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Tenofovir diester compounds with activity of inhibiting HIV-1 (human immunodeficiency virus-1) virus replication and preparation method and pharmaceutical use thereof

A technology of tenofovir and ester compounds, which is applied in the field of nucleoside compounds, can solve the problems of maintaining sufficient concentration in infected parts, only human bioavailability, and no antiviral activity, so as to achieve high activity and improve bioavailability , improve the effect of the effect

Active Publication Date: 2012-11-21
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

[0005] As a prodrug, it has no antiviral activity itself. After entering the body, the original drug must be freed to exert its curative effect, and some drugs are hydrolyzed before being absorbed into the blood; in addition, the released original drug adefovir and tenofovir Wei is also due to the poor membrane permeability, it is quickly excreted from the body and it is difficult to maintain a sufficient concentration in the infected part, so that its bioavailability in the human body is still only about 28%.

Method used

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  • Tenofovir diester compounds with activity of inhibiting HIV-1 (human immunodeficiency virus-1) virus replication and preparation method and pharmaceutical use thereof
  • Tenofovir diester compounds with activity of inhibiting HIV-1 (human immunodeficiency virus-1) virus replication and preparation method and pharmaceutical use thereof
  • Tenofovir diester compounds with activity of inhibiting HIV-1 (human immunodeficiency virus-1) virus replication and preparation method and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0061] L016 was synthesized by the above-mentioned preparation method of L114.

[0062] c) When m=4, n=12, the specific preparation process of L412:

[0063] Its reaction formula is:

[0064]

[0065] L412 was synthesized by the above-mentioned preparation method of L114.

[0066] The preparation process of (R)-9-[2-[[[(S)-1-(isopropoxycarbonyl)]ethyl]methoxyphosphoramidate]propyl]adenine (Ⅲ):

[0067] Its reaction formula is:

[0068]

[0069] In a 500ml round bottom flask, add commercially available tenofovir (7.2g, 25.1mmol) to 200ml of anhydrous acetonitrile solvent, under nitrogen protection, after heating up to 50°C, slowly add thionyl chloride dropwise (1.8ml, 25mmol), warm up to 80°C and stir for 2 hours after dripping; evaporate the solvent, add anhydrous dichloromethane (200ml), and add L-alanine isopropyl hydrochloride at -30°C (4.17g, 25mmol), slowly add triethylamine (16.7ml, 120mmol) dropwise, heat up to -10°C and react for 1h, wash the organic phase wi...

Embodiment 1

[0072] Embodiment 1: A kind of product of the present invention (R)-9-[2-[[hexadecyloxypropyl[(S)-1-(isopropoxycarbonyl)] ethyl] phosphoramidate methoxy] propyl ] adenine (compound 12 is m=1, the compound when n=14), its structural formula is:

[0073]

[0074] The preparation method of (R)-9-[2-[[hexadecyloxypropyl[(S)-1-(isopropoxycarbonyl)]ethyl]phosphoramidate methoxy]propyl]adenine:

[0075] In a 50ml round bottom flask, add (R)-9-[2-[[[(S)-1-(isopropoxycarbonyl)]ethyl]phosphoramidate methoxy]propyl]adenine prepared above in sequence (Ⅲ) (2.0g, 5.0mmol), N,N-dimethylformamide (25ml), L114 prepared above (1.8g, 5.0mmol) and triethylamine (0.85ml, 6.0mmol), at 80°C Stir for 6 hours, distill off the solvent, add ethyl acetate: ethanol 1:1 mixed solvent 100ml fully dissolved, filter, spin the filtrate through the column to obtain a white solid (R)-9-[2-[[hexadecyloxy Propyl[(S)-1-(isopropoxycarbonyl)]ethyl]phosphoramidatemethoxy]propyl]adenine (compound 12) (2.3g, 3.4mmo...

Embodiment 2

[0078] Example 2: Another product of the present invention (R)-9-[2-[[octadecyloxyethyl[(S)-1-(isopropoxycarbonyl)]ethyl]phosphoramidate methoxy]propane Base] adenine (compound 21 is m=0, the compound when n=16), its structural formula is:

[0079]

[0080] The preparation method of the above-mentioned product (R)-9-[2-[[octadecyloxyethyl[(S)-1-(isopropoxycarbonyl)]ethyl]phosphoramidate methoxy]propyl]adenine:

[0081] In a 50ml round bottom flask, add (R)-9-[2-[[[(S)-1-(isopropoxycarbonyl)]ethyl]phosphoramidate methoxy]propyl]adenine prepared above in sequence (Ⅲ) (2.0g, 5.0mmol), N,N-dimethylformamide (25ml), L016 prepared above (1.9g, 5.0mmol) and triethylamine (0.85ml, 6.0mmol), at 80°C Stir for 6 hours, evaporate the solvent, add ethyl acetate: ethanol 1:1 mixed solvent 100ml fully dissolved, filter, spin the filtrate through the column to obtain a white solid (R)-9-[2-[[octadecyloxy Ethyl[(S)-1-(isopropoxycarbonyl)]ethyl]phosphoramidatemethoxy]propyl]adenine (compo...

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Abstract

The invention discloses tenofovir diester compounds with activity of inhibiting HIV-1 (human immunodeficiency virus-1) virus replication and a preparation method and pharmaceutical use thereof. The structure of the compounds is shown in Formula (I), wherein m is 0-4, n is 12-16, and the structural formula is fixed when m is 1 and n is 14. The invention also discloses a preparation method of the compounds shown in the structural formula (I) and a pharmaceutical composition with the compounds. Tests show that the compounds have the activity of inhibiting HIV-1 replication and also much higher lipophilicity than the current HIV treatment drug tenofovir fumarate, and can be applied in development of drugs for treatment of HIV infection.

Description

(1) Technical field: [0001] The invention relates to a group of nucleoside compounds, in particular to a group of tenofovir diexil compounds with the activity of inhibiting HIV-1 virus replication, a preparation method and a pharmaceutical use thereof. (2) Background technology: [0002] In the treatment of viral infectious diseases, 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, has a low incidence of drug resistance itself, and is relatively less toxic, and can be used to treat patients infected with HIV-1 (AIDS virus). However, because the phosphate groups of adefovir and tenofovir are negatively charged, the polarity is too strong, and the biofilm permeability is poor, resulting in very low bioavailability, so that it cannot be used as a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/12A61P31/18
CPCA61K31/675A61K31/683A61P31/12A61P31/18A61P31/20C07F9/65616
Inventor 游国战刘洪海杨松峰段轲伟袁保重王松
Owner 洛阳聚慧新材料科技有限公司
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