Nucleotide phosphonate compound, pharmaceutical composition, preparation method and uses thereof

A compound and solvate technology, which is applied in the direction of drug combinations, chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, etc., can solve problems such as unstable chemical properties and inability to effectively increase drug concentration at the site of action

Active Publication Date: 2015-07-29
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, pharmaceutical composition, preparation method and uses thereof
  • Nucleotide phosphonate compound, pharmaceutical composition, preparation method and uses thereof
  • Nucleotide phosphonate compound, pharmaceutical composition, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0100] 9-{(R)-2-[[(R)[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-2,3-dihydro-1H-indene Preparation of yl-5-oxyphosphonic 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) was refluxed for 3h, cooled to room temperature, concentrated under reduced pressure, then added dichloromethane (15mL), concentrated under reduced pressure once more, and added two Chloromethane (15mL), cooled to -20°C, added diisopropylethylamine (0.35mL, 2.0mmol) to prepare A solution, set aside.

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

Embodiment 2

[0108] Example 2: 9-{(R)-2-[[[[(S)-1-(methoxycarbonyl)2-methylpropyl]amino]-2,3- Preparation of dihydro-1H-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-indenol (134mg, 1.0mmol) and L-valine methyl ester hydrochloride (167mg, 1.0mmol) was used as starting material to generate 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- Preparation of indenyl-5-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-indenol (134mg, 1.0mmol) and L-alanine methyl ester hydrochloride (139mg, 1.0mmol) was used as starting material to generate 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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PUM

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Abstract

The present invention belongs to the field of pharmaceutical and chemical industry, and relates to a nucleotide phosphonate compound, a pharmaceutical composition, a preparation method and uses thereof, particularly to a non-cyclic nucleotide phosphonate compound represented by a general formula, a pharmaceutically acceptable inorganic or organic salt, and a preparation method thereof, and a composition containing the compound represented by the general formula I. The compound of the present invention can be used as the active substance for treatment and/or prevention of viral infection diseases. The formula I is defined in the instruction.

Description

technical field [0001] 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. Background technique [0002] Since the discovery of hepatitis B virus (Hepatitis B virus, HBV) in 1963, hepatitis B virus has been seriously endangering human health, and it is still a worldwide medical problem. According to the statistics of the World Health Organization, about 2 billion people in the world have been infected with hepatitis B virus, of which 360 million people are chronic hepatitis B virus infected people, and about 500,000 to 700,000 people die each year from liver failure, cirrhosis and primary hepatitis caused by hepatitis B. hepatocellular carcinoma. my country is a high-incidence area of ​​hepatitis B, about 120 million people have been infected with hepatitis B virus, and there are about 30 million chronic hepatitis patients in the country. ...

Claims

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Application Information

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Patent Type & Authority Applications(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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