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Nucleotide phosphonate compound, its pharmaceutical composition, preparation method and use

A compound and pharmaceutical technology, applied in the field of nucleotide phosphonate compounds, can solve the problems of unstable chemical properties, inability to effectively increase the concentration of drugs at the action site, etc.

Active Publication Date: 2018-01-19
QILU PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But also there is following shortcoming in this medicine 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 at action site (Pieter A., ​​Pharma.Research.1997, 14( 4): 492-496); (2) There is a certain risk of nephrotoxicity when used in high doses (Taeg H. Drugs of the Future2004, 29(2); 163-177)

Method used

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  • Nucleotide phosphonate compound, its pharmaceutical composition, preparation method and use
  • Nucleotide phosphonate compound, its pharmaceutical composition, preparation method and use
  • Nucleotide phosphonate compound, its pharmaceutical composition, preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Example 1: 9-{(R)-2-[[(S)[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-2,3-dihydro-1H-indene 5-oxyphosphonic acid]methoxy]propyl}adenine (compound 1a); and

[0100] 9-{(R)-2-[[(R)[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-2,3-dihydro-1H-indenyl-5-oxy Of phosphonic acid]methoxy]propyl}adenine (compound 1b)

[0101]

[0102] N 2 Under protection, 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) (287mg, 1.0mmol) was suspended in dichloromethane (20mL), and N, N- Diethylformamide (0.121mL, 1.1mmol), oxalyl chloride (0.31mL, 3.5mmol) were refluxed for 3h, cooled to room temperature, concentrated under reduced pressure, then dichloromethane (15mL) was added, and then concentrated under reduced pressure once, and two Chloromethane (15mL), cool to -20°C, add diisopropylethylamine (0.35mL, 2.0mmol) to make A solution for use.

[0103] Dissolve L-alanine isopropyl ester hydrochloride (167mg, 10mmol) and N,N-diisopropylethylamine (0.71mL, 4.0mmol) in dichloromethane (10mL) and stir at room ...

Embodiment 2

[0108] Example 2: 9-{(R)-2-[[[[((S)-1-(methoxycarbonyl)2-methylpropyl]amino]-2,3-dihydro-1H- Preparation of indenyl-5-oxyphosphonic acid]methoxy]propyl}adenine (compound 2)

[0109]

[0110] According to the operation of Example 1, with 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) (287mg, 1.0mmol), 5-indanol (134mg, 1.0mmol) and L-valine methyl ester hydrochloride (167mg, 1.0mmol) was used as the raw material to react to produce compound 2 (185mg, 36%).

[0111] 1 H-NMR (600MHz, CDCl 3 ,δ ppm ): 8.14(d,1H), 8.10(d,1H), 6.96(m,3H), 6.62(s,2H), 5.39(m,1H), 4.26(m,1H), 4.16(m,1H) ,3.94(m,1H), 3.83(m,2H), 3.65(m,1H), 3.55(d,3H), 2.80(m,4H), 2.00(m,2H), 1.04(m,3H), 0.79 (m, 6H). ES-API(m / z):[M+H] + 517.2.

Embodiment 3

[0112] Example 3: 9-{(R)-2-[[[[((S)-1-(methoxycarbonyl)ethyl]amino]-2,3-dihydro-1H-indenyl-5- Preparation of oxyphosphonic acid]methoxy]propyl}adenine (compound 3)

[0113]

[0114] According to the operation of Example 1, with 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) (287mg, 1.0mmol), 5-indanol (134mg, 1.0mmol) and L-alanine methyl ester hydrochloride (139mg, 1.0mmol) was used as a raw material to react to produce compound 3 (156mg, 32.1%).

[0115] 1 H-NMR (600MHz, CDCl 3 ,δ ppm ): 1 H-NMR (600MHz, CDCl 3 ,δ ppm ): 8.16(d,1H), 8.10(d,1H), 7.01(m,3H), 6.60(s,2H), 4.46(m,1H), 4.20(m,1H), 3.98(m,3H) , 3.71 (d, 3H), 3.65 (m, 1H), 2.82 (m, 4H), 2.01 (m, 2H), 1.27 (m, 6H). ES-API(m / z):[M+H] + 489.2.

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Abstract

The invention belongs to the field of medicine and chemical industry, and relates to a nucleotide phosphonate compound, its pharmaceutical composition, preparation method and application. Specifically, the present invention relates to a class of acyclic nucleotide phosphonate compounds represented by general formula I, their pharmaceutically acceptable inorganic or organic salts and preparation methods, and compositions containing the compound of general formula I. The compounds of the present invention can be used as active substances for the treatment and / or prevention of viral infectious diseases.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical engineering, and relates to a nucleotide phosphonate compound, its pharmaceutical composition, a preparation method and application. Background technique [0002] Since the discovery of Hepatitis B virus (HBV) in 1963, hepatitis B virus has been a serious threat to human health, and it is still a worldwide medical problem. According to statistics from the World Health Organization, about 2 billion people in the world have been infected with hepatitis B virus, of which 360 million are chronic hepatitis B virus infections, and about 500,000-700,000 people die each year from liver failure, cirrhosis and primary hepatitis B caused by hepatitis B. Hepatocellular carcinoma. my country is an area with a high incidence of hepatitis B. About 120 million people have been infected with hepatitis B virus. There are about 30 million patients with chronic hepatitis in the country. Hepatitis B not only brings g...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/12A61P31/20A61P31/14A61P1/16A61P31/18A61P31/22
CPCY02P20/55
Inventor 陈栋范传文郑善松赵树雍程哲刘永康张龙
Owner QILU PHARMA HAINAN
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