Novel acyclic nucleoside phosphonate and its medical use

A nucleoside phosphonate and pharmaceutical technology, applied in the field of acyclic nucleoside phosphonate and its non-toxic pharmaceutically acceptable salts, can solve the problems of low oral bioavailability and difficulty in reaching effective therapeutic concentrations

Inactive Publication Date: 2007-05-23
BEIJING MEIBEITA DRUG RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But because the polarity is too large, the oral bioavailability of (R)-PMPA and (R)-PMPDAP is low, and oral administration is difficult to reach effective therapeutic concentration

Method used

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  • Novel acyclic nucleoside phosphonate and its medical use
  • Novel acyclic nucleoside phosphonate and its medical use
  • Novel acyclic nucleoside phosphonate and its medical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Example 1 9-{2-[bis-(trifluoroethyl)-phosphonomethoxy]-propyl}-adenine (I 1 ) preparation

[0015] 1.1 Synthesis of (R)-1-chloro-2-propanol

[0016] Add 208 g (2 mol) of (R)-methyl lactate to 1200 ml of dimethylformamide, cool in an ice bath, add 96 g (2.4 mol) of 60% sodium hydride in batches under stirring, and react with stirring for 1 hour. Then 408 g (2.4 mol) of benzyl bromide was added dropwise, and after the drop was completed, the mixture was stirred under ice bath for 4 hours, and continued to stir at room temperature for 48 hours. DMF was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography, eluting with ethyl acetate:petroleum ether (1:9), and the desired components were collected and evaporated to dryness under reduced pressure to obtain 188 g of an oily liquid.

[0017] Dissolve 186 g (0.98 mol) of the product from the previous step in 1200 ml of anhydrous tetrahydrofuran, place in an ice bath, add 60 g of ...

Embodiment 2

[0026] Example 2 (R)-9-{2-[bis--(2,2,2-trifluoroethyl)-phosphonomethoxy]-propyl}-2,6-diaminopurine (I 2 ) preparation

[0027] According to the method of Example 1.4, replace adenine with 2,6-diaminopurine, and (R)-2-[bis-(2,2,2-trifluoroethyl)phosphonomethoxy]-propyl Chlorine reaction, prepared (R)-9-{2-[bis--(2,2,2-trifluoroethyl)-phosphonomethoxy]-propyl}-2,6-diaminopurine ( I 2 ). Proton NMR spectrum: δ(DMSO-d 6 , ppm): 7.85 (s, 1H); 5.78 (s, 2H, disappeared after heavy water exchange); 5.32 (s, 2H, disappeared after heavy water exchange); 4.69 (m, 4H); 4.58 (m, 1H); 4.21 (d, 2H); 4.06 (d, 2H); 1.23 (d, 3H).

Embodiment 3

[0028] Example 3 (R)-9-{2-[bis-(trifluoroethyl)-phosphonomethoxy]-propyl}-6-methoxycarboxamido-purine (I 3 ) preparation

[0029] 1 g I 1 Dissolve in 30 ml of dichloromethane, add 2.0 ml of anhydrous pyridine, and cool the reaction solution to -40°C. A solution of 0.4 mg of methyl chloroformate in 10 ml of dichloromethane was added dropwise with stirring. Stir for 30 minutes after the addition is complete, and for another 30 minutes at room temperature. The reaction solution was evaporated to dryness, and the residue was separated by silica gel column chromatography, and eluted with chloroform:methanol (96:4) to give I 5 440 mg, H NMR: δ(DMSO-d 6 , ppm): 10.0 (s, 1H, disappear after heavy water exchange); 8.65 (s, 1H); 8.36 (s, 1H); 4.63-4.69 (m, 4H); 4.54 (m, 1H); 4.18 (d, 2H); 4.06(d, 2H); 3.76(s, 3H); 1.24(d, 3H).

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Abstract

This invention provides trifluoroacetate derivatives of (R)-PMPA or (R)-PMPDAP represented by formula I and their non-toxic biological pharmaceutical acceptable salts, wherein R1 is H or NH2, R2 is H or COO-R3, and R3 is C1-C10 alkyl or phenyl substituted C1-C3 alkyl. This invention also provides drug combinations with acyclic nucleoside phosphonates as shown in formula I and their non-toxic pharmaceutical acceptable salts as active ingredients, and their applications in antiviral drugs, especially in anti-HBV and anti-HIV drugs.

Description

technical field [0001] The present invention relates to novel acyclic nucleoside phosphonates and their non-toxic pharmaceutically acceptable salts. These acyclic nucleoside phosphonates have high oral bioavailability, and can selectively release antiviral active ingredients in the liver after entering the body. The present invention also relates to a pharmaceutical composition containing the acyclic nucleoside phosphonate and its non-toxic pharmaceutically acceptable salt as an active ingredient and its use as an antiviral drug. Background technique [0002] Diseases caused by viral infections, such as viral hepatitis and AIDS, are major diseases that threaten human health. Although the research on antiviral drugs has made important progress, some clinically effective antiviral drugs have been found. For example, interferon, lamivudine, adefovir dipivoxil, and entecavir are used to treat hepatitis B, and zidovudine, stavudine, nevirapine, and indinavir are used to treat A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10A61K31/7064A61P31/12A61P1/16
Inventor 赵明艳仲素玲
Owner BEIJING MEIBEITA DRUG RES
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