CN108586574B - Aminoglucose glycopeptide compound and the preparation method and application thereof - Google Patents

Aminoglucose glycopeptide compound and the preparation method and application thereof Download PDF

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CN108586574B
CN108586574B CN201810387639.8A CN201810387639A CN108586574B CN 108586574 B CN108586574 B CN 108586574B CN 201810387639 A CN201810387639 A CN 201810387639A CN 108586574 B CN108586574 B CN 108586574B
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resin
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洪碧红
王昌森
白锴凯
孙继鹏
黄文文
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Third Institute of Oceanography SOA
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Abstract

The present invention discloses aminoglucose glycopeptide compound and the preparation method and application thereof, and the c-terminus of amino acid (or peptide) is connected resin, be prepared for amino acid (or peptide)-resin by the present invention first with solid phase synthesis process.Then one kettle way is used, amino acid (or peptide)-resin reacts the isocyanates reaction being prepared with tetra-acetylated Glucosamine with triphosgene, n,N-diisopropylethylamine, obtains novel aminoglucose glycopeptide compound.The aminoglucose glycopeptide compound has anti-HSV herpes simplex virus or EV71 enterovirus activity, can be used for preparing the purposes for the treatment of antiviral drug.

Description

Aminoglucose glycopeptide compound and the preparation method and application thereof
Technical field
The present invention relates to pharmaceutical synthesis and application field, it is related to the amino Portugal with anti-herpesvirus Yu enterovirus effect Grape glycopeptide compound and the preparation method and application thereof.
Background technique
Glycopeptide is the hydrolysate of glycoprotein, compares glycoprotein, the molecular weight of glycopeptide is small, and structure is simple, to a certain extent The bioactivity of glycoprotein is remained, provides convenient means to study the activity of glycoprotein.Meanwhile glycopeptide has broad-spectrum antiseptic Property, the bioactivity such as antiviral and antitumor, therefore glycopeptide are as the mode compound of biology and drug research by extensive Concern.
Vanderlinden in 2012, Evelien etc. report a kind of novel anti-influenza virus medicament SA-19, are a kind of Lipophilicity glycopeptide derivatives, antiviral activity are 11 times for not carrying out glycosylated peptide compounds.Further experiment shows, SA-19 can prevent completely influenza virus to the infection of host cell nuclear, be a kind of novel anti influenza with potential clinical meaning Virus drugs.Studies have shown that inverase enfuirtide is after glycosylation, half-life period increases by 15 times by Cheng, SH etc., Antiviral effect is greatly enhanced.Therefore based on polypeptide drug, it is carried out it is glycosylation modified can be applied to exploitation tool There is the novel glycopeptide class drug of stronger pharmaceutical activity.
Summary of the invention
The present invention provides a new class of aminoglucose glycopeptide compound, has and inhibits herpesviral or enterovirus Activity.
Another aspect of the present invention provides the synthetic method of the aminoglucose glycopeptide compound, i.e., with tetra-acetylated amino Portugal Grape sugar, amino acid (or peptide)-resin etc. are raw material, one kettle way and the ingenious combination of solid-phase synthesis, the aminoglucose of synthesizing new Glycopeptide compound.
The aminoglucose glycopeptide compound being shown below:
Application of structural formula such as formula (SS102) compound represented as preparation treatment EV71 type enterovirus medicines.
The application of compound SS101, SS103, SS105 as treatment herpesⅡtype virus drugs.
Application of the compound SS104 as treatment herpesⅠzostertype virus drugs.
The system of another aspect of the present invention offer structural formula aminoglucose glycopeptide compound as shown in (SS101-SS105) Preparation Method,
Itself the following steps are included:
Step 1, synthesis in solid state amino acid (or peptide)-resin
2- chlorine trityl chloride resin, Fmoc- amino acid (peptide), DMF and N, N- bis- are sequentially added in synthesis in solid state pipe Wopropyl ethyl amine reacts at room temperature under nitrogen-burst agitation, filters, and washing obtains Fmoc- amino acid (peptide)-resin, piperazine is then added The DMF solution of pyridine, room temperature reaction, obtains amino acid (or peptide)-resin；
Step 2 prepares aminoglucose glycopeptide
Be added triphosgene and methylene chloride in reaction vessel, stirring to complete dissolution of triphosgene, be cooled to 10 DEG C hereinafter, It is slowly added to n,N-diisopropylethylamine, tetra-acetylated Glucosamine and methylene chloride mixed solution, temperature rising reflux reacts 2- It is cooled to 5-15 DEG C after 12h, amino acid (or peptide)-resin is added, after being stirred to react 0.5~3.0h, filters out liquid, is added 5% trifluoroacetic acid/dichloromethane dissociation solution is stirred at room temperature to end of reaction, filtering, and filtrate decompression distillation is removed solvent, obtained yellow Color grease obtains aminoglucose glycopeptide compound after isolating and purifying.
Further, in the preparation method, mole of tetra-acetylated Glucosamine and amino acid (or peptide)-resin Than for 5:1~1:1, optimum ratio 5:2.
Further, the Fmoc- amino acid is Fmoc-Phe-OH, Fmoc-Ile-OH, Fmoc-Gly-OH.
Further, amino acid (or peptide)-resin is L-phenylalanine resin, l-Isoleucine resin, L- first sulphur Amide glycine resin, L- first sulphamide isoleucine resin, the different bright amide glycine resin of L- hydrocinnamamide.
Further, isolate and purify described in step 2 is with 0.5% aqueous formic acid/recrystallized from acetonitrile, 0.5% first Aqueous acid/acetonitrile volume ratio is 2:1 to 8:1.
Further, the method isolated and purified described in step 2 are as follows: body is added into the yellow oil that step 2 obtains 0.5% aqueous formic acid/acetonitrile of the product than 1:6 is heated to 55 DEG C -65 DEG C, and stirring is cooled to 0 DEG C or so after 2 hours, is precipitated brilliant Body, filtering.
The beneficial effects of the present invention are: aminoglucose glycopeptide compound provided by the invention has through detection inhibits bleb Virus or the effect of EV71 type enterovirus；The present invention also provides the preparation methods of aminoglucose glycopeptide compound, with synthesis in solid state The c-terminus of amino acid (or peptide) is connected resin, is prepared for amino acid (or peptide)-resin, then uses one kettle way, ammonia by method Base acid (or peptide)-resin and triphosgene, N, N- diisopropylethylamine reacted with tetra-acetylated Glucosamine be prepared it is different Polyisocyanate reactant obtains novel aminoglucose glycopeptide compound, and reaction step is short, and reaction condition is mild, convenient post-treatment, Yield is high, at low cost, is suitable for industrial production.
Specific embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.
In the context of the invention: DIC is N, the abbreviation of N- diisopropylcarbodiimide；DMF is N,N-dimethylformamide； HOBT is I-hydroxybenzotriazole；No. CAS of Fmoc-Phe-OH (fluorenylmethyloxycarbonyl-L-phenylalanine) is 35661-40-6； No. CAS of Fmoc-Ile-OH (fluorenylmethyloxycarbonyl-l-Isoleucine) is 71989-23-6；Fmoc-Gly-OH (fluorenylmethyloxycarbonyl- Glycine) No. CAS be 29022-11-5；No. CAS of Fmoc-Met-OH (fluorenylmethyloxycarbonyl-l-methionine) is 71989- 28-1；No. CAS of Fmoc-Ile-OH (fluorenylmethyloxycarbonyl-l-Isoleucine) is 71989-23-6；
Room temperature of the present invention is usually 15 DEG C to 39 DEG C, and preferably 25 DEG C to 30 DEG C.
5% trifluoroacetic acid/dichloromethane refers to the dichloromethane solution containing trifluoroacetic acid 5%；0.5% aqueous formic acid/ Acetonitrile refers to that mass fraction is the volume ratio of 0.5% aqueous formic acid and acetonitrile.
Embodiment one
Structural formula SS101 (N- (tetra-acetylated -2- amino -2- deoxidation-α-D- glucopyanosyl of 1,3,4,6-)-N '-amino Formoxyl-L-phenylalanine) preparation
Step 1 sequentially adds 2- chlorine trityl chloride resin (50g), Fmoc-Phe-OH in synthesis in solid state pipe (36.8g), DMF (500mL) and DIC (23.6mL), react at room temperature 2h under nitrogen-burst agitation, filter, and washing obtains Fmoc- Phe- resin, end capping reaction twice, are then added 20% piperidines/DMF solution, react at room temperature 30min, remove Fmoc, and vacuum is dry It is dry that L-H-Phe- resin is stand-by；
500mg triphosgene and 80mL methylene chloride is added in three-necked flask in step 2, stirs to complete dissolution of triphosgene, 5 DEG C are cooled to, DIC (2520 μ L), tetra-acetylated Glucosamine (1300mg) and methylene chloride mixed solution are slowly added to 100mL, temperature rising reflux react 4h.10 DEG C are cooled to, is added H-Phe- resin (1.9g), after being stirred to react 1h, filters out liquid, 5% trifluoroacetic acid/dichloromethane dissociation solution is added, is stirred to react 2h at room temperature, filters, solvent is removed in filtrate decompression distillation, obtains yellow Color grease obtains aminoglucose glycopeptide SS101 compound, the purity (face HPLC with 0.5% aqueous formic acid/recrystallized from acetonitrile Product normalization method) it is 92.6%, yield 79.0%.1H NMR (400MHz, DMSO-d6)δH: 7.26-7.08 (m, 5H, ArH), 6.33 (d, J=9.36Hz, 1H, NH-Glucosamine), 6.18 (d, J=7.60Hz, 1H, NH-Phe), 5.87 (d, J= 3.60Hz, 1H, H-1), 5.06 (dd, J1=10.0Hz, J2=10.32Hz, 1H, H-3), 4.97 (t, J=9.88Hz, 1H, H- 4), 4.37-4.32 (m, 1H, CH-Phe), 4.17-4.13 (m, 1H, H-2), 4.09-4.03 (m, 2H, H-6a, 6b), 3.96 (dd, J1=2.4Hz, J2=10.16Hz, 1H, H-5), 3.02-2.86 (m, 2H, CH2- Phe), 2.15,1.99,1.97,1.86 (4s, 12H, 4Ac).13C NMR(DMSO-d6, 100MHz) and δC: 173.7 (COOH), 170.5,170.3,169.6,169.5 (4CO Ac), 156.9 (N-CO-N), 137.6,129.5,128.5,127.0 (Ar), 90.1 (C-1), 70.0 (C-5), 69.5 (C-3), 68.3 (C-4), 54.1 (C ɑ), 50.9 (C-2), 37.9 (CH2Ar), 21.2,20.9,20.8,20.8 (4CH3Ac)。HRMS[M+ H]+Theoretical value: 539.1877, measured value: 539.1875.
Embodiment two
Structural formula SS102 (N- (tetra-acetylated -2- amino -2- deoxidation-ɑ-D- glucopyanosyl of 1,3,4,6-)-N '-amino Formoxyl-l-Isoleucine) preparation
Step 1 sequentially adds 2- chlorine trityl chloride resin (5g), Fmoc-Ile-OH in synthesis in solid state pipe (3.36g), DMF (100mL) and DIC (2.36mL), react at room temperature 2h under nitrogen-burst agitation, filter, and washing obtains Fmoc- Ile-- chlorine resin, end capping reaction twice, are then added 20% piperidines/DMF solution, react at room temperature 30min, remove Fmoc, vacuum It is dry that L-H-Ile-- resin is stand-by.
50mg triphosgene and 8mL methylene chloride, stirring to complete dissolution of triphosgene, drop is added in three-necked flask in step 2 Temperature is slowly added to DIC (252 μ L), tetra-acetylated Glucosamine (130mg) and methylene chloride mixed solution 10mL to 5 DEG C, rises Warm back flow reaction 4h.10 DEG C are cooled to, is added H-Ile- resin (0.48g), after being stirred to react 1h, liquid is filtered out, is added 5% Trifluoroacetic acid/dichloromethane dissociation solution is stirred to react 2h at room temperature, filtering, and solvent is removed in filtrate decompression distillation, obtains yellow oily Object obtains aminoglucose glycopeptide SS102 compound, purity (HPLC area normalization with 0.5% aqueous formic acid/recrystallized from acetonitrile Method) 95.0%, yield 64.3%.1H NMR (400MHz, DMSO-d6)δH: 12.60 (s, 1H, COOH), 6.23 (d, J= 8.96Hz, 1H, NH-Glucosamine), 6.16 (d, J=9.52Hz, 1H, NH), 5.90 (d, J=3.52Hz, H-1), 5.07 (dd, J1=9.92Hz, J2=13.10Hz, 1H, H-3), 4.98 (t, J=9.83Hz, 1H, H-4), 4.18-4.14 (m, 1H, H- 2), 4.11-4.06 (m, 2H, H-6a, 6b), 4.05-4.04 (m, 1H, CH-Ile), 3.97 (dd, J1=2.36Hz, J2= 12.42Hz, 1H, H-5), 2.18,2.00,1.97,1.90 (4s, 12H, 4Ac), 1.74-1.67 (m, 1H, CH), 1.35-1.00 (m, 1H, CH2- Ile), 0.85-0.79 (m, 6H, 2CH3-Ile)。13C NMR(DMSO-d6, 100MHz) and δC: 174.1 (COOH), 170.5,170.3,169.6,169.5 (4CO Ac), 157.2 (N-CO-N), 91.2 (C-1), 71.2 (C-5), 69.6 (C-3), 68.1 (C-4), 61.8 (C-6), 57.0 (C ɑ), 51.0 (C-2), 37.7 (Cβ), 24.8 (Cγ), 21.2,20.9,20.8,20.8 (4CH3Ac), 11.9,16.0 (2Me).HRMS[M+H]+Theoretical value: 505.2033, measured value: 505.2036.
Embodiment three
Structural formula SS103 (N- (tetra-acetylated -2- amino -2- deoxidation-ɑ-D- glucopyanosyl of 1,3,4,6-)-N '-amino Formoxyl-L- first sulphamide-glycine) preparation
Step 1 sequentially adds 2- chlorine trityl chloride resin (5g), Fmoc-Gly-OH in synthesis in solid state pipe (2.82g), DMF (100mL) and DIC (2.36mL), react at room temperature 2h under nitrogen-burst agitation, filter, and washing obtains Fmoc- Gly- resin, end capping reaction twice, are then added 20% piperidines/DMF solution, react at room temperature 30min, remove Fmoc.It weighs Fmoc-Met-OH (3.15g) adds 50mL DMF solution to dissolve in 100mL beaker, and HOBT is added, and is cooled to 0-5 DEG C, is added DIC is uniformly mixed, and is added into above-mentioned synthesis in solid state pipe, after reacting 2h under nitrogen-burst agitation, filtering, and 20% piperidines/DMF dissociation Liquid removes Fmoc protection, reacts 30min, be dried in vacuo L- first sulphamide glycine-resin (H-Gly- resin) is stand-by.
50mg triphosgene and 8mL methylene chloride, stirring to complete dissolution of triphosgene, drop is added in three-necked flask in step 2 Temperature is slowly added to DIC (252 μ L), tetra-acetylated Glucosamine (130mg) and methylene chloride mixed solution 10mL to 5 DEG C, rises Warm back flow reaction 4h.10 DEG C are cooled to, first sulphamide glycine-resin (0.11g) is added, after being stirred to react 1h, filters out liquid Body is added 10% trifluoroacetic acid/dichloromethane dissociation solution, is stirred to react 2h at room temperature, filters, and solvent is removed in filtrate decompression distillation, Yellow oil is obtained, aminoglucose glycopeptide SS103 compound, purity are obtained with 0.5% aqueous formic acid/recrystallized from acetonitrile (HPLC area normalization method) is 95.4%, yield 60.7%.1H NMR (400MHz, DMSO-d6)δH: 12.62 (s, 1H, COOH), 8.33 (t, J=6.06Hz, 1H-Gly), 6.29 (d, J=8.18Hz, 1H, NH-Met), 6.24 (d, J=9.44Hz, 1H, NH-Glucosamine), 5.90 (d, J=3.56Hz, 1H, H-1), 5.07 (t, J=10.07Hz, 1H, H-3), 4.99 (t, J=9.78Hz, 1H, H-4), 4.28-4.23 (m, 1H, CH-Met), 4.18-4.14 (m, 1H, C-2), 4.10-4.04 (m, 2H, H-6a, 6b), 3.97 (dd, J1=2.33Hz, J2=12.42Hz, 1H, H-5), 3.73 (m, 2H, CH2- Gly), 2.37 (t, J= 7.97Hz, 2H, S-CH2- Met), 2.17 (s, 3H, CH3- Met), 2.01,2.00,1.98,1.92 (4s, 12H, 4Ac), 1.86- 1.65 (m, 1H, CH2)。13C NMR(DMSO-d6, 100MHz) and δC: 172.23 (COOH), 171.5 (C-CO-N), 170.5, 170.3,169.6,169.5 (4CO AC), 156.9 (N-CO-N), 91.1 (C-1), 71.7 (C-5), 69.5 (C-3), 68.1 (C- 4), 61.8 (C-6), 52.4 (Cα(Met)), 51.0 (C-2), 41.1 (Cα(Gly)), 33.1 (Cβ(Met)), 29.4 (Cγ(Met)), 21.2, 20.9,20.8,20.8 (4CH3AC), 15.0 (Cβ(Met))。HRMS[M+H]+Theoretical value: 580.1812, measured value: 580.1814.
Example IV
Structural formula SS104 (N- (tetra-acetylated -2- amino -2- deoxidation-ɑ-D- glucopyanosyl of 1,3,4,6-)-N '-amino Formoxyl-L- first sulphamide-isoleucine) preparation
Step 1 sequentially adds 2- chlorine trityl chloride resin (5g), Fmoc-Ile-OH in synthesis in solid state pipe (3.36g), DMF (100mL) and DIC (2.36mL), react at room temperature 2h under nitrogen-burst agitation, filter, and washing obtains Fmoc- Ile- resin, end capping reaction twice, are then added 20% piperidines/DMF solution, react at room temperature 30min, remove Fmoc.It weighs Fmoc-Met-OH (2.93g) adds 50mL DMF solution to dissolve in 100mL beaker, and HOBT is added, and is cooled to 0-5 DEG C, is added DIC is uniformly mixed, and is added into above-mentioned synthesis in solid state pipe, after reacting 2h under nitrogen-burst agitation, filtering, and 20% piperidines/DMF dissociation Liquid remove Fmoc protection, react 30min, be dried in vacuo L- first sulphamide isoleucine-resin is stand-by.
50mg triphosgene and 8mL methylene chloride, stirring to complete dissolution of triphosgene, drop is added in three-necked flask in step 2 Temperature is slowly added to DIC (252 μ L), tetra-acetylated Glucosamine (130mg) and methylene chloride mixed solution 10mL to 5 DEG C, rises Warm back flow reaction 4h.10 DEG C are cooled to, first sulphamide isoleucine-resin (0.30g) is added, after being stirred to react 1h, filters out Liquid is added 10% trifluoroacetic acid/dichloromethane dissociation solution, is stirred to react 2h at room temperature, filters, and filtrate decompression distillation is gone molten Agent obtains yellow oil, obtains aminoglucose glycopeptide SS104 compound, purity with 0.5% aqueous formic acid/recrystallized from acetonitrile (HPLC area normalization method) is 96.5%, yield 79.6%.1H NMR (400MHz, DMSO-d6)δH: 12.62 (s, 1H, COOH), 8.11 (d, J=8.10Hz, 1H, NH-Ile), 6.29 (d, J=2.34Hz, 1H, NH-Met), 6.26 (d, J= 3.54Hz, 1H, NH-Glucosamine), 5.89 (d, J=3.56Hz, 1H, H-1), 5.07 (t, J=10.07Hz, 1H, H-3), 4.99 (t, J=9.80Hz, 1H, H-4), 4.36-4.31 (m, 1H, CH-Met), 4.18-4.13 (m, 1H, H-2), 4.12-4.08 (m, 2H, H-6a, 6b), 4.07-4.04 (m, 1H, NCH-Ile), 2.37-2.33 (m, 2H, S-CH2- Met), 2.16 (s, 3H, CH3- Met), 2.01,2.00,1.98,1.96 (4s, 12H, 4Ac), 1.84-1.79 (m, 1H, CH-Ile), 1.78-1.63 (m, 2H, CH2- Met), 1.41-1.13 (m, 2H, CH2- Ile), 0.85-0.81 (m, 6H, 2CH3-Ile)。13C NMR(DMSO-d6, 100MHz)δC: 173.2 (COOH), 172.0 (C-CO-N), 170.5,170.3,169.6,169.5 (4CO AC), 156.9 (N- CO-N), 91.1 (C-1), 71.5 (C-5), 69.6 (C-3), 68.1 (C-4), 61.8 (C-6), 56.9 (C-2), 52.2 (Cα(Ile)), 51.0 (Cα(Met)), 36.5 (Cβ(Ile)), 34.2 (Cβ(Met)), 29.4 (Cγ(Met)), 25.2 (Cγ(Ile)), 21.2, 20.9,20.8,20.8 (4CH3AC), 16.0 (Me Met), 15.1,11.8 (2Me Ile).HRMS[M+H]+Theoretical value: 636.2438 measured value: 636.2433.
Embodiment five
Structural formula SS105 (N- (tetra-acetylated -2- amino -2- deoxidation-ɑ-D- glucopyanosyl of 1,3,4,6-)-N '-amino The different bright amide-glycine of formoxyl-L- hydrocinnamamide -) compound preparation
Step 1 sequentially adds 2- chlorine trityl chloride resin (5g), Fmoc-Gly-OH in synthesis in solid state pipe (2.82g), DMF (100mL) and DIC (2.36mL), react at room temperature 2h under nitrogen-burst agitation, filter, and washing obtains Fmoc- Gly-- resin, end capping reaction twice, are then added 20% piperidines/DMF solution, react at room temperature 30min, remove Fmoc.It weighs Fmoc-Ile-OH (3.00g) adds 50mL DMF solution to dissolve in 100mL beaker, and HOBT is added, and is cooled to 0-5 DEG C, is added DIC is uniformly mixed, and is added into above-mentioned synthesis in solid state pipe, after reacting 2h under nitrogen-burst agitation, filtering, and 20% piperidines/DMF dissociation Liquid removes Fmoc protection, reacts 30min, repeats the above steps, and connects Fmoc-Phe-OH (3.29g, 8.5mmol), removes Fmoc Blocking group, be dried in vacuo the different bright amide glycine-resin of L- hydrocinnamamide is stand-by.
50mg triphosgene and 8mL methylene chloride, stirring to complete dissolution of triphosgene, drop is added in three-necked flask in step 2 Temperature is slowly added to DIC (252 μ L), tetra-acetylated Glucosamine (130mg) and methylene chloride mixed solution 10mL to 5 DEG C, rises Warm back flow reaction 4h.10 DEG C are cooled to, the different bright amide glycine-resin (0.34g) of hydrocinnamamide is added, after being stirred to react 1h, Liquid is filtered out, 10% trifluoroacetic acid/dichloromethane dissociation solution is added, is stirred to react 2h at room temperature, is filtered, filtrate decompression distillation Solvent is removed, yellow oil is obtained, aminoglucose glycopeptide SS105 compound is obtained with 0.5% aqueous formic acid/recrystallized from acetonitrile, Purity (HPLC area normalization method) is 95.0%, yield 71.5%.1H NMR (400MHz, DMSO-d6)δH: 12.64 (s, 1H, COOH), 8.23 (t, J=4.98Hz, 1H, NH-Gly), 8.04 (d, J=9.08Hz, 1H, NH-Ile), 7.20-7.03 (m, 5H, Ar), 6.38 (d, J=9.31Hz, 1H, NH-Glucosamine), 6.12 (d, J=7.82Hz, 1H, NH-Phe), 5.85 (d, J =3.54Hz, 1H, H-1), 5.07 (t, J=10.18Hz, 1H, H-3), 4.97 (t, J=9.80Hz, 1H, H-4), 4.53-4.48 (m, 1H, CH-Phe), 4.20-4.17 (m, 1H, H-2), 4.16-4.13 (m, 1H, H-5), 4.10-4.04 (m, 2H, H-6a, 6b), 3.96 (dd, J1=2.32Hz, J2=12.38Hz, 1H, N-CH-Ile), 3.74 (d, J=2.98,2H, CH2- Gly), 2.95-2.72 (m, 2H, CH2- Phe), 2.14,2.00,1.97,1.84 (4s, 12H, 4Ac), 1.73-1.66 (m, 1H, CH- Ile), 1.44-1.00 (m, 1H, CH2- Ile), 0.83-0.77 (m, 6H, 2CH3-Ile)。13C NMR(DMSO-d6, 100MHz) δC: 171.6 (COOH), 171.5,171.2 (2C-CO-N), 170.5,170.2,169.6,169.5 (4CO AC), 156.8 (N- CO-N), 137.8,129.9,128.3,126.5 (Ar), 90.0 (C-1), 71.0 (C-5), 69.5 (C-3), 69.3 (C-4), 61.8 (C-6), 57.0 (Cα(Ile)), 53.9 (Cα(Phe)), 50.9 (C-2), 41.2 (Cα(Gly)), 38.6 (CH2Ar), 37.3 (Cβ(Ile)), 24.7 (Cγ(Ile)), 21.2,20.9,20.8,20.8 (4CH3AC), 15.0,11.5 (2Me(Ile))。HRMS[M+H]+ Theoretical value: 709.2932, measured value: 709.2933.
Embodiment one to six is with 0.5% aqueous formic acid/recrystallized from acetonitrile method particularly includes: the Huang obtained toward step 2 0.5% aqueous formic acid/acetonitrile of volume ratio 1:6 is added in color grease, it is cooling after being heated to 55 DEG C -65 DEG C, stirring 2 hours It to 0 DEG C or so, precipitates crystal, filters.
Embodiment six
Structural formula SS104 (N- (tetra-acetylated -2- amino -2- deoxidation-ɑ-D- glucopyanosyl of 1,3,4,6-)-N '-amino Formoxyl-L- first sulphamide-isoleucine) anti-herpesⅠzostertype virus activity experiment in vitro
The Vero cell in logarithmic growth is taken, is inoculated on 96 orifice plates, is placed in 5%CO237 DEG C of incubators in cultivated Night.Cell culture fluid is discarded, I viral dilution of HSV is inoculated with, 1h is incubated in cell incubator, discards viral dilution in orifice plate The MEM maintaining liquid of isometric drug containing is added in sample sets for liquid, and every group sets 3 multiple holes.Add isometric Ah former times in positive controls Lip river Wei mixed liquor, and blank assay group is set and is compareed.48h is then incubated in cell incubator.96 orifice plates are washed with water, After residual moisture volatilization is dry, its OD value for representing cell survival rate is detected under 550nm ultraviolet wavelength, to embody cell indirectly Disease.
Inhibiting rate (%)=(ODExperimental group-ODViral group)/(ODControl group-ODViral group) × 100%.
As a result: SS104 reaches 29.0% to the inhibiting rate of I virus of HSV, and the inhibiting rate of positive control drug acyclovir is I virus effectiveness of anti-HSV of 34.3%, SS104 are close to positive control medicine.
Embodiment seven
Compound SS101, SS103 and SS105 anti-herpesⅡtype virus activity experiment in vitro
The Vero cell in logarithmic growth is taken, is inoculated on 96 orifice plates, is placed in 5%CO237 DEG C of incubators in cultivated Night.Cell culture fluid is discarded, II viral dilution of HSV is inoculated with, 1h is incubated in cell incubator, discards viral dilution in orifice plate The MEM maintaining liquid of isometric drug containing is added in sample sets for liquid, and every group sets 3 multiple holes.Add isometric Ah former times in positive controls Lip river Wei mixed liquor, is then incubated for 48h in cell incubator.96 orifice plates are washed with water, after residual moisture volatilization is dry, in 550nm Its OD value for representing cell survival rate is detected under ultraviolet wavelength, to embody the disease of cell indirectly.Inhibiting rate (%)= (ODExperimental group-ODViral group)/(ODControl group-ODViral group) × 100%.
As a result: compound SS101, SS103 and SS105 distinguish the inhibiting rate of II virus of HSV when administration concentration is 5 μM It is 41.6%, 49.2% and 37.2%.
Embodiment eight
Structural formula SS102 (N- (tetra-acetylated -2- amino -2- deoxidation-ɑ-D- glucopyanosyl of 1,3,4,6-)-N '-amino Formoxyl-l-Isoleucine) external anti-EV71 enterovirus activity experiment
The Vero cell in logarithmic growth is taken, is inoculated on 96 orifice plates, is placed in 5%CO237 DEG C of incubators in cultivated Night.In addition to blank control group, cell culture fluid is discarded, EV71 viral dilution is inoculated with, 1h is incubated in cell incubator, is discarded The MEM maintaining liquid of isometric drug containing is added in sample sets for viral dilution in orifice plate, often sets 3 multiple holes of group.In positive controls Add isometric guanidine hydrochloride mixed liquor, and blank assay group is set and is compareed.48h is then incubated in cell incubator.With 96 orifice plate of water washing detects its OD value for representing cell survival rate after residual moisture volatilization is dry under 550nm ultraviolet wavelength, from And the disease of cell is embodied indirectly.
Inhibiting rate (%)=(OD valueExperimental group- OD valueViral group)/(OD valueControl group- OD valueViral group)
As a result: when administration concentration is 10 μM, compound SS102 reaches the inhibitory effect of EV71 type enterovirus 58.4%, the positive control medicine guanidine hydrochloride for being 8 μM with administration concentration compares, and inhibitory effect is substantially better than guanidine hydrochloride.

Claims (10)

1. the aminoglucose glycopeptide compound being shown below:
(SS103),
(SS104),
( SS105)。
2. application of structural formula such as formula (SS102) compound represented as preparation treatment EV71 type enterovirus medicines
(SS102)。
3. structural formula such as formula SS101, SS103, SS105 compound represented is answered as preparation treatment herpesⅡtype virus drugs With
(SS101),
(SS103),
( SS105)。
4. application of the structural formula compound as shown in formula SS104 in preparation treatment herpesⅠzostertype virus drugs
(SS104)。
5. the method for preparing the aminoglucose glycopeptide compound as described in claim 1-4 is any, comprising:
Step 1, synthesis in solid state amino acid-resin or peptide-resin
2- chlorine trityl chloride resin, Fmoc- amino acid (peptide), DMF and N, N- diisopropyl are sequentially added in synthesis in solid state pipe Base ethamine reacts at room temperature under nitrogen-burst agitation, filters, and washing obtains Fmoc- amino acid (peptide)-resin, and piperidines is then added DMF solution, room temperature reaction, obtains amino acid (or peptide)-resin；
Step 2 prepares aminoglucose glycopeptide
Triphosgene and methylene chloride are added in reaction vessel, stirring to complete dissolution of triphosgene is cooled to 10 DEG C hereinafter, slowly N,N-diisopropylethylamine, tetra-acetylated Glucosamine and methylene chloride mixed solution is added, temperature rising reflux reacts 2-12 h After be cooled to 5-15 DEG C, amino acid (or peptide)-resin is added, after being stirred to react 0.5~3.0h, filters out liquid, is added 5% Trifluoroacetic acid/dichloromethane dissociation solution is stirred at room temperature to end of reaction, filtering, and filtrate decompression distillation removes solvent, obtains yellow oil Shape object isolates and purifies and obtains aminoglucose glycopeptide compound.
6. the preparation method of aminoglucose glycopeptide compound as claimed in claim 5, the Fmoc- amino acid is Fmoc- Phe-OH 、Fmoc-Ile-OH、Fmoc-Gly-OH。
7. the preparation method of aminoglucose glycopeptide compound as claimed in claim 5, amino acid (or peptide)-resin is L- L-phenylalanine resin, l-Isoleucine resin, L- first sulphamide glycine resin, L- first sulphamide isoleucine resin, L- benzene The different bright amide glycine resin of propionamide.
8. the preparation method of aminoglucose glycopeptide compound as claimed in claim 5, wherein tetra-acetylated Glucosamine with Amino acid (or peptide)-resin molar ratio is 5:2.
9. the preparation method of aminoglucose glycopeptide compound as claimed in claim 5, wherein isolating and purifying described in step 2 is With 0.5% aqueous formic acid/recrystallized from acetonitrile, 0.5% aqueous formic acid/acetonitrile volume ratio is 2:1 to 8:1.
10. the preparation method of aminoglucose glycopeptide compound as claimed in claim 5, wherein isolated and purified described in step 2 Method are as follows: toward step 2 obtain yellow oil in be added volume ratio 1:6 0.5% aqueous formic acid/acetonitrile, be heated to 55 DEG C -65 DEG C, stirring was cooled to 0 DEG C or so after 2 hours, precipitated crystal, and filtered.
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Citations (3)

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FR2773994A1 (en) * 1998-01-23 1999-07-30 Univ Nice Sophia Antipolis New human immunodeficiency virus protease inhibitor prodrugs for inhibiting viral proliferation in central nervous system - comprising protease inhibitor coupled to substance that improves bioavailability, targeting and/ or delivery to CNS
EP1144420A1 (en) * 1999-01-15 2001-10-17 Board Of Trustees Of The University Of Illinois Sulfated phosphatidylinositols, their preparation and use
JP2003212893A (en) * 2002-01-18 2003-07-30 Japan Science & Technology Corp Amide-linked sugar chain-containing carbosilane dendrimer and method for producing the same

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Publication number Priority date Publication date Assignee Title
EP2281008B1 (en) * 2008-04-04 2017-01-04 University of Utah Research Foundation Alkylated and sulfated hyaluronan compounds, methods for their preparation and use thereof
CN103059074B (en) * 2013-01-11 2015-02-18 国家海洋局第三海洋研究所 Glucosamine peptidomimetic compound as well as preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2773994A1 (en) * 1998-01-23 1999-07-30 Univ Nice Sophia Antipolis New human immunodeficiency virus protease inhibitor prodrugs for inhibiting viral proliferation in central nervous system - comprising protease inhibitor coupled to substance that improves bioavailability, targeting and/ or delivery to CNS
EP1144420A1 (en) * 1999-01-15 2001-10-17 Board Of Trustees Of The University Of Illinois Sulfated phosphatidylinositols, their preparation and use
JP2003212893A (en) * 2002-01-18 2003-07-30 Japan Science & Technology Corp Amide-linked sugar chain-containing carbosilane dendrimer and method for producing the same

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