Five-membered heterocycle modified 4'-spiro nucleoside compounds and application in virus resistance

A nucleoside compound, five-membered heterocycle technology, applied in the field of five-membered heterocycle modified 4'-spirocyclic nucleoside compounds, can solve the problem of lack of specific treatment and the like

Inactive Publication Date: 2013-03-20
JILIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the large number of enterovirus serotypes (nearly 70 types), no effective and feasible vaccine can be made to prevent its infection
At the same time,...

Method used

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  • Five-membered heterocycle modified 4'-spiro nucleoside compounds and application in virus resistance
  • Five-membered heterocycle modified 4'-spiro nucleoside compounds and application in virus resistance
  • Five-membered heterocycle modified 4'-spiro nucleoside compounds and application in virus resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Synthesis

[0048] Hydroxylamine (1.53g, 22mmol) was dissolved in 30mL of water and added to a 250mL three-necked flask. Benzaldehyde (2.12 g, 20 mmol) was dissolved in 50 mL of ethanol and added to the above system. 22 mL of 1N NaOH solution was added dropwise to the system with stirring at room temperature. The dropwise addition was completed within half an hour. After the dropwise addition was completed, TLC detected that the raw material disappeared. Ethanol and water were evaporated by rotary evaporation to obtain a light yellow solid, and 20 mL of water was added to dissolve the white solid, and the aqueous solution was extracted with 10 mL of ethyl acetate for three times, and the combined organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated to obtain a crude product 2.18 g of benzaldoxime light yellow solid. Weigh the crude product benzaldoxime (1.21g, 10mmol) obtained in the previous step, dissolve it in 30mL of D...

Embodiment 2

[0052] Example 2 Synthesis

[0053] Take 1.6mmol of the crude product of chlorobenzaldoxime and dissolve it in 20mL of dichloromethane, and add it dropwise to the compound 2′,3′-tert-butyldimethylsilyl-protected-4′,5′-double bond under ice bath Uridine (1.0 mmol) in dichloromethane (5 ml) solution. After the dropwise addition was completed, a solution of triethylamine (0.24 mL, 1.6 mmol) in 10 mL of dichloromethane was added dropwise under ice-cooling. After the reaction was completed, the solvent was evaporated on a water pump and separated by column chromatography. The cyclization product was obtained. 1 H NMR (300MHz, CDCl 3 )δ7.83 (d, J=8.1Hz, 1H, 6-H), 7.66 (dd, J=7.2, 2.3Hz, 2H, aryl-), 7.44 (dd, J=5.1, 1.8Hz, 3H, aryl -), 5.81(dd, J=5.2, 2.9Hz, 2H, 5-H, 1'-H), 4.26(d, J=2.4Hz, 1H, 3'-H), 4.23(d, J=3.6 Hz, 1H, 2'-H), 3.79(d, J=18.4Hz, 1H, 5'-H), 3.30(d, J=18.4Hz, 1H, 5'-H), 0.95(s, 9H) , 0.88(s, 9H), 0.12(t, J=15.8Hz, 12H); 13 C NMR (75MHz, CDCl 3 )δ163.67, 158...

Embodiment 3

[0055] Example 3: Synthesis

[0056] Weigh 1mmol of the cyclization product and dissolve it in 5ml of anhydrous THF to dissolve it, then add 1NTBAF (tetrabutylammonium fluoride, 3ml) tetrahydrofuran solution, stir at room temperature for 3h, after the reaction is completed, pour the reaction system into 10ml of ice water, a white solid will precipitate out at this time. The white solid was filtered and washed with water, ethanol and methanol successively. The pure product was obtained. Two-step yield: 62%, 1 H NMR (300MHz, DMSO-d 6 )δ=7.70(t, J=8.0Hz, 3H), 7.55-7.40(m, 3H), 6.10(dd, J=9.6, 5.8Hz, 2H), 5.82(d, J=8.3Hz, 1H) , 5.79(d, J=6.2Hz, 1H,), 4.34(d, J=4.1Hz, 1H,), 4.08(t, J=4.5Hz, 1H), 3.81(d, J=18.9Hz, 1H) , 3.45 (d, J=18.8Hz, 1H). 13 C NMR (75MHz, DMSO-d 6 )δ=163.00, 158.03, 150.95, 139.91, 130.70, 128.97, 128.57, 126.80, 117.00, 103.04, 87.40, 73.86, 73.79, 40.70.

[0057] Calculated value of high resolution mass spectrum: C 16 h 16 N 3 o 6 [M+H] + : 346...

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Abstract

The invention belongs to the field of medicinal chemistry, and in particular relates to five-membered heterocycle modified 4'-spiro nucleoside compounds which are synthesized by 1,3-dipolar cycloaddition reaction of 4',5'-double-bond nucleoside and 1,3-dipolar body and have diversified structures. Because the compounds have special physiological activity and biological functions, the compounds can be applied in anti-Coxsackie viruses. The raw materials are easily available, the reaction conditions are mild, the operation is simple, the application range of the substrate is wide, the products are easily diversified, the yield is high (50 to 98 percent), and the compounds have the advantages of high efficiency, high region selectivity and high stereo selectivity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of structure diversification synthesized by 1,3-dipolar cycloaddition reaction of 4',5'-double bond nucleosides and 1,3-dipoles containing multifunctional groups The five-membered heterocyclic modified 4'-spirocyclic nucleoside compound of the present invention can be applied in antiviral because of its special physiological activity and biological function. Background technique [0002] Virus infection can cause various diseases and seriously endanger human health and life. According to statistics, about 60% to 65% of epidemic infectious diseases are caused by viral infections, such as hepatitis B / C, AIDS, hand, foot and mouth disease, cytomegalovirus infection and herpes virus infection, which have seriously threatened people's health and life. [0003] Nucleoside compounds play an important role in antiviral drugs. Among the currently marketed and clin...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H23/00A61K31/7072A61P31/12A61P31/18A61P31/14A61P31/20
Inventor 孙静波李洪明张文银陶强强徐琳姜春来吴劲昌
Owner JILIN UNIV
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