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Tenofovir disoproxil fumarate compounds, preparation method and application to antiviral field

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

Active Publication Date: 2013-08-14
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 fumarate compounds, preparation method and application to antiviral field
  • Tenofovir disoproxil fumarate compounds, preparation method and application to antiviral field
  • Tenofovir disoproxil fumarate compounds, preparation method and application to antiviral field

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1: the preparation of 3-hexadecyloxy-1-propanol (L114)

[0068]

[0069] 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%. 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,t,OCH 2 )...

Embodiment 2

[0070] Embodiment 2: the preparation of 2-octadecyloxyethanol (L016)

[0071]

[0072] Synthesized in a similar manner to Example 1 to obtain 2-octadecyloxyethanol (L016). 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

[0073] Example 3: Preparation of 6-dodecyloxy-1-hexanol (L410)

[0074]

[0075] 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 fumarate compounds with activity for inhibiting HIV(human immunodeficiency virus) / HBV(Hepatitis B Virus) replication, a preparation method and pharmaceutical application of the group of tenofovir disoproxil fumarate compounds. The compounds have a formula I, wherein X=H, Y=H; R1=-CH2(CH2)mCH2OCH2(CH2)nCH3, wherein m ranges from 0 to 4, and n ranges from 10 to 20; and R2=-OCH2OC(O)OCH(CH3)2. The invention also discloses a pharmaceutical composition containing the compounds. Shown by the experiment, the activity of one of the compounds for inhibiting the replication of HIV-1 (Human Immunodeficiency Virus-1) is 4.5 times that of azidothymidine (AZT), about 250 times that of the tenofovir disoproxil fumarate (TDF) which is the best medicine for treating acquired immunodeficiency syndrome at present, and 1.37 times that of the medicine CMX157 (Cefmenoxime) which comes into the clinical stage, and the lipid solubility of the compound is about 2 times that of the CMX157; the compounds also have the activity for inhibiting the replication of HBV (Hepatitis B Virus); and the compounds can be applied to the development of medicines for treating the acquired immune deficiency syndrome / 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 infected with HIV-1. However, because the phosphate group is negatively charged, the polarity is too strong, and the biofilm permeability is poor, resulting in low bioavailability, so that it cannot be used as a drug for clinical use. It...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P31/12C07C51/41A61P31/18C07F9/6561A61K31/661A61P31/20C07C57/15
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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