WO2023197791A1 - 一种环状碳酸酯核苷类化合物及其应用 - Google Patents
一种环状碳酸酯核苷类化合物及其应用 Download PDFInfo
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- WO2023197791A1 WO2023197791A1 PCT/CN2023/080429 CN2023080429W WO2023197791A1 WO 2023197791 A1 WO2023197791 A1 WO 2023197791A1 CN 2023080429 W CN2023080429 W CN 2023080429W WO 2023197791 A1 WO2023197791 A1 WO 2023197791A1
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- 229940125674 nirmatrelvir Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical compound Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229940125675 paxlovid Drugs 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940125286 pruxelutamide Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000003730 rna directed rna polymerase inhibitor Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- BSPJDKCMFIPBAW-JPBGFCRCSA-M sodium;(2s)-1-hydroxy-2-[[(2s)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonate Chemical compound [Na+].N([C@@H](CC(C)C)C(=O)N[C@@H](CC1C(NCC1)=O)C(O)S([O-])(=O)=O)C(=O)OCC1=CC=CC=C1 BSPJDKCMFIPBAW-JPBGFCRCSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000005723 virus inoculator Substances 0.000 description 1
- 150000003751 zinc Chemical class 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
- C07H19/06—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- 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
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
- C07H11/04—Phosphates; Phosphites; Polyphosphates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/12—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
Definitions
- the invention belongs to the field of medical technology, and specifically relates to a cyclic carbonate nucleoside compound and its application.
- viruses that are extremely harmful to humans have been discovered, such as influenza virus, respiratory syncytial virus (RSV), parainfluenza virus, SARS virus, and Middle East respiratory syndrome (MERS).
- RSV respiratory syncytial virus
- SARS virus parainfluenza virus
- MERS Middle East respiratory syndrome
- Viruses, Ebola virus, new coronavirus (SARS-CoV-2), etc., especially the new coronavirus that broke out in 2019, including mutant strains such as Alpha, Beta, Gamma, Delta, and Omicron have caused a serious impact on the global economy or society. It has had a serious impact and has caused more than 400 million infections and more than 6 million deaths worldwide.
- Remdesivir Molnupiravir (monupiravir) and Paxlovid are available for clinical use.
- Remdesivir The efficacy of Remdesivir is relatively poor, with an effective rate of only 30% for patients with mild to moderate new coronavirus pneumonia.
- the World Health Organization has evaluated 1 In comparative trials of more than 10,000 patients with new coronavirus pneumonia, remdesivir had the same effect as hydroxychloroquine, lopinavir, interferon or lopinavir (N.Engl.J.Med., 2021, 384:497), especially for patients with severe novel coronavirus pneumonia, there is an urgent need to invent antiviral drugs for the treatment of novel coronavirus.
- FcoV feline coronavirus
- FIPV feline enteric coronavirus
- FIPV infection is easy to develop into infectious peritonitis (FIP).
- FIP Porcine Epidemic Diarrhea Virus
- PEDV Porcine Epidemic Diarrhea Virus
- the object of the present invention is to provide a nucleoside compound, its pharmaceutically acceptable salt, crystalline hydrate, solvate or tautomer that can effectively treat related diseases caused by viral infection.
- Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned nucleoside compounds, their pharmaceutically acceptable salts, crystalline hydrates, solvates or tautomers, and the above-mentioned nucleoside compounds, their pharmaceutically acceptable salts, crystalline hydrates, solvates or tautomers.
- antivirals e.g. coronaviruses, influenza viruses, respiratory syncytial viruses, Flaviviridae viruses, Filoviridae viruses, feline coronaviruses
- R 1 , R 2 , R 3 and R 4 are the same or different, and are each independently selected from hydrogen, deuterium, halogen, amino, azide, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 3-6 Cycloalkyl, C 2-6 alkenyl or C 2-6 alkynyl, one of C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or more hydrogens may optionally be replaced by the same or different deuterium, halogen, hydroxyl, amino, azide, cyano, mercapto, cyclopropylcyano, carboxyl, carbamoyl, halomethyl or containing one or Substituted methyl substitution of multiple oxygen, nitrogen, phosphorus or sulfur atoms;
- R 5 is selected from hydrogen, -COOH, alkane ester group, aromatic ester group, carbonate group, urethane group, thioester group, thiocarbonate group, S-thiocarbonate group, alkylcarbonyl group , alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, oxymethoxycarbonyl, oxymethylcarbonyl, isobutyrate ester group, pivalate ester group, L- or D-amino acid ester group, N-substituted L- or D-amino acid ester group, N, N-disubstituted L- or D-amino acid ester group, imino acid ester group, hydrazone ester group, oxime ester group, imide group, thioximide group Amino acid ester group, carbonimidate group, isourea group, amino phosphate group, monophosphate group, diphosphate group, tri
- Each occurrence of R 6 is independently selected from deuterium, cyano, halogen, hydroxy, azide, mercapto, amino, carboxyl, sulfonate, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkenyl, aryloxy, arylamino, carbamoyl or halomethyl;
- R 7 and R 8 are the same or different, and are each independently selected from -OR 9 , -SR 9 , -NHR 9 , -N(R 9 ) 2 , aryloxy, heteroaryloxy or
- R 9 is selected from phenol group, naphthol group, alkane ester group, aromatic ester group, carbonate group, urethane group, thioester group, thiocarbonate group, S-thiocarbonate group, alkyl group Carbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, oxymethoxycarbonyl, oxymethylcarbonyl, L- or D-amino acid ester, N-substituted L- or D-amino acid ester base;
- R 10 , R 11 and R 12 are the same or different, and are each independently selected from alkyl, alkenyl, alkynyl, aryl, aromatic alkyl, heteroaryl;
- B is a pyrimidine nucleoside base or a purine nucleoside base.
- the R 1 , R 2 , R 3 and R 4 are the same or different, and each is independent. is selected from hydrogen, halogen, azido, cyano, C 1-6 alkyl, hydroxymethyl, cyclopropyl, ethynyl or halomethyl.
- R 5 is selected from H, C 2-30 alkyl carbonyl, C 2-30 alkene base carbonyl group, C 2-30 alkynyl carbonyl group, aryl carbonyl group, heteroaryl carbonyl group, amino phosphate ester group, isobutyrate ester group, pivalate ester group, amino acid ester group, wherein one or more hydrogens in the C 2-30 alkylcarbonyl group, C 2-30 alkenylcarbonyl group or C 2-30 alkynylcarbonyl group may optionally be substituted by the same or different R 6 ;
- R 7 and R 8 are the same or different, and are each independently selected from -OR 9 , -NHR 9 , Phenol or naphthol group;
- R 9 is selected from phenol group, naphthol group, L- or D-amino acid ester group, N-substituted L- or D-amino acid ester group;
- R 6 , R 10 , R 11 and R 12 are the same as above.
- B is selected from:
- R 13 , R 14 and R 15 are the same or different, and each is independently selected from hydrogen, deuterium, halogen, amino or substituted ammonia. group, azide, cyano, hydroxyl, mercapto or substituted mercapto, hydroxymethyl, trifluoromethyl, cyclopropyl, C 1-6 alkyl or substituted alkyl, -OR 16 , -SR 16 , -NHR 16 , -N(R 16 ) 2 or -NHOR 16 .
- R 16 is selected from H, C 1-6 alkyl, C 2-30 alkylcarbonyl, C 2-30 alkenylcarbonyl, C 2-30 alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminophosphate base, isobutyrate base, pivalate base or amino acid ester base;
- R 13 is selected from hydrogen, deuterium, fluorine, chlorine or amino;
- R 14 is selected from hydrogen, fluorine, chlorine, amino, methyl or trifluoromethyl
- R 15 is selected from -NHOR 16 , amino, methylamino, cyclopropylamino, hydroxyl, methoxy, ethoxy, mercapto, methylmercapto or NHR 16 ;
- R 16 is selected from hydrogen, isobutyrate group, pivalate group or natural amino acid ester group.
- the structural formula of the compound is any one of the following:
- the present invention also provides pharmaceutical compositions comprising at least one of the above-mentioned nucleoside compounds, pharmaceutically acceptable salts, crystalline hydrates, solvates or tautomers thereof.
- the above pharmaceutical composition also contains at least one pharmaceutically acceptable carrier or diluent.
- the pharmaceutical composition of the above-mentioned nucleoside compound, its pharmaceutically acceptable salt, crystalline hydrate, solvate or tautomer is prepared through a formulation process with a suitable pharmaceutically acceptable carrier. and auxiliaries commonly used in medicine to prepare pharmaceutical compositions that are convenient for administration.
- the preparation form of the pharmaceutical composition includes: oral agent, injection, anal plug, nostril inhalation agent, eye drops or skin patch.
- various dosage forms of the above pharmaceutical composition can be prepared by methods commonly used in the pharmaceutical industry. For example, mixing, dissolving, granulating, grinding, emulsifying, capsules, sugar coating, freeze drying, freeze spraying, etc.
- the virus is selected from coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus, Filoviridae virus, novel coronavirus SARS-CoV-2, feline One or any combination of infectious peritonitis virus FCoV and porcine epidemic diarrhea virus.
- the virus is selected from alphavirus, flavivirus or coronavirus, ortho or paramyxovirus, respiratory syncytial virus, parainfluenza virus, SARS virus, MERS virus, Ebola virus, novel coronavirus, influenza virus, Powassan virus, filovirus, Ebola virus, equine encephalitis virus, Zika virus, Ross River virus, influenza A virus, influenza B virus , influenza C virus, rotavirus, human coronavirus, human adenovirus, human papillomavirus, parvovirus, norovirus, rheumatoid arthritis Herpes virus, dengue virus, Bama forest virus, measles virus, mumps virus, rinderpest virus, Japanese encephalitis virus, hantavirus, rabies virus, herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, One or any combination of cytomegalovirus, hepatitis virus
- the virus is novel coronavirus SARS-CoV-2 and feline infectious peritonitis virus FCoV.
- the nucleoside compounds or pharmaceutical compositions of the present invention can be used alone or in combination with one or more other antiviral drugs.
- the antiviral drugs include but are not limited to: RNA-dependent RNA polymerase inhibitor Ri. Desivir, Favipira, Galidesivir, GS-441524, molnupiravir, EIDD-1931; 3CL protease inhibitor Nirmatrelvir, Ensitrelvir (S-217622), GC-376, lopinavir, nelfinavir; and others such as Interferon, hydroxychloroquine, cyclosporine, ivermectin, ribavirin, penciclovir, azivudine, proxalutamide, etc. or their combinations.
- Said combined use can provide "synergistic effects” and “synergistic effects”, to be formulated together and used or delivered simultaneously in the form of a combined preparation, or can be used alternately in separate preparations, such as in separate tablets, pills or capsules , or by different injections from separate syringes, a synergistic effect can be obtained.
- Substituted as used herein means any group that is mono- or poly-substituted by a specified substituent to the extent that such mono- or poly-substitution (including multiple substitutions at the same position) is chemically permissible, each substituent may be located Any available position on the group can be attached via any available atom on the substituent. "Any available position” means any position on the group that is chemically accessible by methods known in the art or as taught herein and does not produce an unduly unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and therefore may be the same or different.
- substituents of the compounds of the present invention are disclosed as groups or ranges. This specifically means that the invention includes every member or every individual subcombination of members of such groups and ranges.
- C 1-4 alkyl specifically means that methyl, ethyl, C 3 alkyl and C 4 alkyl are individually disclosed.
- solvent refers to a stable substance formed by covalent bonds, hydrogen bonds, ionic bonds, van der Waals forces, complexation, inclusion, etc. between the compounds of the present invention and commonly used solvents in chemistry.
- the solvent can be: methanol , ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol, acetone, acetonitrile, diethyl ether, methyl tert-butyl ether, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, etc. .
- “Pharmaceutically acceptable” means that the compound or composition must be chemically, pharmacologically and/or toxicologically compatible with the other ingredients constituting the formulation and/or the mammal being treated therewith.
- Tautomers refers to structural isomers with different energies that can cross a low energy barrier and thereby transform into each other.
- Valence tautomers involve the recombination of some bonding electrons to undergo interconversion.
- “Pharmaceutically acceptable carrier” or “diluent” refers to inactive ingredients in pharmaceutical compositions, including but not limited to: calcium carbonate, calcium phosphate, magnesium carbonate, silica gel, various sugars (such as lactose, mannitol, etc.) , starch, cyclodextrin, magnesium stearate, cellulose, acrylic polymer, methacrylic polymer, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil, hydrogenated castor oil, polyethylene glycol Oxygenated hydrogenated castor oil, sesame oil, corn oil, peanut oil, etc.
- “Pharmaceutically acceptable salt” refers to the compound of the present invention, which is prepared by reacting the active compound of the present invention with an inorganic acid or an organic acid.
- the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid and phosphoric acid.
- the organic acids include benzenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene di- Sulfonic acid, malic acid, malonic acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, parapic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, etc. ; Or sodium salt, zinc salt, potassium salt, calcium salt, aluminum salt or ammonium salt formed with inorganic base.
- Aryloxy means an aryl group attached to another group through an oxygen atom.
- Aryloxy groups in the present invention include but are not limited to: phenoxy group, naphthyloxy group, etc.
- Heteroaryloxy means that a heteroaryl group is attached to another group through an oxygen atom.
- the heteroaryloxy group in the present invention includes but is not limited to: 4-pyridinyloxy group, 2-thienoxy group, etc.
- Test Example 1 Toxic effects of compounds 1-11 and C6 on cells
- Test Example 2 Inhibitory effects of compounds 1-11 and C6 on novel coronavirus (SARS-CoV-2)
- Cell preparation Plate Vero-E6 cells at 2 ⁇ 10 5 /ml with 100ul of cell suspension per well in a 96-well plate, place it in a 37°C, 5% CO 2 incubator overnight, and set aside when the cells grow into a monolayer. .
- Virus dilution Add 0.9 mL of DMEM containing 5% fetal calf serum to the first tube, and add 1.8 mL to the rest; add 0.1 mL of virus preservation solution to the first tube, then replace the pipette tip with a new pipette, draw 0.2 mL from the first tube, and add 0.2 mL of virus preservation solution to the first tube. In two tubes; dilute sequentially to the highest dilution.
- Virus inoculation Wash the cells with serum-free DMEM; add 100 ⁇ L of different virus dilutions to each well, and make a column of wells for each dilution, that is, make 8 parallel wells for each virus dilution. When adding samples, start from the highest At the beginning of the dilution, set a negative control. Add 100 ⁇ L of DMEM containing 5% fetal calf serum to the negative control well to detect cell survival. Culture it in 5% CO 2 at 37°C for 5 days. After 5 days, observe under a microscope and calculate the number of cells in each column. The number of wells where CPE appeared was used to calculate the virus TCID 50 /mL using the KARBER method.
- the microplate method test was used to evaluate the inhibitory effect of the drug on the new coronavirus (the greater the dilution factor, the higher the activity in inhibiting the virus). It can be seen from Table 1: the compounds 1-12 containing cyclic carbonates It has a significant inhibitory effect on the three mutant strains of the new coronavirus (Alpha, Delta and Omicron), and the inhibitory effect is significantly better than the 2,3-free dihydroxy remdesivir, C6, GS-441524, EIDD- 1931 and Monupivir.
- Test Example 3 Inhibitory effects of compound 2-9, GS-441524 and remdesivir on feline coronavirus
- CRFK cat kidney cells
- Virus activity test Add 100uL of 100TCID 50 feline coronavirus (FIPV) to each well, discard the supernatant after overnight adsorption, wash with PBS to prepare 400uM drug, filter and sterilize, use maintenance medium to dilute compounds 2-8, Monupivir, GS-441524 and remdesivir are released into different drug concentrations of 100uM, 50uM, 25uM, 12.5uM, 6.25uM, 3.125uM, 1.5625uM, and 0.78125uM. Add 100ul to each well and wait for the virus set. When the CPE reaches 75% to 100%, CPE observation is performed. Among them, 0%-25% of lesions are counted as 1, 25%-50% are counted as 2, 50%-75% are counted as 3, and 75%-100% are counted as 4. The results are as shown in Table 2.
- the inhibitory effect of the drug on feline coronavirus was evaluated by cell cytopathic effects (CPE). It can be seen from Table 2: when the drug concentration is 12.5 ⁇ M, the compound 2 containing cyclic carbonate -8 pairs all have significant inhibitory effects, and the cytopathic rate is less than 50%. Among them, compound 3-7 has a cytopathic rate of less than 25%. Its inhibitory effect is significantly better than that of 2,3-free dihydroxy compounds such as monopivir and rupi. Desivir and GS-441524.
- Pharmacokinetic process 21 SD male rats (body weight 180-220g) were selected, 3 rats in each group. They were fasted for 12 hours before the experiment, drank water freely, and ate at the same time 2 hours after administration.
- the solvent for administration is DMSO/propylene glycol/0.9% NaCl solution (2/4/14, v/v/v).
- the dosage of GS-441524 is intragastric administration (30 mg/kg)/tail vein injection (15 mg/kg) in rats.
- Standard curve Take about 5ml of rat blank blood, centrifuge at 3000rpm for 10min, separate the plasma, take 6 1.5ml EP tubes, add 0.1, 0.5, 1, 5, 10, 20, 50 ⁇ l of 1931 stock solution respectively, and add the working solvent.
- Test sample processing Take 50 ⁇ l of drug-containing plasma obtained from the pharmacokinetic process into a 1.5 ml EP tube with 450 ⁇ l working solvent (containing 50 ⁇ l water, 50 ⁇ l methanol, 350 ⁇ l acetonitrile), vortex for 5 min, 12000 rpm/min, 5 min, and take Supernatant, centrifuge again at 12000rpm/min for 5 minutes, take the supernatant into a 1.5ml EP tube, and obtain a pharmacokinetic test sample of the compound to be tested.
- working solvent containing 50 ⁇ l water, 50 ⁇ l methanol, 350 ⁇ l acetonitrile
- LC-MS detection Chromatographic column, Kinetex C18 core-shell universal chromatographic column (4.6mm ⁇ 100mm, 2.6 ⁇ m, Phenomenex Company of the United States), column temperature 30°C, injection volume 10 ⁇ L, mobile phase acetonitrile-0.6% ammonium formate (formic acid adjusted pH5.0), flow rate 1.0ml/min, isocratic elution; ion source, electrospray ion source ESI; detection mode, multiple reaction monitoring (MRM); scanning mode, positive ion mode; ESI spray voltage 5000V, ion source temperature 400°C, atomization gas flow rate 150 ⁇ L/min, backflush drying gas flow rate 100 ⁇ L/min; mass spectrometry interface heating temperature 300°C.
- the present invention provides a cyclic carbonate nucleoside compound represented by formula (I), its pharmaceutically acceptable salt, crystal hydrate, solvate or tautomer, and also discloses a compound containing the compound.
- the compound and pharmaceutical composition can be used for the treatment or prevention of viral infections, such as coronavirus, influenza virus, respiratory syncytial virus, Flaviviridae virus, Filoviridae virus, new coronavirus and/or feline coronavirus, etc.
- the treatment or prevention of viral infections has good economic value and application prospects.
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Abstract
本发明涉及一种如式(I)所示的环状碳酸酯核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,同时还公开了包含该化合物的药物组合物及其应用。该化合物及药物组合物,可用于病毒感染的治疗或预防,例如冠状病毒、流感病毒、呼吸道合胞病毒、黄病毒科病毒、丝状病毒科病毒、新型冠状病毒和/或猫冠状病毒等相关病毒感染的治疗或预防。
Description
交叉引用
本申请要求2022年4月11日提交的专利名称为“一种环状碳酸酯核苷类化合物及其应用”的第2022103725801号中国专利申请的优先权,其全部公开内容通过引用整体并入本文。
本发明属于医药技术领域,具体涉及一种环状碳酸酯核苷类化合物及其应用。
目前,已发现多种对人类有极大的危害致病性病毒,如流感病毒、呼吸道合胞病毒(RSV)、副流感病毒、非典型性肺炎(SARS)病毒、中东呼吸综合征(MERS)病毒、埃博拉病毒、新型冠状病毒(SARS-CoV-2)等,特别是2019年爆发的新型冠状病毒,包括Alpha、Beta、Gamma、Delta、Omicron等变异株,对全球的经济或社会造成了严重的影响,目前已经导致全球4亿多人感染和600多万人死亡,而临床仅有瑞德西韦、Molnupiravir(莫努匹韦)和Paxlovid等少数药物可供使用,其中莫努匹韦的疗效相对较差,对轻度至中度新型冠状病毒肺炎患者的有效率仅为30%,而瑞德西韦的临床有效性有一定的异议,如世界卫生组织在30个国家对1万多名新型冠状病毒肺炎患者的对比试验中,瑞德西韦与羟氯喹、洛匹那韦、干扰素或洛匹那韦一样,效果甚微(N.Engl.J.Med.,2021,384:497),特别是对重症新型冠状病毒肺炎患者,急需发明用于治疗抗新型冠状病毒的抗病毒药物。
此外,一些病毒也可感染动物,如冠状病毒也可感染猫、猪、犬、牛、马、骆驼等多种哺乳动物。全世界估计有的猫携带猫冠状病毒(FCoV),FcoV可分为猫肠道冠状病毒(FECV)和猫传染性腹膜炎病毒(FIPV)两种,特别是FIPV感染后容易发展成传染性腹膜炎(FIP),目前仍没有批准针对FIP的治疗药物,致死率高达95%以上。又如引起猪急性肠道传染病的猪流行性腹泻病毒(PEDV),也同样属于冠状病毒,母猪发病率变动很大,约为15-90%,死亡率达到50以上,目前无有效的治疗方法。因此,同样需要发明用于治疗猫传染性腹膜炎或猪流行性腹泻病的药物。
发明内容
本发明的目的是提供一种可有效治疗病毒感染引起的相关疾病的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体。
本发明另一个目的是提供一种含有上述核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体的药物组合物,及上述核苷类化合物、其药学上可
接受的盐、结晶水合物、溶剂化物或互变异构体,以及药物组合物在抗病毒(如冠状病毒、流感病毒、呼吸道合胞病毒、黄病毒科病毒、丝状病毒科病毒、猫冠状病毒、猪流行性腹泻病毒等),特别是抗新型冠状病毒(SARS-CoV-2)中的用途。
为实现上述目的,本发明采用如下技术方案:
一种核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,该化合物分子结构式如式(I)所示:
式中:
R1、R2、R3和R4相同或不同,各自独立地选自氢、氘、卤素、氨基、叠氮基、氰基、羟基、巯基、C1-6烷基、C3-6环烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基中的一个或多个氢可任选地被相同或不同的氘、卤素、羟基、氨基、叠氮基、氰基、巯基、环丙基氰基、羧基、氨甲酰基、卤代甲基或含有一个或多个氧、氮、磷或硫原子的取代甲基取代;
R5为选自氢、-COOH、烷烃酯基、芳香酯基、碳酸酯基、氨基甲酸酯基、硫代酯基、硫代碳酸酯基、S-硫代碳酸酯基、烷基羰基、烯基羰基、炔基羰基、芳基羰基、杂芳基羰基、氧甲氧基羰基、氧甲基羰基、异丁酸酯基、特戊酸酯基、L-或D-氨基酸酯基、N-取代的L-或D-氨基酸酯基、N,N-二取代的L-或D-氨基酸酯基、亚氨基酸酯基、腙酯基、肟酯基、酰亚胺基、硫代亚胺酸酯基、碳酰亚胺酸酯基、异脲基、胺基磷酸酯基、单磷酸酯基、二磷酸酯基、三磷酸酯基、
其中R5中的一个或多个氢可以任选的被相同或不同的R6取代;
R6每次出现时各自独立地选自氘、氰基、卤素、羟基、叠氮基、巯基、氨基、羧基、磺酸基、烷基、烯基、炔基、芳基、杂芳基、环烯基、芳氧基、芳氨基、氨甲酰基或卤代甲基;
R7和R8相同或不同,各自独立地选自-OR9、-SR9、-NHR9、-N(R9)2、芳氧基、
杂芳氧基或
R9选自苯酚基、萘酚基、烷烃酯基、芳香酯基、碳酸酯基、氨基甲酸酯基、硫代酯基、硫代碳酸酯基、S-硫代碳酸酯基、烷基羰基、烯基羰基、炔基羰基、芳基羰基、杂芳基羰基、氧甲氧基羰基、氧甲基羰基、L-或D-氨基酸酯基、N-取代的L-或D-氨基酸酯基;
R10、R11和R12相同或不同,各自独立地选自烷基、烯基、炔基、芳香基、芳香烷基、杂芳香基;
B为嘧啶类核苷碱基或嘌呤类核苷碱基。
优选地,上述核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体中,所述R1、R2、R3和R4相同或不同,各自独立地选自氢、卤素、叠氮基、氰基、C1-6烷基、羟甲基、环丙基、乙炔基或卤代甲基。
优选地,上述核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体中,R5选自H、C2-30烷基羰基、C2-30烯基羰基、C2-30炔基羰基、芳基羰基、杂芳基羰基、胺基磷酸酯基、异丁酸酯基、特戊酸酯基、氨基酸酯基、
其中所述C2-30烷基羰基、C2-30烯基羰基或C2-30炔基羰基中的一个或多个氢可以任选的被相同或不同的R6取代;
R7和R8相同或不同,各自独立地选自-OR9、-NHR9、苯酚基或萘酚基;
R9选自苯酚基、萘酚基、L-或D-氨基酸酯基、N-取代的L-或D-氨基酸酯基;
其中,R6、R10、R11和R12的定义同上。
优选地,上述核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体中,B选自:
或其互变异构体,
其中R13、R14和R15相同或不同,各自独立地选自氢、氘、卤素、氨基或取代氨
基、叠氮、氰基、羟基、巯基或取代巯基、羟甲基、三氟甲基、环丙基、C1-6烷基或取代烷基,-OR16、-SR16、-NHR16、-N(R16)2或-NHOR16。
R16选自H、C1-6烷基、C2-30烷基羰基、C2-30烯基羰基、C2-30炔基羰基、芳基羰基、杂芳基羰基、胺基磷酸酯基、异丁酸酯基、特戊酸酯基或氨基酸酯基;
进一步优选的,R13选自氢、氘、氟、氯或氨基;
R14选自氢、氟、氯、氨基、甲基或三氟甲基;
R15选自-NHOR16、氨基、甲氨基、环丙氨基、羟基、甲氧基、乙氧基、巯基、甲巯基或NHR16;
R16选自氢、异丁酸酯基、特戊酸酯基或天然氨基酸酯基。
优选地,上述核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体中,所述化合物的结构式是下面任意一种:
本发明还提供包含至少一种上述的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体的药物组合物。
优选的,上述药物组合物中,还包含至少一种药学上可接受的载体或稀释剂。
优选的,上述的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体的药物组合物通过制剂(formulation)过程,与适合的药学上可接受的载体及药学上常用的辅剂制备成利于给药的药物组合物。
优选的,上述药物组合物中,所述药物组合物的制剂形式包括:口服剂、注射剂、肛塞剂、鼻孔吸入剂、滴眼剂或皮肤贴剂。
优选的,上述药物组合物的各种剂型可以采用医药工业常用的方法制备。例如,混合、溶解、制粒、研磨、乳化、胶囊、糖衣、冷冻干燥、冷冻喷雾等。
本发明还提供上述的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,或上述的药物组合物在制备治疗或预防病毒感染的药物中的应用。
在一种优选的实施方式中,上述应用中,所述病毒选自冠状病毒、流感病毒、呼吸道合胞病毒、黄病毒科病毒、丝状病毒科病毒、新型冠状病毒SARS-CoV-2、猫传染性腹膜炎病毒FCoV、猪流行性腹泻病毒中的一种或任意几种的组合。
在另一种优选的实施方式中,上述应用中,所述病毒选自甲病毒、黄病毒或冠状病毒、正或副黏病毒、呼吸道合胞病毒、副流感病毒、非典型性肺炎SARS病毒、MERS病毒、埃博拉病毒、新型冠状病毒、流感病毒、波瓦桑病毒、丝状病毒、埃博拉病毒、马脑病毒、寨卡病毒、罗斯河病毒、甲型流感病毒、乙型流感病毒、丙型流感病毒、轮状病毒、人冠状病毒、人腺病毒、人乳头病毒、细小病毒、诺如病毒、风
疹病毒、登革热病毒、巴马森林病毒、麻疹病毒、腮腺炎病毒、牛瘟病毒、日本脑炎病毒、汉坦病毒、狂犬病毒、单纯胞疹病毒、水痘-带状胞疹病毒、EB病毒、巨细胞病毒、肝炎病毒、HIV病毒、牛瘟病毒、猫冠状病毒,猫肠道冠状病毒和猫传染性腹膜炎病毒中的一种或任意几种的组合。
最优选的,所述病毒为新型冠状病毒SARS-CoV-2和猫传染性腹膜炎病毒FCoV。
本发明的核苷类化合物或药物组合物可以作单一使用,或者与一种或多种其它抗病毒药物联合使用,所述的抗病毒药物包括但不限于:RNA依赖的RNA聚合酶抑制剂瑞德西韦、法匹拉、Galidesivir、GS-441524、molnupiravir、EIDD-1931;3CL蛋白酶抑制剂Nirmatrelvir、Ensitrelvir(S-217622)、GC-376、洛匹那韦、奈非那韦;以及其它如干扰素、羟氯喹、环孢菌素、伊维菌素、利巴韦林、喷昔洛韦、阿兹夫定、普克鲁胺等或其组合。
所述的联合使用可提供“增效作用”和“协同作用”,以共同配制并以组合制剂形式同时使用或递送,也可以单独的制剂交替使用,如以单独的片剂、丸剂或胶囊剂,或通过单独注射器的不同注射,可获得协同作用。
术语的定义
以下为本发明中所涉及的术语定义。
“取代”在本文中是指任何基团由指定取代基单取代或多取代至这种单取代或多取代(包括在相同部位的多重取代)在化学上允许的程度,每个取代基可以位于该基团上任何可利用的位置,其可以通过所述取代基上任何可利用的原子连接。“任何可利用的位置”是指通过本领域已知的方法或本文教导的方法可化学得到,并且不产生过度不稳定的分子的所述基团上的任何位置。当在任何基团上有两个或多个取代基时,每个取代基独立于任何其它取代基而定义,因此可以是相同或不同的。
在本说明书的各个位置,本发明化合物的取代基以基团或范围的形式进行公开。这具体意味着本发明包括这样的基团和范围的每个成员或成员中的每个个体的亚组合。如术语“C1-4烷基”具体意味着单独公开了甲基、乙基、C3烷基和C4烷基。
“溶剂合物”指本发明所述化合物与化学上常用的溶剂以共价键、氢键、离子键、范德华力、络合、包合等形成的稳定物质,所述的溶剂可以为:甲醇、乙醇、丙醇、丁醇、乙二醇、丙二醇、聚乙二醇、丙酮、乙腈、乙醚、甲基叔丁醚、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺等。
“药学上可接受”表示化合物或组合物在化学上、药理学上和/或毒理学上必须与构成制剂的其它成分和/或用其治疗的哺乳动物相容。
“互变异构体(tautomers)”在本文中是指具有不同能量的结构同分异构体可以越过低能垒,从而互相转化。诸如质子互变异构体包括通过质子迁移进行互变,如烯醇-酮互变异构体和亚胺-烯胺互变异构体,或者含有连接到环-NH-部分和环=N-部分的
环原子的杂芳基基团的互变异构形式,如吡唑、咪唑、苯并咪唑、三唑和四唑。化合价互变异构体包括一些成键电子重组而进行互变。
“药学上可接受的载体”或”稀释剂”指药物组合物中的非活性成分,包括但不限于:碳酸钙、磷酸钙、碳酸镁、硅胶、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、丙烯酸聚合物、甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油、氢化蓖麻油、多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
“药学上可接受的盐”指本发明所述化合物本发明的活性化合物与无机酸或有机酸反应制得,所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等,所述有机酸包括苯磺酸、马来酸、富马酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、苹果酸、丙二酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸等;或者与无机碱形成的钠盐、锌盐、钾盐、钙盐、铝盐或铵盐等。
“芳氧基”指芳基通过氧原子与其他基团相连。本发明中的芳氧基包括但不限于:苯氧基、萘氧基等。
“杂芳氧基”指杂芳基通过氧原子与其他基团相连。本发明中的杂芳氧基包括但不限于:4-砒啶氧基、2-噻吩氧基等。
下面结合具体实施例对本发明做出进一步地详细阐述,所述实施例只用于解释本发明,并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
实施例1:化合物1的制备
取一干燥的500.0mL烧瓶,将GS-441524(10.00g,34.33mmol,1.0eq)、咪唑(7.01g,103.00mmol,3.0eq)溶解于50.0mL的无水DMF中。在0℃下缓慢加入TBSCl(6.21g,41.20mmol,1.2eq),搅拌1h,TLC(DCM:MeOH=4:1)检测原料反应完全后,加入乙酸乙酯稀释(200mL),用水洗(200mL×2),饱和食盐水洗(200mL×1),收集有机相,加入无水硫酸钠干燥,减压蒸馏除去有机相,得粗品,经硅胶柱层析分离纯化(甲醇:二氯甲烷=1:20),得到白色固体化合物C1(甲醇:
二氯甲烷=1:20,12.53g,90%)。1H NMR(400MHz,CD3OD)δ7.88(s,1H),7.00–6.80(m,2H),4.79(d,J=4.8Hz,1H),4.30–4.12(m,2H),3.94(dd,J=11.6,2.6Hz,1H),3.82(dd,J=11.7,3.3Hz,1H),3.33(p,J=1.7Hz,1H),0.86(s,9H),0.05(s,3H),-0.00(s,3H).13C NMR(101MHz,MeOD)δ155.83,146.83,124.87,116.51,116.27,110.56,101.06,85.31,79.04,74.94,70.22,62.09,24.95,17.76,-6.73,-6.82。
取一干燥的500.0mL烧瓶,将C1(12.00g,29.59mmol,1.0eq)、N,N'-羰基二咪唑(CDI)(9.60g,59.18mmol,2.0eq)溶解于100.0mL乙腈中,45℃加热回流,溶液从浑浊变澄清,反应1h后,TLC(DCM:MeOH=4:1)检测原料反应完全,在40℃减压旋干后,用油泵抽干1h,经硅胶柱层析分离纯化得C2(10.55g,83%)。1H NMR(400MHz,CDCl3)δ7.90(s,1H),6.95(d,J=4.7Hz,1H),6.68(d,J=4.7Hz,1H),5.88(d,J=8.0Hz,1H),5.35(dd,J=8.0,4.7Hz,1H),4.48(q,J=4.5Hz,1H),3.93(qd,J=11.4,4.4Hz,2H),0.84(s,9H),0.02(d,J=14.5Hz,6H).13C NMR(101MHz,CDCl3)δ155.67,153.17,147.72,130.51,120.79,117.18,113.78,112.75,100.71,85.24,80.78,80.59,79.48,61.37,18.20,-5.44,-5.53。
取一干燥的100.0mL烧瓶,将C2(10.00g,23.20mmol,1.0eq)、溶解于20.0mL的THF中,0℃下加入三氟化氢三乙胺盐(448.0μL,34.80mmol,1.5eq),搅拌4h。TLC(DCM:MeOH=10:1)检测原料反应完全。用水泵减压旋干,硅胶柱层析的白色固体化合物1(6.82g,91%)。1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.05–6.89(m,2H),5.97(d,J=7.8Hz,1H),5.41(dd,J=7.8,4.0Hz,1H),5.23(s,1H),4.50(q,J=4.8Hz,1H),3.73–3.57(m,2H).13C NMR(101MHz,DMSO)δ156.03,153.69,148.88,120.61,117.70,114.75,111.26,101.66,86.03,81.90,80.60,79.58,60.30,46.11,9.02。MS-ESI(m/z):计算值C13H12N5O5[M+1]+318.0838;实测值318.0841。
实施例2:化合物2的制备
取一干燥的100.0mL烧瓶,将化合物1(1.20g,3.79mmol,1.0eq)、L-Boc-丙氨酸(0.72g,3.79mmol,1.0eq)、DCC(0.78g,3.79mmol,1.0eq)和催化量的DMAP溶解于20.0mL无水DMF中,反应12h。TLC(DCM:MeOH=10:1)检测原料反应完全,加入乙酸乙酯稀释(60mL),用水洗(20mL×2),饱和食盐水洗涤(20mL×1),收集有机相中,加入无水硫酸钠干燥,然后在40℃减压旋干,硅胶柱层析的白色固体C4(DCM:MeOH=100:3,0.91g,49%)。1H NMR(400MHz,CDCl3)
δ7.96(s,1H),7.07(d,J=4.6Hz,1H),6.71(d,J=4.1Hz,1H),5.37–5.29(m,1H),5.05(d,J=6.9Hz,2H),4.63(q,J=4.8Hz,2H),4.59–4.43(m,2H),4.37–4.27(m,1H),1.43(s,7H),13C NMR(101MHz,CDCl3)δ176.46,171.83,155.38,152.38,146.86,120.97,113.53,113.19,101.33,82.58,80.74,80.47,80.17,79.50,62.38,58.58,28.29,19.09,17.50。
取一干燥的25.0mL烧瓶,将C4(0.50g,1.02mmol,1.0eq)溶解于10.0mL混合的HCl/THF(HCl:THF=1:5)中,反应1h。TLC(DCM:MeOH=10:1)检测原料反应完全。直接减压旋干得白色固体化合物2的盐酸盐(0.35g,83%)。1H NMR(400MHz,CDCl3)δ7.89(s,1H),6.98(dd,J=28.2,4.7Hz,2H),5.94(d,J=8.0Hz,1H),5.43(dd,J=7.9,4.4Hz,1H),4.54(q,J=4.3Hz,1H),4.07(dd,J=10.7,7.2Hz,1H),3.88(d,J=4.4Hz,1H),3.85(s,1H),1.54(d,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ172.72,155.33,152.41,147.61,120.67,117.25,113.52,113.23,100.70,82.55,80.80,80.39,79.38,62.49,28.31,18.41。MS-ESI(m/z):计算值C16H17N6O6[M+1]+389.1210;实测值389.1215。
实施例3:化合物3的制备
取一干燥的100.0mL烧瓶,将化合物1(1.20g,3.79mmol,1.0eq)、Boc-缬氨酸(0.82g,3.79mmol,1.0eq)、DCC(0.78g,3.79mmol,1.0eq)和催化量的DMAP溶解于20.0mL无水的DMF中,反应12h。TLC(DCM:MeOH=10:1)检测原料反应完全,加入乙酸乙酯稀释(60mL),用水洗(20mL×2),饱和食盐水洗涤(20mL×1),收集有机相中,加入无水硫酸钠干燥,然后在40℃减压旋干,硅胶柱层析的白色固体C5(DCM:MeOH=100:3,0.80g,42%)。1H NMR(400MHz,CDCl3)δ=8.02(s,1H),7.07(d,J=4.7,1H),6.78(d,J=4.6,1H),6.34(s,2H),5.98(d,J=8.0,1H),5.33(dd,J=5.2,8.0,1H),5.05(d,J=9.1,1H),4.63(q,J=5.1,1H),4.50(qd,J=5.2,12.0,2H),4.24(dd,J=4.7,8.9,1H),2.15(m,1H),1.43(d,J=2.6,9H),0.97(d,J=6.8,3H),0.87(d,J=6.8,3H)。
取一干燥的25.0mL烧瓶,将C5(0.50g,0.97mmol,1.0eq)溶解于10.0mL混合的HCl/THF(HCl:THF=1:5)中,反应2h,TLC(DCM:MeOH=10:1)检测原料反应完全,直接减压旋干得白色固体化合物3的盐酸盐(0.32g,80%)。1H NMR(400MHz,DMSO-d6)δ=8.28(d,J=2.3,1H),7.49(d,J=4.7,1H),7.06(dd,J=4.7,11.4,
1H),6.08(d,J=7.8,1H),5.61(dd,J=3.9,7.8,1H),4.89(dt,J=3.7,5.7,1H),4.53(d,J=3.5,1H),4.44(m,2H),2.12(m,1H),0.93(m,6H).13C NMR(101MHz,DMSO-d6)δ=168.70,62.78,158.28,153.30,151.63,123.94,116.14,113.87,112.01,100.60,84.79,82.20,80.19,79.07,36.27,34.49,33.78,31.90,28.71,25.79。MS-ESI(m/z):计算值C18H21N6O6[M+1]+417.1523;实测值417.1520。
实施例4:化合物4的制备
取一干燥的100.0mL烧瓶,化合物1(1.20g,3.79mmol,1.0eq)、异丁酸(351.1μL,3.79mmol,1eq)、DCC(0.78g,3.79mmol,1.0eq)和催化量的DMAP溶解于10.0mL无水的DMF中,反应过夜。TLC(DCM:MeOH=10:1)检测原料反应完全,加入乙酸乙酯稀释(30mL),用水洗(20mL×2),饱和食盐水洗涤(20mL×1),收集有机相中,加入无水硫酸钠干燥,在40℃下减压旋干,柱层析的白色固体化合物4(DCM:MeOH=100:3,0.81g,54%)。1H NMR(400MHz,CDCl3)δ8.00(s,1H),6.91(d,J=4.7Hz,1H),6.62(d,J=4.7Hz,1H),6.25(d,J=5.9Hz,1H),6.08–5.66(m,2H),5.51(dd,J=5.9,4.3Hz,1H),4.62(q,J=4.2Hz,1H),4.47–4.30(m,2H),2.57(dt,J=14.0,7.0Hz,1H),1.25(dd,J=7.0,1.6Hz,6H),13C NMR(101MHz,CDCl3)δ180.69,161.91,159.54,156.86,151.10,124.35,121.47,117.31,116.81,105.74,86.68,84.65,83.63,65.76,37.71,29.47,28.79,22.57。MS-ESI(m/z):计算值C17H18N5O6[M+1]+388.1257;实测值388.1256。
实施例5:化合物5的制备
取一干燥的50.0mL烧瓶,将瑞德西韦(1.00g,1.66mmol,1.0eq)、CDI(0.54g,3.32mmol,2.0eq)溶解于10.0mL乙腈中,45℃加热回流,溶液从浑浊变澄清,反应1h后,TLC(DCM:MeOH=4:1)检测原料反应完全,减压浓缩,用硅胶柱层析的白色固体化合物5(DCM:MeOH=4:1,0.73g,73%)。1H NMR(400MHz,CD3OD)
δ7.87(s,1H),7.72(d,J=14.3Hz,2H),7.33–7.26(m,2H),7.20–7.12(m,3H),6.92–6.85(m,2H),4.77(d,J=5.4Hz,2H),4.40(ddt,J=9.3,6.2,3.0Hz,2H),4.35–4.25(m,1H),4.20(t,J=5.5Hz,1H),4.04(dd,J=10.9,5.8Hz,1H),3.97–3.87(m,2H),1.53–1.43(m,1H),1.31(q,J=9.9,8.0Hz,8H),0.86(t,J=7.5Hz,6H).13C NMR(101MHz,MeOD)δ173.72,155.81,150.66,146.89,134.85,129.39,124.77,124.03,121.22,119.98,119.93,116.59,116.22,111.01,101.43,83.04,82.95,79.82,74.37,70.25,67.02,65.84,53.36,50.11,40.24,22.92,22.88,19.65,19.58,10.25,10.21。MS-ESI(m/z):计算值C28H34N6O9P[M+1]+629.2125;实测值629.2112。
实施例6:化合物6的制备
取一干燥的50.0mL烧瓶,将GS-441524(1.00g,3.43mmol,1.0eq)和N-[(S)-(2,3,4,5,6-五氟苯氧基)苯氧基磷酰基]-L-丙氨酸异丙酯(2.33g,5.15mmol,1.5eq)溶解于10.0mL无水吡啶中,再加入干燥好的4A分子筛(1.5g),冰浴下加入二甲基氯化铝(2.0mL,15.44mmol,4.5eq),避光反应1h。TLC(DCM:MeOH=5:1)检测原料反应完全。加入二甲基丙烯脲(DMPU)(2.3mL,15.44mmol,4.5eq),继续反应30min,加30%的酒石酸20mL,用乙酸乙酯萃取(80mL),收集有机相,无水硫酸钠干燥,减压浓缩,硅胶柱层析的淡黄色固体C6(DCM:MeOH=4:1,0.50g,26%)。1H NMR(400MHz,DMSO-d6)δ7.92(s,1H),7.29–7.15(m,4H),7.01(t,J=7.2Hz,1H),6.96–6.86(m,2H),6.10(d,J=6.2Hz,1H),5.20(d,J=5.2Hz,1H),4.92(t,J=5.7Hz,1H),4.64(t,J=5.6Hz,1H),4.06(q,J=4.5Hz,1H),3.96(q,J=5.2Hz,1H),3.86–3.77(m,1H),3.69–3.61(m,1H),3.52(dd,J=11.9,6.3Hz,1H),3.17(d,J=5.1Hz,1H),1.52–0.73(m,9H)。MS-ESI(m/z):计算值C24H30N6O8P[M+1]+561.1863;实测值561.1858。
取一干燥的50.0mL烧瓶,将C6(0.50g,0.89mmol,1.0eq)、CDI(0.29g,1.78mmol,2.0eq)溶解于10.0mL乙腈中,45℃加热回流,溶液从浑浊变澄清,反应1h后,TLC(DCM:MeOH=4:1)检测原料反应完全,在40℃减压浓缩,硅胶柱层析的白色固体6(DCM:MeOH=4:1,0.32,62%)。1H NMR(400MHz,DMSO-d6)δ=7.97(d,J=2.3,1H),7.31(m,2H),7.14(m,3H),6.96(m,2H),6.06(m,1H),5.91(dd,J=7.8,12.3,1H),5.48(ddd,J=1.9,4.0,7.8,1H),4.80(m,2H),4.27(ddd,J=5.7,8.6,11.9,
2H),3.73(m,1H),1.15(m,9H)。MS-ESI(m/z):计算值C25H28N6O9P[M+1]+587.1655;实测值587.1655。
实施例7:化合物7的制备
取一干燥的500mL烧瓶,将胞苷C7(50.00g,0.21mol,1.0eq)、咪唑(42.88g,0.63mol,3.0eq)溶解于200.0mL的无水DMF中。在0℃下用加入TBSCl(37.68g,0.25mol,1.2eq),搅拌1h,TLC(DCM:MeOH=4:1)检测原料反应完全,加入乙酸乙酯稀释(500mL),用水洗(500mL×2),饱和食盐水洗涤(500mL×1),收集有机相,加入无水硫酸钠干燥,减压浓缩,硅胶柱层析纯化,得白色固体C8(69.8g,93%)。1H NMR(400MHz,CDCl3)δ=7.94(d,J=7.4,1H),5.92(d,J=2.7,1H),5.79(d,J=7.3,1H),4.16(d,J=4.7,3H),3.95(d,J=11.0,1H),3.80(d,J=10.7,1H),0.88(s,10H),0.07(s,6H).13C NMR(101MHz,CDCl3)δ=165.48,156.91,141.24,94.96,90.94,85.26,70.36,62.52,25.92,18.36,-5.51。
取一干燥的250mL烧瓶,将C8(10.0g,28.01mmol,1.0eq)、CDI(9.10g,56.02mmol,2.0eq)溶解于50.0mL乙腈中,45℃加热回流,溶液从浑浊变澄清,反应1h,TLC(DCM:MeOH=4:1)检测原料反应完全,减压浓缩,硅胶柱层析纯化,得白色固体C9(9.8g,92%)。1H NMR(400MHz,CDCl3)δ=7.38(d,J=7.5,1H),5.90(d,J=7.4,1H),5.63(d,J=1.5,1H),5.47(dd,J=1.5,7.3,1H),5.24(dd,J=3.3,7.3,1H),4.36(q,J=2.1,1H),3.83(dt,J=5.4,10.9,2H),0.82(s,9H),0.00(s,6H).13C NMR(101MHz,CDCl3)δ=166.76,155.72,153.88,143.00,95.84,95.38,87.83,84.26,81.19,63.03,25.79,18.20,-5.43。
取一干燥的250mL烧瓶,将C9(10g,26.11mmol,1.0eq)、盐酸羟胺(18.07g,0.26mol,10eq)溶解于50mL异丙醇中,75℃加热回流,反应24h后,TLC(DCM:MeOH=8:1)检测原料反应完全,恢复至室温,过滤多余的盐酸羟胺,减压浓
缩,硅胶柱层析得白色固体化合物C10(3g,29%)。1H NMR(400MHz,MeOD)δ=6.83(d,J=8.2,1H),5.64(d,J=2.0,1H),5.45(m,2H),5.18(dd,J=3.6,7.5,1H),4.19(td,J=3.7,5.5,1H),3.78(dd,J=2.1,5.6,2H),0.82(s,9H),0.00(s,6H).13C NMR(101MHz,MeOD)δ=154.18,149.66,133.27,97.92,93.61,86.70,83.45,80.80,62.73。
取一干燥的50mL烧瓶,将C10(1.00g,2.51mmol,1.0eq)、异丁酸(232.5μL,2.51mmol,1.0eq)、DCC(0.52g,2.51mmol,1.0eq)和催化量的DMAP溶解于10.0mL无水的DMF中,反应12h。TLC(DCM:MeOH=10:1)检测原料反应完全,加入乙酸乙酯稀释(20mL),用水洗(20mL×2),饱和食盐水洗涤(20mL×1),收集有机相,加入无水硫酸钠干燥,减压浓缩,硅胶柱层析得白色固体化合物C11(PE:EA=2:1,0.36g,30%)。1H NMR(400MHz,CDCl3)δ=8.34(m,1H),6.86(d,J=8.2,1H),5.76(dd,J=2.0,8.2,1H),5.19(m,2H),4.30(m,1H),3.78(dd,J=1.2,4.5,2H),2.65(m,1H),1.18(m,9H),0.81(s,9H),0.00(d,J=2.1,6H).13C NMR(101MHz,CDCl3)δ=153.14,148.51,147.99,134.62,93.41,32.79,25.80,19.17,18.87。
取一干燥的25mL烧瓶,将C11(0.30g,0.64mmol,1.0eq)溶解于10.0mL混合的HCl/THF(HCl:THF=1:4)中,反应1h,TLC(DCM:MeOH=10:1)检测原料反应完全,减压浓缩,硅胶柱层析得白色固体化合物7(0.20g,90%)。1H NMR(400MHz,MeOD)δ=7.54(d,J=7.4,1H),5.88(d,J=7.3,1H),5.69(m,2H),5.45(dd,J=3.6,7.2,1H),4.48(m,1H),4.40(m,2H),2.59(p,J=7.0,1H),1.17(d,J=7.0,6H).13C NMR(101MHz,MeOD)δ=144.80,96.70,95.32,85.81,84.13,81.74,63.82,33.73,18.69,18.31。MS-ESI(m/z):计算值C14H18N3O8[M+1]+356.1094;实测值356.1098。
实施例8:化合物8的制备
取一干燥的50mL烧瓶,将C10(1.00g,2.51mmol,1.0eq)、L-Boc-缬氨酸(0.54g,2.51mmol,1.0eq)、DCC(0.52g,2.51mmol,1.0eq)和催化量的DMAP溶解于10.0mL无水的DMF中,反应12,TLC(DCM:MeOH=10:1)检测原料反应完全,加入EA稀释(30mL),用水洗(20mL×2),饱和食盐水洗涤(20mL×1),收集有机相中,加入无水硫酸钠干燥,减压浓缩,硅胶柱层析得白色固体化合物C12(PE:EA=2:1,0.52g,35%)。1H NMR(400MHz,CDCl3)δ=9.16(s,1H),6.86(d,J=8.1,1H),5.72(d,J=8.2,1H),5.61(m,1H),5.20(m,2H),5.01(d,J=8.5,1H),4.30(q,J=4.6,1H),
4.07(m,1H),3.77(m,2H),2.05(p,J=6.7,1H),1.37(s,10H),0.93(dd,J=6.8,11.8,6H),0.81(s,9H),-0.00(s,6H)。
取一干燥的25.0mL烧瓶,将C12(0.50g,0.83mmol,1.0eq)溶解于10.0Ml混合的HCl/THF(HCl:THF=1:4)中,反应1h。TLC(DCM:MeOH=10:1)检测原料反应完全,减压浓缩,得白色固体化合物8的盐酸盐(0.28g,88%。1H NMR(400MHz,MeOD)δ=6.85(d,J=8.1,1H),5.59(m,2H),5.34(dd,J=3.9,6.9,1H),5.03(s,1H),4.60(m,1H),4.33(m,2H),3.46(m,1H),2.60(m,1H),1.17(t,J=6.7,6H)。MS-ESI(m/z):计算值C15H21N4O8[M+1]+385.1359;实测值385.1369。
实施例9:化合物9的制备
取一干燥的250mL烧瓶,将C9(10.00g,26.11mmol,1.0eq)、苄基羟胺盐酸盐(25.44g,0.16mol,6.0eq)溶解于80%异丙醇水溶液中(100mL)中,75℃加热回流,反应24h后,TLC(DCM:MeOH=8:1)检测原料反应完全,恢复至室温,过滤多余的盐酸羟胺,减压浓缩,硅胶柱层析分离得白色固体化合物C13(4.1g,41%)。1H NMR(400MHz,MeODδ=7.25(m,5H),6.86(d,J=8.2,1H),5.64(d,J=2.2,1H),5.46(d,J=8.1,1H),5.41(m,1H),5.18(dd,J=4.0,7.6,1H),4.93(s,2H),4.16(td,J=3.9,5.2,1H),3.68(d,J=5.2,2H).13C NMR(101MHz,MeOD)δ=154.15,149.48,144.90,137.94,133.82,127.95,127.70,127.47,97.58,93.33,86.49,83.19,80.25,75.33,61.23。
取一干燥的25mL烧瓶,将C13(1.00g,2.67mmol,1.0eq)、异丁酸(247.3μL,2.67mmol,1.0eq)、DCC(0.55g,2.67mmol,1.0eq)和催化量的DMAP溶解于10.0mL无水的DMF中,反应12h,TLC(DCM:MeOH=10:1)检测原料反应完全,过滤除去DCU,加入乙酸乙酯稀释(50mL),用水洗(20mL×2),饱和食盐水洗涤(20mL×1),收集有机相中,加入无水硫酸钠干燥,减压浓缩,硅胶柱层析分离得白色固体化合物C14(PE:EA=2:1,0.36g,30%)。1H NMR(400MHz,MeOD)δ=7.35(m,5H),6.80(d,J=8.1,1H),5.57(m,2H),5.11(m,2H),5.03(s,2H),4.41(d,J=1.9,2H),4.21(d,J=5.4,1H),2.17(m,1H),0.94(dd,J=6.7,20.0,6H)。
取一干燥的25.0mL烧瓶,将C14(0.30g,0.67mmol,1.0eq)溶解于10ml(4:1=DCM:MeOH)混合溶液中,然后加入10%钯碳0.10g,通氢气,反应24h,TLC(DCM:MeOH=4:1)检测原料反应完全。用硅藻土过滤,收集有机相,减压浓缩,硅胶柱层析分离得白色固体化合物9(DCM:MeOH=8:1,0.09g,40%)。1H NMR
(400MHz,MeOD)δ=7.54(d,J=7.4,1H),5.88(d,J=7.3,1H),5.69(m,2H),5.45(dd,J=3.6,7.2,1H),4.48(m,1H),4.40(m,2H),2.59(p,J=7.0,1H),1.17(d,J=7.0,6H).13C NMR(101MHz,MeOD)δ=176.92,166.75,155.95,154.09,144.80,96.70,95.32,85.81,84.13,81.74,63.82,33.73,18.69,18.31。MS-ESI(m/z):计算值C14H18N3O8[M+1]+356.1094;实测值356.1094。
实施例10:化合物10的制备
取一干燥的25mL烧瓶,将C13(1.00g,2.67mmol,1.0eq)、L-CBz-缬氨酸(0.67g,2.67mmol,1.0eq)、DCC(0.55g,2.67mmol,1.0eq)和催化量的DMAP溶解于10.0mL无水的DMF中,反应12h,TLC(DCM:MeOH=10:1)检测原料反应完全,过滤除去DCU,加入乙酸乙酯稀释(40mL),用水洗(20mL×2),饱和食盐水洗涤(20mL×1),收集有机相,加入无水硫酸钠干燥,减压浓缩,柱层析分离得白色固体化合物C15(PE:EA=2:1,0.57g,35%)。1H NMR(400MHz,MeOD)δ=7.34(m,10H),5.57(m,1H),5.34(dt,J=4.9,18.1,1H),5.07(m,4H),4.48(m,2H),4.32(dq,J=5.1,10.8,1H),4.23(d,J=5.3,1H),2.16(m,1H),0.93(ddd,J=6.7,11.1,23.5,6H)。
取一干燥的25mL烧瓶,将C15(0.50g,0.82mmol,1.0eq)和10%钯碳0.3g加入到10.0mL(4:1=DCM:MeOH)混合溶液中,通氢气,反应24h,TLC(DCM:MeOH=4:1)检测原料反应完全。用硅藻土过滤,收集有机相,加压浓缩,硅胶柱层析分离得白色固体化合物10(DCM:MeOH=8:1,0.13g,40%)。1H NMR(400MHz,MeOD)δ=6.84(d,J=8.1,1H),5.71(dd,J=1.5,7.3,1H),5.61(d,J=8.0,2H),5.44(dd,J=3.6,7.4,1H),4.65(m,1H),4.50(dd,J=4.5,8.0,2H),3.92(d,J=4.4,1H),2.33(pd,J=4.3,7.0,1H),1.08(dd,J=4.9,7.0,6H).13C NMR(101MHz,MeOD)δ=168.15,153.85,149.98,144.48,134.26,98.78,95.39,84.39,83.47,64.67,58.11,29.62,17.29。MS-ESI(m/z):计算值C15H21N4O8[M+1]+385.1359;实测值385.1322。
实施例11:化合物11的制备
取一干燥的25mL烧瓶,将C13(1.00g,2.67mmol,1.0eq)、乙酸酐(0.40g,4.00mmol,1.5eq)和催化量的DMAP溶解于10.0mL无水的CH2Cl2中,反应12h,TLC(DCM:MeOH=10:1)检测原料反应完全,加入乙酸乙酯稀释(40mL),用水洗(20mL×2),饱和食盐水洗涤(20mL×1),收集有机相,加入无水硫酸钠干燥,减压浓缩,得C16的粗产品,直接用于下一步反应。取一干燥的25.0mL烧瓶,将以上粗产品C16溶解于10ml(4:1=DCM:MeOH)混合溶液中,通氢气,反应过夜。TLC(DCM:MeOH=4:1)检测原料反应完全。用硅藻土过滤,收集有机相,然后用水泵在40℃下旋干,硅胶柱层析分离得白色固体化合物11(DCM:MeOH=8:1,0.47g,50%)。1H NMR(400MHz,MeOD)δ=7.53(d,J=7.4,1H),5.77(d,J=7.4,1H),5.60(m,2H),5.30(m,1H),4.39(m,1H),4.27(m,2H),1.95(s,3H).13C NMR(101MHz,MeOD)δ=170.75,166.99,154.07,144.70,96.41,85.58,84.11,81.50,63.90,19.14.MS-ESI(m/z):计算值[M+H]+:calcd for C12H13N3O8,328.0781;实测值328.0791。
实施例12:化合物12的制备
取一干燥的100mL烧瓶,将C10(2.00g,5.01mmol,1.0eq)、溶解于20.0mL的THF中,0℃下加入三氟化氢三乙胺盐(96.8μL,7.52mmol,1.5eq),搅拌4h。TLC(DCM:MeOH=10:1)检测原料反应完全。减压旋干,硅胶柱层析的白色固体C17(DCM:MeOH=100:3,0.9g,63%)。1H NMR(400MHz,DMSO-d6)δ=10.13(s,1H),9.78(s,1H),6.98(d,J=8.2,1H),5.88(d,J=2.6,1H),5.58(d,J=8.1,1H),5.49(dd,J=2.6,7.8,1H),5.23(dd,J=4.1,7.8,3H),4.16(td,J=4.0,5.6,2H).13C NMR(101MHz,DMSO-d6)δ=154.20,149.58,143.66,132.66,99.26,91.55,85.78,82.84,80.59,61.18。
取一干燥的10mL烧瓶,将C17(400.0mg,1.40mmol,1.0eq)、异丁酸(389.1
μL,4.20mmol,3.0eq)、DCC(0.83g,4.20mmol,3.0eq)和催化量的DMAP溶解于10.0mL无水的DMF中,反应过夜。TLC(DCM:MeOH=10:1)检测原料反应完全。加入乙酸乙酯稀释(40mL),用水洗(20mL×2),饱和食盐水洗涤(20mL×1),收集有机相中,加入无水硫酸钠干燥。然后用水泵在40℃下旋干,硅胶柱层析分离得白色固体12(DCM:MeOH=100:3,0.15g,25%)。1H NMR(400MHz,MeOD)δ=8.14(d,J=7.6,1H),7.38(d,J=7.5,1H),6.19(d,J=5.4,1H),5.55(dd,J=4.0,5.4,1H),5.22(dd,J=4.0,5.9,1H),4.01(dt,J=3.5,5.8,1H),3.88(dd,J=3.3,11.5,1H),3.72(dd,J=3.7,11.5,1H),2.48(d,J=7.0,1H),2.27(m,1H),1.05(m,12H).13C NMR(101MHz,Methanol-d4)δ=178.59,174.86,158.40,155.98,144.91,96.61,84.79,81.83,74.76,74.35,61.24,36.15,33.65,25.47,24.78,18.41.MS-ESI(m/z):计算值C18H23N3O9,425.1429;实测值425.1446。
试验例1:化合物1-11及C6对细胞的毒性作用
用胰酶-EDTA消化生长状态良好的Vero-E6细胞,计数;用含10%胎牛血清的DMEM培养液调整细胞浓度为2×105/mL;将上述细胞悬液接种于96孔板培养,每孔100μL,在5%CO2,37℃培养24h形成单层。24h后,弃去培养液,PBS洗涤,甩干后换成新的DMEM培养液,分别加入化合物1-12及C6、瑞德西韦和莫努匹韦,其终浓度为50μM、10μM、5μM、1μM、0.1μM,同时设置空白细胞对照组,培养48小时后,用试剂进行细胞活力检测,并计算细胞的存活率,结果显示在终浓度为50μM、10μM、5μM、1μM、0.1μM时,瑞德西韦和化合物C6在50μM对Vero-E6细胞有一定的细胞毒性(细胞存活率分别为87.5%和85.3%),其它化合物均对对Vero-E6细胞均无细胞毒性,安全性好。
试验例2:化合物1-11及C6对新型冠状病毒(SARS-CoV-2)的抑制作用
细胞制备:以Vero-E6细胞计数2×105/ml每孔100ul细胞悬液铺96孔板,置于37℃、5%CO2培养箱中培养过夜,当细胞长成单层细胞时备用。
病毒稀释:第一管加入0.9mL含5%胎牛血清的DMEM,其余加入1.8mL;第一管中再加入0.1mL病毒保存液,然后换新枪头从第一管中吸取0.2mL加入第二管中;依次倍比稀释至最高稀释度。
病毒接种:用无血清DMEM将细胞洗一遍;于各孔中加入100μL不同的病毒稀释液,每个稀释度做一列孔,即每个病毒稀释度做8个平行复孔,加样时从最高稀释度开始,设置阴性对照,阴性对照孔中加入100μL含5%胎牛血清的DMEM,检测细胞存活情况,于5%CO2,37℃培养5天,5天后显微镜下观察,计算每一列中出现CPE的孔数,用KARBER法计算病毒TCID50/mL。
病毒活力检测:将VeroE6细胞以2×104个/孔接种于96孔培养板中,37℃培养
24h形成单层。化合物1-12、C6、瑞德西韦及莫努匹韦的药物初始浓度为6.0μM(溶液为0.5%DMSO的DMEM培养基溶液),灭活后按1:2,1:4,1:8,1:16,1:32,1:64,1:128稀释,每个稀释度做3个平行孔。然后将上述各组各稀释度的待测药物与100TCID50病毒液等量混合,37℃作用1h后,接种与Vero E6细胞中,于37℃,5%CO2培养5天,观察50%细胞发生病变的最高病毒稀释度。同时设置对照组:包括细胞对照(培养液中仅有细胞,不含病毒血清),阴性对照(培养液中含有100TCID50病毒、细胞以及空白血清)和空白对照组(培养基中含有100TCID50病毒以及细胞,不含血清)。根据细胞病变程度,用Reed-Muench法计算50%药物浓度为终点,即50%细胞不产生细胞病变(CPE)的药物稀释度,试验结果如表1。
表1 50%细胞产生细胞病变(CPE)的药物浓度的稀释度
采用微量板法试验来评价药物对新冠冠状病毒的抑制效果(稀释倍数越大表示抑制病毒的活性越高),从表1中可以看出:所述的含有环状碳酸酯的化合物1-12对新型冠状病毒三种变异株(Alpha、Delta和Omicron)都有显著的抑制效果,而且抑制效果明显优于2,3-位游离二羟基的瑞德西韦、C6、GS-441524、EIDD-1931和莫努匹韦。
试验例3:化合物2-9、GS-441524及瑞德西韦对猫冠状病毒的抑制作用
细胞制备:以猫肾细胞(CRFK)细胞计数1×105/ml每孔100ul细胞悬液铺96
孔板,置于37℃、5%CO2培养箱中培养过夜,分为试验组(不同药物浓度)、正常细胞组(不含病毒和药物)、病毒组(不含药物),每组3个重复孔。
病毒活力检测:每孔加入100TCID50的猫冠状病毒(FIPV)100uL,过夜吸附后弃去上清液,用PBS清洗配置400uM的药物,过滤除菌,用维持培养基稀将化合物2-8、莫努匹韦、GS-441524及瑞德西韦释成100uM、50uM、25uM、12.5uM、6.25uM、3.125uM、1.5625uM、0.78125uM的不同药物浓度,每个孔加100ul,等待病毒组的CPE达到75%~100%,进行CPE观察,其中0%-25%发生病变计1,25%-50%计2,50%-75%计3,75%-100%计4,结果如见表2。
表2在不同药物浓度下细胞产生细胞病变(CPE)的百分比
通过细胞产生细胞病变(CPE)来评价药物对对猫冠状病毒(FIPV)的抑制效果,从表2中可以看出:在药物浓度为12.5μM时,所述的含有环状碳酸酯的化合物2-8对都有显著的抑制效果,细胞病变率小于50%,其中化合物3-7细胞病变率小于25%,其抑制效果明显优于2,3-位游离二羟基的莫努匹韦、瑞德西韦和GS-441524。
试验例4:大鼠体内的药代动力学评价
药动学过程:取SD雄性大鼠(体重180~220g)21只,每组3只,实验前禁食12h,自由饮水,给药后2h统一进食。将GS441524、瑞德西韦与待测化合物采用适当溶剂溶解,给药的溶剂为DMSO/丙二醇/0.9%NaCl溶液(2/4/14,v/v/v),用少量
盐酸调节PH值为3~6使化合物完全溶解,给药剂量GS-441524大鼠灌胃(30mg/kg)/尾静脉注射给药(15mg/kg),化合物1-5及瑞德西韦(103μmol/kg)灌胃给药,EIDD-1931大鼠灌胃(259mg/kg)/尾静脉注射给药(130mg/kg),化合物7-10(1mmol/kg)灌胃给药。每组大鼠给药后,分别于0.25、0.5、1、2、3、4、8、12h用微量采血吸管取眼眶血0.3~0.5ml,置于1.5ml EP管(肝素预处理)中,4℃,3000rpm/min离心10min,分取上层含药血浆,于-80℃冰箱中冷冻待测。冰水浴操作,采用LC-MS-MS法测定血浆中GS-441524或EIDD-1931的浓度,计算药动学参数。
标准曲线:取大鼠空白血约5ml,3000rpm离心10min,分取血浆,取1.5ml EP管6只,分别加入0.1、0.5、1、5、10、20、50μl的1931储备液,工作溶媒补至450μl,混匀,各加入空白血浆50μl,涡旋5min,12000rpm/min离心5min,取上清,12000rpm/min再次离心5min,取上清于1.5ml EP管中,得10、50、100、500、1000、2000、5000ng/ml GS-441524或EIDD-1931标准曲线样品(含内标6,7-Dimethyl-2,3-Bis(2-pyridyl)quinoxaline,QX 100ng/ml)。
检测样品处理:分别取药物动力学过程所得含药血浆50μl于加有450μl工作溶媒(含50μl水、50μl甲醇、350μl乙腈)的1.5ml EP管中,涡旋5min,12000rpm/min,5min,取上清,12000rpm/min再次离心5min,取上清于1.5ml EP管中,得待测化合物药物动力学检测样品。
LC-MS检测:色谱柱,Kinetex C18核壳通用色谱柱(4.6mm×100mm,2.6μm,美国Phenomenex公司),柱温30℃,进样量10μL,流动相乙腈-0.6%甲酸铵(甲酸调pH5.0),流速1.0ml/min,等度洗脱;离子源,电喷雾离子源ESI;检测方式,多重反应监测(MRM);扫描方式,正离子模式;ESI喷雾电压5000V,离子源温度400℃,雾化气流速150μL/min,反吹干燥气流速100μL/min;质谱接口加热温度300℃。
药动学结果详见表3:
表3所有化合物药物动力学参数结果
注:a表示化合物相对于GS-441524口服生物利用度的百分比;b表示化合物相对于EIDD-1931口服生物利用度的百分比。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
本发明提供一种如式(I)所示的环状碳酸酯核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,同时还公开了包含该化合物的药物组合物及其应用。该化合物及药物组合物,可用于病毒感染的治疗或预防,例如冠状病毒、流感病毒、呼吸道合胞病毒、黄病毒科病毒、丝状病毒科病毒、新型冠状病毒和/或猫冠状病毒等相关病毒感染的治疗或预防,具有较好的经济价值和应用前景。
Claims (10)
- 一种核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,该化合物分子结构式如式(I)所示:
式中:R1、R2、R3和R4相同或不同,各自独立地选自氢、氘、卤素、氨基、叠氮基、氰基、羟基、巯基、C1-6烷基、C3-6环烷基、C2-6烯基或C2-6炔基,其中C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基中的一个或多个氢可任选地被相同或不同的氘、卤素、羟基、氨基、叠氮基、氰基、巯基、环丙基氰基、羧基、氨甲酰基、卤代甲基或含有一个或多个氧、氮、磷或硫原子的取代甲基取代;R5为选自氢、-COOH、烷烃酯基、芳香酯基、碳酸酯基、氨基甲酸酯基、硫代酯基、硫代碳酸酯基、S-硫代碳酸酯基、烷基羰基、烯基羰基、炔基羰基、芳基羰基、杂芳基羰基、氧甲氧基羰基、氧甲基羰基、异丁酸酯基、特戊酸酯基、L-或D-氨基酸酯基、N-取代的L-或D-氨基酸酯基、N,N-二取代的L-或D-氨基酸酯基、亚氨基酸酯基、腙酯基、肟酯基、酰亚胺基、硫代亚胺酸酯基、碳酰亚胺酸酯基、异脲基、胺基磷酸酯基、单磷酸酯基、二磷酸酯基、三磷酸酯基、 其中R5中的一个或多个氢可以任选的被相同或不同的R6取代;R6每次出现时各自独立地选自氘、氰基、卤素、羟基、叠氮基、巯基、氨基、羧基、磺酸基、烷基、烯基、炔基、芳基、杂芳基、环烯基、芳氧基、芳氨基、氨甲酰基或卤代甲基;R7和R8相同或不同,各自独立地选自-OR9、-SR9、-NHR9、-N(R9)2、芳氧基、杂芳氧基或R9选自苯酚基、萘酚基、烷烃酯基、芳香酯基、碳酸酯基、氨基甲酸酯基、硫代酯基、硫代碳酸酯基、S-硫代碳酸酯基、烷基羰基、烯基羰基、炔基羰基、芳基羰基、杂芳基羰基、氧甲氧基羰基、氧甲基羰基、L-或D-氨基酸酯基、N-取代的L-或D-氨基酸酯基;R10、R11和R12相同或不同,各自独立地选自烷基、烯基、炔基、芳香基、芳香烷基、杂芳香基;B为嘧啶类核苷碱基或嘌呤类核苷碱基。 - 根据权利要求1所述的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,其中,R1、R2、R3和R4相同或不同,各自独立地选自氢、卤素、叠氮基、氰基、C1-6烷基、羟甲基、环丙基、乙炔基或卤代甲基。
- 根据权利要求1或2所述的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,其中,R5选自H、C2-30烷基羰基、C2-30烯基羰基、C2-30炔基羰基、芳基羰基、杂芳基羰基、胺基磷酸酯基、异丁酸酯基、特戊酸酯基、氨基酸酯基、其中所述C2-30烷基羰基、C2-30烯基羰基或C2-30炔基羰基中的一个或多个氢可以任选的被相同或不同的R6取代;R7和R8相同或不同,各自独立地选自-OR9、-NHR9、苯酚基或萘酚基;R9选自苯酚基、萘酚基、L-或D-氨基酸酯基、N-取代的L-或D-氨基酸酯基;其中,R6、R10、R11和R12是如权利要求1所定义的。
- 根据权利要求1或2所述的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,其中,B选自:或其互变异构体,其中R13、R14和R15相同或不同,各自独立地选自氢、氘、卤素、氨基或取代氨基、叠氮、氰基、羟基、巯基或取代巯基、羟甲基、三氟甲基、环丙基、C1-6烷基或取代烷基,-OR16、-SR16、-NHR16、-N(R16)2或-NHOR16;R16选自H、C1-6烷基、C2-30烷基羰基、C2-30烯基羰基、C2-30炔基羰基、芳基羰基、杂芳基羰基、胺基磷酸酯基、异丁酸酯基、特戊酸酯基或氨基酸酯基。
- 根据权利要求4所述的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,其中,R13选自氢、氘、氟、氯或氨基;R14选自氢、氟、氯、氨基、甲基或三氟甲基;R15选自NHOR16、氨基、甲氨基、环丙氨基、羟基、甲氧基、乙氧基、巯基、甲巯基或NHR16;R16选自氢、异丁酸酯基、特戊酸酯基或天然氨基酸酯基。
- 根据权利要求1所述的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,其中,所述化合物的结构式为下面任意一种:
- 包含权利要求1-6任一项所述的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体的药物组合物。
- 包含权利要求1-6任一项所述的核苷类化合物、其药学上可接受的盐、结晶水合物、溶剂化物或互变异构体,或权利要求7所述的药物组合物在制备治疗或预防病毒感染引起的疾病的药物中的应用。
- 根据权利要求8所述的应用,其中,所述病毒选自冠状病毒、流感病毒、呼吸道合胞病毒、黄病毒科病毒、丝状病毒科病毒、新型冠状病毒SARS-CoV-2、猫传染性腹膜炎病毒FCoV、猪流行性腹泻病毒中的一种或任意几种的组合。
- 根据权利要求9所述的应用,其中,所述病毒为新型冠状病毒SARS-CoV-2和猫传染性腹膜炎病毒FCoV。
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