Preparation method and use for purine compounds double amino acid ester

A double amino acid ester and compound technology, applied in the field of medicinal chemistry and antiviral infection therapeutics, can solve the problems of highly sensitive hydrolysis reaction, inability to effectively increase drug concentration at the site of action, unstable chemical properties, etc.

Inactive Publication Date: 2007-09-12
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But also there is following major defect in ADV application: (1) chemical property is unstable, and it is highly sensitive to the hydrolysis reaction mediated by serum enzyme, can not effectively increase drug concentration of action site (Pieter Annaert, Pharmaceutical Research.1997, 14 (4) : 492-496); (2) Transporting one molecule of nucleic acid requires the release of two equivalents of potentially toxic formaldehyde and pivalic acid (Jae-Taeg Hwang. Drugs of the Future 2004, 29(2); 163-177)

Method used

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  • Preparation method and use for purine compounds double amino acid ester
  • Preparation method and use for purine compounds double amino acid ester
  • Preparation method and use for purine compounds double amino acid ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1: (2S, 2'S)-9-{2-[O, O'-bis[(2-tert-butoxycarbonylamino-3-methylpentanoyloxy)ethyl]phosphonomethoxy base] ethyl} adenine (compound 1)

[0094] 1.1 Preparation of (1S)-tert-butyl-1-[(2-bromoethoxy)carbonyl]-2-methylbutylcarbamate (a)

[0095]

[0096] Dissolve N-tert-butoxycarbonyl-L-isoleucine (5.00g, 0.02mol), 2-bromoethanol (2.98g, 0.024mol) in 200ml of dry dichloromethane, cool to 10°C in an ice-water bath , added N,N-dimethylaminopyridine (2.92 g, 0.023 mol) in portions. After the addition, the system was kept warm and stirred for 15 minutes. Then a solution of dicyclohexylcarbodiimide (4.53 g, 0.022 mol) in 30 ml of dichloromethane was slowly added dropwise. After the addition, the reaction temperature was naturally raised to room temperature for 12 hours. The insoluble matter in the system was filtered, and the solvent was distilled off. 100 ml of ethyl acetate was added to the obtained residue, and the solids in the system were fully settled at l...

Embodiment 2

[0102] Example 2: (2S, 2'S)-9-{2-[O, O'-bis[(2-tert-butoxycarbonylamino-acetoxy)ethyl]phosphonomethoxy]ethyl} Preparation of adenine (compound 2)

[0103] 2.1: Preparation of tert-butyl-1-[(2-bromoethoxy)carbonyl]methylcarbamate (a)

[0104]

[0105] Dissolve N-tert-butoxycarbonyl-glycine (3.70g, 0.021mol), 2-bromoethanol (3.47g, 0.028mol) in 200ml of dry dichloromethane, cool to 10°C in an ice-water bath, and add N , N-Dimethylaminopyridine (3.10 g, 0.025 mol). After the addition, the system was kept warm and stirred for 15 minutes. Then a solution of dicyclohexylcarbodiimide (4.53 g, 0.022 mol) in 30 ml of dichloromethane was slowly added dropwise. The subsequent process was similar to the synthesis of compound 1.1. 3.21 g of a colorless oil (a) was obtained, with a yield of 54.39%.

[0106] 2.2: (2S,2′S)-9-{2-[O,O′-bis[(2-tert-butoxycarbonylamino-acetoxy)ethyl]phosphonomethoxy]ethyl}adenine (Compound 2) Preparation

[0107]

[0108] At room temperature, (a) (0.9...

Embodiment 3

[0110] Example 3: (2S, 2'S)-9-{2-[O, O'-bis[(2-tert-butoxycarbonylamino-3-methylbutyrylthio)ethyl]phosphonomethoxy Preparation of ]ethyl}adenine (compound 3)

[0111] 3.1: Preparation of (S)-2-tert-butoxycarbonylamino-3-methylmonothiobutanoic acid (a)

[0112]

[0113] Dissolve N-tert-butoxycarbonyl-L-valine (2.50g, 0.0115mol) in 25ml of dry tetrahydrofuran, cool to -15°C in an ice-salt bath, add N-methylmorpholine (11.54g, 0.0575 mol) and isobutyl chloroformate (1.74g, 0.0126mol), the system was kept stirring for 30 minutes. Keep the internal temperature of the reaction system below -15°C, feed self-made hydrogen sulfide gas for 1.5-2 hours, until the hydrogen sulfide gas in the system is absorbed to saturation, then keep the temperature for another 2 hours to complete the reaction. Add 40ml of anhydrous ether, adjust the pH of the system to 3 with 0.1M hydrochloric acid, separate the organic layer, wash with 2 x 20ml of water, 2 x 20ml of saturated brine, dry over anhyd...

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Abstract

This invention provides a kind of purine compound diplo-amino acid ester shown as formula (I), and the acceptance of inorganic or organic salt in pharmacology, in which, R1 is amino, R2 is the free L-amino amino acid or with the protection of amino, n is 0 or 1, X is O or S. The invention also provides the preparation method of this compound and its application in medicine for the treatment of viral infectious disease as active materials.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and antiviral infection therapeutics, in particular to purine compounds and their use in the preparation of antiviral drugs. Background technique [0002] Hepatitis B is a disease that seriously endangers human health caused by hepatitis B virus (HBV). According to statistics, there are about 350 million chronic HBV carriers in the world, and about 1 million people die of diseases caused by HBV every year. In my country, about 120 million people are carriers of hepatitis B virus, and there are 28 million hepatitis B patients. One-third of hepatitis B patients will develop into chronic hepatitis, cirrhosis or primary liver cancer (HCC). The main drugs for the treatment of chronic hepatitis B include interferon, nucleoside antiviral drugs and immunomodulators. Nucleoside antiviral drugs are inhibitors of viral DNA polymerase or reverse transcriptase, which can terminate the synthesis of viral D...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/12A61P31/18
CPCC07F9/65616A61P31/12A61P31/18
Inventor 杨玉社付晓钟李战嵇汝运
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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