption, achieve the effects of reducing lattice energy, increasing bioavailability, and improving fat solubility

Inactive Publication Date: 2009-06-10
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Adefovir diphosphate can replace the natural deoxyadenosine triphosphate to intercalate into the DNA chain. Since it does not hav

Method used

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  • Nucleotide analogs and use thereof, and medicament composition containing nucleotide analogs
  • Nucleotide analogs and use thereof, and medicament composition containing nucleotide analogs
  • Nucleotide analogs and use thereof, and medicament composition containing nucleotide analogs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] Example 1: 9-[2-[bis(trifluoroethoxymethoxy)phosphorylmethoxy]ethyl]purine (6)

[0119] In a 100ml single-necked bottle, add 1g of PMEA, add 50ml of thionyl chloride, add a catalytic amount of DMF, heat and reflux for 3 hours to obtain a dark red liquid, evaporate the thionyl chloride, add 30ml of anhydrous acetonitrile, stir to dissolve, and obtain a solution A; Dissolve 1.46g of trifluoroethanol and 0.6ml of anhydrous pyridine in 20ml of anhydrous acetonitrile to obtain solution B; add solution A dropwise to solution B at 70°C, after the addition, heat to reflux for 8h, concentrate, and silica gel Column chromatography, eluting with dichloromethane:methanol=30:1, yielded 0.20g of the product, yield 11.8%, melting point: 141.4-141.8°C,

[0120] 1 H-NMR (DMSO-d 6 )δ (ppm) 3.88-3.92 (m, 2H, 2-H), 4.09-4.12 (d, 2H, OCH2P), 4.31-4.34 (m, 2H, 1-H), 4.53-4.66 (m, 4H, OCH2CF3), 7.39(s, 1H, 2-H), 8.12(s, 1H, 8-H)

Embodiment 2

[0121] Example 2: 6-Ethoxycarboxamido-9-[2-[bis(trifluoroethoxymethoxy)phosphorylmethoxy]ethyl]purine (7a)

[0122] In a 100ml three-necked round-bottomed flask, add 1.75g ​​9-[2-[bis(trifluoroethoxymethoxy)phosphorylmethoxy]ethyl]purine, add 50ml of dry dichloromethane to dissolve, cool with ice, Add 0.32ml of anhydrous pyridine, dropwise add 0.35ml of ethyl chloroformate, react for 2h, add ice water, separate layers, separate the organic phase, CaCI 2 Drying, concentration, silica gel column chromatography, eluting with dichloromethane:methanol=30:1, the product was 1.74g, the yield was 85.6%, m.p: 122.7-123.2°C,

[0123] 1 H-NMR (CDCI 3 )δ (ppm): 1.32-1.37 (m, 3H, N6-CH3), 3.92-3.94 (d, 2H, OCH2P), 4.01-4.05 (t, 2H, N6-CH2), 4.29-4.38 (m, 6H , 2-H, OCH2CF3), 4.48-4.51 (m, 2H, 1-H2), 7.99 (s, 1H, 2-H), 8.712 (s, 1H, 8-H)

[0124] The following compounds were prepared in a similar manner:

[0125] 6-n-propoxycarboxamido-9-[2-[bis(trifluoroethoxymethoxy)phosphorylmethoxy]...

Embodiment 3

[0143] Example 3: n-propoxycarboxamide-5-fluoro-9-[bis(2,2,2-trifluoroethyl)-phosphonomethoxy]ethylcytosine (9a)

[0144] In a 100ml three-neck round bottom flask, add 0.86g of 5-fluoro-9-[bis(2,2,2-trifluoroethyl)-phosphonomethoxy]ethylcytosine and dissolve it in 50ml of anhydrous dichloromethane In the middle, cool on ice, add 0.2ml of anhydrous pyridine, dropwise add 0.2ml of isobutyl chloroformate, and stir for 2h. After the reaction was complete, the solvent was evaporated, followed by silica gel column chromatography, eluting with dichloromethane:methanol=30:1 to obtain 1.0 g of the product, with a yield of 72.7%, and a melting point of 84-85°C.

[0145] 1 H-NMR (CDCI 3 )δ (ppm): 0.97-0.99 (m, 3H, N6-CH3), 1.71-1.75 (t, 2H, N6-CH2CH3), 3.86-3.88 (m, 2H, OCH2P), 3.95-3.96 (m, 4H , NCH2CH2O), 4.13-4.15 (m, 2H, N6-OCH2), 4.38-4.45 (m, 4H, OCH2CF3), 7.42-7.43 (d, 1H, 4-H)

[0146] The following compounds were prepared in a similar manner:

[0147] 6-isobutoxyamide-5-flu...

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Abstract

The invention relates to nucleotide analogues and application of the nucleotide analogues and pharmaceutical compositions containing the nucleotide analogues, in particular to compounds with a structure of the formula (I) on the right and or salts of the compounds. In the formula (I), R1 and R2 are selected from OR4, NH2 and other groups respectively, R3 represents any substituted linear chain having 1 to 20 carbon atoms or branch alkyl group and so on, B is selected by the following groups independently. The invention also relates preparation methods and application of the compounds. The compounds have strong antiviral activity to RNA viruses and DNA viruses such as Aids virus, and hepatitis B.

Description

technical field [0001] The present invention relates to a novel nucleotide analog, and further relates to the application of the compound and the pharmaceutical composition containing the compound. Background technique [0002] Hepatitis B virus is a major disease that seriously threatens the health of our people. my country's hepatitis B virus carriers account for about one-tenth of the total population, and there are as many as 30 million people with clinical symptoms. At present, there are few clinically effective anti-HBV drugs, some of which have inaccurate curative effects, and some have a high incidence of drug resistance. There is an urgent need for good anti-HBV drugs in clinic. [0003] Nucleoside phosphates have strong activity against HIV, hepatitis B virus and other DNA viruses and RNA viruses. Due to the strong polarity of nucleoside phosphates and their phosphate groups, they are not easy to pass through the gastrointestinal membrane, so they are generally ...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07F9/6512A61K31/675A61P31/12A61P1/16
Inventor 李科吴广余建鑫刘嘉邱晓敏王甜甜吕志良牛春娟
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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