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Phosphonate prodrug of adenine derivative and medical application of phosphonate prodrug

A technology for medicinal salts and drugs, applied in the field of phosphonate prodrugs or isomers thereof, can solve the problems of renal toxicity, potential safety hazards and the like

Active Publication Date: 2017-03-29
HANGZHOU HEZE PHARMA TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, TAF still has a certain degree of degradation in plasma, and 1-2% of tenofovir can be detected, which will cause a certain degree of kidney and bone toxicity, and there are certain safety hazards

Method used

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  • Phosphonate prodrug of adenine derivative and medical application of phosphonate prodrug
  • Phosphonate prodrug of adenine derivative and medical application of phosphonate prodrug
  • Phosphonate prodrug of adenine derivative and medical application of phosphonate prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: the preparation of O-methyl-serine isopropyl ester

[0026]

[0027] step 1:

[0028] Add 5.00g of serine to 50mL of isopropanol, add 11.32g of SOCl dropwise 2 . After the reaction was refluxed overnight, it was directly concentrated to obtain 8.47 g of white serine isopropyl ester hydrochloride with a yield of 96.9%.

[0029] Step 2:

[0030] Get in the 6.00g serine isopropyl ester hydrochloride DCM that obtains in the step 1 of above-mentioned embodiment 1, then dropwise add 8.25gEt 3 N. Add 8.64g Boc under ice bath 2 O, and react overnight at room temperature. Add water, separate the layers, wash the organic layer with brine, dry, and pass through the column to obtain 7.41 g of white solid (N-tert-butoxycarbonyl-serine isopropyl ester), with a yield of 91.7%.

[0031] Step 3:

[0032] Take 7.36g of N-tert-butoxycarbonyl-serine isopropyl ester obtained in step 2 of the above example 1 and add it to 147mL of DCM, then add 35.46g of silver oxide...

Embodiment 2

[0035] Example 2: Preparation of 9-[(R)-2-(phenylphosphonomethoxy)propyl]adenine

[0036]

[0037] Add 1.01g tenofovir (PMPA) into 14mL pyridine at room temperature, add 3.24g triphenyl phosphite into the reaction solution at room temperature, heat to reflux temperature 115°C for 8 hours, the solution becomes clear first, then A large amount of white solid precipitated, cooled to about -5°C to 5°C, added 14mL of acetone, stirred for 1.5 hours, filtered, washed the filter cake with 1mL of acetone and dried at 60°C to 70°C for 5 hours, the obtained white solid was the obtained target product , giving a total of 1.12 g of 9-[(R)-2-(phenylphosphonomethoxy)propyl]adenine as a white solid.

Embodiment 3

[0038] Embodiment 3: the synthesis of compound Ia-1

[0039]

[0040] Get the 0.67g 9-[(R)-2-(phenylphosphonomethoxy) propyl group] adenine obtained in Example 2 and add 5mLSOCl 2 In, reflux reaction for 2 hours, concentrated for later use. Take 1.30 g of O-methyl-serine isopropyl ester and 0.36 g of triethylamine obtained in Step 4 of Example 1 and add them into 10 mL of DCM, cool down to -10° C., and then add the above-mentioned concentrate to be used. After the addition, react at -10°C for about 2h, then move to room temperature and stir for about 1h. After concentration, 0.75 g of compound Ia-1 was obtained with a yield of 80.6%.

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PUM

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Abstract

The invention relates to a phosphonate prodrug of an adenine derivative and medical application of the phosphonate prodrug. Specifically, the invention relates to a compound shown in a general formula (I) or an optical isomer, or a pharmaceutical salt, or a hydrate or a solvate of the compound, and application of the compound or the optical isomer, or the pharmaceutical salt, or the hydrate or the solvate of the compound to preparation of medicines for curing virus infective diseases, especially hepatitis B (HBV) and acquired immune deficiency syndrome (HIV), wherein the definitions of all substituents in the general formula (I) are the same as the definitions in the specification.

Description

technical field [0001] The present invention relates to a phosphonate prodrug of adenine derivative or its isomer, pharmaceutically acceptable salt, hydrate or solvate, and its application in medicine. Background technique [0002] According to statistics in 2015, there are as many as 90 million hepatitis B virus (HBV) carriers in my country, and more than 20 million hepatitis B patients. Therefore, hepatitis B is still a serious infectious disease that endangers the health of our people. Nucleoside compounds are currently used clinically for the treatment of hepatitis B, including lamivudine, adefovir dipivoxil, and tenofovir disoproxil. Tenofovir disoproxil fumarate (TDF) is an oral nucleotide phosphonate analogue prodrug developed by Gilead Sciences for the treatment of HBV and HIV infection. And recently, the tenofovir alafenamide hemifumarate (TAF) invented by the company has a very high antiviral effect when the dose is lower than 1 / 10 of TDF, and its plasma stability...

Claims

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Application Information

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IPC IPC(8): C07F9/6561A61K31/675A61P1/16A61P31/14
CPCC07F9/65616A61K31/675A61P1/16A61P31/18C07F9/6561
Inventor 倪晟陈鸿翔盛荣毛建丰吴光姜维斌赵航周亮刘进军
Owner HANGZHOU HEZE PHARMA TECH
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