N4-glycine methyl ester and derivative substituted nucleoside compound thereof, and pharmaceutical application of N4-glycine methyl ester and derivative substituted nucleoside compound

Abstract

The invention relates to N4-glycine methyl ester and a derivative substituted nucleoside compound thereof, the general formula of the N4-glycine methyl ester substituted nucleoside compound is as follows: # imgabs0 #, and R is H or C1-C10 straight-chain or branched-chain alkyl. Tests show that N4-glycine methyl ester and a derivative substituted nucleoside compound thereof have better anti-coxsackie virus (CVB3) activity, and can be used for preparing the anti-coxsackie virus active medicine.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry and specifically relates to a class of N 4 -Study on the activity of glycine methyl ester and its derivatives substituted nucleoside compounds and their anti-Coxsackievirus (CVB3). Background Art

[0002] Coxsackievirus B3 (CVB3) is a single-stranded positive-chain virus belonging to the genus Enterovirus and the family Picornaviridae. CVB3 is transmitted through the digestive tract and respiratory tract, and causes diseases such as viral myocarditis (VMC) and pancreatitis after infecting the body. It is reported that about 20% of myocarditis patients and 10% of pancreatitis patients are related to CVB3 infection. However, there is still a lack of effective therapeutic drugs in the clinic. Therefore, it is extremely important to develop new drugs to treat CVB3 infection.

[0003] Nucleoside drugs have good antiviral activity and have been the focus of pharmacists and chemists. Nucleosides and their analogs play an extremely important role in fighting HIV, HBV, and HCV. Viral infections have seriously affected human health and quality of life. It is necessary to continue to study and design new nucleoside analogs to prevent the emergence of drug-resistant mutants. Therefore, it is necessary to continuously develop new drugs to protect human life and health.

[0004] Based on this, this application was developed. Summary of the invention

[0005] The present invention aims to overcome the defects of the prior art and provide a type of N 4 -Glycine methyl ester and its derivatives substituted nucleoside compounds, which have anti-Coxsackie virus (CVB3) activity.

[0006] Another object of the present invention is to provide the N 4 -Application of glycine methyl ester and its derivatives to replace nucleoside compounds in the preparation of anti-Coxsackie virus (CVB3) active drugs.

[0007] To achieve the above object, the present invention adopts the following technical solution:

[0008] Class N 4 -Glycine methyl ester and its derivatives substituted nucleoside compounds, the general formula of which is as follows:

[0009] Wherein, R is H or a C1-C10 straight or branched chain alkyl group.

[0010] Furthermore, the N 4-Glycine methyl ester and its derivatives substituted nucleoside compounds, preferably at least one of the compounds shown below:

[0011]

[0012] The present invention discloses a 4 - Preparation method of glycine methyl ester and its derivatives substituted nucleoside compounds, the synthesis route is as follows:

[0013]

[0014] Wherein, R is H or a C1-C10 straight or branched chain alkyl group;

[0015] The specific steps include:

[0016] Compound 1 was dissolved in anhydrous dichloromethane, 4-dimethylaminopyridine (DMAP) and triethylamine were added, the reaction mixture was dispersed uniformly by stirring at room temperature under nitrogen protection, 2,4,6-triisopropylbenzenesulfonyl chloride (TPSCI) was added, and then the stirring reaction was continued (generally more than 10 hours were required), and the reaction of the raw materials was completed by TLC monitoring to obtain compound 2;

[0017] Without treatment, glycine methyl ester hydrochloride was directly added, and the reaction was stirred at room temperature under nitrogen protection (generally, the reaction required more than 12 hours). The reaction of the raw material was completed by TLC monitoring. After purification (generally including adding water, saturated sodium bicarbonate solution, dichloromethane extraction, combining organic phases, drying over anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure), methanol was added, cooled to below zero, and potassium carbonate was added and the temperature was raised to room temperature for reaction (generally, the reaction required more than 12 hours). The reaction of the raw material was completed by TLC monitoring. After filtration, washing, concentration under reduced pressure, and column chromatography separation and purification, compound 3 was obtained;

[0018] Take compound 3, add various alkylamine aqueous solutions, and after the reaction is complete at room temperature, concentrate to dryness under reduced pressure to obtain the product.

[0019] Specifically, the molar ratio of compound 1 to 2,4,6-triisopropylbenzenesulfonyl chloride is 1:1.4-2.0. The molar ratio of compound 1 to glycine methyl ester hydrochloride is 1:1.5-2.0. In actual operation, in order to obtain a better synthesis effect, part of DMAP and triethylamine are generally added when adding glycine methyl ester hydrochloride. In addition, after the addition of glycine methyl ester hydrochloride is completely reacted, water, saturated sodium bicarbonate solution, dichloromethane extraction, organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure for purification.

[0020] The present invention also provides the above-mentioned N 4-Application of glycine methyl ester and its derivatives to replace nucleoside compounds in the preparation of anti-Coxsackie virus (CVB3) active drugs.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] The present invention can efficiently synthesize series N 4 -Glycine methyl ester and its derivatives replace the nucleoside structure compounds. The present invention is the first innovative synthesis of such compounds, and the reaction conditions are mild, the operation is simple, the yield is high, the reaction path is reasonable, the post-treatment is simple, and the target compound with high yield and high purity is obtained. The present invention has been found through experiments: N 4 -Glycine methyl ester and its derivative substituted nucleoside compounds have good anti-Coxsackie virus (CVB3) activity and can be used to prepare anti-Coxsackie virus active drugs. DETAILED DESCRIPTION

[0023] The technical solution of the present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto.

[0024] In the following examples, unless otherwise specified, the raw materials used are common commercial products that can be directly purchased or can be prepared using conventional techniques in the art.

[0025] Room temperature refers to 25±5°C.

[0026] In the following examples, compound 1, chemical name: 2'-deoxy-2'-fluoro-3'-benzoyl-4'-azido-5'-m-chlorobenzoyl chloride-uridine, its synthesis method can refer to Chinese patent CN201410013037.8 "3-methyluridine and 4-methylcytidine nucleoside compounds, synthesis methods and pharmaceutical uses thereof".

[0027] Example 1: Synthesis of compound a:

[0028]

[0029] Compound 1 (5.30 g, 10.0 mmol) was dissolved in anhydrous dichloromethane (DCM, 80.0 ml), and DMAP (0.20 g, 1.60 mmol) and triethylamine (TEA, 8.3 mL, 60.0 mmol) were added in sequence. After the reaction mixture was stirred at room temperature under nitrogen protection for 1 hour, TPSCI (4.60 g, 15.2 mmol) was added, and the reaction was continued to be stirred. The reaction of the raw material was completed (about 10 hours) monitored by TLC to obtain compound 2. Without treatment, glycine methyl ester hydrochloride (1.44 g, 16.0 mmol), DMAP (0.98 g, 8.0 mmol) and triethylamine (3.3 mL, 24.0 mmol) were directly added, and the reaction was stirred at room temperature under nitrogen protection. The reaction of the raw material was completed by TLC monitoring (stirring for 12 h) to obtain a red solution. Water, saturated sodium bicarbonate solution, and dichloromethane were added for extraction three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was dissolved in methanol (15 ml), cooled to zero degrees, and potassium carbonate (2.50 g, 18.3 mmol) was added. The temperature was slowly raised to room temperature for reaction. The reaction of the raw material was completed by TLC monitoring (about 12 h). The mixture was filtered, washed with methanol, and concentrated under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 10: 1, V / V) to obtain compound 3 (2.08 g, 58%, total yield). Compound 3 (0.36 g, 9.0 mmol) was added into aqueous methylamine solution (2 ml, 60%) and stirred at room temperature for 4 hours. After TLC monitoring, the reaction of the raw material was complete and the mixture was concentrated to dryness under reduced pressure to obtain white powder compound a (0.36 g, 99.0%).

[0030] Hydrogen spectrum and carbon spectrum of compound 3: 1 HNMR (400MHz, CD3OD): δ=7.755-7.733 (dd, J=0.8, 7.6Hz, 1H), 6.499-6.455 (dd, J=4.8, 12.4Hz, 1H), 6.00 (d, J=7.2Hz, 1H), 5 .277-5.119 (ddd, J=4.8, 9.6, 53.6Hz, 1H), 4.507-4.441 (dd, J=4.8, 21.6Hz, 1H), 4.187 (s, 2H), 3.837 (s, 2H), 3.731 (s, 3H); 13 CNMR (101MHz, CD3OD): δ=171.8, 165.8, 157.9, 142.0, 98.5, 96.9, 95.0, 84.7, 64.3, 52.7, 42.9.

[0031] Hydrogen spectrum and carbon spectrum of compound a: 1HNMR (400MHz, CD3OD): δ=7.752-7.730 (dd, J=0.8, 7.6Hz, 1H), 6.489-6.445 (dd, J=4.8, 12.4Hz, 1H), 5.98 (d, J=7.2Hz, 1H), 5 .260-5.102 (ddd, J=4.8, 9.6, 53.6Hz, 1H), 4.501-4.435 (dd, J=4.8, 21.6Hz, 1H), 4.186 (s, 2H), 3.831 (s, 2H), 2.687 (s, 3H); 13 CNMR (101MHz, CD3OD): δ=172.3, 166.3, 158.4, 142.5, 99.0, 97.3, 95.4, 85.1, 64.6, 52.6, 38.4.

[0032] Example 2: Synthesis of compound b:

[0033]

[0034] Refer to Example 1, except that: Compound 3 was used in an amount (0.36 g, 9.0 mmol), ethylamine aqueous solution (2 ml, 60%) was added, and the reaction was stirred at room temperature for 4 hours. TLC monitored the completion of the reaction of the raw materials, and the mixture was concentrated to dryness under reduced pressure to obtain white powder Compound b (0.37 g, 100%).

[0035] Hydrogen spectrum and carbon spectrum of compound b: 1 HNMR (400MHz, CD3OD): δ=7.748-7.726 (dd, J=0.8, 7.6Hz, 1H), 6.484-6.440 (dd, J=4.8, 12.4Hz, 1H), 5.97 (d, J=7.2Hz, 1H), 5.258-5 .100 (ddd, J=4.8, 9.6, 53.6Hz, 1H), 4.498-4.432 (dd, J=4.8, 21.6Hz, 1H), 4.123 (s, 2H), 3.731 (s, 2H), 3.220 (m, 2H), 1.124 (s, 3H); 13 CNMR (101MHz, CD3OD): δ=172.5, 166.4, 158.6, 142.8, 99.3, 97.6, 95.8, 85.6, 64.7, 52.4, 38.4, 23.5.

[0036] Example 3: Synthesis of Compound C:

[0037]

[0038] Refer to Example 1, except that: Compound 3 was used in an amount (0.36 g, 1.0 mmol), isopropylamine aqueous solution (4 ml, 50%) was added, and the reaction was stirred at room temperature for 6 h. The reaction was completed after monitoring by TLC, and the mixture was concentrated to dryness under reduced pressure to obtain white powder Compound C (0.38 g, 99%).

[0039] Hydrogen spectrum and carbon spectrum of compound c: 1 HNMR (400MHz, CD3OD): δ=7.746-7.724 (dd, J=0.8, 7.6Hz, 1H), 6.482-6.438 (dd, J=4.8, 12.4Hz, 1H), 5.980 (d, J=7.2Hz, 1H), 5.262- 5.104 (ddd, J=4.8, 9.6, 53.6Hz, 1H), 4.499-4.433 (dd, J=4.8, 21.6Hz, 1H), 4.126 (s, 2H), 3.726 (s, 2H), 3.458 (m, 1H), 1.132 (m, 6H); 13 CNMR (101MHz, CD3OD): δ=173.1, 166.9, 159.2, 142.1, 99.8, 97.9, 96.5, 85.2, 65.1, 53.6, 44.6, 27.5.

[0040] Example 4: Synthesis of Compound d:

[0041]

[0042] Refer to Example 1, except that: Compound 3 (0.36 g, 1.0 mmol) was used, n-butylamine (4 ml) and water (4 ml) were added, and the reaction was stirred at room temperature for 6 h. The reaction was completed after monitoring by TLC, and the mixture was concentrated to dryness under reduced pressure to obtain white powder Compound C (0.40 g, 100%).

[0043] Hydrogen spectrum and carbon spectrum of compound d: 1 HNMR (400MHz, CD3OD): δ=7.743-7.721 (dd, J=0.8, 7.6Hz, 1H), 6.480-6.436 (dd, J=4.8, 12.4Hz, 1H), 5.99 (d, J=7.2Hz, 1H), 5.260-5.102 (d dd, J=4.8, 9.6, 53.6Hz, 1H), 4.496-4.430 (dd, J=4.8, 21.6Hz, 1H), 4.123 (s, 2H), 3.724 (s, 2H), 2.456 (m, 2H), 1.458 (m, 4H), 1.116 (m, 3H); 13CNMR (101MHz, CD3OD): δ=173.6, 166.3, 159.7, 142.6, 99.3, 97.6, 96.8, 85.9, 66.1, 52.8, 45.1, 38.6, 26.1, 24.8, 22.6.

[0044] The method of the present invention is used to synthesize N 4 -Glycine methyl ester and its derivatives replace compounds of nucleoside structure. The method has the following advantages: the present invention is universal, the reaction conditions are mild, the cost is low, the post-treatment is simple, the reaction path is reasonable, and this type of compound can be efficiently prepared.

[0045] Application example: Anti-Coxsackievirus activity:

[0046] 1 Experimental Materials

[0047] 1.1 Experimental cells and viruses

[0048] Human cervical cancer cell line (Hela) and coxsackievirus B3 (CVB3) were maintained in the laboratory.

[0049] 1.2 Test compounds

[0050] The positive control drug, ribavirin injection, was purchased from Suicheng Pharmaceutical Co., Ltd.

[0051] The test compound is the compound ad synthesized in Examples 1 to 4 above.

[0052] 1.3 Reagents

[0053] DMEM medium Beijing Solarbio Technology Co., Ltd. Fetal bovine serum (FBS) Gemini Corporation Dimethyl sulfoxide (DMSO) Beijing Solarbio Technology Co., Ltd. Methyl tetrazolium blue (MTT) Beijing Solarbio Technology Co., Ltd. <![CDATA[Potassium dihydrogen phosphate (KH2PO4)]]> Tianjin Fengchuan Chemical Reagents Co., Ltd. <![CDATA[Disodium hydrogen phosphate (Na2HPO4)]]> Tianjin Fengchuan Chemical Reagents Co., Ltd. Sodium chloride (NaCl) Tianjin Fengchuan Chemical Reagents Co., Ltd. Potassium chloride (KCl) Tianjin Fengchuan Chemical Reagents Co., Ltd. Trypsin Beijing Biotoda Technology Co., Ltd. Ethylenediaminetetraacetic acid (EDTA) Beijing Bondtech Biotechnology Co., Ltd.

[0054] 1.4 Instruments

[0055]

[0056]

[0057] 2 Experimental methods:

[0058] 2.1 Determination of the toxicity of compound ad to Hela cells

[0059] The MTT method was used to detect the toxicity of ad to Hela cells after 72 hours of action, and the inhibition rate of different concentrations of drugs on cells was calculated, and the half toxic concentration CC was calculated. 50 , the specific steps are as follows:

[0060] (1) Collect Hela cells in the logarithmic growth phase and adjust the cell suspension concentration to 5×10 4The cells were inoculated into 96-well plates, 100 μl of cell suspension was added to each well, and cultured at 37°C with 5% CO2.

[0061] (2) On the second day, the cells were observed to be growing well. The supernatant was discarded and 100 μl of drug-containing culture medium of different concentrations was added to each well. A positive control and a blank control were set up. The cells were cultured for 72 h and the cell growth status was observed every day.

[0062] (3) Take out the 96-well plate, add 20 μl of MTT to each well, continue to culture for 4 h, carefully aspirate and discard the supernatant in the wells, add 150 μl of DMSO to each well, place on a shaker, and shake at 37°C in the dark at a low speed for 10 min to allow the blue-purple crystals to fully dissolve.

[0063] (4) The absorbance of each well was measured by an ELISA instrument (detection wavelength 490 nm, reference wavelength 630 nm), and the inhibition rate of cells by different concentrations of ad was calculated, formula (1.1):

[0064]

[0065] (5) Based on the concentration inhibition rate gradient trend, the half toxic concentration CC of al for Hela cells was calculated using SPSS Statistics 17 software 50 value.

[0066] 2.2 CVB3 virus amplification

[0067] When Hela cells are fully grown in a monolayer, discard the culture medium and wash twice with sterile PBS to control dryness, add 500μl of CVB3 virus stock solution, place in a 5% CO2, 37℃ incubator, shake once every 30min, evenly distribute, add 4.5ml of fresh culture medium after virus adsorption for 2h, and continue to culture. Observe the cytopathic effect (CPE) under a microscope. When the cell pathological volume reaches 75%, place the culture bottle in a -80℃ refrigerator, freeze and thaw repeatedly 3 times to fully lyse the cells and release the virus. Collect the virus solution after fully blowing with a 5ml pipette, centrifuge at 3000rpm / min for 10min, take the supernatant and package it in a cryopreservation tube, and store it at -80℃ for later use.

[0068] 2.3 CVB3 titer determination

[0069] In this experiment, the Reed-Mnench method was used to calculate the TCID of CVB3 virus. 50 value.

[0070] lgTCID 50= the logarithm of the highest dilution with a CPE positive rate greater than 50% + distance ratio × logarithm of the interval between dilutions, where distance ratio = (percentage of CPE positive rates greater than 50% - 50) / (percentage of CPE positive rates greater than 50% - percentage of CPE positive rates less than 50%).

[0071] (1) Digest Hela cells in good growth condition and adjust the cell suspension concentration to 8×10 4 The cells were inoculated into 96-well plates, 100 μl of cell suspension was added to each well, and cultured at 37°C with 5% CO2.

[0072] (2) Pre-thaw the virus stock solution and blow it evenly for later use. Endpoint dilution method for titration of TCID of CVB3 50 , use DMEM medium containing 10% fetal bovine serum (FBS) to dilute the original solution 10 times, -1 to 10 -12 The sample was diluted in a gradient manner, with 8 replicate wells for each concentration and a blank control.

[0073] (3) When Hela cells grow to a monolayer, discard the supernatant and add 100 μl of virus dilution to each well. Continue culturing and observe and record the number of wells with lesions every day. When the cell lesions no longer develop (usually about 7 days), calculate the TCID of CVB3 using the formula 50 , determine the optimal amount of CVB3 used in subsequent experiments.

[0074] 2.4 In vitro anti-CVB3 activity test of compound ad

[0075] According to the cytotoxicity and virus titer, set the appropriate compound concentration gradient and virus infection dose. Set up a blank cell control group, a model control group, a test substance group, and a positive drug ribavirin control group. Use the MTT method to detect the activity against CVB3 virus and calculate the IC 50 value.

[0076] (1) Count the Hela cells that are growing well and adjust the cell concentration to 5×10 4 / ml, inoculated into 96-well plates, 100 μl per well, cultured overnight, and observed the cells growing into a monolayer.

[0077] (2) Different concentrations of drug-containing culture medium and virus dilution solution were added at 50 μl / well. Five concentrations of each drug group were set up, with three replicates. A blank cell control group, a model control group, and a positive drug ribavirin control group were also set up. The cells were cultured for 5 days.

[0078] (3) Observe the cells. When the CPE of the model control group reaches more than 75% and the cells of the blank control group grow normally, add 20 μl of MTT to each well. After culturing for 4 h, discard the supernatant, add 150 μl of DMSO to each well, place on a shaker, and shake at 37°C in the dark at a low speed for 10 min to allow the blue-purple crystals to fully dissolve.

[0079] (4) The absorbance was detected by an ELISA instrument, and the inhibition rate of CVB3 virus at different drug concentrations was calculated. The half effective concentration (IC) was calculated using SPSS Statistics 17 software. 50 value.

[0080] 3 Experimental results

[0081] 3.1 Compound ad cytotoxicity results

[0082] The blank control group grew well, with plump, permeable cells and tightly arranged cells. After 72 hours of exposure to different concentrations of ad, cells shrank, broke and stopped growing under high concentrations of the drug. The MTT method was used to detect the toxicity results, and the absorbance value was read by the microplate reader. The formula was used to calculate the inhibitory effect of the drug on the cells, and the half-toxic dose CC of the compound ad on Hela cells was calculated. 50 The CC values ​​of positive drug ribavirin 50 The results in Table 1 show that the toxicity of ad is much lower than that of ribavirin.

[0083] Table 1a-d Cytotoxicity and anti-CVB3 activity of compounds

[0084] Compound <![CDATA[CC 50 (μM)]]> <![CDATA[IC 50 (μM)]]> Therapeutic index TI a ＞1000 21.35 ＞42.68 b ＞1000 2.37 ＞384.47 c ＞1000 16.38 ＞55.63 d ＞1000 51.91 ＞17.55 Ribavirin 911.2 33.5 27.2

[0085] 3.2 Virus titer results of CVB3

[0086] Normal Hela cells are plump and translucent, and resemble polygonal epithelial cells. However, after infection with CVB3 virus, lesions occur, the cells shrink and become round, the gaps increase, the connections become loose, the refractive index decreases, the adhesion decreases, and some cells break and float. It was observed that the lesions did not progress until the 7th day, and the number of lesion holes in different virus dilution groups was recorded. The TCID 50 =10 -10.5 .

[0087] 3.3ad in vitro anti-CVB3 activity results

[0088] Observation under a microscope showed that the cells in the blank control group (normal Hela cells) were normal in morphology, permeable, and tightly arranged. Five days after CVB3 virus inoculation, the virus control group was completely lesioned. After treatment with compound ad, the degree of lesions was alleviated, and as the drug dose increased, the lesion effect weakened, showing a dose-dependent relationship. Calculate the virus inhibition rate and calculate the half inhibitory concentration IC of compound ad on CVB3 virus 50 The half inhibitory concentration IC of compounds a, b, c, and d against CVB3 virus is 50 are 21.35, 2.37, 16.38, and 51.91 μM, respectively; the IC of ribavirin 50 The results in Table 1 show that compounds a, b, c, and d all have significant inhibitory effects on CVB3 virus, and the anti-CVB3 activity of compounds a, b, and c is better than that of ribavirin.

[0089] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. Type N 4 -Glycine methyl ester and its derivatives substituted nucleoside compounds, characterized in that, The general formula is as follows: Wherein, R is H or a C1-C10 straight or branched chain alkyl group.

2. According to claim 1, N 4 -Glycine methyl ester and its derivatives substituted nucleoside compounds, characterized in that, At least one of the compounds selected from the following: 。 3. N according to claim 1 or 2 4 - A method for preparing glycine methyl ester and its derivatives substituted nucleoside compounds, characterized in that: The synthetic route is as follows: Wherein, R is H or a C1-C10 straight or branched chain alkyl group; The specific steps include: Compound 1 was dissolved in anhydrous dichloromethane, 4-dimethylaminopyridine and triethylamine were added, and the mixture was dispersed evenly at room temperature under nitrogen protection, 2,4,6-triisopropylbenzenesulfonyl chloride was added, and then the reaction was continued by stirring. The reaction of the raw materials was completed by TLC monitoring, and compound 2 was obtained; Glycine methyl ester hydrochloride was added to react. After TLC monitoring, the reaction of the raw material was complete. After purification, methanol was added, cooled to below zero degrees, potassium carbonate was added and the temperature was raised to room temperature to react. After TLC monitoring, the reaction of the raw material was complete, the raw material was filtered, washed, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3; Take compound 3, add various alkylamine aqueous solutions, and after the reaction is complete at room temperature, concentrate to dryness under reduced pressure to obtain the product.

4. N according to claim 3 4 - A method for preparing glycine methyl ester and its derivatives substituted nucleoside compounds, characterized in that: The molar ratio of compound 1 to 2,4,6-triisopropylbenzenesulfonyl chloride is 1:1.4-2.

0.

5. N according to claim 3 4 - A method for preparing glycine methyl ester and its derivatives substituted nucleoside compounds, characterized in that: The molar ratio of compound 1 to glycine methyl ester hydrochloride is 1:1.5-2.

0.

6. N according to claim 1 or 2 4 -Application of glycine methyl ester and its derivatives in the preparation of anti-coxsackie virus active drugs.

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