CN109627272A - With the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its medicinal usage - Google Patents
With the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its medicinal usage Download PDFInfo
- Publication number
- CN109627272A CN109627272A CN201811577487.4A CN201811577487A CN109627272A CN 109627272 A CN109627272 A CN 109627272A CN 201811577487 A CN201811577487 A CN 201811577487A CN 109627272 A CN109627272 A CN 109627272A
- Authority
- CN
- China
- Prior art keywords
- compound
- independently
- configuration
- tautomer
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229910019142 PO4 Inorganic materials 0.000 title abstract description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title abstract description 11
- 239000010452 phosphate Substances 0.000 title abstract description 9
- 239000002773 nucleotide Substances 0.000 title abstract description 5
- 125000003729 nucleotide group Chemical group 0.000 title abstract description 5
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 230000029812 viral genome replication Effects 0.000 title abstract description 3
- -1 nucleoside phosphate analogs Chemical class 0.000 claims abstract description 16
- 208000006454 hepatitis Diseases 0.000 claims abstract description 8
- 239000002777 nucleoside Substances 0.000 claims abstract description 8
- 125000004437 phosphorous atom Chemical group 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 19
- 241000711549 Hepacivirus C Species 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 239000002585 base Substances 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000003112 inhibitor Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 102100036286 Purine nucleoside phosphorylase Human genes 0.000 claims description 8
- 108010009099 nucleoside phosphorylase Proteins 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 7
- 231100000283 hepatitis Toxicity 0.000 claims description 7
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 claims description 5
- 101800001014 Non-structural protein 5A Proteins 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims description 5
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 claims description 4
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000003835 nucleoside group Chemical group 0.000 claims description 4
- 229960000329 ribavirin Drugs 0.000 claims description 4
- 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 claims description 4
- 241000710781 Flaviviridae Species 0.000 claims description 3
- 102100034343 Integrase Human genes 0.000 claims description 3
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 claims description 3
- 229940122806 Cyclophilin inhibitor Drugs 0.000 claims description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 2
- 102000014150 Interferons Human genes 0.000 claims description 2
- 108010050904 Interferons Proteins 0.000 claims description 2
- 229940125977 NS4B inhibitor Drugs 0.000 claims description 2
- 101800001020 Non-structural protein 4A Proteins 0.000 claims description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000000134 cyclophilin inhibitor Substances 0.000 claims description 2
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 2
- 229910052805 deuterium Inorganic materials 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 229940079322 interferon Drugs 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 238000001990 intravenous administration Methods 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 238000002156 mixing Methods 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
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 1
- 239000003018 immunosuppressive agent Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 4
- 230000000840 anti-viral effect Effects 0.000 abstract description 3
- 150000001413 amino acids Chemical class 0.000 abstract description 2
- 230000003013 cytotoxicity Effects 0.000 abstract 1
- 231100000135 cytotoxicity Toxicity 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 150000001720 carbohydrates Chemical group 0.000 description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000000714 pyrimidinyl group Chemical group 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 238000004679 31P NMR spectroscopy Methods 0.000 description 10
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 9
- 235000021317 phosphate Nutrition 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 4
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical compound COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 2
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229960000517 boceprevir Drugs 0.000 description 2
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 2
- 125000006364 carbonyl oxy methylene group Chemical group [H]C([H])([*:2])OC([*:1])=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229960002091 simeprevir Drugs 0.000 description 2
- JTZZSQYMACOLNN-VDWJNHBNSA-N simeprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCN(C)C(=O)[C@H]1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)NS(=O)(=O)C1CC1 JTZZSQYMACOLNN-VDWJNHBNSA-N 0.000 description 2
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 2
- 229960002063 sofosbuvir Drugs 0.000 description 2
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- WYAHEORVCZJINH-UHFFFAOYSA-N 1-fluoropyrimidin-2-one Chemical compound FN1C=CC=NC1=O WYAHEORVCZJINH-UHFFFAOYSA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000003760 hair shine Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 201000011200 hepatorenal syndrome Diseases 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000013139 quantization Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- FSDYDBAXNANUQE-UHFFFAOYSA-N tris(2,4-dichlorophenyl) phosphate Chemical compound ClC1=CC(Cl)=CC=C1OP(=O)(OC=1C(=CC(Cl)=CC=1)Cl)OC1=CC=C(Cl)C=C1Cl FSDYDBAXNANUQE-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 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
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- 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
- 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
- C07H19/056—Triazole or tetrazole radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- 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 discloses one group to have the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its medicinal usage.Novel nucleoside phosphate analogs disclosed by the invention are significantly superior to the Suo Feibuwei of clinical application in terms of anti-hepatitis activity, on chiral phosphorus atoms, alkoxycarbonyloxyalkyl substituted-phenyl and amino acid, cytotoxicity is significantly reduced in surveyed cell line, antiviral activity is improved, there is extraordinary potential applicability in clinical practice.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of novel nucleotide phosphate similar to object preparation method and
Its pharmaceutical composition and purposes, especially as the purposes for the treatment of hepatitis C.
Background technique
U.S. FDA had approved multiple HCV drugs, including protease inhibitors, ucleosides and non-nucleoside polymerization in recent years
Enzyme inhibitor and NS5A inhibitor etc..There are three the protease inhibitors class drugs of FDA approval: VX-950
(Telaprevir), the shortcomings that SCH-503034 (Boceprevir) and TMC435 (Simeprevir), protease inhibitors
It is to be also easy to produce that mutation, toxicity is big, poor bioavailability, it is effective to a other gene type.Telaprevir is as the first generation
Protease inhibitors has logged out market.The second generation of high activity and wide spectrum and third generation protease inhibitors is mainly used as and it
One of the component of drug combination of his hepatitis drug.
The patient that Hepatitis C Virus (HCV) has 3-4 million newly-increased every year, the World Health Organization estimate in global sense
Dye person is more than 200,000,000, and in China more than 10,000,000 patients, HCV belongs to flaviviridae hepatovirus virus.Long-term hepatitis C virus
Poison infection is gently to inflammation, weight to cirrhosis, liver cancer.And when hepatitis cirrhosis patients in decompensation, various complication, such as abdomen can occur
Water abdominal cavity infection, upper gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, the performance such as hepatic failure.
Hepatitis C pathogenesis is fully aware of not yet, causes liver cell structure and function when HCV is replicated in liver cell
Change or interference Hepatocyte synthesizes, degeneration of liver cells can be caused downright bad, show that HCV directly damages liver, cause to fall ill
Certain effect.
The polymerase inhibitors of hepatitis is generally divided into ucleosides and two kinds of non-nucleoside.Currently, clinically only having Suo Feibu
One ucleosides hepatitis drug of Wei is ratified to list by FDA, and Sofosbuvir and other HCV-Ab IgGs are in the clinical examination for grinding drug combination
It tests and also shows good effect.But since bioavilability is low in vivo by sofosbuvir, need with biggish to medicament
Amount, hepatitis patient need to receive long-term treatment, and bring virus drug resistance and long-term safety problem can not be ignored therewith, because
This, develops new bioavilability height, and the low HCV infection therapeutic agent of drug effect high toxicity is still clinical urgent need.
Summary of the invention:
The purpose of the present invention is the structures to nucleotide phosphate similar to object to be further transformed, and obtains having higher
The active novel nucleoside phosphate analogs of bioavilability, more hypotoxicity and more highly resistance HCV virus, for from now on further investigation with
The antiviral application of exploitation the compounds of this invention lays the foundation.
To solve the above problems, the technical solution adopted by the present invention are as follows:
The present invention provides the compound with general formula structure (Ia), salt, tautomer or free alkalis
Wherein, Base is B1, B2, B3, B4, B5;
Here, R1、R2、R3、R4、R5It is H, D, F, Cl, CH each independently3、NH2Or cyclopropylamino.
Ri is five yuan of ribose Ri1、Ri2、Ri3;
Here, X2、Y2、X3、Y3、Y4It is H, F, Cl, OH, CH each independently3Or N3。
Z1=O, C=CH2;
Z2=O, CH2;
Z3、Z4It is O or S each independently;
X, Y is H or D each independently;
A=OC (O) O, OC (O) or C (O) O;
R22=H, C1- C6Alkyl;
Rb=R0, R2, R4;Here, R0=H, C1- C6Alkyl;R2=CH2AR22;R4=aryl.
As further preferred scheme, compound (Ia) of the present invention, salt, tautomer or free alkali,
It is preferred that A=OC (O) O;R22It is preferred that isopropyl, isobutyl group, neopentyl;R4It is preferred that phenyl.
As further preferred scheme, compound of the present invention, salt, tautomer or free alkali, phosphorus
Atom is chiral atom, preferably its single configuration S(P)Configuration or R(P)Configuration or S(P)Configuration and R(P)Configuration any proportion mixes
Close object.
As scheme still more preferably, compound of the present invention, salt, tautomer or free alkali, institute
Preferred structural formula of compound is as follows:
The synthetic route of nucleoside phosphorylase ester compounds of the present invention is as follows:
Here: Base, Ri, X, Y, A, R22、RbDefinition is the same as claim 1.
Under alkaline condition, R is added with after phosphorus oxychloride reaction in K2bOH reaction, adds Pentafluorophenol reaction
Close object F2B-1 and F2B-2;Under cryogenic, compound F2B-1 or F2B-2 are reacted with nucleosides, respectively obtain chemical combination
Object N2B-2 or N2B-1.
Nucleoside phosphorylase ester compounds of the present invention mix system with pharmaceutically acceptable carrier, diluent or excipient
It is standby at pharmaceutical preparation and nanometer formulation, to be suitable for oral or parenteral;Medication include, but are not limited to it is intradermal,
In intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.
A kind of medical composition comprising nucleoside phosphorylase ester compounds of the present invention.
Medical composition of the present invention also contains the other therapeutic agents independently selected from following drug: Ribavirin
(Ribavirin), interferon, hepatitis NS3 protease inhibitors, HCV reverse transcriptase NS5B non-nucleosidic inhibitors, HCV reverse transcription
Enzyme NS5B nucleosidic inhibitors, the synergist of NS5A inhibitor and NS5A inhibitor, entry inhibitor, cyclosporine immunosupress
Agent, NS4A antagonist, NS4B inhibitor, cyclophilin inhibitor.
Nucleoside phosphorylase ester compounds and its Pharmaceutical composition of the present invention are in the drug for preparing anti-Flaviviridae
In application, the flaviviridae is Hepatitis C Virus.
The dosage form of pharmaceutical composition of the present invention is tablet, injection or capsule.
Specific embodiment
The present invention is further elaborated by the following examples, but the present invention is not limited to these Examples.This hair
Reagent used in bright embodiment and raw material are the commercially available gained in market.
Embodiment 1
(R)-(isopropoxy carbonyl oxygroup) methyl pentafluorophenyl group phosphate (FP020-1) and (S)-(isopropoxy
Carbonyloxy group) methyl pentafluorophenyl group phosphate (FP020-2) synthesis.
Phosphorus oxychloride (5g, 3.04ml, 32.6mmol) is added in reaction flask, adds acetonitrile 200mL, is cooled to -70 DEG C,
Acetonitrile (60mL) solution of K2 (4.37g, 32.6mmol) and triethylamine (3.3g, 4.53ml, 32.6mmol) is slowly added dropwise, drips
It adds complete, is slowly increased to room temperature, after reaction overnight, is cooled to 0 DEG C, by Pentafluorophenol (5.4g, 29.4mmol) and triethylamine
The acetonitrile solution 60mL liquid of (7.3g, 10ml, 72mmol) is added drop-wise in above-mentioned solution, is stirred 1 hour at 0 DEG C, is risen to room
Temperature after being stirred overnight, is added 100ml methylene chloride and 100ml water, separates organic phase, dense with depressurizing after anhydrous sodium sulfate drying
Contracting, residue obtain 6.2g white solid, 10% tert-butyl of solid with silica gel post separation (0-30% ethyl acetate/n-hexane)
Methyl ether/n-hexane recrystallization, obtains white solid FP020-2 (2.5g), mother liquor with silica gel post separation (50% ethyl acetate/oneself
Alkane) FP020-1 (1.8g) and FP020-2 (0.3g), FP020-2 and FP020-1 purity are all larger than 99%.
FP020-1:1H NMR (400MHz, CDCl3) δ (ppm): 1.12-1.23 (6H, m, 2 × CH3), 4.68-
4.79 (1H, m, OCH), 5.31-5.43 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -1.57.
FP020-2:1H NMR (400MHz, CDCl3) δ (ppm): 1.16-1.28 (6H, m, 2 × CH3), 4.71-
4.79 (1H, m, OCH), 5.32-5.49 (2H, m, OCH2O)。
31P NMR (162MHz, CDCl3) δ -1.83.
Embodiment 2
The synthesis of two ((isopropoxy carbonyl oxygroup) methyl) pentafluorophenyl group phosphates (FP2020).
Phosphorus oxychloride (5g, 3.04ml, 32.6mmol) is added in reaction flask, adds acetonitrile 200mL, is cooled to -70 DEG C,
Acetonitrile (60mL) solution of K2 (8.7g, 65.2mmol) and triethylamine (6.6g, 9.06ml, 65.2mmol) is slowly added dropwise, is added dropwise
It finishes, is slowly increased to room temperature, after reaction overnight, be cooled to 0 DEG C, by Pentafluorophenol (5.4g, 29.4mmol) and triethylamine (7.3
Gram, 10ml, 72mmol) acetonitrile solution 60mL liquid be added drop-wise in above-mentioned solution, 0 DEG C stir 1 hour, be warmed to room temperature, stir
After mixing overnight, 100 milliliters of methylene chloride and 100 milliliters of water are added, separate organic phase, it is dense with being depressurized after anhydrous sodium sulfate drying
Contracting, residue obtain 8.3g white solid, 10% tert-butyl first of solid with silica gel post separation (0-30% ethyl acetate/hexane)
Base ether/hexane recrystallization, obtains white solid FP11 (3.2g), mother liquor with silica gel post separation (50% ethyl acetate/hexane) again
FP11 (2.1g), FP11 purity are greater than 99%.
1H NMR (400MHz, CDCl3) δ (ppm): 1.10-1.25 (12H, m, 4 × CH3), 4.61-4.81 (2H, m, 2
× OCH), 5.30-5.46 (4H, m, 2 × OCH2O)。
Embodiment 3
The synthesis of two ((neopentyl oxygen carbonyl oxygroup) methyl) pentafluorophenyl group phosphates (FP2323).
FP2323 is closed in the similar method of embodiment 2.
1H NMR (400MHz, CDCl3) δ (ppm): 0.82-0.95 (18H, m, 6 × CH3), 4.30-4.49 (4H, m, 2
×COOCH2), 5.33-5.48 (4H, m, 2 × OCH2O)。
Embodiment 4
(R)-((phenyl-pentafluoride oxygroup) (phenoxy group) phosphoryl oxygroup) methyl carbonic acid isopropyl ester (FP24-1) and (S)-
The synthesis of ((phenyl-pentafluoride oxygroup) (phenoxy group) phosphoryl oxygroup) methyl carbonic acid isopropyl ester (FP24-2).
Dichloro-phenyl phosphate (6.88g, 3.04ml, 32.6mmol) is added in reaction flask, adds acetonitrile 200mL, it is cooling
To -70 DEG C, the acetonitrile of K2 (4.37g, 32.6mmol) and triethylamine (3.3 grams, 4.53ml, 32.6mmol) is slowly added dropwise
(60mL) solution, is added dropwise, and is slowly increased to room temperature, after reaction overnight, is cooled to 0 DEG C, by Pentafluorophenol (5.4g,
It 29.4mmol) is added drop-wise in above-mentioned solution with the acetonitrile solution 60mL liquid of triethylamine (7.3 grams, 10ml, 72mmol), at 0 DEG C
Stirring 1 hour, is warmed to room temperature, after being stirred overnight, 100 milliliters of methylene chloride and 100 milliliters of water is added, organic phase are separated, with nothing
It is concentrated under reduced pressure after aqueous sodium persulfate is dry, residue obtains 7.6g white with silica gel post separation (0-30% ethyl acetate/hexane) and consolidates
Body, solid are recrystallized with 10% t-butyl methyl ether/hexane, are obtained white solid FP24-2 (3g), mother liquor silica gel post separation
(50% ethyl acetate/hexane) obtains FP24-1 (2.3g) and FP24-2 (0.4g), FP24-2 and FP24-1 purity are all larger than
99%.
FP24-1:1H NMR (400MHz, CDCl3) δ (ppm): 1.12-1.23 (6H, m, 2 × CH3), 4.68-4.79
(1H, m, OCH), 5.31-5.43 (2H, m, OCH2O), 7.17-7.30 (H in 3H, m, OPh ortho para position), 7.33-7.37
(H in 2H, m, OPh meta position).31P NMR (162MHz, CDCl3) δ -1.62.
FP24-2:1H NMR (400MHz, CDCl3) δ (ppm): 1.16-1.25 (6H, m, 2 × CH3), 4.70-4.83
(1H, m, OCH), 5.32-5.48 (2H, m, OCH2O), 7.18-7.34 (H in 3H, m, OPh ortho para position), 7.37-7.41
(H in 2H, m, OPh meta position).31P NMR (162MHz, CDCl3) δ -1.98.
Embodiment 5
(((2R, 3R, 4R, 5R) -5- (2,4 (1H, 3H)-hybar X -1- base) fluoro- 3- hydroxyl-of -4-
4- methyltetrahydrofuran -2- base) methyl) two ((isopropoxy carbonyl oxygroup) methyl) phosphotriesters (SOF2020) synthesis
Nucleosides SOF (260.2mg, 1mmol) and the anhydrous THF of 5.0mL are added into 50mL flask, mixture is in ice-water bath
It is cooled to 0 DEG C.It is added dropwise tert-butyl magnesium chloride 1.0MinTHF solution (3.0mL, 3.0mmol), reaction mixture stirs at 0 DEG C
The solution of phosphorus reagent FP2020 (794mg, 1.6mmol) in 5mLTHF is then added dropwise in 30min at 0 DEG C.It will be obtained clear
Clearance response solution is warmed to room temperature, and after stirring 20 hours, saturation NH is added4Cl (15mL) is stirred 5 minutes, by mixture acetic acid
Ethyl ester (200mL) dilution, separates organic phase, aqueous layer with ethyl acetate (30mL) is extracted twice.Combined organic layer water
(30mL), saturation NaHCO3The washing of (2x30mL), salt water (30mL), and through Na2SO4Decompression boils off solvent, residue after drying
It is purified via silica gel column chromatography (methylene chloride of 0-10% methanol), obtains white solid product SOF2020 (315mg), yield
55%).
1H NMR (400MHz, CDCl3) δ (ppm): 1.09-1.39 (15H, m, 5 × CH3), 4.09-4.14 (1H, m,
H on saccharide ring 3 '-position), 4.28 (1H, brs, the OH on saccharide ring 3 '-position), 4.34-4.41 (1H, m, on saccharide ring 4 '-position
H), 4.47-4.52 (2H, m, the H on saccharide ring 5 '-position), 4.87-4.99 (2H, m, 2 × COOCH), 5.55-5.72 (5H,
M, 2 × OCH2H on O and pyrimidine ring 5), 6.19 (1H, s, the H on saccharide ring 1 '-position), 7.22-7.51 (1H, d, pyrimidine
H on 6, ring), 9.75 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ3.27;
ESI+MS:(M+H)+573.4。
Embodiment 6
(R)-(((2S, 3S, 5R) -5- (5- methyl -2,4 (1H, 3H)-hybar X -1- base) -3- nitrine
Tetrahydrofuran -2- base) methyl) ((isopropoxy carbonyl oxygroup) methyl) phosphate (AZT020-2) synthesis.
AZT020-1 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 1.09-1.39 (6H, m, 2 × CH3), 1.95 (3H, s, pyrimidine rings 5
CH on position3), 2.30-2.53 (3H, m, the H on 3 '-position of Hand saccharide ring on saccharide ring 2 '-position, 4.06-4.23 (1H, m,
H on saccharide ring 4 '-position), 4.27-4.44 (2H, m, the H on saccharide ring 5 '-position), 4.87-4.99 (1H, m, COOCH),
5.55-5.72 (2H, m, OCH2O), 6.15 (1H, t, the H on saccharide ring 1 '-position, 7.25 (1H, s, the H on pyrimidine ring 6),
9.25 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ3.79;
ESI+MS:(M+H)+464.3。
Embodiment 7
(S)-(((2S, 3S, 5R) -5- (5- methyl -2,4 (1H, 3H)-hybar X -1- base) -3- nitrine
Tetrahydrofuran -2- base) methyl) ((isopropoxy carbonyl oxygroup) methyl) phosphate (AZT020-2) synthesis.
AZT020-2 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 1.12-1.43 (6H, m, 2 × CH3), 1.95 (3H, s, pyrimidine rings 5
CH on position3), 2.32-2.55 (3H, m, the H on 3 '-position of Hand saccharide ring on saccharide ring 2 '-position, 4.09-4.26 (1H, m,
H on saccharide ring 4 '-position), 4.30-4.45 (2H, m, the H on saccharide ring 5 '-position), 4.89-5.01 (1H, m, COOCH),
5.58-5.75 (2H, m, OCH2O), 6.17 (1H, t, the H on saccharide ring 1 '-position, 7.27 (1H, s, the H on pyrimidine ring 6),
9.25 (1H, s, the NH on pyrimidine ring 3).
31P NMR (162MHz, CDCl3)δ3.92;
ESI+MS:(M+H)+464.3。
Embodiment 8
(((2R, 5S) -5- (fluoro- -2 (1H)-pyrimidone -1- base of 4- amino of 5-) -1,3- oxygen sulphur Polymorphs
Alkane -2- base) methyl) two ((neopentyl oxygen carbonyl oxygroup) methyl) phosphotriesters (FTC2323) synthesis.
FTC2323 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 0.89 (18H, m, 6 × CH3), 3.06-3.51 (2H, m, saccharide ring
H on 2 '-positions), 3.86-4.06 (4H, m, 2 × COOCH2), 4.26-4.47 (1H, m, the H on saccharide ring 4 '-position),
5.29-5.42 (2H, m, the H on saccharide ring 5 '-position), 5.55-5.72 (5H, m, 2 × OCH2On 1 '-position of O and saccharide ring
H), 5.81-6.21 (2H, dbrs, the NH on pyrimidine ring 42), 7.92-8.16 (1H, s, the H on pyrimidine ring 6).
31P NMR (162MHz, CDCl3)δ4.52;
ESI+MS:(M+H)+616.6。
Embodiment 9
((S)-(((2R, 5S) -5- (4- amino -2 (1H)-pyrimidone -1- base) -1,3- oxygen sulphur Polymorphs
Alkane -2- base) methyl oxygroup) (phenoxy group) phosphoryl oxygroup) and methyl carbonic acid isopropyl ester (3TC24-1) synthesis.
3TC24-1 is synthesized in the similar method of embodiment 5
1H NMR (400MHz, CDCl3) δ (ppm): 1.08-1.39 (6H, m, 2 × CH3), 3.06-3.51 (2H, m, sugar
H on ring 2 '-position), 4.26-4.47 (1H, m, the H on saccharide ring 4 '-position), 4.87-4.99 (1H, m, COOCH), 5.29-
5.42 (3H, m, the H on saccharide ring 5 '-position and pyrimidine ring 5), 5.55-5.72 (3H, m, OCH2On 1 '-position of O and saccharide ring
H), 5.81-6.21 (2H, dbrs, the NH on pyrimidine ring 42), 7.23-7.29 (2H, m, the H on phenyl ring ortho position),
7.32-7.39 (3H, m, the H between phenyl ring in contraposition), 8.32-8.72 (1H, d, the H on pyrimidine ring 6).
31P NMR (162MHz, CDCl3)δ4.28;
ESI+MS:(M+H)+502.5。
Embodiment 10
((R)-(((2R, 5S) -5- (4- amino -2 (1H)-pyrimidone -1- base) -1,3- oxygen sulphur Polymorphs
Alkane -2- base) methyl oxygroup) (phenoxy group) phosphoryl oxygroup) and methyl carbonic acid isopropyl ester (3TC24-2) synthesis.
3TC24-2 is synthesized in the similar method of embodiment 5.
1H NMR (400MHz, CDCl3) δ (ppm): 1.10-1.42 (6H, m, 2 × CH3), 3.09-3.55 (2H, m, sugar
H on ring 2 '-position), 4.29-4.42 (1H, m, the H on saccharide ring 4 '-position), 4.90-5.03 (1H, m, COOCH), 5.31-
5.44 (3H, m, the H on saccharide ring 5 '-position and pyrimidine ring 5), 5.58-5.74 (3H, m, OCH2On 1 '-position of O and saccharide ring
H), 5.85-6.24 (2H, dbrs, the NH on pyrimidine ring 42), 7.27-7.31 (2H, m, the H on phenyl ring ortho position),
7.36-7.47 (3H, m, the H between phenyl ring in contraposition), 8.34-8.64 (1H, d, the H on pyrimidine ring 6).
31P NMR (162MHz, CDCl3)δ4.57;
ESI+MS:(M+H)+502.5。
Embodiment 11
Biological assessment
1. antiviral activity detection of the compound of the present invention in HCV replicon (HCVpp) system
HCV replicon mensuration program
General procedure: make the cell in the source Huh-7 with HCV genotype 1b replicon and luciferase reporter gene
It is (Zluc) in supplement 10% fetal calf serum, 2mMGlutaMAX, 1%MEM nonessential amino acid, 100IU/mL penicillin, 100 μ
The Dulbecco of g/mL streptomysin and 0.5mg/mL (G418) improve growth in Eagle culture medium (DMEM).By using being based on
Lipid/histone transfection process transiently transfects Zluc cell with mankind's carbonyl acid ester enzyme 1 (CES1).After transfection 24 and 48 hours,
Using anti-CES1 and anti-tag antibody, the expression of CES1 is confirmed by Western blotting (Westernblot).For dose response
Test, with 7.5xl03 cells/well, in 50 μ L volumes, by cell inoculation in 96 orifice plates, and in 37 DEG C/5%CO2Under incubate
It educates.Fresh drug solution is as 2X liquid storage in Huh-7 culture medium.From these liquid storage systems in the DMEM without G418
Standby 10 5 times of other dilutions.At least 3 hours after being inoculated with Huc cell, by being added 50 μ L's in duplicate into plate
Drug dilution liquid is to start drug-treated.The range of drug final concentration is 100nM-0.0000512n Μ.Then cell is existed
37 DEG C/5%CO2Lower incubation.Or compound is tested with two kinds of concentration (10nM and 100nM).In all cases, Huh-7
(it is not with HCV replicon) is used as negative control.It, will by Fluc by quantization after being incubated for 72 hours
5 '-fluorine luciferin list oxygen synthesize the photon that oxygroup fluorine luciferin (oxyfIuoroluciferin) is emitted, to measure HCV
The inhibition of duplication.For this purpose, removing culture medium from plate by tapping, 50 microlitres of ONE-glo luciferase assay kits being added
Enter each hole.Plate is gently vibrated 3 minutes at room temperature, using 700nm cut-off filter, there is 1 second readout time
It measures and shines on Victor3V1420 multiple labeling counter (PerkinElmer).By Microsoft Excel and
The dose-effect curve for the gained best fit equation formula that XLfit4.1 software is found out calculates EC50Value.
For Cytotoxic evaluation, Zluc cell is handled with above compound, using CellTiter-Blue cell
It survives amylograph (Promega), 20 μ L measurement solution is added in each hole, to monitor cell viability.Then by plate 37
DEG C/5%CO2It is lower to be incubated at least 3 hours.It is more in Victor3V1420 respectively with the excitation and launch wavelength of 560 and 590nm
The fluorescence for marking detection plate in counter (Perkin Elmer), finds out using Microsoft Excel and XLfit4.1 software
CC50Value.
The compound that following table provides is measured according to above-mentioned replicon measuring method.
+++ indicate 1-10nM;++ indicate 10-100nM;+ indicate 0.1-1 μM;
* Suo Feibuwei is according to bibliography J.Org.Chem.2011,76,8311 preparations.
Claims (10)
1. the compound with structure (Ia), salt, tautomer or free alkali
Wherein, Base is B1, B2, B3, B4, B5;
Here, R1、R2、R3、R4、R5It is H, D, F, Cl, CH each independently3、NH2Or cyclopropylamino;
Ri is five yuan of ribose Ri1、Ri2、Ri3;
Here, X2、Y2、X3、Y3、Y4It is H, F, Cl, OH, CH each independently3Or N3;
Z1=O, C=CH2;
Z2=O, CH2;
Z3、Z4It is O or S each independently;
X, Y is H or D each independently;
A=OC (O) O, OC (O) or C (O) O;
R22=H, C1- C6Alkyl;
Rb=R0, R2, R4;Here, R0=H, C1- C6Alkyl;R2=CH2AR22;R4=aryl.
2. compound (Ia) as described in claim 1, salt, tautomer or free alkali, which is characterized in that preferred A=
OC(O)O;R22It is preferred that isopropyl, isobutyl group, neopentyl;R4It is preferred that phenyl.
3. such as compound claimed in claims 1-2, salt, tautomer or free alkali, which is characterized in that phosphorus atoms are
Chiral atom, preferably its single configuration S(P)Configuration or R(P)Configuration or S(P)Configuration and R(P)The mixture of configuration any proportion.
4. the compound as described in claim 1-3, salt, tautomer or free alkali, which is characterized in that institute is preferred
Structural formula of compound is as follows:
5. a kind of method for preparing nucleoside phosphorylase ester compounds described in claim 1-4, which is characterized in that the method
Synthetic route is as follows:
Here: Base, Ri, X, Y, A, R22、RbDefinition is the same as claim 1;
Under alkaline condition, R is added with after phosphorus oxychloride reaction in K2bOH reaction, adds Pentafluorophenol and reacts to obtain compound
F2B-1 and F2B-2;Under cryogenic, compound F2B-1 or F2B-2 are reacted with nucleosides, respectively obtain compound
N2B-2 or N2B-1.
6. nucleoside phosphorylase ester compounds described in -4 according to claim 1, it is characterized in that: with pharmaceutically acceptable carrier, dilute
It releases agent or excipient is prepared by mixing into pharmaceutical preparation and nanometer formulation, to be suitable for oral or parenteral;Medication
Include, but are not limited in intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.
7. a kind of medical composition comprising nucleoside phosphorylase ester compounds described in claim 1.
8. medical composition according to claim 7, it is characterized in that: also containing the other treatment independently selected from following drug
Agent: the non-nucleosides of Ribavirin (Ribavirin), interferon, hepatitis NS3 protease inhibitors, HCV reverse transcriptase NS5B inhibits
Agent, HCV reverse transcriptase NS5B nucleosidic inhibitors, NS5A inhibitor and NS5A inhibitor synergist, entry inhibitor, ring spore
Plain immunosuppressor, NS4A antagonist, NS4B inhibitor, cyclophilin inhibitor.
9. a kind of nucleoside phosphorylase ester compounds described in claim 1 and its Pharmaceutical composition are preparing anti-Flaviviridae
Application in drug, it is characterized in that: the flaviviridae is Hepatitis C Virus.
10. the pharmaceutical composition as described in claim 7-9, it is characterised in that: the dosage form of described pharmaceutical composition be tablet,
Injection or capsule.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811577487.4A CN109627272A (en) | 2018-12-21 | 2018-12-21 | With the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its medicinal usage |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811577487.4A CN109627272A (en) | 2018-12-21 | 2018-12-21 | With the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its medicinal usage |
Publications (1)
Publication Number | Publication Date |
---|---|
CN109627272A true CN109627272A (en) | 2019-04-16 |
Family
ID=66076682
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811577487.4A Pending CN109627272A (en) | 2018-12-21 | 2018-12-21 | With the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its medicinal usage |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109627272A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113501847A (en) * | 2021-09-13 | 2021-10-15 | 南京颐媛生物医学研究院有限公司 | High-efficiency anti-hepatitis B virus compound and preparation method and application thereof |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102137676A (en) * | 2007-12-27 | 2011-07-27 | 伊皮芬尼生物科学公司 | Antiviral compounds |
CN108276463A (en) * | 2017-01-06 | 2018-07-13 | 米文君 | A new class of compound and application thereof |
-
2018
- 2018-12-21 CN CN201811577487.4A patent/CN109627272A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102137676A (en) * | 2007-12-27 | 2011-07-27 | 伊皮芬尼生物科学公司 | Antiviral compounds |
CN108276463A (en) * | 2017-01-06 | 2018-07-13 | 米文君 | A new class of compound and application thereof |
Non-Patent Citations (1)
Title |
---|
寿雪枫等: "抗丙型肝炎药物索磷布韦的设计合成研究进展", 《国际药学研究杂志》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113501847A (en) * | 2021-09-13 | 2021-10-15 | 南京颐媛生物医学研究院有限公司 | High-efficiency anti-hepatitis B virus compound and preparation method and application thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102241604B (en) | Amino acid modified curcumin, synthesis method thereof, and application thereof | |
US8629263B2 (en) | Nucleoside phosphoramidates | |
US8735569B2 (en) | Nucleoside phosphoramidates | |
ES2744587T3 (en) | 1-Substituted pyrimidine N-nucleoside analogs for antiviral treatment | |
EP2552930B1 (en) | Crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1-(2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate | |
IL250389A (en) | Subsituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes useful for treating hcv infections | |
IL217228A (en) | Nucleoside phosphoramidate prodrugs of 2'-deoxy-2'-fluoro-2'-c-methyluridine | |
EA027929B1 (en) | Uracyl spirooxetane nucleosides | |
CN105829334B (en) | Uracil nucleotides are like object and its preparation method and application | |
TW201329096A (en) | Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections | |
CN104039774A (en) | Hcv ns3 protease inhibitors | |
JP2022549923A (en) | Crystal forms of N-hetero pentacyclic ring-containing capsid protein assembly inhibitors and uses thereof | |
CN109651452A (en) | With the active nucleoside phosphorylase long-chain dibasic acid esters analog of suppressing virus replication, preparation method and its medicinal usage | |
CN109627272A (en) | With the active nucleotide phosphate of suppressing virus replication similar to object, preparation method and its medicinal usage | |
CN108350008B (en) | Novel acyclic nucleoside analogue and pharmaceutical composition thereof | |
CN108129366B (en) | Antiviral compounds, methods of preparation and uses thereof | |
Liu et al. | Design, synthesis and identification of silicon-containing HCV NS5A inhibitors with pan-genotype activity | |
CN109651468A (en) | With the active nucleoside phosphoramidate analog of suppressing virus replication, preparation method and its medicinal usage | |
CN109503688A (en) | With the active nucleoside phosphorylase long-chain ester analogs of suppressing virus replication, preparation method and its medicinal usage | |
CN103183722B (en) | Glyoxalase I inhibitor, preparation method and medical application thereof | |
CN105504007B (en) | Phosphoramidate derivatives, preparation method thereof and application thereof in pharmacy | |
CN112194694B (en) | Urodylate phenylpropionate phosphoramidate compound, pharmaceutical composition thereof, and preparation method and application thereof | |
CN106967141B (en) | Nucleoside phosphoramidate compounds and pharmaceutical compositions and uses thereof | |
CN112142809B (en) | Uretidine dipropionate phosphoramidate compound, pharmaceutical composition thereof, and preparation method and application thereof | |
CN105777829B (en) | A kind of prodrug containing class nucleotide structure, preparation method, medical composition and its use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190416 |