7-deazapurine ribonucleoside compound, synthesis method and pharmaceutical use thereof

A technology of purine ribonucleosides and compounds, which is applied in the field of medicinal chemistry and can solve problems such as the synthesis of 7-deaza-like purine ribonucleoside compounds that have not yet been discovered

Active Publication Date: 2016-02-17
HIGH & NEW TECH RES CENT OF HENAN ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the existing literature, there is no report on the synthesis of ribonucleoside compounds containing 7-deazapurines and their application in anti-HBV drugs.

Method used

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  • 7-deazapurine ribonucleoside compound, synthesis method and pharmaceutical use thereof
  • 7-deazapurine ribonucleoside compound, synthesis method and pharmaceutical use thereof
  • 7-deazapurine ribonucleoside compound, synthesis method and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Preparation of 4-ethylamino-9-(2′-deoxy-2′-β-fluoro-β-D-furanosyl)pyrrolo[2,3-d]pyrimidine (1)

[0042]In a 50 mL closed reactor, add 4-chloro-9-(2′-deoxy-2′-β-fluoro-3′,5′-di-O-benzoyl-β-D-furanosyl) in sequence Pyrrole[2,3-d]pyrimidine (a) (0.29g, 0.59mmol), 60-70% ethylamine aqueous solution (30mL), tetrahydrofuran (10mL) and methanol (7mL), in 90℃ oil bath, react After 12 hours, TLC detected that the reaction of the raw materials was completed, and after evaporation to dryness, ammonia methanol (30 mL) was added and left overnight. After evaporating to dryness, dichloromethane:methanol=13:1 was used as the eluent and separated by column chromatography to obtain compound (1) (0.17g, 0.59mmol) as white foam, yield: 99.65%. HRMS[M+H]:297.1357; 1 H-NMR(DMSO,400Hz),δ:8.14(1H,s,H-2),7.55-7.53(1H,m,H-NHCH 2 CH 3 ),7.25-7.24(1H,m,H-8),6.63-6.62(1H,m,H-7),6.57-6.52(1H,m,H-1'),5.89-5.88(1H,m, H-O),5.15-5.05(1H,m,H-3'),5.04-5.00(1H,m,H-O),4.37-4.32(1H,m,H-2'),3.79-3.78(1H...

Embodiment 2

[0044] Preparation of 4-(3-aminomethylpyridine)-9-(2′-deoxy-2′-β-fluoro-β-D-furanosyl)pyrrole[2,3-d]pyrimidine (2)

[0045] In a 50 mL closed reactor, add 4-chloro-9-(2′-deoxy-2′-β-fluoro-3′,5′-di-O-benzoyl-β-D-furanosyl) in sequence Pyrrolo[2,3-d]pyrimidine (a) (0.29g, 0.59mmol), 3-aminomethylpyridine (6mL) and tetrahydrofuran (40mL), reacted in an oil bath at 90°C for 12h, detected by TLC, raw material reaction After evaporating to dryness, ammonia methanol (30 mL) was added and left overnight. After evaporating to dryness, use column chromatography to separate and purify, first use dichloromethane:methanol=20:1 as the eluent to remove 3-aminomethylpyridine, and then use 2% triethylamine in dichloromethane:methanol=3: 1 was the eluent, and finally ethyl acetate:methanol=10:1 was used as the eluent to obtain compound (2) (0.14g, 0.28mmol) as a white foam, yield: 47.23%. HRMS[M+H]:360.1472; 1 H-NMR(DMSO,400Hz),δ:8.58(1H,s,H-2),8.45-8.44(1H,m,H-N),8.18-8.17(1H,m,H-8),8.16-8....

Embodiment 3

[0047] Preparation of 4-(3-methoxypropylamino)-9-(2′-deoxy-2′-β-fluoro-β-D-furanosyl)pyrrole[2,3-d]pyrimidine (3)

[0048] In a 50 mL closed reactor, add 4-chloro-9-(2′-deoxy-2′-β-fluoro-3′,5′-di-O-benzoyl-β-D-furanosyl) in sequence Pyrrole[2,3-d]pyrimidine (a) (0.32g, 0.64mmol), 3-methoxypropylamine (6mL) and tetrahydrofuran (40mL), reacted in an oil bath at 90°C for 12h, detected by TLC, raw material reaction After evaporating to dryness, ammonia methanol (30 mL) was added and left overnight. After evaporation to dryness, it was separated and purified by column chromatography, and eluted with dichloromethane:methanol=10:1 as the eluent to obtain compound (3) (0.21g, 0.62mmol) as a white foam, yield: 96.59%. HRMS[M+H]:341.1620; 1 H-NMR(DMSO,400Hz),δ:8.14(1H,s,H-2),7.56(1H,brs,H-N),7.26-7.25(1H,m,H-8),6.64-6.63(1H, m,H-7),6.57-6.56(1H,m,H-1'),5.89-5.88(1H,m,H-O),5.15-5.00(1H,m,H-3'),5.07-5.04( 1H,m,H-O),4.38-4.32(1H,m,H-4'),3.79-3.78(1H,m,H-2'),3.64-3.61(2H,m,H-5'),3.51 -...

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Abstract

The invention discloses 7-deazapurine ribonucleoside compounds, and a synthesis method and medical application thereof, belonging to the field of medical chemistry. The 7-deazapurine ribonucleoside compounds have a structure shown in a general formula (I), wherein R1 is H or F, R2 is one of the following substituent groups described in the specification, R3 is H or CH3, R4 is H or CH3, and R5 is H or CH3; R2 is one of the following substituent groups of (CH2)Nch3, wherein n is equal to 0-4; CH2(CH2)nCH2OCH3, wherein n is equal to 0-18; CH2(CH2)nCH2NH2, wherein n is equal to 0-18; and CH2(CH2)nCH2N(CH3)2, wherein n is equal to 0-18. According to the 7-deazapurine ribonucleoside compounds, basic groups of the 7-deazapurine ribonucleoside compounds are modified, series 4-substituent-9-(2'-deoxy-2'-beta-fluoro-beta-D-furanose) pyrrole [2,3-d] pyrimidine derivatives are synthesized, and the compounds have anti-hepatitis B virus activities; the preparation method is feasible; the 7-deazapurine ribonucleoside compounds are wide in application prospect when applied to preparation of virus treating medicines.

Description

technical field [0001] The invention relates to nucleoside compounds, in particular to 7-deazapurine ribonucleoside compounds, a synthesis method and a medicinal application thereof, and belongs to the field of medicinal chemistry. Background technique [0002] Viruses are a group of tiny, simple structures with nucleic acid as the center and protein as the outer shell, without cell particles, and are hereditary and variable. They parasitize inside cells and utilize host cell metabolic system for value-added replication. Many human epidemic infectious diseases are caused by viruses, such as influenza, measles, viral hepatitis and AIDS. Hepatitis B is a disease caused by hepatitis B virus (HBV), mainly characterized by liver inflammatory lesions, and can cause multiple organ damage. Hepatitis B is widely prevalent in all countries in the world, mainly invading children and young adults, and a small number of patients can transform into liver cirrhosis or liver cancer. Ther...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/23C07H1/00A61K31/7064A61P31/20
Inventor 郭晓河李玉江陶乐常俊标王强董黎红
Owner HIGH & NEW TECH RES CENT OF HENAN ACAD OF SCI
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