CN114773417A - Cordycepin phosphate and preparation method and application thereof - Google Patents
Cordycepin phosphate and preparation method and application thereof Download PDFInfo
- Publication number
- CN114773417A CN114773417A CN202210357818.3A CN202210357818A CN114773417A CN 114773417 A CN114773417 A CN 114773417A CN 202210357818 A CN202210357818 A CN 202210357818A CN 114773417 A CN114773417 A CN 114773417A
- Authority
- CN
- China
- Prior art keywords
- cordycepin
- phosphate
- chlorophosphate
- preparation
- virus
- 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.)
- Granted
Links
- OFEZSBMBBKLLBJ-UHFFFAOYSA-N cordycepine Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)CC1O OFEZSBMBBKLLBJ-UHFFFAOYSA-N 0.000 title claims abstract description 72
- KQLDDLUWUFBQHP-UHFFFAOYSA-N Cordycepin Natural products C1=NC=2C(N)=NC=NC=2N1C1OCC(CO)C1O KQLDDLUWUFBQHP-UHFFFAOYSA-N 0.000 title claims abstract description 71
- OFEZSBMBBKLLBJ-BAJZRUMYSA-N cordycepin Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)C[C@H]1O OFEZSBMBBKLLBJ-BAJZRUMYSA-N 0.000 title claims abstract description 67
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 41
- 239000010452 phosphate Substances 0.000 title claims abstract description 41
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 17
- 241000700721 Hepatitis B virus Species 0.000 claims abstract description 8
- 241000725303 Human immunodeficiency virus Species 0.000 claims abstract description 7
- 241000712431 Influenza A virus Species 0.000 claims abstract description 7
- -1 cordycepin phosphate ester Chemical class 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 14
- 241000700605 Viruses Species 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 8
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- ZJEHRMYJNACSLL-UHFFFAOYSA-N 1-[butoxy(chloro)phosphoryl]oxybutane Chemical compound CCCCOP(Cl)(=O)OCCCC ZJEHRMYJNACSLL-UHFFFAOYSA-N 0.000 claims description 6
- 239000002207 metabolite Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- BTJUVGVQUQYMKY-UHFFFAOYSA-N 1-[chloro(pentoxy)phosphoryl]oxypentane Chemical compound CCCCCOP(Cl)(=O)OCCCCC BTJUVGVQUQYMKY-UHFFFAOYSA-N 0.000 claims description 5
- WREDNUONGSTUAU-UHFFFAOYSA-N 1-[chloro(3-methylbutoxy)phosphoryl]oxy-3-methylbutane Chemical compound CC(C)CCOP(Cl)(=O)OCCC(C)C WREDNUONGSTUAU-UHFFFAOYSA-N 0.000 claims description 4
- MGWMBNBSQQGLAW-UHFFFAOYSA-N 1-[chloro(propoxy)phosphoryl]oxypropane Chemical compound CCCOP(Cl)(=O)OCCC MGWMBNBSQQGLAW-UHFFFAOYSA-N 0.000 claims description 4
- DAGAQTLMZAEUKX-UHFFFAOYSA-N 3-bromo-1h-pyrrolo[2,3-c]pyridine Chemical compound N1=CC=C2C(Br)=CNC2=C1 DAGAQTLMZAEUKX-UHFFFAOYSA-N 0.000 claims description 4
- NGFFLHMFSINFGB-UHFFFAOYSA-N [chloro(methoxy)phosphoryl]oxymethane Chemical compound COP(Cl)(=O)OC NGFFLHMFSINFGB-UHFFFAOYSA-N 0.000 claims description 4
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical class OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 12
- 210000000170 cell membrane Anatomy 0.000 abstract description 3
- 230000004060 metabolic process Effects 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 230000001309 inhibitory effect on influenza Effects 0.000 abstract description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 17
- 150000001875 compounds Chemical class 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 13
- 239000002777 nucleoside Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 150000003833 nucleoside derivatives Chemical class 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 230000000840 anti-viral effect Effects 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 230000003612 virological effect Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000003760 magnetic stirring Methods 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 101000600434 Homo sapiens Putative uncharacterized protein encoded by MIR7-3HG Proteins 0.000 description 3
- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003753 real-time PCR Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 239000011543 agarose gel Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 229940127073 nucleoside analogue Drugs 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- NWTUPGIBLHOQQV-UHFFFAOYSA-N bis(3-methylbutyl) hydrogen phosphite Chemical compound CC(C)CCOP(O)OCCC(C)C NWTUPGIBLHOQQV-UHFFFAOYSA-N 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- BVXOPEOQUQWRHQ-UHFFFAOYSA-N dibutyl phosphite Chemical compound CCCCOP([O-])OCCCC BVXOPEOQUQWRHQ-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 description 1
- MGJHACFZFDVYIL-UHFFFAOYSA-N dipentyl hydrogen phosphite Chemical compound CCCCCOP(O)OCCCCC MGJHACFZFDVYIL-UHFFFAOYSA-N 0.000 description 1
- NFORZJQPTUSMRL-UHFFFAOYSA-N dipropan-2-yl hydrogen phosphite Chemical compound CC(C)OP(O)OC(C)C NFORZJQPTUSMRL-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- CHJUOCDSZWMLRU-UHFFFAOYSA-N oxo(dipropoxy)phosphanium Chemical compound CCCO[P+](=O)OCCC CHJUOCDSZWMLRU-UHFFFAOYSA-N 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000013379 physicochemical characterization Methods 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XTTGYFREQJCEML-UHFFFAOYSA-N tributyl phosphite Chemical compound CCCCOP(OCCCC)OCCCC XTTGYFREQJCEML-UHFFFAOYSA-N 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
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
-
- 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
-
- 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
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
- A61P31/20—Antivirals for DNA viruses
-
- 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
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Pulmonology (AREA)
- Genetics & Genomics (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses cordycepin phosphate and a preparation method and application thereof. Compared with the parent drug, the lipophilic anticancer drug has better lipophilicity, better affinity to cell membranes, longer time of remaining in the body and longer half-life of the drug in the metabolism in the body. Cordycepin phosphate has good inhibitory effect on influenza A virus, human immunodeficiency virus and hepatitis B virus.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to cordycepin phosphate, a preparation method thereof and application thereof in preparing antiviral products.
Background
Viruses are pathogens that are seriously harmful to human health, and it is statistically estimated that about 60% of infectious diseases are caused by viral infections. In recent years, the worldwide epidemic spread of Human Immunodeficiency Virus (HIV), severe acute respiratory syndrome SARS virus, novel coronavirus pneumonia (COV), avian influenza virus, Hepatitis B Virus (HBV) and the like has attracted unprecedented attention to viral diseases by people all over the world. Viral diseases are highly infectious and are easy to cause other diseases such as tumors and the like, so that the development of effective viral disease treatment is very important, and the great significance in the vigorous development of safe and effective antiviral drugs is achieved.
Nucleoside analogs have high antiviral activity and are useful as inhibitors of nucleic acid metabolism to interfere with viral propagation. The first representative nucleoside antibiotics, cordycepin (3' -deoxyadenosine), which was isolated in 1950, were the first nucleoside antibiotics, which have antibacterial activity and also have anti-RNA virus activity. Because the lipid solubility of the nucleoside analogue is poor, the nucleoside analogue is difficult to absorb, is easy to be metabolized and inactivated by deaminase, has short half-life period, has larger toxicity to normal cells, and is easy to generate drug resistance and the like by some tumor cells or viruses, the use effect of the nucleoside medicament is greatly reduced. One way to overcome these drawbacks is to attach the drug to a non-toxic carrier molecule to protect the drug from degradation and transport to the target cell, and then release the drug by enzymatic or chemical action to exert its pharmacological effect. The method utilizes lipophilic fatty acid ester, amide or phosphate of the nucleoside drugs as a molecular reservoir of parent drugs.
The nucleoside phosphate ester compounds all show certain antiviral activity, and have the following characteristics: 1. has better lipophilicity than nucleoside parent drug, and can play a therapeutic role through biological barrier; 2. the nucleoside is protected from metabolic inactivation and difficult hydrolysis, and the active parent drug is released in cells under the action of enzyme, so that the activity is high and the toxicity is low; 3. the production of a truly cellular active ingredient without the action of a kinase is an essential precursor of nucleoside triphosphates; 4. the protein has higher affinity to cell membranes, and most of the protein is absorbed by macrophages, thereby being beneficial to the virus treatment of the cells; 5. has larger tissue retention than free nucleoside, longer time of remaining in cells than nucleoside, and lasting effect; 6. can spontaneously aggregate to form a helical strand similar to DNA in an aqueous medium, and further form a super structure similar to the DNA. Thus, such compounds also have broader biological properties and, for their use as pharmaceuticals, can be administered not only orally, but also as injectables. Therefore, the invention provides cordycepin phosphate, a preparation method thereof and application of the cordycepin phosphate in preparation of antiviral products.
Disclosure of Invention
The invention aims to: the invention aims to solve the technical problem of the prior art and provides cordycepin phosphate.
The invention also aims to solve the technical problem of providing a composition containing cordycepin phosphate.
The invention also aims to solve the technical problem of providing a preparation method of the cordycepin phosphate.
The invention finally aims to solve the technical problem of providing the application of the cordycepin phosphate and the composition.
In order to solve the first technical problem, the invention discloses cordycepin phosphate shown as a formula I, or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug or metabolite thereof;
wherein R is selected from alkyl, preferably C1-C5 alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or isopentyl, and even more preferably any one of the structures represented by formula 1-formula 7.
In order to solve the second technical problem, the present invention discloses a composition, wherein the active ingredient of the composition comprises the cordycepin phosphate, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug, or metabolite thereof.
In order to solve the third technical problem, the invention discloses a preparation method of the cordycepin phosphate, which is prepared by reacting cordycepin, a chlorophosphate compound and amine in an organic solvent; preferably, the cordycepin and the phosphorochloridite compound are dissolved in an organic solvent and then added with amine for reaction to prepare the cordycepin and the phosphorochloridite compound.
Wherein the organic solvent includes, but is not limited to, pyridine.
Wherein, the chlorophosphate compounds include but are not limited to dimethyl chlorophosphate, diethyl chlorophosphate, di-n-propyl chlorophosphate, diisopropyl chlorophosphate, dibutyl chlorophosphate, diamyl chlorophosphate, and diisoamyl chlorophosphate; the chlorophosphate compound can be prepared according to the prior art, can be sold in the market, and can be prepared according to the following method: dissolving tert-butyl hypochlorite in dichloromethane at room temperature, stirring continuously, slowly adding phosphite ester compound, reacting for 2 hours in a dark place, removing solvent under reduced pressure, adding toluene, and vacuum evaporating to obtain corresponding chlorophosphate ester compound; the phosphite ester compound is dimethyl phosphite, diethyl phosphite, di-n-propyl phosphite, diisopropyl phosphite, dibutyl phosphite, dipentyl phosphite and diisoamyl phosphite.
Wherein the amine includes, but is not limited to, triethylamine.
Wherein the molar ratio of the cordycepin to the chlorophosphate compound to the amine is 6 (25-35): 40-50, preferably 6 (28-32): 48-52, and more preferably 6:30.6: 45.9.
Wherein the concentration of the cordycepin is 20-100 mmol/L, preferably 40-80 mmol/L, and more preferably 60 mmol/L.
Wherein the reaction temperature is 70-85 ℃.
Wherein, after the reaction is finished, saturated ammonium chloride is used for stopping the reaction, ethyl acetate is used for extraction, brine is used for washing, anhydrous magnesium sulfate is used for drying, and the cordycepin acid ester is obtained by a chromatographic column.
In order to solve the fourth technical problem, the invention discloses the application of the cordycepin phosphate, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, prodrugs or metabolites thereof, or the composition in preparing medicaments for preventing and treating diseases.
Wherein the virus is any one of influenza A virus, Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV).
The term "control" in the present invention means that a compound or formulation described herein is administered to prevent, ameliorate or eliminate a virus or one or more symptoms associated with the virus and includes:
i. inhibiting a virus or viral state, i.e., arresting its development;
alleviating the viral or disease-toxic state, i.e., causing regression of the disease or disease state.
The term "prevention" in the present invention means that a compound or formulation described herein is administered to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the disease or condition from occurring in a mammal, particularly when such mammal is susceptible to the viral condition, but has not been diagnosed as having been infected with the viral condition.
The term "pharmaceutically acceptable" in the context of this invention is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Has the advantages that: compared with the prior art, the invention has the following advantages:
the cordycepin phosphate provided by the invention can inhibit the replication of viruses and has a certain antiviral proliferation effect. Compared with the parent drug, the lipophilic anticancer drug has better lipophilicity, better affinity to cell membranes, longer time of remaining in the body and longer half-life of the drug in the metabolism in the body. Cordycepin phosphate has good inhibitory effect on influenza A virus, human immunodeficiency virus and hepatitis B virus.
Detailed Description
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
Dibutyl chlorophosphate prepared in the following examples according to this method, tributyl phosphite 0.05mol, 3% 1, 3-dimethyl imidazolidinone dissolved in 15mL of dichloromethane, triphosgene 0.017mol (dissolved in 5mL of dichloromethane) slowly added dropwise at 5 deg.C, when completely mixed, stirred at 30-35 deg.C for 2 hours, then the solvent was removed by rotary evaporation, and vacuum evaporation was performed to obtain dibutyl chlorophosphate. The diamyl chlorophosphate is also prepared by a similar method.
Example 1: preparation of cordycepin phosphate formula 1
Accurately weighing 100mL of pyridine, 6mmol of cordycepin, 45.9mmol of triethylamine and 30.6mmol of dimethyl chlorophosphate, putting the weighed pyridine, cordycepin and dimethyl chlorophosphate into a three-neck flask, putting the triethylamine into a constant-pressure dropping funnel, starting to slowly drop (after dropping for 10 min), reacting for 24h at 80 ℃ under magnetic stirring, stopping the reaction by using saturated ammonium chloride, extracting by using ethyl acetate, washing an organic phase by using brine, drying the organic phase by using anhydrous magnesium sulfate, and passing through a chromatographic column (methanol: dichloromethane ═ 2: 9) to obtain 1.745g of the compound of the formula 1, wherein the yield is 81%.
Example 2: preparation of cordycepin phosphate formula 2
Accurately weighing 100mL of pyridine, 6mmol of cordycepin, 45.9mmol of triethylamine and 30.6mmol of diethyl chlorophosphate, putting the weighed pyridine, cordycepin and diethyl chlorophosphate into a three-neck flask, putting the triethylamine into a constant-pressure dropping funnel, starting to slowly drop (after dropping for 10 min), reacting for 23h at 75 ℃ under magnetic stirring, stopping the reaction by using saturated ammonium chloride, extracting by using ethyl acetate, washing an organic phase by using brine, drying the organic phase by using anhydrous magnesium sulfate, and passing through a chromatographic column (methanol: dichloromethane ═ 3: 9) to obtain 1.812g of the compound of the formula 2, wherein the yield is 78%.
Example 3: preparation of cordycepin phosphate formula 3
Accurately weighing 100mL of pyridine, 6mmol of cordycepin, 45.9mmol of triethylamine and 30.6mmol of di-n-propyl chlorophosphate, putting the weighed pyridine, cordycepin and di-n-propyl chlorophosphate into a three-neck flask, putting triethylamine into a constant-pressure dropping funnel, starting to slowly drop the triethylamine (after dropping the triethylamine for 10 min), reacting for 24h at 85 ℃ under magnetic stirring, stopping the reaction by saturated ammonium chloride, extracting by ethyl acetate, washing the organic phase by using brine, drying the organic phase by using anhydrous magnesium sulfate, and passing the organic phase through a chromatographic column (methanol: dichloromethane ═ 1: 4) to obtain 1.993g of the compound of the formula 3, wherein the yield is 80%.
Example 4: preparation of cordycepin phosphate formula 4
Accurately weighing 100mL of pyridine, 6mmol of cordycepin, 45.9mmol of triethylamine and 30.6mmol of diisopropyl chlorophosphate, putting the weighed pyridine, cordycepin and diisopropyl chlorophosphate into a three-neck flask, putting triethylamine into a constant-pressure dropping funnel, starting to slowly drop the triethylamine (after dropping the triethylamine for 10 min), reacting for 25h at 70 ℃ under magnetic stirring, stopping the reaction by saturated ammonium chloride, extracting by ethyl acetate, washing an organic phase by using brine, drying by using anhydrous magnesium sulfate, and passing through a chromatographic column (methanol: dichloromethane ═ 1: 4) to obtain 1.868g of the compound of the formula 4, wherein the yield is 75%.
Example 5: preparation of cordycepin phosphate formula 5
Accurately weighing 100mL of pyridine, 6mmol of cordycepin, 45.9mmol of triethylamine and 30.6mmol of dibutyl chlorophosphate, putting the weighed pyridine, cordycepin and dibutyl chlorophosphate into a three-neck flask, putting the triethylamine into a constant-pressure dropping funnel, starting to slowly drop the triethylamine (after dropping the triethylamine for 10 min), reacting for 30h at 70 ℃ under magnetic stirring, stopping the reaction by using saturated ammonium chloride, extracting by using ethyl acetate, washing an organic phase by using brine, drying the organic phase by using anhydrous magnesium sulfate, and passing through a chromatographic column (methanol: dichloromethane ═ 2: 9) to obtain 1.915g of the compound shown in the formula 5, wherein the yield is 72%.
Example 6: preparation of cordycepin phosphate formula 6
Accurately weighing 100mL of pyridine, 6mmol of cordycepin, 45.9mmol of triethylamine and 30.6mmol of dipentyl chlorophosphate, putting the weighed pyridine, cordycepin and dipentyl chlorophosphate into a three-neck flask, putting triethylamine into a constant-pressure dropping funnel, starting to slowly drop the triethylamine (after the dropping of the triethylamine for 10 min), reacting for 25h at 80 ℃ under magnetic stirring, stopping the reaction by saturated ammonium chloride, extracting by ethyl acetate, washing an organic phase by using brine, drying by using anhydrous magnesium sulfate, and passing through a chromatographic column (methanol: dichloromethane ═ 1: 5) to obtain 2.121g of the compound shown in the formula 6, wherein the yield is 75%.
Example 7: preparation of cordycepin phosphate formula 7
Accurately weighing 100mL of pyridine, 6mmol of cordycepin, 45.9mmol of triethylamine and 30.6mmol of diisoamyl chlorophosphate, putting the weighed pyridine, cordycepin and diisoamyl chlorophosphate into a three-neck flask, putting the triethylamine into a constant-pressure dropping funnel, starting to slowly drop the triethylamine (the dropping is finished for 10 min), reacting for 25h at 80 ℃ under magnetic stirring, stopping the reaction by using saturated ammonium chloride, extracting by using ethyl acetate, washing an organic phase by using brine, drying the organic phase by using anhydrous magnesium sulfate, and then passing through a chromatographic column (methanol: dichloromethane ═ 1: 5) to obtain 2.205g of the compound of the formula 7, wherein the yield is 78%.
The physicochemical characterization data of the compounds represented by formulas 1 to 7 are shown in Table 1,1HNMR、13the CNMR and high resolution mass spectral data are shown in table 1.
Process for producing compounds represented by formulas 1 to 7 in Table 11HNMR、13CNMR and high resolution mass spectral data
Example 8: inhibitory effect of cordycepin phosphate on influenza A virus
(1) Adding medicine and infecting: MDCK cells were prepared in a 5X 10 format4Each well was plated on a 24-well plate, a vitramin-containing MEM medium (200. mu.L/well) was added thereto, the mixture was cultured at 37 ℃ for 12 hours, thereafter, cordycepin phosphate esters represented by formulas 1 to 7 (10. mu.g/mL, 100. mu.g/mL, 1mg/mL, and 10mg/mL) were added thereto at different concentrations, influenza A virus with an MOI of 0.1 was infected to each well, the solution was changed after 4 hours of infection, and the supernatant was collected after 24 hours.
(2) Determination of Plaque-Forming Unit (PFU): preparing a MDCK cell 12-hole culture plate with the cell fusion degree of more than or equal to 95%, discarding cell culture solution, washing for 2 times by PBS (phosphate buffer solution), diluting the collected supernatant to the required dilution degree in a gradient manner by 10 times, inoculating 500 mu L of supernatant dilution solution into each cell hole, and incubating for 1 hour at 37 ℃. Preheating 2 XMEM culture medium at 37 deg.C, preparing 2% low melting point agarose gel, dissolving completely, and placing in 50 deg.C water bath to prevent coagulation. After 1 hour, the virus supernatant was discarded, washed 2 times with PBS, and mixed 1:1 in 2% low-melting agarose gel and 2 XMEM mediumTPCK pancreatin with a final concentration of 2. mu.g/mL, 0.2% Bovine Serum Albumin (BSA) and 100U/mL penicillin-streptomycin were combined and mixed well. 1mL of agarose MEM medium was added to each well, and after complete coagulation, the cells were inverted and placed in CO at 37 deg.C2And (5) observing and counting the plaques after 48 hours in an incubator. Index of antiviral Activity IC50Calculated according to the curve of the inhibition rate and the concentration.
Example 9: test of anti-HIV-1 Activity of Cordycepin phosphate Compounds
Methods for testing anti-HIV-1 activity references (Antimicrob. AgentsChemother.,1992,36,2423) were performed in PBM lymphocytes. The cordycepin phosphate prodrug is prepared into a DMSO (20-40mM) solution, and then diluted into a series of different concentrations to react with HIV-1LAIVirus-infected PBM cells were co-cultured. HIV-1LAIThe MOI of the number ratio of virus to PBM cells is 0.01, the DMSO solvent has no influence on virus propagation, the AZT is used as a reference, and the antiviral activity index EC is used as an index50Calculated from inhibition-concentration curves (adv. enzymeregul.,1984,22, 27).
Example 10: test of anti-HBV activity of Cordycepin phosphate ester Compound
Huh7 cells were transfected with plasmid pCI _ HBVpg1820, cordycepin phosphate represented by formulas 1 to 7 was diluted 1000-fold (5 μ g/mL) with DMSO, stored at-20 ℃, and further diluted to a final concentration of 10 μ M in DMEM cell culture medium. After 4 days of culture at 37 ℃, double real-time fluorescent quantitative PCR was used to quantify the viral DNA within the capsid. Cells were quantified by real-time PCR using primers. In Huh7 cells, cells were seeded at a rate of 50,000 cells/well in collagen-coated 96-well plates. Test compounds were added to Huh7 cells to a final concentration of 10 μ M.
Real-time PCR amplification of HBV DNA was performed with LightCycler480, and the experiment was continued for 7 days. On day 7, total DNA was purified from the supernatant. Inhibition of HBV DNA replication by 50% (IC) as determined by linear regression50) The concentration of the compound (c).
TABLE 2 inhibitory Effect of cordycepin phosphate on influenza A Virus, HIV-1 and HBV, respectively (IC)50)
The invention provides a cordycepin phosphate, a preparation method thereof, and a thought and a method for application in preparation of antiviral products, and a method and a way for realizing the technical scheme are many, the above description is only a preferred embodiment of the invention, and it should be noted that for those skilled in the art, without departing from the principle of the invention, a plurality of improvements and embellishments can be made, and should be regarded as the protection scope of the invention. All the components not specified in the present embodiment can be realized by the prior art.
Claims (10)
1. Cordycepin phosphate shown as formula I, or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug, or metabolite thereof;
wherein R is selected from alkyl; preferably, R is selected from C1-C5 alkyl; preferably, R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl or isopentyl.
2. The cordycepin phosphate ester according to claim 1, wherein the cordycepin phosphate ester is any one of structures represented by formula 1 to formula 7;
3. a composition, characterized in that its active ingredient comprises the cordycepin phosphate of claim 1 or claim 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug thereof, or metabolite thereof.
4. The method for preparing cordycepin phosphate according to claim 1 or 2, wherein the cordycepin phosphate is prepared by reacting cordycepin, a chlorophosphate compound and amine in an organic solvent.
5. The preparation method according to claim 4, wherein the phosphorochloridite compound is any one or a combination of dimethyl chlorophosphate, diethyl chlorophosphate, di-n-propyl chlorophosphate, diisopropyl chlorophosphate, dibutyl chlorophosphate, diamyl chlorophosphate and diisoamyl chlorophosphate.
6. The preparation method according to claim 4, wherein the molar ratio of the cordycepin to the phosphorochloridates is 6 (25-35); preferably, the molar ratio of the cordycepin to the chlorophosphate compound is 6 (28-32); preferably, the molar ratio of the cordycepin to the chlorophosphate compound is 6: 30.6.
7. The preparation method according to claim 4, wherein the molar ratio of the cordycepin to the amine is 6 (40-50); preferably, the molar ratio of the cordycepin to the amine is 6 (48-52); preferably, the molar ratio of cordycepin to amine is 6: 45.9.
8. The preparation method according to claim 4, wherein the concentration of cordycepin is 20-100 mmol/L; preferably, the concentration of the cordycepin is 40-80 mmol/L; preferably, the concentration of the cordycepin is 60 mmol/L.
9. The method according to claim 4, wherein the reaction temperature is 70 to 85 ℃.
10. The use of the cordycepin phosphate as defined in claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, prodrug, or metabolite thereof, or the composition as defined in claim 2, or the cordycepin phosphate prepared by the method as defined in any one of claims 6 to 8, for the preparation of a medicament for the prevention or treatment of diseases;
preferably, the virus is any one of influenza a virus, human immunodeficiency virus and hepatitis b virus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210357818.3A CN114773417B (en) | 2022-04-06 | 2022-04-06 | Cordycepin phosphate and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210357818.3A CN114773417B (en) | 2022-04-06 | 2022-04-06 | Cordycepin phosphate and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114773417A true CN114773417A (en) | 2022-07-22 |
| CN114773417B CN114773417B (en) | 2023-08-22 |
Family
ID=82426606
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210357818.3A Active CN114773417B (en) | 2022-04-06 | 2022-04-06 | Cordycepin phosphate and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114773417B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120108533A1 (en) * | 2007-02-27 | 2012-05-03 | Katholieke Universiteit Leuven, K.U.Leuven R&D | Novel phosphate modified nucleosides useful as substrates for polymerases and as antiviral agents |
| CN102659843A (en) * | 2012-04-24 | 2012-09-12 | 北京大学 | D, L-guanosine nucleoside analog monophosphate, and preparation method and application thereof |
| CN105408341A (en) * | 2013-06-26 | 2016-03-16 | 艾丽奥斯生物制药有限公司 | Substituted nucleosides, nucleotides and analogs thereof |
| CN108640959A (en) * | 2018-07-06 | 2018-10-12 | 成果 | Bis- dehydrogenation nucleoside compound of 3`- deoxidations -3`, 4`- and its application |
| CN110678473A (en) * | 2017-04-25 | 2020-01-10 | 大原药品工业株式会社 | 5' -dibenzyl monophosphate derivatives of nucleoside anticancer or antiviral drugs |
-
2022
- 2022-04-06 CN CN202210357818.3A patent/CN114773417B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120108533A1 (en) * | 2007-02-27 | 2012-05-03 | Katholieke Universiteit Leuven, K.U.Leuven R&D | Novel phosphate modified nucleosides useful as substrates for polymerases and as antiviral agents |
| CN102659843A (en) * | 2012-04-24 | 2012-09-12 | 北京大学 | D, L-guanosine nucleoside analog monophosphate, and preparation method and application thereof |
| CN105408341A (en) * | 2013-06-26 | 2016-03-16 | 艾丽奥斯生物制药有限公司 | Substituted nucleosides, nucleotides and analogs thereof |
| CN110678473A (en) * | 2017-04-25 | 2020-01-10 | 大原药品工业株式会社 | 5' -dibenzyl monophosphate derivatives of nucleoside anticancer or antiviral drugs |
| CN108640959A (en) * | 2018-07-06 | 2018-10-12 | 成果 | Bis- dehydrogenation nucleoside compound of 3`- deoxidations -3`, 4`- and its application |
Non-Patent Citations (3)
| Title |
|---|
| C MCGUIGAN 等: "Synthesis and biological evaluation of haloalkyphosphate triester derivatives of araA and araC", 《ANTIVIRAL CHEMISTRY CHEMOTHERAPY》, vol. 3, no. 2, pages 79 - 84 * |
| 葛晓斌等: "核苷类及5\' 位磷酸酯修饰药物的研究进展", 《大连大学学报》, vol. 39, no. 6, pages 28 - 34 * |
| 蒙卓明等: "6 -取代氨基-L-D4G/ddG -5\'- 单磷酸酯的合成与抗HIV活性研究", 《中国药物化学杂志》, vol. 25, no. 2, pages 93 - 99 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114773417B (en) | 2023-08-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP4141007A1 (en) | Antiviral application of nucleoside analog or combination formulation containing nucleoside analog | |
| JP5969471B2 (en) | Methods and compounds for treating Paramyxoviridae viral infections | |
| CA2969372C (en) | Phosphoramidates for the treatment of hepatitis b virus | |
| CA3139977A1 (en) | Peptidomimetics for the treatment of coronavirus and picornavirus infections | |
| JP2019069986A (en) | 2'-substituted carba-nucleoside analogs for antiviral treatment | |
| RU2664534C9 (en) | Tenofovir prodrug and pharmaceutical uses thereof | |
| KR20140091459A (en) | 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment | |
| CA3029315A1 (en) | Phosphoramidates for the treatment of hepatitis b virus | |
| US20230248754A1 (en) | Patentiflorin A Analogs as Antiviral Agents | |
| CN111410661A (en) | Cap-dependent endonuclease inhibitors and uses thereof | |
| JP2017502975A (en) | Uracil nucleotide analogues, methods for their production, and uses thereof | |
| US20190085013A1 (en) | Nucleotide and nucleoside therapeutic compositions and uses related thereto | |
| US20230062181A1 (en) | Alkyne containing nucleotide and nucleoside therapeutic compositions and uses related thereto | |
| WO2022081973A1 (en) | Phospholipid compounds and uses thereof | |
| CN113321694A (en) | N4-hydroxycytidine derivative and preparation method and application thereof | |
| US20100311681A1 (en) | Stable 6-methoxy-2',3'-dideoxyguanosine, method for preparing the same and pharmaceutical composition containing the same | |
| CN114773417B (en) | Cordycepin phosphate and preparation method and application thereof | |
| CN108129366B (en) | Antiviral compounds, methods of preparation and uses thereof | |
| CN112245424B (en) | Application of bisabolane sesquiterpene structural analogue in preparation of anti-coronavirus medicines | |
| RU2665037C2 (en) | Isopropyl n-[{[(1r)-2-(6-amino-9h-purin-9-il)-1-methyletoxy]methyl} (1,3-benzotiazol-6-il-oxy)phosphoryl]-l-alaninate fumarat as an antiviral drug - prodrug of tenofovir | |
| CN114805458B (en) | Fatty acid prodrug of nucleoside broad-spectrum antiviral drug, preparation method and application thereof | |
| JP2021515811A (en) | 3 ", 5" -dialcosibenzoyl-3'-amino-3'-deoxyadenosine-5'-triphosphate and its pharmaceutical uses | |
| KR20190137080A (en) | Cyclobutyl (S) -2-[[[((R) -2- (6-aminopurin-9-yl) -1-methyl-ethoxy] methyl-phenoxy-phosphoryl] amino] -propanoate and Its production process and application | |
| WO2023085242A1 (en) | Antiviral agent | |
| CN100357284C (en) | Compounds against influenza virus and their preparing process and application |
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 |