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Tenofovir lipid monoester compound as well as preparation method and application thereof

A technology of tenofovir, compound, applied in the field of chemical pharmacy, can solve the problems of nephrotoxicity and poor oral bioavailability

Inactive Publication Date: 2020-01-07
ANHUI BIOCHEM UNITED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main reason is that the ester hydrolase is widely distributed in the body, causing the prodrug of tenofovir disoproxil to be hydrolyzed into highly negatively charged tenofovir before reaching the target cells of hepatitis B / AIDS
Tenofovir itself is not easily transported to target cells, but is actively transported to the proximal tubule of the kidney, resulting in certain nephrotoxicity and poor oral bioavailability

Method used

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  • Tenofovir lipid monoester compound as well as preparation method and application thereof
  • Tenofovir lipid monoester compound as well as preparation method and application thereof
  • Tenofovir lipid monoester compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Example 1 Preparation of tenofovir mono(hexadecyloxyethoxyethyl) ester (HDEE-TFV)

[0110]

[0111] 1) Slowly add 120 ml of oxalyl chloride dropwise to 100 g of tenofovir (TFV), 50 g of N,N-dimethylformamide and 1 liter of dichloromethane under nitrogen protection at 15-25°C with stirring. In the mixture composed of methane, stir and reflux for 4 to 6 hours, then cool to room temperature; concentrate under reduced pressure at 50°C to remove volatiles, add 1 liter of dichloromethane to dissolve the residue for later use;

[0112] 2) Under nitrogen protection, 0 ~ 10 ° C, under stirring, slowly drop the mixture of 125 grams of hexadecyloxyethoxyethanol (HDEE), 200 milliliters of triethylamine and 500 milliliters of dichloromethane to step 1 ) into the dichloromethane solution obtained, stirred at room temperature for 4 hours, concentrated under reduced pressure at 50° C. to remove volatile matter; added 500 milliliters of ethyl acetate, stirred at room temperature to...

Embodiment 2

[0118] Example 2 Preparation of tenofovir mono(hexadecyloxyethoxyethyl) ester (HDEE-TFV)

[0119]

[0120] 1) Under anhydrous and anaerobic conditions, 100 grams of tenofovir (TFV), 125 grams of hexadecyloxyethoxyethanol (HDEE), 110 grams of N,N,-dicyclohexylcarbodiimide and The mixture composed of 600 ml of pyridine was stirred at 90°C for 18 hours, then cooled to room temperature; filtered, the filter cake was rinsed with dichloromethane, and the combined filtrate was concentrated under reduced pressure at 60°C to remove volatiles;

[0121] 2) Add 500 ml of ethyl acetate, stir at room temperature to disperse evenly, add 500 ml of 3N hydrochloric acid, and continue stirring for 30 minutes;

[0122] 3) Static layering, after the aqueous layer was extracted with 200 ml of ethyl acetate, the pH was adjusted to 3 with 35% sodium hydroxide; the aqueous phase was extracted with dichloromethane (500 ml x 2); the dichloromethane was distilled off under reduced pressure , add 50...

Embodiment 3

[0125] Example 3 Preparation of tenofovir mono(hexadecyloxyethoxyethyl) ester (HDEE-TFV)

[0126]

[0127] 1) Stir a mixture of 100 grams of tenofovir (TFV), 20 grams of sodium hydroxide and 500 milliliters of N,N-dimethylformamide at room temperature for 3 hours, then concentrate under reduced pressure at 80°C to remove volatiles ; Add 500 milliliters of N,N-dimethylformamide and 150 grams of hexadecyloxyethoxyethanol methanesulfonate (HDEEMs), under nitrogen protection, stir at 100 ° C for 18 hours, then cool to room temperature; , concentrated under reduced pressure at 80°C to remove volatiles;

[0128] 2) Add 500 ml of ethyl acetate, stir at room temperature to disperse evenly, add 500 ml of 3N hydrochloric acid, and continue stirring for 30 minutes;

[0129] 3) Static layering, after the aqueous layer was extracted with 200 ml of ethyl acetate, the pH was adjusted to 3 with 35% sodium hydroxide; the aqueous phase was extracted with dichloromethane (500 ml x 2); the ...

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Abstract

The invention discloses a tenofovir lipid monoester compound represented by formula (1) or a pharmaceutically acceptable salt thereof, wherein X is selected from O, S or SS; when X is selected from O,s is selected from an integer of 2-10, r is selected from an integer of 2-5, and t is selected from an integer of 0-17; when X is selected from S, s is an integer from 1 to 10, r is an integer from 2to 5, and t is an integer from 0 to 17; and when X is selected from SS, s is selected from an integer of 1-10, r is selected from 3, and t is selected from an integer of 0-17. The invention also provides application of the compound in preparation of antiviral drugs.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a tenofovir lipid monoester compound and a preparation method and application thereof. Background technique [0002] Tenofovir (Tenofovir, TFV) is so far the most active anti-hepatitis B, HIV non-cyclic nucleoside reverse transcriptase inhibitors. Since the phosphonic acid in tenofovir is highly negatively charged under physiological acid-base conditions, it has poor intestinal penetration, poor cell penetration, limited target tissue distribution, short plasma half-life, and oral bioavailability Poor and large kidney and gastrointestinal side effects and other defects, thereby limiting its therapeutic effect on the disease. [0003] Tenofovir Disoproxil Fumarate (TDF, US005935946A1) is a prodrug of tenofovir, which was launched in 2001 for the treatment of hepatitis B and AIDS, and its antiviral part is tenofovir. Tenofovir disoproxil is sequentially: (a) absorbed into the pla...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61P31/18A61P31/20A61K31/675
CPCA61P31/18A61P31/20C07F9/65616
Inventor 岳祥军王志邦徐靖坤田磊邹慧邹春伟王瑞陈小峰刘安友
Owner ANHUI BIOCHEM UNITED PHARMA CO LTD
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