Novel acyclic nucleoside phosphonate predrug

A prodrug and a new type of technology, applied in the field of anti-hepatitis B and anti-HIV drugs, can solve the problems of oxidative pathway metabolism, low carnitine level, toxicity, etc.

Inactive Publication Date: 2010-06-30
北京利乐生制药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Compared with the active tenofovir (R-PMPA), its prodrug tenofovir dipivoxil (R)-(POC) 2 -The bioavailability of PMPA is significantly improved, and the bioavailability of oral administration in dogs can reach 30%, but human oral (R)-(POC) 2 -The bioavailability of PMPA is only 25%, and (R)-(POC) 2 - Bioavailability of PMPA is affected by food
[0009] Literature (pharmaceutical research 1997:14,1824-1829) reports that (R)-(bis-pivaloyloxymethyl)-PMPA (abbreviation: (R)-(POM) 2 -PMPA) has a ratio (R)-(POC) 2 -Higher bioavailability of PMPA, but due to (R)-(POM) 2 -The combination of pivalic acid and coenzyme A, the hydrolyzed product of PMPA in the body, cannot be metabolized through the oxidation pathway, and is easy to accumulate in the cell to produce toxicity
Therefore, (R)-(POM) 2 -PMPA was significantly more cytotoxic than (R)-(POC) 2 -PMPA, long-term use of pivalic acid-containing prodrugs will cause low plasma carnitine levels

Method used

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  • Novel acyclic nucleoside phosphonate predrug
  • Novel acyclic nucleoside phosphonate predrug
  • Novel acyclic nucleoside phosphonate predrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] The preparation of embodiment 1 compound I

[0016] 20 g of R-PMPA, 100 ml of N-methylpyrrolidone, 50 ml of triethylamine, and 80 ml of chloromethyl isobutyrate were sequentially added to the reaction flask, and the reaction was stirred at 60° C. for 2.5 hours. Add 200ml of ethyl acetate at room temperature, stir for 10min, filter, add 100ml of water, shake and separate the liquids, extract the aqueous phase with 100ml of ethyl acetate, combine the organic phases, wash with 150ml of water, and dry the organic phase over anhydrous sodium sulfate. Filter, concentrate to about 150ml volume, add 6.7g oxalic acid dihydrate, stir for 3h. Filter, wash twice with a small amount of ethyl acetate, drain, transfer the resulting solid to a 500ml Erlenmeyer flask, add 300ml of water, and heat in a water bath at 55°C to dissolve. Then slowly add saturated aqueous sodium bicarbonate solution at room temperature to adjust the pH to about 7, extract twice with dichloromethane, 200ml ea...

Embodiment 2

[0017] The preparation of the fumarate of embodiment 2 compound I

[0018] Dissolve 10 g of compound I in 100 ml of isopropanol, add 2.5 g of fumaric acid, heat in a water bath at 50°C to dissolve, and stir at room temperature. After full crystallization, it was filtered, washed twice with ethyl acetate, and dried under reduced pressure at 45°C to obtain 8.0 g of white solid. Yield 65%.

[0019] 1 H-NMR (d 6 -DMSO, ppm): 1.03~1.08(m, 15H), 2.52~2.59(m, 2H), 3.88~3.98(m, 3H), 4.13~4.17(m, 1H), 4.23~4.27(m, 1H) , 5.47~5.56 (m, 4H), 6.62 (s, 2H), 7.27 (s, 2H), 8.03 (s, 1H), 8.13 (s, 1H). ESI-MS: 488.1, 510.2.

Embodiment 3

[0020] The preparation of the L-tartrate of embodiment 3 compound I

[0021] Dissolve 12.7g of compound I in 100ml of acetone, add 3.7g of L-tartaric acid-200ml of acetone solution, and stir at room temperature. After fully analyzing the crystallization, it was filtered, washed twice with an appropriate amount of acetone, and dried under reduced pressure at 45°C to obtain 11.4 g of a white solid. Yield 69%.

[0022] 1 H-NMR (d 6 -acetone, ppm): 1.15~1.23(m, 15H), 2.60~2.65(m, 2H), 3.88~4.10(m, 3H), 4.25~4.44(m, 2H), 4.60(s, 2H), 5.59 ~5.68 (m, 4H), 7.08 (s, 2H), 8.13 (s, 1H), 8.24 (s, 1H). ESI-MS: 488.2, 510.2.

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Abstract

The present invention provides a novel R-PMPA predrug as shown in formula I and various medical salts thereof. Meanwhile, the present invention also relates to a medical composition using the compounds as active ingredients and an application of the medical composition as an antiviral drug, particularly a drug for treating and preventing hepatitis B and AIDS viruses.

Description

technical field [0001] The present invention relates to a novel prodrug of R-PMPA and its various pharmaceutically acceptable salts, and also relates to the pharmaceutical composition of these compounds as active ingredients and their use as antiviral drugs, especially anti-hepatitis B and anti-HIV drugs . Background technique [0002] (R)-9-[2-(phosphonomethoxy)propyl]-adenine (tenofovir, R-PMPA) is an acyclic nucleoside phosphonic acid compound with strong anti-HIV and anti- HBV activity, and low cytotoxicity, but its oral bioavailability is low, oral administration is difficult to achieve effective therapeutic concentration. [0003] The structural formula of R-PMPA is as follows: [0004] [0005] Its prodrug tenofovir dipivoxil (R)-(POC) 2 -PMPA was approved for marketing in the United States in 2001, and it was approved to be used in combination with other antiretroviral drugs to treat HIV-1 infection. This is the first nucleotide analog approved for the treatme...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/12A61P1/16A61P31/18
Inventor 姚勇敢
Owner 北京利乐生制药科技有限公司
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