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Single isomer of phosphoric acid/phosphonic acid derivative and medical application of single isomer

A technology of phosphonic acid derivatives, diastereomers, applied in the field of pharmaceutically acceptable salts

Inactive Publication Date: 2018-06-08
BEIJING MEIBEITA DRUG RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in clinical applications, it was found that the combination of sofosbuvir and other antiviral drugs can cause symptomatic bradycardia

Method used

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  • Single isomer of phosphoric acid/phosphonic acid derivative and medical application of single isomer
  • Single isomer of phosphoric acid/phosphonic acid derivative and medical application of single isomer
  • Single isomer of phosphoric acid/phosphonic acid derivative and medical application of single isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 19

[0055] Example 1 9-[(R)-2-[[(R)-[[(S)-1-(isopropoxycarbonyl)-ethyl]-amino]-phenoxyphosphono]-methanol Preparation of Oxy]-Propyl]-Adenine (Ia-1-1)

[0056]

[0057] Add 14.6g 9-[(R)-2-(phosphonomethoxy)-propyl]-adenine (PMPA) and 9.6g phenol to 50ml N-methylpyrrolidone, heat to 85°C, add 6.3 ml triethylamine. Slowly add 13.4g of DCC under stirring, heat and stir overnight at 100°C, add 30ml of water after cooling. Set aside, filter off the solid, combine the washed filtrates, evaporate to dryness under reduced pressure, add 30ml of water, adjust the pH to 11 with 25% sodium hydroxide, filter off the solids, combine the washed filtrates, and extract with 30ml of ethyl acetate. The pH of the aqueous solution was adjusted to 3.1 with 37% hydrochloric acid, and a solid was precipitated upon standing. The solid was collected by filtration, added with 50ml of methanol, stirred and washed, filtered, and vacuum-dried to obtain 7.2g of phenol monoester derivative i of PMPA.

[0...

Embodiment 25

[0059] Example 2 5'-[(S)-[[(S)-1-(isopropoxycarbonyl)-ethyl]-amino]-phenoxyphosphoryl]-β-D-2'-deoxy - Preparation of 2'-a-fluoro-2'-β-C-methyluridine (Ia-2-1)

[0060] 2.1 Small-scale preparation of (S)-2-[(R)-(2-chloro-4-nitro-phenoxy)-phenoxy-phosphorylamino]propionic acid isopropyl ester (vi-b)

[0061] Dissolve 10 g (47.3 mmol) of phenyl dichlorophosphate in 50 mL of dry dichloromethane, cool to 0°C; add 7.94 g (47.3 mmol) of L-alanine isopropyl hydrochloride (iii-1) Solid, cooled to -78°C. A solution of 13.8ml of triethylamine (94.6mmol) dissolved in 50mL of dry dichloromethane was added dropwise with stirring, and the rate of addition was controlled to keep the reaction temperature at -78°C. Stir for 30 minutes after the addition, and then warm up to 0°C; within 5-10 minutes, add 8.2 grams (47.3 mmol) of 2-chloro-4-nitro-phenol and 6.6 ml (47.3 mmol) of triethylamine dropwise under stirring Dissolve in 20 mL of dry dichloromethane; keep at 0°C and continue stirring fo...

Embodiment 3

[0067] Example 3 Subacute Toxicity Evaluation and Tissue Distribution Evaluation of Continuous Administration of Tenofovir Alafenamide (TAF) and Ia-1-1 Beagle Dogs

[0068] Male Beagle dogs (7-8 months old, weighing 7-10kg) were randomly divided into groups of 4 and weighed. Carboxymethylcellulose sodium suspension containing 30 mg / kg TAF (purchased from Shanghai Hanxiang Biotechnology Co., Ltd., HPLC content 98%) or Ia-1-1 was given by intragastric administration once a day for 14 consecutive days. After the last administration, fasting without food and water for 4 hours, taking blood from vein to prepare serum for determination of blood biochemical indexes. Then, they were executed, and the organs and tissues were taken and divided into two parts. Take a part of the tissue, weigh it, add pure water to a homogenizer to make a 10% homogenate, and use high performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) to determine the active form of tenofovir in each ...

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PUM

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Abstract

The invention relates to a phosphoric acid / phosphonic acid derivative shown in a formula Ia and non-toxic pharmaceutically-acceptable salt thereof. The content of diastereoisomers shown in formula Ibis smaller than 2%; in the structural formulas Ia and Ib, Ar denotes a substituted or unsubstituted benzene ring or naphthalene ring, R1 denotes H or alkyl with the carbon atom number being 1-6; R2 denotes alkyl with the carbon atom number being 1-6 or naphthenic base; D denotes a residue of a pharmacological active molecule containing phosphoric acid / phosphonic acid groups, and that is, the groupshown in the specification denotes a pharmacological active molecule containing phosphoric acid / phosphonic acid groups.

Description

technical field [0001] The present invention relates to novel liver targeting prodrug derivatives of single isomers of pharmacologically active molecules containing phosphate or phosphonate groups and non-toxic pharmaceutically acceptable salts thereof. Background technique [0002] The liver is the target organ of viral hepatitis, liver cirrhosis, and liver cancer. The research on therapeutic drugs for these diseases has made important progress in the past ten years, but it is far from meeting the clinical needs. [0003] Compounds containing phosphate or phosphonic acid groups in molecules with the following structures are important pharmacologically active molecules in the treatment of liver diseases: [0004] [0005] For example, adefovir (PMEA), tenofovir (PMPA) and PMPDAP are acyclic nucleoside phosphonate analogs with anti-HIV and HBV activity: [0006] [0007] Nucleoside analogs such as lamivudine, entecavir, and acyclovir are all phosphorylated to form pha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07H19/10A61K31/675A61K31/7072A61P1/16A61P31/14A61P31/20
CPCC07F9/65616C07H19/10
Inventor 仲伯华王建明靳雪峰
Owner BEIJING MEIBEITA DRUG RES
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