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4-aspartic acid substituted cytosine nucleoside compound and medicinal application thereof

A technology of cytidine nucleoside derivatives and aspartic acid, which is applied in the fields of sugar derivatives, sugar derivatives, organic chemistry, etc., can solve problems such as 4-substituted-cytidine nucleoside compounds that have not been found, and achieve good application foreground effect

Active Publication Date: 2021-01-22
HIGH & NEW TECH RES CENT OF HENAN ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the existing literature, there is no relevant report on the application of 4-substituted-cytidine nucleoside compounds in anti-CVB virus drugs

Method used

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  • 4-aspartic acid substituted cytosine nucleoside compound and medicinal application thereof
  • 4-aspartic acid substituted cytosine nucleoside compound and medicinal application thereof
  • 4-aspartic acid substituted cytosine nucleoside compound and medicinal application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: the synthesis of compound 2:

[0029] Compound 1 (1.06g, 2mmol, 1.0eq) was dissolved in anhydrous dichloromethane (200ml), DMAP (0.05g, 0.40mmol) and N-ethyldiisopropylammonia (1.95g, 15mmol) were added, and the reaction After the mixture was stirred at room temperature under nitrogen protection for 1 hour, TPSCl (1014 g, 3.8 mmol) was added, and the stirring reaction was continued for 22 hours, and water (100 ml) was added to quench the reaction, and the organic phase was separated, extracted twice with dichloromethane, and combined The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, then L-dimethyl aspartic acid dimethyl ester hydrochloride (0.47g, 2.4mmol, 1.2eq) and DMAP (0.12g, 1mmol, 1eq ), under nitrogen protection, anhydrous acetonitrile (15ml) was added, and diisopropylethylamine (0.78g, 6mmol, 3eq) was added. The reaction was stirred overnight at room temperature to obtai...

Embodiment 2

[0030] Embodiment 2: the synthesis of compound 3:

[0031] After compound 2 (0.90g, 1.3mmol, 1.0eq), tetrahydrofuran (8ml) and methanol (2.5ml) mixture was cooled to zero, potassium carbonate (0.37g, 2.6mmol) was added, and the reaction was continued for 1 hour under ice-bath conditions , after the reaction was complete, filtered, washed with methanol and concentrated under reduced pressure, column chromatography (dichloromethane:methanol=10:1) gave white powder compound 3 (0.55g, 95%). 1 HNMR (400Hz, DMSO-d 6 ):8.33(1H,d,J=8.0Hz),7.62(1H,d,J=7.2Hz),6.41-6.37(2H,m),5.95(1H,d,J=7.6Hz),5.76-5.66 (1H,m),5.27-5.11(1H,ddd,J=4.8,4.2,44.0Hz),5.01-4.94(1H,m),4.47-4.39(1H,ddd,J=4.8,5.2,12.0Hz) ,3.77-3.72(2H,m),3.66(3H,s),3.63(3H,s),2.93-2.82(3H,m); 13 C NMR (100Hz, DMSO-d 6 ): 171.0, 170.4, 163.1, 154.2, 141.4, 96.9 (J FC =8.4Hz), 95.5(J FC =191.0Hz), 94.6, 82.3 (J FC =15.9Hz), 74.9(J FC =24.3Hz), 62.3, 54.9, 51.8, 49.2, 35.5.m / z (ESI) 453 (M + +Na,100%)[found: M + +Na,453.11...

Embodiment 3

[0032] Embodiment 3: the synthesis of compound BG006:

[0033] Compound 3 (43mg, 0.1mmol) was dissolved in methanol (4ml), sodium hydroxide solution (0.5ml, 0.5mmol, 1M) was added, stirred at room temperature for 6 hours, acetic acid (35ml, 0.6mmol) was added, and separated by climbing a large plate ( Dichloromethane:methanol:acetic acid=10:1:1) to obtain white powder BG006 (38mg, 95%). 1 H NMR (400Hz, CD3OD): 7.10 (1H, d, J = 6.8Hz), 6.56-6.52 (1H, dd, J = 4.8, 10.8Hz), 6.05 (1H, d, J = 6.8Hz), 5.15 ( 1H,d,J=54.0Hz),4.75(1H,brs),4.59-4.53(1H,dd,J=4.0,22.8Hz),3.89(2H,s),3.21-3.15(1H,dd,J= 6.8,14.4Hz),2.80(2H,m); 13 C NMR (100Hz, CD3OD): 164.4, 158.3, 141.5, 98.34, 98.00, 97.50 (J FC =192.0Hz), 94.97, 84.43 (J FC =8.4Hz), 75.97 (J FC =15.9Hz), 63.02, 54.25, 47.32, 40.18.

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Abstract

The invention discloses a novel 4-aspartic acid substituted cytosine nucleoside compound and a medicinal application thereof, and belongs to the field of medicinal chemistry. The compound has a structure shown in a general formula (a), wherein R is OH, NH2, methylamine, ethylamine, C3-C10 alkylamine, C6-C12 aromatic alkylamine or C3-C6 heterocyclic alkylamine. Preferably, R is equal to OH, NH2 orNHCH2CH3. A 4-aspartic acid substituted cytosine nucleoside derivative is synthesized by modifying aspartic acid dimethyl ester hydrochloride of 4- aspartic acid dimethyl ester hydrochloride-1-(2 '-deoxy-2'-beta-fluoro-4 '-alpha-azide-beta-D-furanosyl) cytosine, the compound has anti-coxsackie virus activity, is applied to drugs for treating viral myocarditis, and good application prospects are realized.

Description

technical field [0001] The invention relates to cytidine nucleoside compounds, in particular to 4-aspartic acid substituted cytidine nucleoside compounds, a synthesis method and a medicinal application thereof, and belongs to the field of medicinal chemistry. Background technique [0002] The heart is one of the most important parts of the human body, and it is directly related to people's vital signs. Myotropic virus infection can lead to viral myocarditis in patients, which mainly manifests as primary non-specific inflammation in the myocardial interstitium, and has a high incidence in adolescents. The main viruses that cause diseases include measles virus, Coxsackie virus, and epidemic hemorrhagic fever. Patients with viral myocarditis have abnormal gene and protein expression during the onset, and have a greater chance of sudden death. Patients mainly present with arrhythmia, ventricular fibrillation, ventricular tachycardia, etc., which can lead to Acute cardiac dysfu...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00A61K31/7068A61P31/12A61P31/14A61P31/18A61P31/20
CPCA61P31/12A61P31/14A61P31/18A61P31/20C07H1/00C07H19/073
Inventor 陶乐郭晓河李玉江常俊标董黎红王强余学军郑果
Owner HIGH & NEW TECH RES CENT OF HENAN ACAD OF SCI
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