Valine protected imidazo-[1,2-a] purine three-loop base opened-loop nucleoside compounds, preparation method and application thereof

A compound, imidazolo technology, applied in the field of antiviral drugs, can solve the problems of poor oral absorption, large clinical dosage, and low bioavailability, and achieve the goals of reducing clinical dosage, improving oral bioavailability, and strong antiviral activity Effect

Inactive Publication Date: 2008-12-03
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Acyclovir (ACV) and Ganciclovir (Ganciclovir, GCV) have strong antiviral activity, but their water solubility is poor, oral absorption is poor, bioavailability is low, and clinical dosage is relatively large, so still There is a need to find new antiviral drugs

Method used

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  • Valine protected imidazo-[1,2-a] purine three-loop base opened-loop nucleoside compounds, preparation method and application thereof
  • Valine protected imidazo-[1,2-a] purine three-loop base opened-loop nucleoside compounds, preparation method and application thereof
  • Valine protected imidazo-[1,2-a] purine three-loop base opened-loop nucleoside compounds, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] III-12: 2-[(3,9-dihydro-6-p-bromophenyl-9-one-5H-imidazo[1,2-a]purine)-3-methoxy]-CBZ-L - Preparation of valine ethyl ester

[0051]Add 3,9-dihydro-3-(hydroxyethoxymethyl)-6-(p-bromophenyl)-9-ketone-5H imidazo[1,2-a]purine 900mg ( 2.27mmol), Cbz-L-Valine740mg (2.95mmol), DCC515mg (2.5mmol), DMAP 40mg (Cat.), anhydrous DMF20ml dried by calcium hydrogen, magnetic stirring, reaction at room temperature, TLC tracking reaction, reaction 24 After 1 hour, DCC 515mg (2.5mmol) was added and reacted for another 24 hours until the reaction reached equilibrium. Filtrate, wash the solid with methanol, evaporate the mother liquor to dryness under reduced pressure, mix in 8g of 100-200 mesh silica gel, and perform pressure column chromatography after drying. Eluent: chloroform: methanol = 30:1. After washing with ethyl acetate, 1000 mg of intermediate product was obtained.

[0052] Yield: 69.3%, mp: 203.5-205.5°C

[0053] MS (EI) m / e: [M]+636, isotope peak 638 (1:1), [M-side chai...

Embodiment 2

[0058] III-9: 2-[(3,9-dihydro-6-m-chlorophenyl-9-one-5H-imidazo[1,2-a]purine)-3-methoxy]-CBZ-L - Preparation of valine ethyl ester

[0059] Add 3,9-dihydro-3-(hydroxyethoxymethyl)-6-(m-chlorophenyl)-9-ketone-5H imidazo[1,2-a]purine 1000mg ( 2.78mmol), Cbz-L-Valine905mg (3.61mmol), DCC640mg (3.11mmol), DMAP 50mg (Cat.), anhydrous DMF25ml dried by calcium hydrogen, magnetic stirring, reaction at room temperature, TLC tracking reaction, reaction 24 After one hour, 640 mg (3.11 mmol) of DCC was added and reacted for another 24 hours, and the reaction reached equilibrium. Filtrate, wash the solid with methanol, evaporate the mother liquor to dryness under reduced pressure, mix in 8g of 100-200 mesh silica gel, and perform pressure column chromatography after drying. Eluent: chloroform: methanol = 30:1. After washing with ethyl acetate, 704 mg of intermediate product was obtained.

[0060] Yield: 42.8%, mp: 78-80°C

[0061] MS (EI) m / e: [M]+592, isotope peak 592 (1:1)

[0062]...

Embodiment 3

[0068] III-10: 2-[(3,9-dihydro-6-p-methylphenyl-9-one-5H-imidazo[1,2-a]purine)-3-methoxy]-CBZ- Preparation of L-valine ethyl ester

[0069] Add 3,9-dihydro-3-(hydroxyethoxymethyl)-6-(p-methylphenyl)-9-one-5H imidazo[1,2-a]purine 900mg into 100ml egg-shaped bottle (2.65mmol), Cbz-L-Valine833mg (3.32mmol), DCC600mg (2.92mmol), DMAP 50mg (Cat.), anhydrous DMF25ml dried by calcium hydrogen, magnetic stirring, reaction at room temperature, TLC tracking reaction, reaction After 24 hours, 600 mg (2.92 mmol) of DCC was added and reacted for another 24 hours until the reaction reached equilibrium. Filter, wash the solid with methanol, evaporate the mother liquor to dryness under reduced pressure, mix in 6g of 100-200 mesh silica gel, and perform pressure column chromatography after drying. Eluent: chloroform: methanol = 30:1. After washing with ethyl acetate, 318 mg of intermediate product was obtained.

[0070] Yield: 21%, mp: 107-109°C

[0071] MS(EI)m / e: [M]+572, [M-side chain]...

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Abstract

The invention provides a compound shown as the formula (I), wherein R1 is substituted or unsubstituted aryl or cycloalkyl, the aryl or the cycloalkyl optionally contains heteroatom such as N, S, and O in the aromatic ring or cycloalkyl ring, and the substituent is alkyl, alkoxyl or halogen; and R is H or substituted or unsubstituted phenyl. The invention also discloses a preparation method of the compound shown as the formula (I) and the application in the preparation of antiviral drugs.

Description

technical field [0001] The invention relates to antiviral drugs, in particular to valine-protected imidazo[1,2-a]purine tricyclic base ring-opening nucleoside compounds, intermediate compounds, preparation methods and uses thereof. Background technique [0002] Viral diseases are common and frequently-occurring diseases that seriously endanger and affect human health today. There are more than 150 kinds of human pathogenic viruses, which are divided into two categories: DNA viruses and RNA viruses. According to statistics, viral diseases account for as much as 60%-65% of human infectious diseases. The most common viral diseases include measles, influenza, mumps, chickenpox, polio, rabies, epidemic hemorrhagic fever and various diseases caused by herpes. Herpes viruses are divided into skin and mucous membrane herpes simplex (HSV- I, HSV-II), herpes zoster (HZV), cytomegalovirus (CMV), etc. In the past ten years, AIDS (AIDs) infected by human immunodeficiency virus (HIV) a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/14C07D473/00A61K31/519A61P31/12
CPCY02P20/55
Inventor 肖旭华孙文劼马维勇奚宏伟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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