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Tenofovir disoproxil compounds, and preparation method and application thereof in anti-virus aspects

A technology of tenofovir disoproxil and compound, applied in the field of nucleoside-like compounds

Active Publication Date: 2013-07-31
洛阳聚慧新材料科技有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the fat solubility of the above two prodrugs still needs to be further improved, so as to improve the bioavailability of the human body

Method used

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  • Tenofovir disoproxil compounds, and preparation method and application thereof in anti-virus aspects
  • Tenofovir disoproxil compounds, and preparation method and application thereof in anti-virus aspects
  • Tenofovir disoproxil compounds, and preparation method and application thereof in anti-virus aspects

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Embodiment 1: the preparation of 3-hexadecyloxy-1-propanol (L114)

[0073]

[0074] In a 250ml three-neck round bottom flask, add 1,3-propanediol (9.13g, 0.12mol), potassium tert-butoxide (6.8g, 0.06mol) and tert-amyl alcohol (50ml) in sequence, and slowly add A mixture of hexadecane bromide (12.17g, 12.2ml, 0.04mol) and tetrahydrofuran (50ml) was added dropwise over 3 hours. After refluxing and stirring for 50 hours, cool to room temperature, pour the reaction solution into 50ml of water, stir, acidify with 10% hydrochloric acid to pH=7, add n-hexane (100ml), separate the organic phase, and extract the aqueous phase with n-hexane , the organic phases were combined, dried and concentrated, and then recrystallized with n-pentane to obtain 3-hexadecyloxy-1-propanol (L114) (7.8 g, 0.026 mol), yield: 65%.

[0075] 1 H NMR (400MHz, CDCl 3 )δ,(ppm):0.88(3H,t,CH 3 ),1.14-1.37(26H,m,13×CH 2 ),1.48-1.65(2H,m,CH 2 ), 1.71-1.94 (2H, m, CH 2 ),2.38-2.53(1H,br,OH),3.43(2H,...

Embodiment 2

[0076] Embodiment 2: the preparation of 2-octadecyloxyethanol (L016)

[0077]

[0078] Synthesize 2-octadecyloxyethanol (L016) with the method similar to embodiment 1

[0079] 1 H NMR (400MHz, CDCl 3 )δ,(ppm):0.88(3H,t,CH 3 ),1.06-1.49(30H,m,15×CH 2 ), 1.53-1.654 (2H, m, CH 2 ), 1.90-2.10 (1H, br, OH), 3.47 (2H, t, OCH 2 ),3.53(2H,t,OCH 2 ),3.73(2H,t,OCH 2 ). ESI-MS:[M+H] + 315.3, [M+Na] + 337.3.

Embodiment 3

[0080] Example 3: Preparation of 6-dodecyloxy-1-hexanol (L410)

[0081]

[0082] 6-dodecyloxy-1-hexanol (L410) was synthesized in a similar manner to Example 1. 1 H NMR (400MHz, CDCl 3 )δ,(ppm):0.88(3H,t,CH 3 ),1.14-1.34(18H,m,9×CH 2 ),1.35-1.42(4H,m,2×CH 2 ),1.48-1.64(6H,m,3×CH 2 ),1.93-2.01(1H,br,OH),3.28-3.48(4H,m,2×OCH 2 ),3.62(2H,t,OCH 2 ). ESI-MS:[M+H] + 287.3, [M+Na] + 309.3.

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Abstract

The invention discloses a group of tenofovir disoproxil compounds with activity for inhibiting HIV-1 / HBV virus replication and pharmaceutically acceptable salts thereof, and a preparation method and pharmaceutical applications thereof. The group of the compounds have a general formula I, wherein X=H, Y=H, R1=-CH2(CH2)mCH2O(CH2)nCH3, m=0-4, n=10-20, and R2, R3 and R4 are respectively described in the specification. The invention also discloses a pharmaceutical composition containing the group of the compounds. Experiments show that one of the compounds has the advantages that an activity for inhibiting HIV-1 virus replication is 20 times that of a positive control medicine zidovudine (AZT), 1,000 times that of TDF that is the best medicine for treating Aids and about 9 times that of CMX157 in a clinical stage, and lipid solubility is about 2 times that of CMX157. Experiments also show that the compounds provided by the invention have the activity for inhibiting HBV virus replication, and can be used for development of drugs for treating the Aids and hepatitis B.

Description

Technical field: [0001] The invention relates to a group of nucleoside compounds, in particular to a group of tenofovir disoproxil compounds with the activity of inhibiting HIV-1 virus replication, a preparation method and an antiviral application thereof. Background technique: [0002] In the treatment of viral infectious diseases in humans, the problem of viral drug resistance has become increasingly prominent. Compared with cyclic nucleoside reverse transcriptase inhibitors, adefovir and tenofovir, acyclic nucleoside compounds, have obvious advantages in preventing viral drug resistance. The virus strain is effective, the incidence of drug resistance itself is low, and the toxicity is relatively small, so it can be used to treat patients who are co-infected with HIV-1 and HBV. However, due to the negative charge of the phosphate group, the polarity is too strong, and the biofilm permeability is poor, resulting in very low bioavailability, so that it cannot be used as a d...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/20
Inventor 游国战刘洪海杨松峰
Owner 洛阳聚慧新材料科技有限公司
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