CN114732822B - 氨基葡萄糖及其衍生物作为抗病毒药物的应用 - Google Patents
氨基葡萄糖及其衍生物作为抗病毒药物的应用 Download PDFInfo
- Publication number
- CN114732822B CN114732822B CN202210314424.XA CN202210314424A CN114732822B CN 114732822 B CN114732822 B CN 114732822B CN 202210314424 A CN202210314424 A CN 202210314424A CN 114732822 B CN114732822 B CN 114732822B
- Authority
- CN
- China
- Prior art keywords
- virus
- acid
- substituted
- group
- mice
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 239000003443 antiviral agent Substances 0.000 title claims abstract description 10
- 229960002442 glucosamine Drugs 0.000 title claims abstract description 10
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 title description 5
- -1 glucosamine compound Chemical class 0.000 claims abstract description 58
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 241000700605 Viruses Species 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 4
- 241001669084 Coxsackievirus A6 Species 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 19
- 230000000840 anti-viral effect Effects 0.000 abstract description 18
- 230000000694 effects Effects 0.000 abstract description 8
- 239000012453 solvate Substances 0.000 abstract description 6
- 241000699670 Mus sp. Species 0.000 description 41
- 238000012360 testing method Methods 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 229940126214 compound 3 Drugs 0.000 description 20
- 230000004083 survival effect Effects 0.000 description 17
- 241000712461 unidentified influenza virus Species 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 241000711975 Vesicular stomatitis virus Species 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 210000004072 lung Anatomy 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 8
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 229950006780 n-acetylglucosamine Drugs 0.000 description 8
- 241000701386 African swine fever virus Species 0.000 description 7
- 241000709661 Enterovirus Species 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 150000001720 carbohydrates Chemical class 0.000 description 6
- 235000014633 carbohydrates Nutrition 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 235000005911 diet Nutrition 0.000 description 6
- 230000037213 diet Effects 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 102000003996 Interferon-beta Human genes 0.000 description 5
- 108090000467 Interferon-beta Proteins 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229960001388 interferon-beta Drugs 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 241001115402 Ebolavirus Species 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- 241000710842 Japanese encephalitis virus Species 0.000 description 4
- 206010023927 Lassa fever Diseases 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 241001535172 Severe fever with thrombocytopenia virus Species 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 241000712891 Arenavirus Species 0.000 description 3
- 241000711573 Coronaviridae Species 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000711950 Filoviridae Species 0.000 description 3
- 241000035314 Henipavirus Species 0.000 description 3
- 101001011382 Homo sapiens Interferon regulatory factor 3 Proteins 0.000 description 3
- 102100029843 Interferon regulatory factor 3 Human genes 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 3
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 3
- 235000019797 dipotassium phosphate Nutrition 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 3
- 229960003752 oseltamivir Drugs 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000004344 phenylpropyl group Chemical group 0.000 description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 241000238557 Decapoda Species 0.000 description 2
- 241000725619 Dengue virus Species 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 241000710945 Eastern equine encephalitis virus Species 0.000 description 2
- 241000710781 Flaviviridae Species 0.000 description 2
- 241000710831 Flavivirus Species 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 102100023727 Mitochondrial antiviral-signaling protein Human genes 0.000 description 2
- 101710142315 Mitochondrial antiviral-signaling protein Proteins 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 241000150350 Peribunyaviridae Species 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 241000711931 Rhabdoviridae Species 0.000 description 2
- 241000315672 SARS coronavirus Species 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006251 butylcarbonyl group Chemical group 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229960000448 lactic acid Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- BZHCGFBZBPVRFE-UHFFFAOYSA-N monopotassium phosphite Chemical compound [K+].OP(O)[O-] BZHCGFBZBPVRFE-UHFFFAOYSA-N 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000004673 propylcarbonyl group Chemical group 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000004576 sand Substances 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- AQMNWCRSESPIJM-UHFFFAOYSA-N sodium;phosphenic acid Chemical compound [Na+].O[P+]([O-])=O AQMNWCRSESPIJM-UHFFFAOYSA-N 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PKUPAJQAJXVUEK-UHFFFAOYSA-N 2-phenoxyacetyl chloride Chemical compound ClC(=O)COC1=CC=CC=C1 PKUPAJQAJXVUEK-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000712892 Arenaviridae Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical group CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- VMFPMURPVWIZCO-UHFFFAOYSA-N C(=O)OC(OCCC)(OCC)OC Chemical group C(=O)OC(OCCC)(OCC)OC VMFPMURPVWIZCO-UHFFFAOYSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 241000709687 Coxsackievirus Species 0.000 description 1
- 241001429382 Coxsackievirus A16 Species 0.000 description 1
- 241000709675 Coxsackievirus B3 Species 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- LKDRXBCSQODPBY-VRPWFDPXSA-N D-fructopyranose Chemical compound OCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-VRPWFDPXSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 208000006825 Eastern Equine Encephalomyelitis Diseases 0.000 description 1
- 201000005804 Eastern equine encephalitis Diseases 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 206010014587 Encephalitis eastern equine Diseases 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000712431 Influenza A virus Species 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001115401 Marburgvirus Species 0.000 description 1
- 108700011259 MicroRNAs Proteins 0.000 description 1
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 1
- OVRNDRQMDRJTHS-PVFLNQBWSA-N N-acetyl-alpha-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-PVFLNQBWSA-N 0.000 description 1
- 101150080862 NA gene Proteins 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 241000713112 Orthobunyavirus Species 0.000 description 1
- 241000150452 Orthohantavirus Species 0.000 description 1
- 241000711504 Paramyxoviridae Species 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000009341 RNA Virus Infections Diseases 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- 241000713124 Rift Valley fever virus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000710959 Venezuelan equine encephalitis virus Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000710886 West Nile virus Species 0.000 description 1
- 241000710951 Western equine encephalitis virus Species 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- 241000907316 Zika virus Species 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000004263 amino monosaccharides Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- MSWZFWKMSRAUBD-QZABAPFNSA-N beta-D-glucosamine Chemical compound N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-QZABAPFNSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 229960004979 fampridine Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Chemical group CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910000402 monopotassium phosphate Chemical group 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000003349 osteoarthritic effect Effects 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical group [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229950002929 trinitrophenol Drugs 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供以下通式I所示的氨基葡萄糖化合物、其药学上可接受的盐或者溶剂合物在制备抗病毒药物中的用途。所述化合物具有良好的抗病毒作用，特别是抗病毒效应的广谱性非常明显，可以用于制备抗病毒药物。
Description
本申请是中国专利申请“氨基葡萄糖及其衍生物作为抗病毒药物的应用”(申请号： 201910192721X，申请日：2019年3月13日)的分案申请。
技术领域
本发明属于医药领域，具体而言，涉及一种氨基葡萄糖及其衍生物在制备抗病毒药物中的应用及其制备方法。
背景技术
N-乙酰-D-氨基葡萄糖是甲壳素成分的最小组成单位，也是生物细胞内许多重要多糖的基本组成单位。它是由葡萄糖分子内2位上的OH基被乙酰氨基取代后生成的一种氨基单糖。在化学上可以通过乙酰化氨基葡萄糖分子内2位上的氨基而容易合成，天然型 N-乙酰-D-氨基葡萄糖则可以通过生物技术水解甲壳类动物(如蟹和虾)的外壳后再经精制而获得。该物质在生物体内具有许多重要的生理功能。主要的应用功效有以下几种：
1.抗癌、抗肿瘤和免疫调节功效；
2.促进骨损愈合和质量骨关节炎的效果；和
3.改善皮肤保水性、缓解皮肤粗糙、抑制细纹生成等。
虽然N-乙酰基-氨基葡萄糖具有多种的生理功效，但是未见报道其在抗病毒领域的应用，本发明的发明人在实验的过程中发现，N-乙酰基-氨基葡萄糖及其衍生物对多种病毒具有明显的抑制作用，N-乙酰氨基葡萄糖的安全性已经在各个方面的得到了验证，因此其作为抗病毒药物的开发具有广阔的前景。
发明内容
本发明的一方面，提供通式I所示的氨基葡萄糖化合物、其药学上可接受的盐或者溶剂合物在制备抗病毒药物中的用途：
其中，R和R’各自独立地选自氢、取代的或未取代的C1-C8烷基、取代的或未取代的C1-C8烷基羰基、取代的或未取代的C6-C15芳基、取代的或未取代的C7-C15芳烷基、取代的或未取代的C6-C15芳基羰基、取代的或未取代的C6-C15芳基磺酰基、取代的或未取代的C7-C15芳氧基羰基以及取代的或未取代的含有选自N、O和S的1至3个杂原子的饱和或不饱和5元或6元杂环基氨基羰基；
在上述R和R’的各种取代基中，所述“取代的”是指所述取代基上还含有1至3个选自C1-C4烷基、C1-C4烷氧基、C2-C4甲酸酯基和卤素的取代基。
R1、R2、R3和R4各自独立地为氢、取代的或未取代的C1-C8烷基、取代的或未取代的C3-C8环烷基、取代的或未取代的C1-C8烷基羰基、取代的或未取代的氨基、取代的或未取代的C5至C12的芳基、取代的或未取代的C6至C13的芳烷基、取代的或未取代的含有选自N、O和S的1至3个杂原子的饱和或不饱和5元或6元杂环基、磷酸根、二钾磷酸根、一钾亚磷酸根、二钠磷酸根和一钠亚磷酸根。
所述卤素选自氟、氯、溴或碘。
优选地，所述R和R’各自独立地选自氢、取代的或未取代的C1-C6烷基、取代的或未取代的C1-C6烷基羰基、取代的或未取代的C6-C10芳基、取代的或未取代的C7-C10 芳烷基、取代的或未取代的C6-C10芳基羰基、取代的或未取代的C6-C10芳基磺酰基、取代的或未取代的C7-C10芳氧基羰基以及取代的或未取代的含有选自N、O和S的1至 3个杂原子的饱和或不饱和6元杂环基氨基羰基。
进一步优选地，所述R和R’各自独立地选自氢、取代的或未取代的C1-C4烷基、取代的或未取代的苯基C1-C4烷基羰基、取代的或未取代的苯基、取代的或未取代的苯基C1-C4烷基、取代的或未取代的苯基羰基、取代的或未取代的苯基磺酰基、取代的或未取代的苄基羰基以及取代的或未取代的含有1至3个N的杂原子的饱和或不饱和6元杂环基氨基羰基。
优选地，在上述R和R’的各种取代基中，所述“取代的”是指所述取代基上还含有1或2个选自甲基、乙基、丙基、甲氧基、乙氧基、丙氧基、甲酸甲酯基、甲酸乙酯基、甲酸丙酯基、氟和氯的取代基。
进一步优选地，所述R和R’各自独立地选自氢、甲基、乙基、丙基、丁基、甲基羰基、乙基羰基、丙基羰基、丁基羰基、一氯代甲基羰基、一氯代乙基羰基、一氯代丙基羰基、一氯代丁基羰基、二氯代甲基羰基、二氯代乙基羰基、二氯代丙基羰基、二氯代丁基羰基、一氟代甲基羰基、一氟代乙基羰基、一氟代丙基羰基、一氟代丁基羰基、二氟代甲基羰基、二氟代乙基羰基、二氟代丙基羰基、二氟代丁基羰基、苯基、苯甲基、苯乙基、苯丙基、苯丁基，甲氧基取代的苯甲基、甲氧基取代的苯乙基、甲氧基取代的苯丙基、甲氧基取代的苯丁基，乙氧基取代的苯甲基、乙氧基取代的苯乙基、乙氧基取代的苯丙基、乙氧基取代的苯丁基、甲酸甲酯基取代的苯基、甲酸乙酯基取代的苯基、甲酸丙酯基取代的苯基、吡啶基氨基羰基、苯基羰基、甲基苯基羰基、乙基苯基羰基、丙基苯基羰基、甲基苯基磺酰基、乙基苯基磺酰基、丙基苯基磺酰基和苄基羰基。
优选地，所述R1、R2、R3和R4各自独立地为氢、取代的或未取代的C1-C6烷基、取代的或未取代的C1-C6烷基羰基、取代的或未取代的氨基、取代的或未取代的C6至 C10的芳基、取代的或未取代的C6至C10的芳烷基、磷酸根、二钾磷酸根、一钾亚磷酸根、二钠磷酸根和一钠亚磷酸根。
进一步优选地，所述R1、R2、R3和R4各自独立地为氢、甲基、乙基、丙基、丁基、甲基羰基、乙基羰基、丙基羰基、丁基羰基、一氯代甲基羰基、一氯代乙基羰基、一氯代丙基羰基、一氯代丁基羰基、二氯代甲基羰基、二氯代乙基羰基、二氯代丙基羰基、二氯代丁基羰基、一氟代甲基羰基、一氟代乙基羰基、一氟代丙基羰基、一氟代丁基羰基、二氟代甲基羰基、二氟代乙基羰基、二氟代丙基羰基、二氟代丁基羰基、苯基、苯甲基、苯乙基、苯丙基、苯丁基，甲氧基取代的苯甲基、甲氧基取代的苯乙基、甲氧基取代的苯丙基、甲氧基取代的苯丁基，乙氧基取代的苯甲基、乙氧基取代的苯乙基、乙氧基取代的苯丙基、乙氧基取代的苯丁基、二钾磷酸根和一钾亚磷酸根。
优选地，根据本发明的式I所示的化合物选自以下化合物中：
本发明的另一方面，提供一种抗病毒药物组合物，其含有作为活性成分的式I所示化合物、其药学上可接受的盐或者溶剂合物，以及药学上可接受的载体。
根据本发明的所述抗病毒药物组合物可用于治疗和预防选自黄病毒、肠道病毒、流感病毒、冠状病毒、丝状病毒、沙粒病毒、披膜病毒、副黏病毒、弹状病毒鼻病毒、和非洲猪瘟病毒等可激活线粒体抗病毒信号蛋白(MAVS)通路的RNA病毒引起的病毒性疾病；
其中，所述黄病毒选自登革病毒、寨卡病毒、日本脑炎病毒、黄热病毒、西尼罗病毒、基萨纳脑炎病毒；所述肠道病毒选自EV71、EV68、柯萨奇病毒A6、柯萨奇病毒B3、柯萨奇病毒A16，脊髓灰质炎病毒；所述流感病毒选自H1N1(WSN，CA06，PR8)、H2N3、 H5N1、H7N9、耐药性甲流、奥司他韦耐药性流感病毒、登革热病毒；所述冠状病毒选自 SARS和MERS；所述布尼亚病毒选自发热伴血小板减少综合症病毒(SFTSV)、裂谷热病毒、汉坦病毒等疾病；所述丝状病毒选自埃博拉病毒和马尔堡病毒；所述沙粒病毒为拉沙热病毒；所述披膜病毒选自东方马脑炎病毒、西方马脑炎病毒、委内瑞拉马脑炎病毒等：所述副黏病毒选自亨尼帕病毒；所述弹状病毒选自疱疹性口炎病毒和狂犬病毒。
根据本发明的另一方面，根据本发明的通式I所示的氨基葡萄糖化合物、其药学上可接受的盐或者溶剂合物的用途为与选自奥司他韦、帕拉米韦、扎那米韦、索非布韦和利巴韦林中的至少一种药物连用在制备抗病毒药物中的用途。
根据本发明的所述病毒药物组合物可以制为多种制剂形式，包括但不限于胶囊剂，片剂，注射剂，栓剂，输液剂，搽剂，乳剂等。
有益效果
根据本发明的所述化合物具有良好的抗病毒作用，特别是抗病毒效应的广谱性非常明显，可以用于制备抗病毒药物。
附图说明
图1为测试实施例1中针对化合物3的干扰素β(IFN-β)及干扰素诱导蛋白Ifit1的表达水平差异的对照图；
图2为测试实施例2中针对化合物3的磷酸化IRF3(pIRF3)的激活水平的示意图；
图3为测试实施例2中针对不同给药量的化合物3的磷酸化IRF3(pIRF3)的激活水平的对照图；
图4为测试实施例3中给药组与对照组小鼠肺组织中IFN-β及Ifit1mRNA表达水平的对照图；
图5为测试实施例3中给药组与对照组小鼠肺组织中的病毒载量的对照图；
图6为测试实施例3中给药组与对照组肺组织中炎性细胞浸润程度的对照图；
图7为测试实施例4中给药组与对照组IAV感染小鼠的生存率的对照图；
图8为测试实施例4中给药组与对照组IAV-H274Y感染小鼠的生存率的对照图；
图9为测试实施例5中给药组与对照组感染VSV的两组小鼠生存率的对照图；
图10为测试实施例5中给药组与对照组感染SA14的两组小鼠生存率的对照图；
图11为测试实施例5中给药组与对照组感染SFTAV的两组小鼠生存率的对照图；
图12为测试实施例5中给药组与对照组感染CA6的两组小鼠生存率的对照图；
图13为测试实施例5中给药组与对照组感染SARS的两组小鼠生存率的对照图；
图14为测试实施例5中给药组与对照组感染Ebola的两组小鼠生存率的对照图；
图15为测试实施例5中给药组与对照组感染拉沙热病毒的两组小鼠生存率的对照图；
图16为测试实施例5中给药组与对照组感染EEE的两组小鼠生存率的对照图；
图17为测试实施例5中给药组与对照组感染RhV的两组小鼠生存率的对照图；
图18为测试实施例5中给药组与对照组感染亨帕尼病毒的两组小鼠生存率的对照图；
图19为测试实施例5中给药组与对照组感染ASFV的两组小鼠生存率的对照图；
图20为测试实施例5中给药组与对照组感染HCV的两组小鼠生存率的对照图。
具体实施方式
以下，将详细地描述本发明。在进行描述之前，应当理解的是，在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义，而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上，根据与本发明的技术方面相应的含义和概念进行解释。因此，这里提出的描述仅仅是出于举例说明目的的优选实例，并非意图限制本发明的范围，从而应当理解的是，在不偏离本发明的精神和范围的情况下，可以由其获得其他等价方式或改进方式。
本发明的发明人发现根据本发明的通式I所示的氨基葡萄糖化合物、其药学上可接受的盐或者溶剂合物可以有效抑制病毒性疾病的发生。
另外根据所述通式I表示的化合物在制备抗病毒药物中的用途，本发明开发了新的药物组合物，其中含有作为活性成分的通式I所示化合物、其药学上可接受的盐或者溶剂合物，以及药学上可接受的载体。
所述“药学上可接受的盐”为通式(I)化合物与无机酸或有机酸反应形成的常规的无毒盐。例如，所述常规的无毒盐可通过通式(I)化合物与无机酸或有机酸反应制得，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者通式(I)化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式(I)化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐；或者通式(I)化合物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸和乙磺酸形成的对应的有机酸盐。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington：The Science和Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位剂量中包含0.05-200mg通式(I)化合物，优选地，制剂配方的单位剂量中包含0.1mg-100mg通式(I)化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径。最优选为口服。最佳优选日剂量为0.01-200mg/kg 体重，一次性服用，或0.01-100mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。
以下实施例仅是作为本发明的实施方案的例子列举，并不对本发明构成任何限制，本领域技术人员可以理解在不偏离本发明的实质和构思的范围内的修改均落入本发明的保护范围。除非特别说明，以下实施例中使用的试剂和仪器均为市售可得产品。
实验实施例1
市售cas:90-77-7
实验实施例2
市售cas:10034-20-5
实验实施例3
市售cas:10036-64-3
实验实施例4
化合物的合成参考文献Journal of Biotechnology,115(2),157-166；2005
1H NMR(400MHz,D2O):0.95(3H,m),2.16(2H,m),3.29(1H,dd,),3.62(1H,dd),3.58(1H,dd),3.61–3.67(2H,m),3.72(1H,dd),4.99(1H,d,J＝3.5Hz,H-1).ESI-MS:236.5 [M+H]+
实验实施例5
化合物的合成参考文献Journal of Biotechnology,115(2),157-166；2005
1H NMR(400MHz,D2O):0.95(3H,m),1.32(2H,m),2.16(2H,m),3.29(1H,dd,), 3.62(1H,dd),3.58(1H,dd),3.61–3.67(2H,m),3.72(1H,dd),4.99(1H,d,J＝3.5Hz,H-1). ESI-MS:250.1[M+H]+
实验实施例6
市售Cas:7784-54-5
实验实施例7
参考文献Organic&Biomolecular Chemistry,12(45),9180-9183；2014制备得到。
1H NMR(DMSO-d6，400MHz)δ:8.55(3H,s,NH3),7.48-7.45(2H,m,ArCH),7.42-7.27(16H,m,ArCH),7.16-7.14(2H,m ArCH),4.89(1H,d,J＝11.0Hz,PhCHH),4.86(1H,d,J＝8.5Hz,H-1),4.84(1H,d,J＝12.0Hz,PhCHH),4.81(1H,d,J＝11.0Hz,PhCHH),4.70(1H,d, J＝11.5Hz,PhCHH),4.65(1H,d,J＝11.0Hz,PhCHH),4.58(1H,d,J＝11.5Hz,PhCHH), 4.56(1H,d,J＝11.0Hz,PhCHH),4.52(1H,d,J＝12.0Hz,PCHH),3.95(1H,dd,J＝10.5和 8.5Hz,H-3),3.74-3.58(4H,m,H-4&H-5&H-6a&H-6b),3.05(1H,dd,J＝10.5和8.5Hz, H-2)；1.84(3H,s,Me).ESI-MS:604.3[M+Na]+
实验实施例8
参考文献Carbohydrate Research,340(11),1876-1884；2005制备得到。
1H NMR(CD3OD，400MHz)δ:5.32(1H,d),4.57(1H,d),3.72(1H,m),3.30(1H,m),2.96(2H,dq),2.90(2H,m),2.79(1H,dd),2.39(1H,dd),1.22(3H,t),1.15(3H,t).MS:m/z 208.2(M+H)+
实验实施例9
参考文献Carbohydrate Research,340(11),1876-1884；2005制备得到。
1H NMR(CD3OD，400MHz)δ:5.40(1H,d),4.70(1H,d),3.84(1H,dd),3.45(1H,dd),3.37(1H,t),3.01(2H,m),2.99(1H,dd),2.98(2H,m),2.56(1H,dd),1.69(2H,m),1.00(3H,t),0.98(3H,t)。MS:m/z 222.2(M+H)+,244.1(M+Na)+.
实验实施例10
1.80g(10mmol)D-(-)-果糖加入50ml三口瓶中，在0℃加入新蒸的苄氨中(3-8equiv.).反应升温至室温后，加热至40℃反应20h.点板检测反应完毕后，过量的苄氨用石油醚洗除。粗品通过柱分离纯化得白色固体1.05克产率41.18％.1H NMR (DMSO-d6，400MHz)δ:α-anomer 5.02(H-1dd),6.21(C1-OH,d),2.69(H-2,dd),1.97(NH,br), 3.82,3.70(CH2,d),7.17-7.40(Ph m),3.66(H-3,m),4.50(C3-OH,d),3.32(H-4,m),4.67(C4-OH,d),3.51(H-5,m),3.47(H-6x,m),3.62(H-6y,m),4.36(C6-OH,t)；β-anomer 4.95(H-1dd), 6.15(C1-OH,d),2.89(H-2,dd),2.22(NH,br),3.79,3.67(CH2,d),7.17-7.40(Phm),4.10 (H-3,m),4.50(C3-OH,d),3.67(H-4,m),4.76(C4-OH,br),3.77(H-5,m),3.33(H-6x,m),3.57 (H-6y,m),4.35(C6-OH,t).MS:m/z 256.2(M+H)+
实验实施例11
合成方法参照实施例10。1H NMR(DMSO-d6，400MHz)δ:α-anomer 5.05(H-1dd),6.23(C1-OH,d),2.73(H-2,dd),2.01(NH,br),3.82,3.72(CH2,d),7.19-7.40(Ph，m), 3.65(H-3,m),4.51(C3-OH,d),3.33(H-4,m),4.68(C4-OH,d),3.53(H-5,m),3.49(H-6x,m),3.61(H-6y,m),4.33(C6-OH,t)；β-anomer 4.93(H-1dd),6.16(C1-OH,d),2.89(H-2,dd),2.25 (NH,br),3.77,3.65(CH2,d),7.17-7.40(Ph，m),4.11(H-3,m),4.51(C3-OH,d),3.66(H-4,m), 4.77(C4-OH,br),3.78(H-5,m),3.35(H-6x,m),3.58(H-6y,m),4.35(C6-OH,t),3.85(Ome, s).MS:m/z 300.2(M+H)+
实验实施例12
参考文献Tetrahedron Letters,43(15),2705-2708；2002制备得到。
1H NMR(DMSO-d6，400MHz)δ:5.02(H-1dd),6.22(C1-OH,d),2.69(H-2,dd), 1.97(NH,br),3.82,3.70(CH2,d),7.23-7.38(Ph,m),3.66(H-3,m),4.50(C3-OH,d),3.32(H-4,m),4.67(C4-OH,d),3.51(H-5,m),3.47(H-6x,m),3.62(H-6y,m),4.36(C6-OH,t)；3.50(OCH3,s),MS:m/z 284.3(M+H)+
实验实施例13
参考文献Organic&Biomolecular Chemistry,10(35),7103-7107；2012制备得到。
1H NMR(400MHz,D2O)δ4.48(d,J＝8.5Hz,1H,H-1),3.79(dd,J＝12.6Hz,4.3Hz,1H,H-6a),3.61(dd,J＝12.4Hz,6.4Hz,1H,H-6b),3.52(dd,J＝10.6,8.4Hz,1H,H-3),3.45(s,3H,OCH3),3.39–3.28(m,2H,H-5,H-4),2.85(dd,J＝10.6Hz,8.5Hz,1H,H-2),2.52(s,3H,NCH3).MS:m/z 206.1(M+H)+
实验实施例14
参考文献Tetrahedron,46(16),5533-42；1990制备得到。
1HNMR(400MHz,D2O):4.93(IH,d.J＝4.0Hz,I-H).4.3-3.6(5H,m,3,4,5,6和6’-H),3.42(3H,s,-OMe),2.76(iH,dd,Jp10.0,4.0Hz,2-H)和2.51(6H,s,NMe2)。MS:m/z 222.1 (M+H)+
实验实施例15
参考文献Tetrahedron,74(1),19-27；2018制备得到。
1H NMR(400MHz,CD3OD)δ5.55(d,J＝3.4Hz,1H),4.05(dd,J＝10.9,8.6Hz,1H),3.80-3.76(m,2H,),3.74(dd,J＝12.8,7.4Hz),3.45(dd,J＝9.8,8.4Hz,1H),3.27(dd,J＝10.8, 3.4Hz,1H),3.03(s,6H).MS:m/z 208.1(M+H)+
实验实施例16
参考文献Journal of Carbohydrate Chemistry,32(7),411-423；2013制备得到。
1H NMR(400MHz,D2O)δ7.71-7.36(m,5H),5.02(s,0.81H),4.92-4.81(m,0.35H),4.13(t,J＝9.7Hz,0.85H),4.00-3.65(m,4.15H),3.58(t,J＝9.6Hz,1.04H),3.53-3.31(m,0.77H).MS:m/z 256.1(M+H)+
实验实施例17
参考文献Journal of Carbohydrate Chemistry,32(7),411-423；2013制备得到。
1H NMR(400MHz,D2O)δ7.45(t,J＝9.4Hz,2H),7.15(d,J＝8.7Hz,2H),5.01(s,0.83H),4.08(t,J＝9.8Hz,0.84H),3.96-3.58(m,7.45H),3.51(t,J＝9.5Hz,1.1H),3.35(s, 1.8H),MS:m/z 286.1(M+H)+
实验实施例18
参考文献Journal of Carbohydrate Chemistry,32(7),411-423；2013制备得到。
1H NMR(400MHz,D2O)δ7.40(t,J＝8.4Hz,1H),6.91(d,J＝8.4Hz,1H),6.81(t,J＝8.4Hz,1H),6.68(t,J＝8.4Hz,1H),5.03(s,0.83H),4.06(t,J＝9.2Hz,0.84H),3.95-3.54(m, 7.45H),3.53(t,J＝9.4Hz,1.1H),3.38(s,1.8H),MS:m/z 286.1(M+H)+
实验实施例19
参考文献Journal of Carbohydrate Chemistry,32(7),411-423；2013制备得到。
1H NMR(400MHz,D2O)δ7.42(t,J＝8.2Hz,1H),7.39(d,J＝8.2Hz,1H),7.08(d,J＝8.2Hz,1H),7.03(s,1H),5.05(s,0.83H),4.03(t,J＝9.2Hz,0.84H),3.954-3.55(m,7.45H), 3.54(t,J＝9.4Hz,1.1H),3.39(s,1.8H),MS:m/z 314.1(M+H)+
实验实施例20
室温下将220mg(0.74mmoL)三光气溶于10mL无水四氢呋喃中，氮气保护下，缓慢滴加溶有0.89g(2mmoL)1,3,4,6-四-O-乙酰基-a-D-氨基葡萄糖和0.38mL(2.2 mmoL)二异丙基乙胺的四氢呋喃溶液5mL，滴加时间约为5分钟。继续搅拌反应30分钟后，加入溶有0.18g(2mmoL)4-氨基吡啶和0.38mL(2.2mmoL)二异丙基乙胺的四氢呋喃溶液15mL。反应混合物搅拌5小时后，停止搅拌，减压蒸馏除去有机溶剂，加入50mL乙酸乙酯稀释，用20mL 10％NaHCO3洗涤3次，加入无水MgSO4干燥过夜。次日减压蒸馏除去有机溶剂，得黄色浸膏。柱层析分离(硅胶300-400目，流动相为乙酸乙酯：甲醇＝20:1)，得白色固体。用甲醇结晶得到白色晶体0.81g，收率82％。
1H NMR(DMSO-d6，400MHz)δ8.90(s，1H，NH)，8.30(d，2H，J＝6Hz，PyH)， 7.34(d，2H，J＝6Hz，PyH)，6.53(d，J＝9.2Hz，1H，NH)，6.02(d，J＝3.2Hz，1H， H-1)，5.18(t，J＝9.60Hz，1H，H-3)，5.05(t，J＝10Hz，1H，H-4)，4.20-3.99(m，4H， H-2，H-5，H-6a，6b)，2.20，2.02，2.00，1.95(12H，4Ac)：8.90(s，1H，NH)，8.30 (d，2H，J＝6Hz，PyH)，7.34(d，2H，J＝6Hz，PyH)，6.53(d，J＝9.2Hz，1H，NH)， 6.02(d，J＝3.2Hz，1H，H-1)，5.18(t，J＝9.60Hz，1H，H-3)，5.05(t，J＝10Hz，1H， H-4)，4.20-3.99(m，4H，H-2，H-5，H-6a，6b)，2.20，2.02，2.00，1.95(12H，4Ac) ESI-MS:300[M+1]+
实验实施例21
参考文献Huaxue Yanjiu Yu Yingyong,20(3),290-294；2008制备得到；产率：96.0％。
1HNMR(DMSO-d6，400MHz)δ:7.95～7.54(m,5H,Ar),7.45～7.42(m,1H,J1,2＝7.6Hz,H-1,β-),6.52(d,JNH,2＝4.8Hz,1H,NH),5.04～4.57(m,4H,4OH),3.81～3.72(m,1H,H-4),3.73～3.71(m,1H,H-3),3.66～3.63(m,2H,H-6和H-6'),3.51～3.42(m,1H,H-5), 3.20～3.16(m,1H,H-2)。ESI-MS:284[M+1]+
实验实施例22
参考文献Huaxue Yanjiu Yu Yingyong,20(3),290-294；2008制备得到；产率：96.0％。
1HNMR(DMSO-d6，400MHz)δ:7.92～7.54(m,4H,Ar),7.45～7.42(m,1H,J1,2＝7.6Hz,H-1,β-),6.52(d,JNH,2＝4.8Hz,1H,NH),5.04～4.57(m,4H,4OH),3.81～3.72(m,1H,H-4),3.73～3.71(m,1H,H-3),3.66～3.63(m,2H,H-6和H-6'),3.51～3.42(m,1H,H-5), 3.20～3.16(m,1H,H-2)，2.35(s,3H)。ESI-MS:298[M+1]+
实验实施例23
参考文献Advanced Synthesis&Catalysis,356(14-15),3199-3213；2014制备得到。
1H NMR(400MHz,D2O)δ5.33(H-1,dd)3.21(H-2,m),3.80(H-3,dd),3.71(H-4,dd),3.86(H-5,dt),3.43(H-6,m),2.61(PH),1.84(3H,CH3).ESI-MS:301.1[M+1]+
实验实施例24
参考文献Advanced Synthesis&Catalysis,356(14-15),3199-3213；2014制备得到。
1H NMR(400MHz,D2O)δ5.38(H-1,dd)3.20(H-2,m)4 3.80(H-3,dd)3.72(H-4, dd),3.88(H-5,dt)3.45(H-6,m)2.66(PH).ESI-MS:260[M+1]+
实验实施例25
参考文献：Khimiya Prirodnykh Soedinenii,(6),787-90；1987制备得到。
1H NMR(400MHz,CD3OD)δ:4.46(1H,d,J＝8.5Hz,H-1),3.67-3.65(2H,m,H-6a和H-6b),3.66(3H,s,CH3),3.56(3H,s,CH3),3.55(3H,s,CH3),3.44(1H,ddd,J＝3.5,6.0和9.5Hz,H-5),3.42(3H,s,CH3),3.39(1H,dd,J＝8.5和10.5Hz,H-3),3.29(1H,dd,J＝8.5 和9.5Hz,H-4),2.85(1H,dd,J＝8.5和10.5Hz,H2)；ESI-MS:300.2[M+Na]+
实验实施例26
参考文献：Organic&Biomolecular Chemistry,12(45),9180-9183；2014制备得到。
1H NMR(400MHz,CD3OD)δ:4.46(1H,d,J＝8.5Hz,H-1),3.67-3.65(2H,m,H-6a和H-6b),3.66(3H,s,CH3),3.56(3H,s,CH3),3.55(3H,s,CH3),3.44(1H,ddd,J＝3.5,6.0和9.5Hz,H-5),3.42(3H,s,CH3),3.39(1H,dd,J＝8.5和10.5Hz,H-3),3.29(1H,dd,J＝8.5 和9.5Hz,H-4),2.85(1H,dd,J＝8.5和10.5Hz,H2)；ESI-MS:258.1[M+Na]+
实验实施例27
参考文献：Journal of Biological Chemistry,289(46),32056-32063；2014制备得到。
1H-NMR:(400MHz,CDCl3)δ[ppm]2.03(s,3H,-N-CO-CH3),2.06(s,6H,2× -O-CO-CH3),3.27(s,3H,-O-CH3),3.34(s,3H,-O-CH3),3.69(dd,3JH,H＝9.8,4.9Hz,1H, H-3),3.83(ddd,3JH,H＝10.1,5.7,2.3Hz,1H,H-5),4.04(dd,2JH,H＝12.2,3JH,H＝2.4Hz, 1H,H-6a),4.21(dd,2JH,H＝12.2,3JH,H＝5.7Hz,1H,H-6b),4.52(ddd,3JH,H＝7.6,4.9,1.5Hz,1H,H-2),4.75(d,3JH,H＝1.4Hz,1H,H-1),4.92(dd,3JH,H＝10.0,10.0Hz,1H,H-4),5.82(d,3JH,H＝7.7Hz,1H,NH).ESI-MS:[M+Na]+356.1
实验实施例28
参考文献：Organic Letters,19(5),1040-1043；2017制备得到。
1HNMR(DMSO-d6，400MHz)δ7.74(d,2H),7.70(s,1H),7.41(d,2H),5.62(d,1H),3.54-3.79(m,7H),2.87(s,1H),2.35(s,3H).ESI-MS:334.1[M+1]+
实验实施例29
将D-氨基葡萄糖盐酸盐(1.0g，0.0046mol)溶于40mL甲醇与3倍量的甲醇钠溶液中，室温连续搅拌0.5-1h。苯氧乙酰氯(1.28g，0.007mol)用滴液漏斗缓慢滴入游离的氨基糖溶液中，滴加过程可观察到有白色沉淀生成，滴加完毕室温搅拌4h。反应液用 12mol/L盐酸液调pH＝2-3，将生成的白色沉淀常压过滤，得白色固体，冰甲醇(2mL×3)，冰乙醚(2mL×3)，冰水(2mL×3)洗涤，红外烘干。得白色粉末状固体1.35g，收率： 68％；白色固体。
1H NMR(400MHz,DMSO)δ7.59(d,J＝8.3Hz,1H,NH),7.29(d,J＝5.3Hz,2H,ArH),6.98–6.96(m,3H,ArH),6.57(t,J＝4.9Hz,1H,OH),5.22(d,J＝3.6Hz,1H,1-H),4.99(dd, J＝8.0,4.1Hz,2H,OH),4.51(d,J＝0.8Hz,2H,OCH2CO),4.43(s,1H,OH),3.67(d,J＝1.7 Hz,1H,2-H),3.60(d,J＝4.9Hz,2H,3-H,5-H),3.50-3.44(m,2H,6-H,6’-H),3.16(d,J＝9.1Hz,1H,4-H)；ESI-MS:300[M+1]+。
测试实施例1：化合物3(N-乙酰基-氨基葡萄糖)在细胞水平上抗病毒效应评价
在体外分化并培养小鼠的原代巨噬细胞(BMDM)，分化至第七天，给予细胞终浓度为20mM的化合物3预处理3小时(给药组)，以PBS处理组作为对照(对照组)。之后以1MOI感染复数的流感病毒(IAV)感染细胞，感染3小时、6小时后收集细胞样品，提取RNA并利用实时荧光定量PCR方法检测干扰素β(IFN-β)及干扰素诱导蛋白Ifit1的表达水平差异。如图1所示，IAV感染后给药组细胞中的IFN-β(左)及Ifit1(右)mRNA的表达水平相比对照组均有显著的提高，这证明在细胞水平上化合物3可以增强病毒感染诱导的干扰素通路表达水平，进而发挥抗病毒效应。
测试实施例2
利用点突变试剂盒对IAV的NA基因进行H274Y突变，并基于病毒反向遗传学技术，利用质粒系统包装获得突变株恢复病毒。恢复病毒经测序验证后，利用MDCK细胞进行扩增，收集病毒，即为流感病毒的耐药株突变株(IAV-H274Y)。研究表明IAV-H274Y突变株对市面上在售的抗病毒药物奥斯他韦具有显著的耐药性，我们通过实验验证化合物3 对流感病毒耐药株具有一定的抗病毒活性。在体外分化并培养BMDM，分化至第七天，给予细胞终浓度为20mM或40mM的化合物3预处理3小时(给药组)，以PBS处理组作为对照(对照组)。之后以1MOI感染复数的IAV-H274Y感染细胞，感染3小时、6小时后收集细胞样品进行检测。一方面提取细胞的总蛋白并利用蛋白质印迹法(Western blot) 检测磷酸化IRF3(pIRF3)的激活水平(图2)，另一方面，提取RNA并利用实时荧光定量 PCR检测干扰素β(IFN-β)mRNA的表达水平差异(图3)。结果显示，IAV-H274Y感染后， 20mM及40mM给药组细胞中的pIRF3激活水平相比对照组有显著增强(图2)，同时发现给药组细胞中的IFN-βmRNA的表达水平相比对照组也具有显著水平的提高(图3)，这证明化合物3具有一定抗耐药流感病毒感染的效应。
化合物1至29针对流感病毒的耐药株突变(IAV-H274Y)的抗耐药流感病毒感染的实验数据列于下表1中。
测试实施例3：化合物3在动物成体水平下抗病毒活性评价
选取性别、周齡、体重一致的C57小鼠，把小鼠平均分为两组，一组小鼠喂食含化合物3的鼠粮(25mg/kg)(给药组)，另一组小鼠喂食不含化合物3的普通鼠粮作为对照 (对照组)。喂食3天后，给小鼠滴鼻感染流感病毒IAV(1×105PFU/只)。感染24小时后，脱颈处死小鼠，解剖小鼠，取出感染小鼠的肺组织进行裂解，检测肺组织中干扰素激活水平及病毒复制情况。结果显示，给药组小鼠肺组织中IFN-β及Ifit1mRNA表达水平相比对照组都具有显著性提高(图4)。同时，空斑实验显示给药组小鼠肺组织中的病毒载量相比对照组显著降低(图5)，且肺组织中炎性细胞浸润程度也有所缓解(图6)，通过以上实验检测感染后肺组织样品证明化合物3在动物成体水平具有一定的抗病毒活性。
测试实施例4：
为了进一步验证化合物3在体内的抗病毒效应，选取性别、周齡、体重一致的C57小鼠，把小鼠平均分为两组，一组小鼠喂食含化合物3的鼠粮(25mg/kg)(给药组)，另一组小鼠喂食不含化合物3的普通鼠粮作为对照(对照组)。喂食3天后，给小鼠滴鼻感染流感病毒IAV(1*105PFU/只)，统计两组小鼠生存情况差异。结果显示，喂食化合物3可以显著提升IAV感染小鼠的生存率(图7)。
测试实施例5：对化合物3抗病毒效应的广谱性进行评价
在实验中利用不同种属的RNA病毒，如弹状病毒科水泡性病毒属的水疱性口炎病毒 (Vesicular Stomatitis Virus,VSV)、微RNA病毒科肠病毒属的柯萨奇6型病毒(Coxsachievirus A6,CA6)、布尼亚病毒科白蛉病毒属的严重发热伴血小板减少综合症病毒 (Severe fever with thrombocytopenia syndrome virus,SFTSV)、黄病毒科黄病毒属的乙型脑炎病毒SA14株(Japanese encephalitis virus,JEV,SA14)、冠状病毒科冠状病毒属的SARS 病毒、丝状病毒科埃博拉病毒属的埃博拉病毒(Ebola virus)、沙粒病毒科沙粒病毒属的拉沙热病毒(Lassa fever virus)、披膜病毒科甲病毒属的东方马脑炎病毒(eastern equine encephalitis,EEE)、小RNA病毒科鼻病毒属的鼻病毒(rhinovirus，RhV)、副黏病毒科的亨尼帕病毒及非洲猪瘟病毒科的非洲猪瘟病毒(African Swine fevervirus,ASFV)，选取性别、周齡、体重一致的C57及ICR小鼠，把小鼠平均分为两组，一组小鼠喂食含化合物 3的鼠粮(25mg/kg)(给药组)，另一组小鼠喂食不含化合物3的普通鼠粮作为对照(对照组)。喂食3天后，给小鼠分别感染IAV-H274Y病毒(图8)、VSV病毒(图9)、SA14病毒(图10)、SFTSV病毒(图11)、CA6病毒(图12)、SARS病毒(图13)、Ebola病毒(图14)、拉沙热病毒(图15)、EEE病毒(图16)、RhV病毒(图17)、亨尼帕病毒(图18)、 ASFV病毒(图19)和HCV病毒(图20)。结果显示，喂食化合物3可以显著提高上述RNA 病毒感染后小鼠的生存率。
化合物1至29针对弹状病毒科水泡性病毒属的水疱性口炎病毒(VesicularStomatitis Virus,VSV)、微RNA病毒科肠病毒属的柯萨奇6型病毒(Coxsachievirus A6,CA6)、布尼亚病毒科白蛉病毒属的严重发热伴血小板减少综合症病毒(Severe fever withthrombocytopenia syndrome virus,SFTSV)以及黄病毒科黄病毒属的乙型脑炎病毒SA14株(Japanese encephalitis virus,JEV,SA14)的抗病毒效应的广谱性实验数据列于下表1中。
Claims (1)
1.式1所示的氨基葡萄糖化合物或其药学上可接受的盐在制备抗病毒药物中的用途：
所述病毒为柯萨奇病毒A6。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210314424.XA CN114732822B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910192721.XA CN109771432B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
| CN202210314424.XA CN114732822B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910192721.XA Division CN109771432B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114732822A CN114732822A (zh) | 2022-07-12 |
| CN114732822B true CN114732822B (zh) | 2023-06-30 |
Family
ID=66487968
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210316603.7A Active CN114732823B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
| CN201910192721.XA Active CN109771432B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
| CN202210316621.5A Active CN114681472B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
| CN202210314424.XA Active CN114732822B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
Family Applications Before (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210316603.7A Active CN114732823B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
| CN201910192721.XA Active CN109771432B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
| CN202210316621.5A Active CN114681472B (zh) | 2019-03-13 | 2019-03-13 | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (4) | CN114732823B (zh) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110279693B (zh) * | 2019-07-25 | 2021-06-15 | 军事科学院军事医学研究院微生物流行病研究所 | 一种组合物在制备预防和/或治疗发热伴血小板减少综合征病毒的药物中的应用 |
| CN112336733B (zh) * | 2020-10-26 | 2022-03-11 | 南湖实验室 | 氨基葡萄糖及其衍生物作为抗新型冠状病毒药物的用途 |
| GB2628963A (en) * | 2023-02-08 | 2024-10-16 | Univ Of Lincoln | Formulations and uses thereof |
| CN117860712A (zh) * | 2024-01-18 | 2024-04-12 | 中国人民解放军军事科学院军事医学研究院 | 一种吸入用氨糖组合物及其制备方法和其应用 |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1533776A (zh) * | 2003-03-27 | 2004-10-06 | 中国人民解放军第三军医大学 | N-乙酰氨基葡萄糖在制备用于治疗病毒或细菌感染所致的局部损伤和全身症状的药物中的应用 |
| CN101190912A (zh) * | 2006-12-01 | 2008-06-04 | 黄振华 | 新的抗病毒化合物及其制备方法 |
| WO2010141932A1 (en) * | 2009-06-05 | 2010-12-09 | Link Medicine Corporation | Aminopyrrolidinone derivatives and uses thereof |
| AU2013205384A1 (en) * | 2011-04-15 | 2013-05-23 | Marine Polymer Technologies, Inc. | Treatment of disease with poly-n-acetylglucosamine nanofibers |
| AU2015200865A1 (en) * | 2006-06-02 | 2015-03-19 | Synedgen, Inc. | Chitosan-Derivative Compounds and Methods of Controlling Microbial Populations |
| CA2946742A1 (en) * | 2014-04-23 | 2015-10-29 | The Regents Of The University Of California | Analogs of n-acetylglucosamine and uses thereof |
| CN108778308A (zh) * | 2015-12-22 | 2018-11-09 | 库瑞瓦格股份公司 | 生产rna分子组合物的方法 |
| CN114681473A (zh) * | 2020-10-26 | 2022-07-01 | 南湖实验室 | 氨基葡萄糖及其衍生物作为抗新型冠状病毒药物的用途 |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2247584T3 (es) * | 1992-04-14 | 2006-03-01 | The Mount Sinai School Of Medicine Of The City University Of New York | Virus atenuados por ingenieria genetica. |
| US20050032065A1 (en) * | 2002-06-24 | 2005-02-10 | Afar Daniel E. H. | Methods of prognosis of prostate cancer |
| JP2005015451A (ja) * | 2003-06-30 | 2005-01-20 | Japan Science & Technology Agency | 硫酸化グルコース化合物 |
| US7968122B2 (en) * | 2003-12-10 | 2011-06-28 | Adventrx Pharmaceuticals, Inc. | Anti-viral pharmaceutical compositions |
| WO2006113429A2 (en) * | 2005-04-13 | 2006-10-26 | Xc Research, Inc. | Viral inhibitors |
| CN101190913A (zh) * | 2006-12-01 | 2008-06-04 | 黄振华 | 具有抗病毒活性的新化合物 |
| EP2148678A4 (en) * | 2007-05-23 | 2010-08-04 | Siga Technologies Inc | ANTIVIRAL DRUGS FOR THE TREATMENT AND PREVENTION OF DENGUE INFECTION |
| US7928077B2 (en) * | 2008-07-11 | 2011-04-19 | Academia Sinica | Alpha-galactosyl ceramide analogs and their use as immunotherapies |
| ES2524361T3 (es) * | 2009-06-12 | 2014-12-05 | United Therapeutics Corporation | Iminoazúcares para su uso en el tratamiento de enfermedades por bunyavirus y togavirus |
| US20120172329A1 (en) * | 2009-09-14 | 2012-07-05 | Thailand Excellence Center For Tissue Engineering | Phytochemical compositions including xanthones for anti-inflammatory, anti-cytokine storm, and other uses |
| MY180220A (en) * | 2009-09-14 | 2020-11-25 | Chiang Mai Univ | Phytochemical compositions including sesamin for anti-inflammatory, anti-cytokine storm, and other uses |
| WO2011071535A2 (en) * | 2009-12-11 | 2011-06-16 | Mount Sinai School Of Medicine Of New York University | Compositions and methods for inhibiting human host cell factors required for influenza virus replication |
| CA2851801A1 (en) * | 2011-10-21 | 2013-04-25 | Glaxosmithkline Llc | Compounds and methods for enhancing innate immune responses |
| CN103880975B (zh) * | 2014-04-03 | 2015-10-21 | 中国海洋大学 | 一种岩藻聚糖硫酸酯及其制备方法和在制备抗流感病毒药物中的应用 |
| CN104327128A (zh) * | 2014-11-19 | 2015-02-04 | 北大医药重庆大新药业股份有限公司 | 一种氨基葡萄糖盐酸盐的制备方法 |
| CN105267985B (zh) * | 2015-05-05 | 2018-10-19 | 中国人民解放军第二军医大学 | N-乙基马来酰亚胺敏感因子在防治乙型脑炎病毒感染中的应用 |
| CN107267579B (zh) * | 2016-04-05 | 2020-08-21 | 孙镧 | 微生物发酵生产n-乙酰-d-氨基葡萄糖和/或d-氨基葡萄糖盐的方法 |
| UY37695A (es) * | 2017-04-28 | 2018-11-30 | Novartis Ag | Compuesto dinucleótido cíclico bis 2’-5’-rr-(3’f-a)(3’f-a) y usos del mismo |
| US20210228738A1 (en) * | 2017-07-17 | 2021-07-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Compositions and methods for increasing or enhancing transduction of gene therapy vectors and for removing or reducing immunoglobulins |
| CN107281199A (zh) * | 2017-07-27 | 2017-10-24 | 吉林省始祖生物波医学研究院有限公司 | N‑乙酰‑d‑氨基葡萄糖及其药物可接受盐在制备治疗病毒性肝炎药物中的应用及药物 |
| KR102007421B1 (ko) * | 2019-01-18 | 2019-08-05 | 한국생명공학연구원 | 락토바실러스 플란타륨(Lactobacillus plantarum) 유래의 다당체를 유효성분으로 포함하는 항-인플루엔자 바이러스용 조성물 및 상기 다당체의 제조방법 |
| MX2023009332A (es) * | 2021-02-11 | 2023-11-09 | Danstar Ferment Ag | Composiciones que comprenden exopolisacáridos y usos de las mismas. |
-
2019
- 2019-03-13 CN CN202210316603.7A patent/CN114732823B/zh active Active
- 2019-03-13 CN CN201910192721.XA patent/CN109771432B/zh active Active
- 2019-03-13 CN CN202210316621.5A patent/CN114681472B/zh active Active
- 2019-03-13 CN CN202210314424.XA patent/CN114732822B/zh active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1533776A (zh) * | 2003-03-27 | 2004-10-06 | 中国人民解放军第三军医大学 | N-乙酰氨基葡萄糖在制备用于治疗病毒或细菌感染所致的局部损伤和全身症状的药物中的应用 |
| WO2004084916A1 (fr) * | 2003-03-27 | 2004-10-07 | Third Military Medical University, Chinese People's Liberation Army, P.R. Of China | Utilisation de n-acetyle-d-aminoglycosamine dans le traitement de lesions locales et de symptomes systematiques lies aux infections virales ou bacteriennes |
| AU2015200865A1 (en) * | 2006-06-02 | 2015-03-19 | Synedgen, Inc. | Chitosan-Derivative Compounds and Methods of Controlling Microbial Populations |
| CN101190912A (zh) * | 2006-12-01 | 2008-06-04 | 黄振华 | 新的抗病毒化合物及其制备方法 |
| WO2010141932A1 (en) * | 2009-06-05 | 2010-12-09 | Link Medicine Corporation | Aminopyrrolidinone derivatives and uses thereof |
| AU2013205384A1 (en) * | 2011-04-15 | 2013-05-23 | Marine Polymer Technologies, Inc. | Treatment of disease with poly-n-acetylglucosamine nanofibers |
| CA2946742A1 (en) * | 2014-04-23 | 2015-10-29 | The Regents Of The University Of California | Analogs of n-acetylglucosamine and uses thereof |
| CN108778308A (zh) * | 2015-12-22 | 2018-11-09 | 库瑞瓦格股份公司 | 生产rna分子组合物的方法 |
| CN114681473A (zh) * | 2020-10-26 | 2022-07-01 | 南湖实验室 | 氨基葡萄糖及其衍生物作为抗新型冠状病毒药物的用途 |
Non-Patent Citations (7)
| Title |
|---|
| 2010年我国生化药物研究进展;王凤山;谭海宁;张天民;;中国药学杂志(第15期);第7-12页 * |
| A subset of mouse monoclonal antibodies cross-reactive with cytoskeletal proteins and group A streptococcal M proteins recognizes N-acetyl-beta-D-glucosamine;A R Shikhman，等;J Immunol .;第151卷(第1期);第3902-3913页 * |
| MAVS O-GlcNAcylation Is Essential for Host Antiviral Immunity against Lethal RNA Viruses;Nan Song，等;Cell Rep .;第28卷(第9期);第2386-2396页 * |
| Receptor-independent augmentation of adenovirus-mediated gene transfer with chitosan in vitro;Yosei Kawamata，等;Biomaterials .;第23卷(第23期);第4573-4579页 * |
| Synthesis and antiviral activity of 1,2,3-triazolyl nucleoside analogues with N-acetyl-D-glucosamine residue;Bulat F Garifullin，等;Nucleosides Nucleotides Nucleic Acids .;第1-23页 * |
| 天然食品中的抗病毒因子;罗明姬;食品科学(第08期);第179-186页 * |
| 热毒宁注射液抗A16型柯萨奇病毒的研究;曹泽彧，等;中草药;第45卷(第10期);第1450-1455页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109771432B (zh) | 2022-04-19 |
| CN114681472A (zh) | 2022-07-01 |
| CN114732823A (zh) | 2022-07-12 |
| CN109771432A (zh) | 2019-05-21 |
| CN114732823B (zh) | 2023-05-23 |
| CN114732822A (zh) | 2022-07-12 |
| CN114681472B (zh) | 2023-06-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114732822B (zh) | 氨基葡萄糖及其衍生物作为抗病毒药物的应用 | |
| NO327812B1 (no) | Dimere forbindelser, slike forbindelser som farmasoytiske midler, farmasoytiske preparater inneholdende slike, anvendelse av slike for fremstilling av medikamenter for behandling av sykdom samt en in vitro metode for pavisning av influensavirus | |
| US20230248754A1 (en) | Patentiflorin A Analogs as Antiviral Agents | |
| CN108473477A (zh) | 用于在流感病毒感染中使用的芳基取代的嘧啶 | |
| WO2010083732A1 (zh) | N-乙酰神经氨酸类化合物、其药物组合物及其制备方法和用途 | |
| CN112010916B (zh) | 核苷化合物的氨基磷酸酯衍生物及其用途 | |
| CN115490681A (zh) | 三嗪衍生物 | |
| EP2279750A1 (en) | Aniline derivative having anti-rna viral activity | |
| JP6767011B2 (ja) | 抗ｄｎａウィルス活性などの生理活性を有するヌクレオシド誘導体 | |
| EP2504326B1 (en) | Sialochimeric compounds | |
| EP0882721A1 (en) | 4-substituted-2,7-dideoxy-7-fluoro-2,3-didehydrosialic acids | |
| JP2021511354A (ja) | 新規なヌクレオシドまたはヌクレオチド誘導体およびこれらの用途 | |
| CN114805458A (zh) | 类核苷广谱抗病毒药物的脂肪酸前药及其制备方法和用途 | |
| CN111423483A (zh) | 环二核苷酸前药分子及其制备方法和应用 | |
| CN112661801A (zh) | 一种核苷类似物及其氘代物及其制备方法和用途 | |
| CN112300147B (zh) | 一种吡啶类化合物及其制备方法和应用、药物组合物 | |
| CN113336816B (zh) | 胞苷类化合物及其抗肿瘤用途 | |
| CN115141206B (zh) | 一种ɑ-硫辛酸石蒜碱偶联物及其制备方法和应用 | |
| CN114751914B (zh) | 一种倍半萜类衍生物及其在制备广谱抗病毒药物中的应用 | |
| JPS63135399A (ja) | サイクリツクａｍｐ誘導体 | |
| JP2003246792A (ja) | 抗インフルエンザウイルス化合物 | |
| JP2023072634A (ja) | 抗ウイルス剤 | |
| CN117343072A (zh) | 一种1-取代肉桂酰基-2-氧代石蒜碱类化合物及其制备方法和应用 | |
| JPH07188205A (ja) | α−グルコシダーゼ阻害剤 | |
| CN113185534A (zh) | 一种2,4-二甲氧基苄脲类化合物的制备及其用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |