CN113735927A - Nucleotide analogue and preparation method and application thereof - Google Patents
Nucleotide analogue and preparation method and application thereof Download PDFInfo
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- CN113735927A CN113735927A CN202111212683.3A CN202111212683A CN113735927A CN 113735927 A CN113735927 A CN 113735927A CN 202111212683 A CN202111212683 A CN 202111212683A CN 113735927 A CN113735927 A CN 113735927A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 125000003729 nucleotide group Chemical group 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 241000700605 Viruses Species 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 15
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 14
- 241000711573 Coronaviridae Species 0.000 claims abstract description 11
- 241000712461 unidentified influenza virus Species 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
- -1 amino, methyl Chemical group 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 235000019253 formic acid Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 6
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 6
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 6
- 239000001099 ammonium carbonate Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical group [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 claims description 6
- 238000007280 thionation reaction Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 238000005805 hydroxylation reaction Methods 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- JBWYRBLDOOOJEU-UHFFFAOYSA-N 1-[chloro-(4-methoxyphenyl)-phenylmethyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 JBWYRBLDOOOJEU-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 238000007098 aminolysis reaction Methods 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- NXPHCVPFHOVZBC-UHFFFAOYSA-N hydroxylamine;sulfuric acid Chemical compound ON.OS(O)(=O)=O NXPHCVPFHOVZBC-UHFFFAOYSA-N 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- ZOCLAPYLSUCOGI-UHFFFAOYSA-M potassium hydrosulfide Chemical compound [SH-].[K+] ZOCLAPYLSUCOGI-UHFFFAOYSA-M 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 241001678559 COVID-19 virus Species 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- HTNPEHXGEKVIHG-QCNRFFRDSA-N molnupiravir Chemical compound C(OC(=O)C(C)C)[C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C(=O)N=C(NO)C=C1 HTNPEHXGEKVIHG-QCNRFFRDSA-N 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 10
- XCUAIINAJCDIPM-XVFCMESISA-N N(4)-hydroxycytidine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=NO)C=C1 XCUAIINAJCDIPM-XVFCMESISA-N 0.000 abstract description 9
- 239000013641 positive control Substances 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 32
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
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- 239000007758 minimum essential medium Substances 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
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- 241000699670 Mus sp. Species 0.000 description 6
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- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
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- 230000004199 lung function Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 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
- 239000002773 nucleotide Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
Classifications
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- 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
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- 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
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- 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
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a compound with a structure shown in a formula (I), a preparation method and application thereof, wherein R is1Is H, halogen, or straight or branched C1‑C6An alkyl group; r2Is H,
Wherein R is3、R4Independently selected from linear or branched C1‑C6Alkyl radical, R5Is H, halogen, amino, or straight or branched C1‑C6An alkyl group. The nucleotide analogue with the structure shown in the formula (I) has better antiviral activity, and particularly has better antiviral effect on the currently circulating novel coronavirus and influenza virus. Compared with positive control drugs EIDD-1931 or EIDD-2801, the compound provided by the invention has significantly improved antiviral activity. It is worth mentioning that there is little relationship between these viruses, which also indicates that the compounds of the present invention have broad spectrum antiviral activity.
Description
Technical Field
The present invention relates to the field of medicine. In particular to a nucleotide analogue and a preparation method and application thereof.
Background
By the end of 2019, the sudden new crown pneumonia (COVID-19) epidemic situation brings unprecedented threat and challenge to the life health of human beings. According to the statistical data of the world health organization, as long as 10 months and 15 days in 2021, the total number of confirmed cases of new crown pneumonia exceeds 2.39 hundred million cases and the total number of death cases exceeds 487 ten thousand cases. However, no effective drug against the new coronavirus (SARS-CoV-2) has been found so far.
EIDD-2801 was originally discovered by the university of Emmeriy researchers in the United states and was later purchased by the company Ridgeback Biotherpeutics in the United states. The Sanshadong reaches an agreement with the Ridgeback, and the EIDD-2801 is cooperatively promoted to be researched and developed as a new crown specific medicine.
EIDD-2801 is a prodrug of EIDD-1931 (structure shown below) that acts by mimicking ribonucleotides, which are the main components of RNA molecules. During virus replication, molecules of these drugs can be incorporated into the viral RNA strand to replace the nucleotide base sequence of some original viruses that normally replicate, causing errors in the nucleic acid sequence of virus replication, and the accumulation of these fatal misarrangement of nucleic acids, i.e., mismutation, ultimately prevents virus replication, amplification and transmission.
EIDD-2801 inhibits the replication of a variety of RNA viruses, including SARS-CoV-2. In animal studies with two different coronaviruses (SARS-CoV-1 and MERS), EIDD-2801 was shown to improve lung function, reduce weight loss and reduce viral load in the lungs.
However, some potential drug candidates are either compromised in clinical trials or are awaiting the results of clinical trials. Therefore, experts call for the development of "broad-spectrum antiviral drugs" in the pharmaceutical industry to cope with outbreaks of coronavirus epidemics.
Therefore, there is currently a need for drugs with better antiviral activity, in particular drugs with better activity against the new coronaviruses.
Disclosure of Invention
Accordingly, it is an object of the present invention to provide a nucleotide analog having a superior antiviral activity, particularly, a superior activity against the novel coronavirus (SARS-CoV-2).
Another objective of the invention is to provide a preparation method of the nucleotide analogue.
It is still another object of the present invention to provide a pharmaceutical composition comprising the nucleotide analog of the present invention.
It is a further object of the present invention to provide a use of the nucleotide analog of the present invention.
The purpose of the invention is realized by the following technical scheme:
in one aspect, the present invention provides a compound having the structure shown in formula (I):
wherein R is1Is H, halogen, or straight or branched C1-C6An alkyl group;
R2is H,
Wherein R is3、R4Independently selected from linear or branched C1-C6Alkyl radical, R5Is H, halogen, amino, or straight or branched C1-C6An alkyl group.
Preferably, in the compound of formula (I), R1H, F, Cl, Br, I, methyl, ethyl, propyl or isopropyl; r3、R4Independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, and neopentyl; r5Represents one or more substituents on the phenyl ring independently selected from H, F, Cl, Br, I, amino, methyl, ethyl, propyl and isopropyl.
Preferably, it is represented by the formula (I)In the compound of the structure (I), R1H, F, methyl; r2Is H,
Preferably, in the compound of formula (I), R2Is composed of
Preferably, the compound of the structure represented by formula (I) is selected from the following compounds:
in another aspect, the present invention provides a process for preparing a compound of the structure of formula (I) according to the present invention,
wherein when R is2Is composed of
The method comprises the following steps:
(a) reacting a compound of formula (1) with a compound of formula (2) to produce a compound of formula (3);
(b) subjecting the compound of formula (3) to a thionation reaction to produce a compound of formula (4);
(c) carrying out N-hydroxylation reaction on the compound of the formula (4) to generate a compound of a formula (5), namely the compound shown in the formula (I);
when R is2Is composed of
The method comprises the following steps:
(a') reacting the compound of formula (6) with a first hydroxy protecting reagent to produce a compound of formula (7);
(b') subjecting the compound of formula (7) to a thionation reaction to produce a compound of formula (8);
(c') N-hydroxylating the compound of formula (8) to produce a compound of formula (9);
(d') reacting the compound of formula (9) with a second hydroxy protecting reagent to produce a compound of formula (10);
(e') reacting the compound of formula (10) with the compound of formula (11) to produce a compound of formula (12);
(f') removing the hydroxyl protecting group from the compound of formula (12) to obtain a compound of formula (13), i.e., a compound represented by formula (I); or
When R is2When H, the method comprises the following steps:
(a') reacting a compound of formula (5) to produce a compound of formula (14), i.e. a compound of formula (I), preferably said compound of formula (5) is prepared by steps (a) to (c) above;
wherein R is1、R2、R3、R4And R5As defined above, R6And R7Is a hydroxyl protecting group.
Preferably, wherein said compound of formula (11) is prepared by a process comprising the steps of:
(i) reacting a compound of formula (15) with a compound of formula (16) and paranitrophenol in the presence of a base in sequence to produce a compound of formula (11); preferably, the base is triethylamine, diisopropylethylamine, trimethylamine or DBU or the like.
Preferably, in the method of the present invention:
the thionation reaction in steps (b) and (b') is carried out in the presence of a thionating agent and a base; preferably, the thioreagent is sodium hydrosulfide or potassium hydrosulfide, and the alkali is ammonium bicarbonate or sodium bicarbonate;
the N-hydroxylation reaction in steps (c) and (c') is carried out in the presence of hydroxylamine sulphate;
the first hydroxyl protecting reagent in the step (a') is acetone, butanone or pentanone and the like; the second hydroxy protecting agent in the step (d') is DMT-Cl, chlorotrityl or chlorodi (p-nitrophenyl) methyl;
said step (f ') is carried out under acidic conditions, preferably said step (f') is carried out in the presence of formic acid or acetic acid; and/or
Said step (a') is an aminolysis reaction of the compound of formula (5) in the presence of ammonia to produce the compound of formula (14).
In another aspect, the invention provides a pharmaceutical composition, which contains the compound with the structure shown in formula (I) and pharmaceutically acceptable auxiliary materials.
In a further aspect, the invention provides the use of a compound of formula (I) according to the invention or a pharmaceutical composition according to the invention in the manufacture of a medicament for use in the antiviral treatment of a disease; preferably, the virus is a coronavirus or an influenza virus; more preferably, the coronavirus is SARS-CoV-2.
The nucleotide analogue with the structure shown in the formula (I) has better antiviral activity, and particularly has better antiviral effect on the currently circulating novel coronavirus and influenza virus. Compared with positive control drugs EIDD-1931 or EIDD-2801, the compound provided by the invention has significantly improved antiviral activity. It is worth mentioning that there is little relationship between these viruses, which also indicates that the compounds of the present invention have broad spectrum antiviral activity. The preparation method has the advantages of high yield, short route and high product purity, and is suitable for industrial large-scale production.
Detailed Description
The present invention will be explained in detail below with reference to specific examples so that those skilled in the art can more fully understand the present invention, and the specific examples are only for illustrating the technical solutions of the present invention and do not limit the present invention in any way.
Example 1Synthesis of Compound A
Step 1:
y-1(4g) was added to DMPU (8mL), 4M dioxane hydrochloride solution (6.5mL) was added, and after stirring at 20 ℃ for 15 minutes, isobutyryl chloride (2mL) was added thereto at 0 ℃ and the reaction was carried out at room temperature for 16 hours.
MTBE was added thereto and stirred at 0 ℃ for 15 minutes, and the clear solution was discarded. 40mL of methanol was added to the viscous oily liquid, and the pH was adjusted to 9-10 with stirring using a sodium methoxide solution. Spin-dry column chromatography to obtain white solid Y-24.1 g, yield 77%. MS (m/z): 314.2(M + H)+。
Step 2:
y-2(1.6g), ammonium bicarbonate (2g) and sodium hydrosulfide (1.4g) were added to 20mL of DMF under a nitrogen atmosphere, and reacted at room temperature for 16 hours. Oil pump spin-drying, column chromatography to obtain 1g yellow solid Y-3 with 61% yield. MS (m/z): 330.1(M + H)+。
And step 3:
y-31 g and hydroxylamine sulfate 2g were added to 15mL of isopropanol and reacted under reflux for 20 hours. After spin-drying, column chromatography was carried out to obtain 0.9g of compound A, with a yield of 86.7%. MS (m/z): 330.1(M + H)+。1H-NMR(400MHz，D2O)δ8.35(d，1H)，6.97(d，1H)，6.79(d，1H)，4.49-4.33(m，3H)，4.28(dd，2H)，2.79(m，1H)，1.19(d，3H)，1.18(d，3H)。
Example 2Synthesis of Compound B
Step 1:
y-4(4g) was added to DMPU (8mL), 4M dioxane hydrochloride solution (6mL) was added, the mixture was stirred at 20 ℃ for 15 minutes, cooled to 0 ℃ and isobutyryl chloride (2mL) was added and reacted at room temperature for 16 hours.
MTBE was added thereto and stirred at 0 ℃ for 15 minutes, and the clear solution was discarded. 40mL of methanol was added to the viscous oily liquid, and the pH was adjusted to 9-10 with stirring using a sodium methoxide solution. The white solid Y-54.3 g is obtained by spin-dry column chromatography, and the yield is 82%. MS (m/z): 328.2(M + H)+。
Step 2:
y-5(1.65g), ammonium bicarbonate (2g) and sodium hydrosulfide (1.4g) were added to 20mL of DMF under a nitrogen atmosphere, and reacted at room temperature for 16 hours. Oil pump spin-drying, column chromatography to obtain 1.1g yellow solid Y-6 with yield 64%. MS (m/z): 344.1(M + H)+。
And step 3:
y-61.1 g and hydroxylamine sulfate 2g were added to 15mL of isopropyl alcohol and reacted under reflux for 20 hours. After spin-drying, column chromatography was carried out to obtain 0.8g of compound B, yield 69%. MS (m/z): 360.2(M + H)+。
1H-NMR(400MHz，D2O)δ8.25(s，1H)，6.99(d，1H)，4.19-3.85(m，3H)，3.75(dd，2H)，2.78(m，1H)，1.79(s，3H)，1.18(d，3H)，1.17(d，3H)。
Example 3Synthesis of Compound C
Step 1:
y-7(4g) was added to DMPU (8mL), 4M dioxane hydrochloride solution (6mL) was added, the mixture was stirred at 20 ℃ for 15 minutes, cooled to 0 ℃ and isobutyryl chloride (2mL) was added and reacted at room temperature for 16 hours.
MTBE was added thereto and stirred at 0 ℃ for 15 minutes, and the clear solution was discarded. 40mL of methanol was added to the viscous oily liquid, and the pH was adjusted to 9-10 with stirring using a sodium methoxide solution. Spin-drying column chromatography to obtain white solidY-84.2 g, yield 83%. MS (m/z): 332.2(M + H)+。
Step 2:
y-8(1.65g), ammonium bicarbonate (2g) and sodium hydrosulfide (1.4g) were added to 20mL of DMF under a nitrogen atmosphere, and reacted at room temperature for 16 hours. Oil pump spin-drying, column chromatography to obtain 1.2g yellow solid Y-9 with 69% yield. MS (m/z): 348.1(M + H)+。
And step 3:
y-91.2 g and hydroxylamine sulfate 2g were added to 15mL of isopropyl alcohol and reacted under reflux for 20 hours. After spin drying, column chromatography was carried out to obtain 0.9g of compound C, yield 72%. MS (m/z): 364.1(M + H)+。1H-NMR(400MHz，D2O)δ8.45(d，1H)，6.98(d，1H)，4.51-4.25(m，3H)，3.95(dd，2H)，2.80(m，1H)，1.20(d，3H)，1.18(d，3H)。
Example 4Synthesis of Compound D
Step 1:
y-1(10g) was added to acetone (180mL), 1.5g of concentrated sulfuric acid was added thereto, and the mixture was replaced with nitrogen three times and reacted at room temperature for 16 hours. Adding triethylamine to adjust the PH value to be neutral, spin-drying to obtain viscous oily liquid, and carrying out column chromatography to obtain 11g of white-like solid Y-10 with the yield of 91%. MS (M/z):284.2(M + H)+。
Step 2:
y-10(11g), ammonium bicarbonate (16g) and sodium hydrosulfide (11g) were added to 150mL of DMF under a nitrogen atmosphere, and reacted at room temperature for 16 hours. Oil pump spin-drying, column chromatography to obtain 7.5g yellow solid Y-11 with yield of 65%. MS (M/z):300.1(M + H)+。
And step 3:
y-11(4g) and hydroxylamine sulfate (6g) were added to 45mL of isopropanol and reacted at reflux for 20 hours. Spin-drying, and performing column chromatography to obtain Y-123.2 g with a yield of 76%. MS (M/z) 316.1(M + H)+。
And 4, step 4:
y-12(3.2g) was added to 50mL DCM, 2g triethylamine and 0.3gDMAP was added thereto, and the mixture was stirred at room temperature for 20 minutes. A solution of 3.4g DMT-Cl in DCM (10mL) was added dropwise from the dropping funnel and reacted at room temperature for 16 hours. Water was added to quench DCM for extraction, the solution was separated, dried over anhydrous sodium sulfate, spin dried, and column chromatographed to give 5.3g of Y-13 as a yellow solid in 85% yield. MS (M/z) 618.2(M + H)+。
And 5:
at 0 deg.C, Y-13(5.3g) was added to dichloromethane followed by DIPEA (2g), EDCI (2.1g), DMAP (0.3g) and Y-14(2.4g), slowly warmed to room temperature for 16 hours and quenched by TLC with water after showing no material. Separating, washing organic phase with 0.1N hydrochloric acid, washing with water, washing with sodium bicarbonate water solution, washing with brine, drying, spin-drying, and performing column chromatography to obtain 7g of yellow solid Y-15. The yield thereof was found to be 73%. MS (m/z): 817.3(M + H)+。
Step 6:
y-153 g was added to 15mL of methanol and 15mL of 80% formic acid, and reacted at room temperature for 16 hours. Adding water to quench sodium bicarbonate to adjust the pH value to be neutral, spin-drying, performing column chromatography to obtain a crude product, adding 30mL of ethyl acetate and 1mL of 4M hydrochloric acid methanol solution, stirring for 1 hour at room temperature, performing suction filtration, washing with a small amount of ethyl acetate, and drying to obtain a compound D0.7 g with the yield of 45%. MS (m/z): 375.2(M + H)+。
1H-NMR(400MHz，D2O)δ8.33(d，1H)，6.95(d，1H)，6.77(d，1H)，4.45-4.31(m，3H)，4.25(dd，2H)，3.94-3.95(m，1H)，2.25-2.34(m，1H)，0.92-0.98(m，6H)。
Example 5Synthesis of Compound E
Step 1:
60g Y-16 was suspended in 600ml DCM and 75g Y-17 was added. The temperature is reduced to-10 ℃, and 100mL of triethylamine is slowly dropped into the dropping funnel. After the reaction was completed for 30 minutes, 47.3g of nitrophenol was added, 47mL of triethylamine was added again, and after completion of the reaction at room temperature, the mixture was reacted until completion of the TLC detection reaction, and 750mL of MTBE was added. Filtering, washing filter cake MTBE, concentrating under reduced pressure, and purifying by column chromatography to obtain Y-20 with a ratio of 1: 1Enantiomeric mixture, yield 73%. MS (m/z): 409.1(M + H)+。
Step 2:
30g Y-20 was dissolved in 120mL of isopropyl ether. Then, n-hexane was added with stirring until the solution became cloudy. Adding seed crystal at room temperature, slowly stirring the suspension for 16 hours, cooling to 0 ℃, stirring for 2 hours, filtering and collecting solid as Y-20S crude product, and spin-drying mother liquor to obtain Y-20R crude product. The solid was recrystallized from isopropyl ether again to give 3.8g of diastereomer Y-20S at 99% yield 25%.
And step 3:
y-200.41 g and Y-130.62 g were added to 20ml of acetonitrile, and the mixture was stirred at room temperature for 15 min. Heating the reaction solution to 50 ℃, stirring for 10min, then dropwise adding 0.32g of DIPEA, reacting for 30min, detecting complete reaction by TLC, and cooling to room temperature. EA extraction, 5% citric acid washing, saturated ammonium chloride washing, 5% sodium carbonate washing, organic layer anhydrous sodium sulfate drying, filtration, spin drying, column chromatography purification to obtain Y-0210.66 g, yield 75%. MS (m/z): 887.3(M + H)+。
And 4, step 4:
y-0210.66 g was dissolved in 5ml of methanol and 5ml of 80% aqueous formic acid, and the mixture was reacted at room temperature for 16 hours. Adding water to quench sodium bicarbonate to adjust the pH value to be neutral, spin-drying and carrying out column chromatography to obtain a compound E0.25 g with the yield of 61%. MS (m/z): 545.2(M + H)+。
1H-NMR(400MHz，CD3OD)δ8.31(d，1H)，δ7.49-6.99(m，6H)，6.77(d，1H)，4.49-4.33(m，4H)，4.28(m，2H)，3.88(m，1H)，1.48-1.19(9H，m)。
Example 6Synthesis of Compound F
Step 1:
Y-20S 0.41g and Y-130.62 g were added to 20ml of acetonitrile, and the mixture was stirred at room temperature for 15 min. Heating the reaction solution to 50 ℃, stirring for 10min, then dropwise adding 0.32g of DIPEA, reacting for 30min, detecting complete reaction by TLC, and cooling to room temperature. The EA is extracted to obtain the extract,washing with 5% citric acid, saturated ammonium chloride, 5% sodium carbonate, drying with anhydrous sodium sulfate, filtering, spin-drying, and purifying by column chromatography to obtain Y-220.62 g with yield of 70%. MS (m/z): 887.3(M + H)+。
Step 2:
y-220.62 g was dissolved in 5ml of methanol and 5ml of 80% aqueous formic acid, and the mixture was reacted at room temperature for 16 hours. Adding water to quench sodium bicarbonate to adjust the pH value to be neutral, spin-drying and carrying out column chromatography to obtain a compound F0.22 g with the yield of 58%. MS (m/z): 545.2(M + H)+。
Example 7Synthesis of Compound G
Step 1:
74.6g Y-23 was suspended in 600ml DCM and 75g Y-17 was added. The temperature is reduced to-10 ℃, and 100mL of triethylamine is slowly dropped into the dropping funnel. After the reaction was completed for 30 minutes, 47.3g of nitrophenol was added, 47mL of triethylamine was added again, and after completion of the reaction at room temperature, the mixture was reacted until completion of the TLC detection reaction, and 750mL of MTBE was added. Filtration, washing of the filter cake MTBE, concentration under reduced pressure, column chromatography purification gave Y-24 as a mixture of diastereomers in a 1: 1 ratio in 75% yield. MS (m/z): 409.1(M + H)+。
Step 2:
30g Y-24 was dissolved in 120mL isopropyl ether. Then, n-hexane was added with stirring until the solution became cloudy. Adding seed crystal at room temperature, slowly stirring the suspension for 16 hours, cooling to 0 ℃, stirring for 2 hours, filtering and collecting solid as Y-24S crude product, and spin-drying mother liquor to obtain Y-24R crude product. The solid was recrystallized from isopropyl ether again to give 4.5g of diastereomer Y-24S at 99% yield 30%.
And step 3:
y-240.44 g and Y-130.62 g were added to 20ml of acetonitrile, and the mixture was stirred at room temperature for 15 min. Heating the reaction solution to 50 ℃, stirring for 10min, then dropwise adding 0.32g of DIPEA, reacting for 30min, detecting complete reaction by TLC, and cooling to room temperature. EA extraction, 5% citric acid washing, saturated ammonium chloride washing, 5%Washing with sodium carbonate, drying the organic layer with anhydrous sodium sulfate, filtering, spin-drying, and purifying by column chromatography to obtain Y-250.67 g with 73% yield. MS (m/z): 915.4(M + H)+。
And 4, step 4:
y-0250.67 g was dissolved in 5m1 methanol and 5ml of 80% aqueous formic acid, and the mixture was reacted at room temperature for 16 hours. Adding water to quench sodium bicarbonate to adjust the pH value to be neutral, spin-drying, and carrying out column chromatography to obtain a compound G with the yield of 60.25G. MS (m/z): 573.2(M + H)+。
1H-NMR(400MHz，CD3OD)δ8.30(d，1H)，δ7.51-6.99(m，6H)，6.79(d，1H)，4.52-4.31(m，4H)，4.25(m，2H)，3.86(m，1H)，1.51-1.29(m，7H)，0.94-0.87(t，6H)。
Example 8Synthesis of Compound H
Step 1:
Y-24S 0.44g and Y-130.62 g were added to 20ml of acetonitrile, and the mixture was stirred at room temperature for 15 min. Heating the reaction solution to 50 ℃, stirring for 10min, then dropwise adding 0.32g of DIPEA, reacting for 30min, detecting complete reaction by TLC, and cooling to room temperature. EA extraction, 5% citric acid washing, saturated ammonium chloride washing, 5% sodium carbonate washing, organic layer anhydrous sodium sulfate drying, filtration, spin drying, column chromatography purification to obtain Y-260.65 g, yield 71%. MS (m/z): 915.4(M + H)+。
Step 2:
y-260.65 g was dissolved in 5ml of methanol and 5ml of 80% aqueous formic acid, and the mixture was reacted at room temperature for 16 hours. Adding water to quench sodium bicarbonate to adjust the pH value to be neutral, spin-drying, and carrying out column chromatography to obtain a compound H0.26 g with the yield of 63%. MS (m/z): 573.2(M + H)+。
Example 9Synthesis of Compound I
The method comprises the following steps:
0.7g of Compound A was added to 10ml of a 7N methanol solution of ammonia, and reacted at 20 ℃ for 16 hours. The reaction was complete by TLC. Spin-drying, and purifying by column chromatography to obtain 0.47g of compound I with 85% yield. MS (m/z): 276.1(M + H)+。
1H-NMR(400MHz，D2O)δ8.32(d，1H)，6.88(d，1H)，6.70(d，1H)，4.31-4.23(m，2H)，4.05(m，1H)，3.94(m，1H)，3.81(m，1H)。
Example 10Synthesis of Compound J
The method comprises the following steps:
0.72g of Compound B was added to 10ml of a 7N methanol solution of ammonia, and reacted at 20 ℃ for 16 hours. The reaction was complete by TLC. Spin-drying, and purifying by column chromatography to obtain compound J0.47 g with 81% yield. MS (m/z): 289.1(M + H)+。
1H-NMR(400MHz，D2O)δ8.15(s，1H)，6.78(d，1H)，4.23-4.07(m，2H)，3.98(m，1H)，3.79(m，1H)，3.71(m，1H)，1.78(s，3H)。
Example 11Synthesis of Compound K
The method comprises the following steps:
0.73g of Compound C was added to 10ml of a 7N ammonia methanol solution, and reacted at 20 ℃ for 16 hours. The reaction was complete by TLC. Spin-drying, and purifying by column chromatography to obtain compound K0.49 g with 83% yield. MS (m/z): 294.1(M + H)+。
1H-NMR(400MHz，D2O)δ8.42(d，1H)，6.93(d，1H)，4.31-4.23(m，2H)，4.13(m，1H)，3.95(m，1H)，3.86(m，1H)。
Example 12: test for anti-influenza Virus Activity (CPE inhibitory Effect)
< materials >
1.2% FCS E-MEM (prepared by adding kanamycin and FCS to MEM (minimum essential medium)).
2.0.5% BSA E-MEM (in MEM (minimum essential medium) adding kanamycin and BSA to prepare).
HBSS (Hanks Balanced salt solution).
MDBK cells: the number of cells was adjusted to an appropriate number (3X 10) with 2% FCS E-MEM5/mL)。
MDCK cells: the cells were washed 2 times with HBSS and then adjusted to the appropriate number of cells (5X 10) with 0.5% BSA E-MEM5/mL)。
6. Trypsin solution: trypsin (SIGMA) from porcine pancreas was dissolved in PBS (-) and filtered through a 0.45 μm filter.
EnVision (microplate reader) (PerkinElmer).
WST-8 kit (Kishida chemical).
9.10% SDS solution.
< procedure flow >
1. Dilution and dispensing of test sample
2% FCS E-MEM was used for MDBK cells, and 0.5% BSA E-MEM was used for MDCK cells. The same culture medium was used for dilution of viruses, cells, and test samples.
The test sample was diluted in a culture medium to an appropriate concentration in advance, and a 2-to 5-fold serial dilution series (50. mu.L/well) was prepared in a 96-well plate. Two blocks for measuring influenza resistance and cytotoxicity were prepared. Triplicate assays were performed for each drug.
In the case of MDCK cells, trypsin was added to the cells to a final concentration of 3. mu.g/mL only for measurement of anti-influenza activity.
2. Dilution and dispensing of influenza Virus
Influenza virus culture medium was diluted to an appropriate concentration in advance, and each was dispensed into a 96-well plate to which test samples were added at 50. mu.L/well. The culture medium was dispensed at 50. mu.L/well into the plate for measuring cytotoxicity.
3. Dilution and dispensing of cells
Cells adjusted to an appropriate number of cells were dispensed into a 96-well plate containing a test sample at 100. mu.L/well.
Mixing with a plate mixer (plate mixer) in CO2Culturing in an incubator. The cells were cultured for 3 days for both influenza resistance and cytotoxicity.
Dispensing of WST-8
The 96-well plate cultured for 3 days was observed with the naked eye under a microscope to confirm the morphology of the cells, the presence or absence of crystals, and the like. The supernatant was removed from the plate without aspiration of the cells.
The WST-8 kit was diluted 10-fold with a culture medium, and the WST-8 solution was dispensed into each well at 100. mu.L each. Mixing with a perforated plate mixer, then in CO2Culturing for 1-3 hours in an incubator.
After the plate for measuring anti-influenza activity was cultured, 10. mu.L of 10% SDS solution was dispensed into each well, and the virus was inactivated.
5. Measurement of absorbance
For the mixed 96-well plate, absorbance was measured at 450nm/620nm of two wavelengths using EnVision.
< calculation of values of measurement items >
The calculation was performed using Microsoft Excel or a program having equivalent calculation processing capability based on the following calculation formula.
50% inhibitory concentration of influenza-infected cell death (EC)50) The calculation of (2):
EC50＝10^Z
Z＝(50％-High％)/(High％-Low％)×{log(Highconc.)-log(Lowconc.)}+log(Highconc.)
the measurement results of example 12 are shown in the following table 1:
TABLE 1
| Compound (I) | CPE EC50(nM) | CC50(nM) |
| EIDD-1931 | 1500 | Greater than 20000 |
| I | 50 | Greater than 20000 |
| J | 490 | Greater than 20000 |
| K | 90 | Greater than 20000 |
| A | 5000 | Greater than 20000 |
As can be seen from Table 1, the activity of both compounds I, J and K of the present invention was greatly improved compared to the positive control drug EIDD-1931. It can be seen that the substitution of the carbonyl oxygen atom on the pyrimidine ring by a sulfur atom unexpectedly significantly increases the activity of the compounds, while the compounds of the present invention all have lower cytotoxicity. In addition, compound a is a prodrug of compound I and therefore has poor in vitro activity.
Example 13: determination of anti-SARS-CoV-2 Activity
In 12-well disposable cell culture plates, confluent cell culture monolayers were prepared. Vero16 cells were maintained in DMEM supplemented with 10% FBSAnd supplemented with 1% penicillin/streptomycin. The apical surface of Vero16 cell cultures was washed 24 hours and 1 hour prior to infection with 1 XPBS and then infected with 1 XPBS for 1.5 hours at 37 ℃. Vero16 cells were infected at a multiplicity of infection of 0.1 pfu/cell using recombinant SARS-CoV-2 expressing green fluorescent protein (SARS-CoV-2 RFP). For Vero16 cells, the apical wash was removed, the viral inoculum was added, and the inoculated culture was incubated at 37 ℃ with 5% CO2Incubate for 3 hours. The inoculum was removed and the apical surface of the Vero16 cells was washed 3 times with 500. mu.L of 1 XPBS to remove residual virus. 3-fold serial dilutions of the example compounds were prepared in triplicate starting at 10uM and added to Vero16 cell culture medium on the outside of the culture substrate approximately 30 minutes prior to infection. Viral replication was assessed by fluorescence imaging of cell cultures after 48 hours incubation. In addition, viral replication was quantified by measuring the yield of infectious virus in Vero16 apical wash by plaque assay on Vero cell monolayers and quantifying the yield of viral RNA from total cellular RNA by real-time PCR assay.
The measurement results of example 13 are shown in the following table 2:
TABLE 2
| Compound (I) | CPE EC50(nM) | CC50(nM) |
| EIDD-1931 | 250 | Greater than 20000 |
| I | 8 | Greater than 20000 |
| J | 90 | Greater than 20000 |
| K | 15 | Greater than 20000 |
| A | 700 | Greater than 20000 |
All compounds tested had outstanding activity against SARS-CoV-2. Compared with a positive control medicament EIDD-1931, the compound disclosed by the invention has obviously improved anti-SARS-CoV-2 activity. In particular, the activity of the compound I against SARS-CoV-2 is more than 30 times that of EIDD-1931. In addition, compound a is a prodrug of compound I and therefore has poor in vitro activity.
Example 12Lethal inhibition test for influenza virus infected mice
< mice >
BALB/c 7 week old mice were used for the experiments.
< preparation of Virus solution >
A/WS/33, A/Victoria/3/75 or B/Maryland/1/59(ATCC) were passaged in mouse lungs to make mouse-domesticated viruses. The cryopreserved mouse-adapted virus solution was rapidly thawed and diluted with DPBS to form the infectious titer (infectious titer) used (A/WS/33: 800-50Mouse, B/Maryland/1/59: 100TCID50Mice).
< infection >
Under anesthesia with a mixture of ketamine and xylazine, 100. mu.l of the prepared virus solution was inoculated nasally to directly infect the lungs of mice.
< preparation of test sample >
Test samples were dissolved in PEG400 solution at appropriate concentrations.
< administration to infected mice >
For mice immediately after or after a certain period of time of infection with virus, 200. mu.L of the diluted test sample was orally administered.
< evaluation of drug efficacy >
After viral infection, the animals were kept for 14 days and the daily dose ED required for 50% lethal inhibition was calculated50(mg/kg/day) was compared with a control group to evaluate the virus-inhibitory effect.
Pulmonary titer test
CO2Animals were euthanized and lung tissue was harvested and snap frozen in 10 volumes (volume: lung weight: 10: 1, mL/g) of DPBS solution. Virus titre measurements in lung tissue (plaque experiments) and lung titre results were calculated using log10(pfu/g lung).
< results >
Table 3 shows ED for a single administration50The value is obtained.
TABLE 3
| Compound (I) | ED50(mg/kg/day) |
| EIDD-2801 | 18 |
| A | 5 |
| D | 30 |
| E | 1 |
| H | 3 |
| G | 6 |
As can be seen from the results in table 3, all tested compounds showed varying degrees of in vivo influenza virus inhibition, with half the effective doses of compounds A, E, H and G of the invention being significantly less than EIDD-2801, with a further significant reduction in the half effective doses of compounds E and H. The compound has higher in-vivo antiviral activity, better drug metabolism parameters and higher safety, and has the dosage less than EIDD-2801 in clinical application or longer drug application interval time and lower corresponding toxic and side effects. Compound E and H lung viral titers were <3.000(LLOD ═ 3.000) and 3.980, and EIDD-2801 lung viral titers were 5.520, determined at a dose level of 20 mg/kg/day for test compound titers. The results show that the compounds of the invention have very low pulmonary viral titers. In clinical application, the compound has better toxin expelling effect and high lung distribution.
In addition, compound A, D, E, H, G of the present invention is a prodrug of compound I of the present invention, but has a large difference in the activity of inhibiting influenza virus in vivo. In particular, compound D, while its prodrug (i.e., compound I) had significantly better anti-influenza virus activity than the prodrug of EIDD-2801 (i.e., EIDD-1931) when tested in vitro (as shown in table 1), compound D had significantly lower activity than EIDD-2801 when tested in vivo to inhibit influenza virus activity. It can be seen that the choice of prodrug modifying moiety structure is critical to the in vivo activity of the compounds, and that the significantly better antiviral effects achieved by compounds A, E, H and G of the present invention over EIDD-2801 are unexpected.
Claims (10)
1. A compound having the structure of formula (I):
wherein R is1Is H, halogen, or straight or branched C1-C6An alkyl group;
R2is H,
Wherein R is3、R4Independently selected from linear or branched C1-C6Alkyl radical, R5Is H, halogen, amino, or straight or branched C1-C6An alkyl group.
2. The compound of claim 1, wherein R1H, F, Cl, Br, I, methyl, ethyl, propyl or isopropyl; r3、R4Independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, and neopentyl; r5Represents one or more substituents on the phenyl ring independently selected from H, F, Cl, Br, I, amino, methyl, ethyl, propyl and isopropyl.
3. A compound according to claim 1 or 2, wherein R1H, F, methyl; r2Is H,
4. A compound according to any one of claims 1 to 3, wherein R2Is composed of
5. The compound according to claim 1, selected from the following compounds:
6. a process for the preparation of a compound as claimed in any one of claims 1 to 5,
wherein when R is2Is composed of
The method comprises the following steps:
(a) reacting a compound of formula (1) with a compound of formula (2) to produce a compound of formula (3);
(b) subjecting the compound of formula (3) to a thionation reaction to produce a compound of formula (4);
(c) carrying out N-hydroxylation reaction on the compound of the formula (4) to generate a compound of a formula (5), namely the compound shown in the formula (I);
when R is2Is composed of
The method comprises the following steps:
(a') reacting the compound of formula (6) with a first hydroxy protecting reagent to produce a compound of formula (7);
(b') subjecting the compound of formula (7) to a thionation reaction to produce a compound of formula (8);
(c') N-hydroxylating the compound of formula (8) to produce a compound of formula (9);
(d') reacting the compound of formula (9) with a second hydroxy protecting reagent to produce a compound of formula (10);
(e') reacting the compound of formula (10) with the compound of formula (11) to produce a compound of formula (12);
(f') removing the hydroxyl protecting group from the compound of formula (12) to obtain a compound of formula (13), i.e., a compound represented by formula (I); or
When R is2When H, the method comprises the following steps:
(a') reacting a compound of formula (5) to produce a compound of formula (14), i.e. a compound of formula (I), preferably said compound of formula (5) is prepared by steps (a) to (c) above;
wherein R is1、R2、R3、R4And R5As defined in claims 1 to 5, R6And R7Is a hydroxyl protecting group.
7. The process of claim 6, wherein the compound of formula (11) is prepared by a process comprising the steps of:
(i) reacting a compound of formula (15) with a compound of formula (16) and paranitrophenol in the presence of a base in sequence to produce a compound of formula (11); preferably, the base is triethylamine, diisopropylethylamine, trimethylamine or DBU.
8. The method of claim 6, wherein:
the thionation reaction in steps (b) and (b') is carried out in the presence of a thionating agent and a base; preferably, the thioreagent is sodium hydrosulfide or potassium hydrosulfide, and the alkali is ammonium bicarbonate or sodium bicarbonate;
the N-hydroxylation reaction in steps (c) and (c') is carried out in the presence of hydroxylamine sulphate;
the first hydroxyl protecting reagent in step (a') is acetone, butanone or pentanone; the second hydroxy protecting agent in the step (d') is DMT-Cl, chlorotrityl or chlorodi (p-nitrophenyl) methyl;
said step (f ') is carried out under acidic conditions, preferably said step (f') is carried out in the presence of formic acid or acetic acid; and/or
Said step (a') is an aminolysis reaction of the compound of formula (5) in the presence of ammonia to produce the compound of formula (14).
9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and a pharmaceutically acceptable adjuvant.
10. Use of a compound of any one of claims 1 to 5 or a pharmaceutical composition of claim 9 in the manufacture of a medicament for use in the antiviral treatment of a disease; preferably, the virus is a coronavirus or an influenza virus; more preferably, the coronavirus is SARS-CoV-2.
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