CN112047945B - 螺环吡啶酮衍生物及应用 - Google Patents
螺环吡啶酮衍生物及应用 Download PDFInfo
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- CN112047945B CN112047945B CN202010947508.8A CN202010947508A CN112047945B CN 112047945 B CN112047945 B CN 112047945B CN 202010947508 A CN202010947508 A CN 202010947508A CN 112047945 B CN112047945 B CN 112047945B
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- influenza
- spiro
- compound
- triazine
- benzyloxy
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 13
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 claims abstract description 11
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 claims abstract description 10
- 241000712431 Influenza A virus Species 0.000 claims abstract description 9
- 230000000694 effects Effects 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 claims description 17
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 206010022000 influenza Diseases 0.000 claims description 9
- AYVGBNGTBQLJBG-UHFFFAOYSA-N [3-(hydroxymethyl)cyclopentyl]methanol Chemical compound OCC1CCC(CO)C1 AYVGBNGTBQLJBG-UHFFFAOYSA-N 0.000 claims description 6
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000005764 inhibitory process Effects 0.000 abstract description 7
- -1 spiro pyridone derivative Chemical class 0.000 abstract description 7
- 238000011160 research Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000001035 drying Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 241000712461 unidentified influenza virus Species 0.000 description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 230000003612 virological effect Effects 0.000 description 6
- JBIHUDRUDVZFPT-UHFFFAOYSA-N 4-oxo-3-phenylmethoxypyran-2-carbaldehyde Chemical compound O1C=CC(=O)C(OCC=2C=CC=CC=2)=C1C=O JBIHUDRUDVZFPT-UHFFFAOYSA-N 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical group 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 4
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 3
- LQDVCPYRCOKNMV-UHFFFAOYSA-N 2-methyl-3-phenylmethoxypyran-4-one Chemical compound O1C=CC(=O)C(OCC=2C=CC=CC=2)=C1C LQDVCPYRCOKNMV-UHFFFAOYSA-N 0.000 description 3
- KJSJBKBZMGSIPT-UHFFFAOYSA-N 4-oxo-3-phenylmethoxypyran-2-carboxylic acid Chemical compound O1C=CC(=O)C(OCC=2C=CC=CC=2)=C1C(=O)O KJSJBKBZMGSIPT-UHFFFAOYSA-N 0.000 description 3
- 108090000331 Firefly luciferases Proteins 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 208000037797 influenza A Diseases 0.000 description 3
- BZFFGGJUFFRTON-UHFFFAOYSA-N methyl 1-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-3-phenylmethoxypyridine-2-carboxylate Chemical compound O=C1C=CN(NC(=O)OC(C)(C)C)C(C(=O)OC)=C1OCC1=CC=CC=C1 BZFFGGJUFFRTON-UHFFFAOYSA-N 0.000 description 3
- ALZICFZRRUCCCD-UHFFFAOYSA-N methyl 4-oxo-3-phenylmethoxypyran-2-carboxylate Chemical compound O1C=CC(=O)C(OCC=2C=CC=CC=2)=C1C(=O)OC ALZICFZRRUCCCD-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 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 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 2
- 229960002218 sodium chlorite Drugs 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000013595 supernatant sample Substances 0.000 description 2
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 2
- FIDLLEYNNRGVFR-CTNGQTDRSA-N (3R)-2-[(11S)-7,8-difluoro-6,11-dihydrobenzo[c][1]benzothiepin-11-yl]-11-hydroxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound OC1=C2N(C=CC1=O)N([C@@H]1COCCN1C2=O)[C@@H]1C2=C(SCC3=C1C=CC(F)=C3F)C=CC=C2 FIDLLEYNNRGVFR-CTNGQTDRSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- FKIDVJSXQKIUOT-UHFFFAOYSA-N 3-(2-methoxyethyl)-5-phenylmethoxyspiro[1H-pyrido[2,1-f][1,2,4]triazine-2,1'-cyclohexane]-4,6-dione Chemical compound COCCN1C(=O)C2=C(C(=O)C=CN2NC13CCCCC3)OCC4=CC=CC=C4 FKIDVJSXQKIUOT-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 1
- QUGCGRKJBDNHBP-UHFFFAOYSA-N C1=C2C(=O)OC(C(=O)CC)=CC2=CC2=C1OCO2 Chemical compound C1=C2C(=O)OC(C(=O)CC)=CC2=CC2=C1OCO2 QUGCGRKJBDNHBP-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229940123734 Endonuclease inhibitor Drugs 0.000 description 1
- 102000004533 Endonucleases Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 241000491226 Influenza A virus (A/WSN/1933(H1N1)) Species 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 1
- 108091092724 Noncoding DNA Proteins 0.000 description 1
- RRQIDDGRIQVTGM-UHFFFAOYSA-N Orientalone Chemical compound CC1=C(C(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1 RRQIDDGRIQVTGM-UHFFFAOYSA-N 0.000 description 1
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000005727 virus proliferation Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了螺环吡啶酮类衍生物，具有通式I所示结构。研究表明，所述螺环吡啶酮类衍生物对甲型病毒RNA聚合酶活性具有较强的抑制作用，可在制备抑制甲型流感病毒RNA聚合酶活性和抗甲型流感药物中的应用。通式I如下：
Description
技术领域
本发明属于制药领域，具体涉及具有5`帽状结构(CAP)依赖性内切酶抑制活性的螺环吡啶酮衍生物，以及使用该化合物用来制备抑制甲型流感病毒RNA聚合酶活性和抗甲型流感分子药物中的应用。
技术背景
流型性感冒(influenza,简称流感)是一种由流感病毒引起急性呼吸道传染病。每年流感都会导致300至500万例的严重病例，25至50万人的死亡。流感病毒具有患病率高、流行广泛、以及传播迅速等特点。美国食品药品监督管理局(FDA)批准了三类治疗流感的小分子，2种M2离子通道阻滞剂，分别为金刚烷胺和金刚乙胺；3种神经氨酸酶抑制剂，分别为奥司他韦、扎那米韦和帕拉米韦；以及一种PA帽依赖性核酸内切酶抑制剂巴洛沙韦。由于流感病毒的高突变率，耐药性流感病毒株的出现是常见的并且也难以预测的。因此，流感病毒对现有抑制剂的耐药性和时效性仍然是当前最主要挑战。考虑到这一点，迫切需要开发预防和治疗流感感染的新药。
流感病毒是负性，分段的单链RNA病毒，属于正黏病毒家族。流感病毒基因组具有八个基因组片段：PB2，PB1，PA，HA，NP，NA，M和NS。其中PB2，PB1和PA组成聚合酶复合物，并负责病毒基因组的转录和复制。病毒复制以“帽捕捉”开始，分为三个步骤。首先，PB2亚基结合宿主细胞的5'-mRNA帽；第二步，PA亚基在下游切割10-13个核苷酸，产生5'-端的RNA片段；这些片段用作第三步中PB1亚基催化的病毒mRNA延伸的引物。流感病毒RNA聚合酶适合作为抗流感药物的靶点用于新型抗流感药物的开发。
发明内容
本发明的目的在于提供一种螺环吡啶酮衍生物，是一种通过抑制甲型流感病毒RNA聚合酶活性而抑制流感病毒增殖的化合物，本发明的螺环吡啶酮衍生物具有以下结构通式I：
通式I中，
R1是氢、低级烷烃、低级烷基氧基、低级烷基羰基、碳环低级烷基、杂环基；其中低级烷烃选自C1-C4烷烃，低级烷基氧基选自C1-C4烷基氧基，低级烷基羰基选自C2-C3烷基羰基，碳环低级烷基选自C5-C7碳环，杂环基选自呋喃基、噻吩基。
R2是氢、CY1Y2，Y1和Y2独立地选自氢、取代的芳基、取代的杂芳基，或Y1和Y2在一起形成取代的三环的环烯基、取代的三环的杂环基，其中取代的芳基选自氢、卤素、烷烃、烷氧基取代，取代的杂芳基选自氢、卤素、烷烃、烷氧基取代，取代的三环的环烯基选自氢、卤素、烷烃、烷氧基取代，取代的三环的三环的杂环基选自氢、卤素、烷烃、烷氧基取代；
n＝1、2、3、4。
X＝O、CH2、NZ，其中Z独立选自氢、C1-C3烷烃、C2-C3烷基羰基；
及其药学上可接受的盐。
本发明所述的多环吡啶酮衍生物为如下任一化合物：
1'-二苯甲基-5'-羟基-3'-(2-甲氧基乙基)-1'H，3'H-螺[环丁烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮盐酸盐，
1'-二苯甲基-5'-羟基-3'-(2-甲氧基乙基)-1'H，3'H-螺[环戊烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮盐酸盐，
1'-二苯甲基-5'-羟基-3'-(2-甲氧基乙基)-4,5-二氢-1'H，2H，3'H-螺[呋喃-3,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮盐酸盐，
1'-二苯甲基-5'-羟基-3'-(2-甲氧基乙基)-1'H，3'H-螺[环己烷-1,2'-吡啶基[2,1-f][1,2,4]三嗪]-4'，6'-二酮盐酸盐，
1'-二苯甲基-5'-羟基-3'-(2-甲氧基乙基)-2,3,5,6-四氢-1'H，3'H-螺[吡喃-4,2'-吡啶[2，1-f][1,2,4]三嗪]-4'，6'-二酮盐酸盐，
1'-苯甲酰基-3'-苄基-5'-羟基-1'H，3'H-螺[环戊烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮盐酸盐，
1'-二苯甲基-3'-(环己基甲基)-5'-羟基-1'H，3'H-螺[环戊烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮盐酸盐。
以下列举本发明化合物的一般制备方法，另外，萃取、纯化等只要进行通常有机化合物的实验中进行的处理即可。原料化合物可以使用市售的化合物、本说明书中记载的化合物和其他公知化合物。在常规的合成法以及实施例中，各缩写的意思如以下所示。
DMF:N,N-二甲基甲酰胺，
DBU:1,8-二氮杂二环十一碳-7-烯，
PPTS:对甲苯磺酸吡啶盐，
DMA:N,N-二甲基乙酰胺，
THF:四氢呋喃，
DCM:二氯甲烷，
反应式如下：
第一步骤
在95％乙醇中，向市售的苄基麦芽酚(化合物1)中加入苄基和氢氧化钠水溶液，使其在60摄氏度下反应6小时，反应完成后，减压旋去乙醇，加二氯甲烷萃取水相(3×)，合并有机层，有机层用水洗涤(3×)，饱和食盐水洗涤，无水硫酸钠干燥，减压旋蒸后可以得到化合物2。
第二步骤
将2-甲基-3-(苄氧基)-4H-吡喃-4-酮(化合物2)和二氧化硒溶于溴苯中，140度搅拌6小时。反应完成后，冷却至室温，用带有硅藻土的抽滤装置抽滤，收集滤液，减压旋干，硅胶柱层析分离得化合物3。
第三步骤
将3-(苄氧基)-4-氧代-4H-吡喃-2-甲醛(化合物3)和H2O的混合溶剂中，冰浴条件下向溶液中加入氨基磺酸，然后再分批次加入亚氯酸钠，体系在室温条件下反应约4小时，反应完成后，减压旋干丙酮后抽滤，收集滤饼得化合物4。
第四步骤
将3-(苄氧基)-4-氧代-4H-吡喃-2-羧酸(化合物4)溶于DMF，再依次加入碘甲烷与DBU，并于室温下搅拌约10小时，反应完成后，向体系中加入10％的氯化铵溶液，乙酸乙酯萃取后饱和食盐水洗涤，干燥，减压旋干后得化合物5。
第五步骤
将3-(苄氧基)-4-氧代-4H-吡喃-2-羧酸甲酯(化合物5)溶于DMA中，再依次加入对甲苯磺酸吡啶盐与叔丁氧羰基肼于60摄氏度条件下反应约12h，反应结束后，向体系中加入水，乙酸乙酯萃取，有机层饱和氯化铵溶液洗涤用饱和食盐水洗涤，干燥，柱层析得化合物6。
第六步骤
将1-((叔丁氧基羰基)氨基)-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸甲酯(化合物6)溶于四氢呋喃中，依次加入胺和DBU，于60摄氏度条件下搅拌12小时，反应完成后，冷却至室温析出固体，抽滤得化合物7。
第七步骤
将化合物7溶于冰醋酸中，再加入环酮于85度下搅拌约8小时，反应完成后，减压旋干冰醋酸，加入乙酸乙酯并用饱和碳酸氢钠洗涤，有机层再用水洗涤，饱和食盐水洗涤后干燥，旋干柱层析得化合物8。
第八步骤
将化合物8与卤代烃溶于二氯甲烷中，再加入无水碳酸钾于室温下搅拌约12小时，反应结束后，加入水，并加二氯甲烷萃取，有机层经饱和食盐水洗涤，干燥，减压旋干过柱得化合物9。
第九步骤
将化合物9溶于四氢呋喃中，再加入氯化锂于回流状态下反应12小时，反应完成后，减压旋干溶剂，加入水，乙酸乙酯萃取，有机层饱和食盐水洗涤，干燥，减压旋干后加入盐酸乙醚析出固体，抽滤得终产物I。
本发明的另一个目的是提供所述螺环吡啶酮衍生物在制备抑制甲型流感病毒RNA聚合酶活性和抗甲型流感药物中的应用。
本发明公开了具有所示通式I的螺环吡啶酮类衍生物，能够有效地抑制甲型流感RNA聚合酶的活性，且对在细胞水平上能够有效地抗甲型流感。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中，下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1 1'-二苯甲基-5'-羟基-3'-(2-甲氧基乙基)-1'H，3'H-螺[环己烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮
步骤：
原料1：2-甲基-3-羟基-4H-吡喃-4-酮按照文献CN108947950(A)的方法制备。
原料2：2-甲基-3-(苄氧基)-4H-吡喃-4-酮的制备：
将2-甲基-3-羟基-4H-吡喃-4-酮(1g，8.0mmol)溶解于8ml的95％乙醇中，称取氢氧化钠(352mg，8.8mmol)溶于5ml的蒸馏水中后加入体系，待体系溶清后再向混合体系中加入苄氯(831ul，7.2mmol)，60度反应约6小时，反应完成后，减压旋去乙醇，加二氯甲烷萃取水相(3×)，合并有机层，有机层用水洗涤(3×)，饱和食盐水洗涤，无水硫酸钠干燥，旋干得化合物2(1.52g，收率88％)。1H NMR(500MHz,CHCl3)δ7.59(d,J＝5.5Hz,1H),7.40–7.31(m,5H),6.36(d,J＝5.5Hz,1H),5.15(s,2H),2.08(s,3H).HRMS(ESI):m/z calcd for(C13H12O3+Na)+:239.0679；found:239.0682。
原料3：3-(苄氧基)-4-氧代-4H-吡喃-2-甲醛3，3-(苄氧基)-4-氧代-4H-吡喃-2-甲醛
将2-甲基-3-(苄氧基)-4H-吡喃-4-酮(1g，4.6mmol)和二氧化硒(1.53g，13.8mmol)溶于10ml的溴苯中，140度搅拌6小时。反应完成后，冷却至室温，用带有硅藻土的抽滤装置抽滤，收集滤液，减压旋干，硅胶柱层析(流动相为纯DCM)分离得到化合物3(857mg，收率81％)。1H NMR(500MHz,CDCl3)δ9.85(s,1H),7.74(d,J＝5.5Hz,1H),7.35–7.32(m,5H),6.48(d,J＝5.5Hz,1H),5.49(s,2H).HRMS(ESI):m/z calcd for(C13H10O4+Na)+:253.0471；found:253.0472。
原料4：3-(苄氧基)-4-氧代-4H-吡喃-2-羧酸
将3-(苄氧基)-4-氧代-4H-吡喃-2-甲醛3，3-(苄氧基)-4-氧代-4H-吡喃-2-甲醛(1.2g，5.2mmol)溶于10ml丙酮和10ml H2O的混合溶剂中，冰浴条件下再向溶液中加入氨基磺酸(708mg，7.3mmol)，然后再分批次加入亚氯酸钠(774mg，8.6mmol)，体系在室温条件下反应约4小时，反应完成后，减压旋干丙酮后抽滤，收集滤饼即得化合物4(1.09g，收率85％)。1H NMR(500MHz,DMSO)δ14.25(s,1H),8.21(d,J＝5.5Hz,1H),7.46–7.44(m,2H),7.38–7.31(m,3H),6.55(d,J＝5.5Hz,1H),5.12(s,2H).HRMS(ESI):m/z calcd for(C13H10O5+Na)+:269.0420；found:269.0423。
原料5：3-(苄氧基)-4-氧代-4H-吡喃-2-羧酸甲酯
将3-(苄氧基)-4-氧代-4H-吡喃-2-羧酸(1g，4.1mmol)溶于10mlDMF，再依次加入碘甲烷(461ul，7.4mmol)与DBU(926ul，6.2mmol)，并于室温下搅拌约10小时，反应完成后，向体系中加入10％的氯化铵溶液，乙酸乙酯萃取后饱和食盐水洗涤，干燥，减压旋干后得化合物5(959mg，收率89％)。1H NMR(500MHz,CDCl3)δ7.73(d,J＝5.5Hz,1H),7.45–7.43(m,2H),7.36–7.31(m,3H),6.46(d,J＝5.5Hz,1H),5.29(s,2H),3.85(s,3H).HRMS(ESI):m/zcalcd for(C14H12O5+Na)+:283.0577；found:283.0577。
原料6：1-((叔丁氧基羰基)氨基)-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸甲酯
将3-(苄氧基)-4-氧代-4H-吡喃-2-羧酸甲酯(1g，3.8mmol)溶于10mlDMA中，再依次加入对甲苯磺酸吡啶盐(2.9g，11.4mmol)与叔丁氧羰基肼(0.6g，4.6mmol)于60摄氏度条件下反应约12h，反应结束后，向体系中加入水，乙酸乙酯萃取，有机层饱和氯化铵溶液洗涤用饱和食盐水洗涤，干燥，柱层析(流动相为DCM/MeOH＝100:1)得化合物6(1.04g，收率73％)。1H NMR(500MHz,CDCl3)δ8.78(s,1H),7.39–7.28(m,5H),7.24(d,J＝7.5Hz,1H),6.35(d,J＝7.5Hz,1H),5.21(s,2H),3.74(s,3H),1.43(s,9H).HRMS(ESI):m/z calcd for(C19H22N2O3+H)+:375.1551；found:375.1555。
原料7：(3-(苄氧基)-2-(((2-甲氧基乙基)氨基甲酰基)-4-氧嘧啶-1(4H)-基)氨基甲酸叔丁酯
将1-((叔丁氧基羰基)氨基)-3-(苄氧基)-4-氧代-1,4-二氢吡啶-2-羧酸甲酯(2g，4.8mmol)溶于5ml四氢呋喃中，依次加入2-甲氧基乙胺(1.2ml，14.4mmol)和DBU(72ul，0.48mmol)，于60摄氏度条件下搅拌12小时，反应完成后，冷却至室温析出固体，抽滤得化合物7(1.84g，收率92％)。1H NMR(500MHz,DMSO)δ10.89(s,1H),8.69(s,1H),7.65(d,J＝7.5Hz,1H),7.41–7.29(m,5H),6.21(d,J＝7.5Hz,1H),5.09(s,2H),3.32–3.27(m,4H),3.18(s,3H),1.43(s,9H).HRMS(ESI):m/z calcd for(C21H27N3O6+H)+:418.1973；found:418.1973。
原料8：3'-(2-甲氧基乙基)-5'-(苄氧基)-1'H，3'H-螺[环己烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮
将(3-(苄氧基)-2-(((2-甲氧基乙基)氨基甲酰基)-4-氧嘧啶-1(4H)-基)氨基甲酸叔丁酯(1.25g，3mmol)溶于10ml冰醋酸中，再加入环己酮(1.55ml，15mmol)与85度下搅拌约8小时，反应完成后，减压旋干冰醋酸，加入乙酸乙酯并用饱和碳酸氢钠洗涤，有机层再用水洗涤，饱和食盐水洗涤后干燥，旋干柱层析(流动相为DCM/MeOH＝30:1)得化合物8(607mg，收率51％)。1H NMR(500MHz,CDCl3)δ7.38–7.36(m,2H),7.32–7.27(m,3H),6.90(d,J＝7.5Hz,1H),6.77(s,1H),6.43(d,J＝7.5Hz,1H),5.28(s,2H),3.42–3.35(m,4H),3.24(s,3H),2.42(t,J＝6.5Hz,2H),2.21(t,J＝6.5Hz,2H),1.83–1.78(m,2H),1.76–1.71(m,2H),1.66–1.62(m,2H).HRMS(ESI):m/z calcd for(C22H27N3O4+H)+:398.2074；found:398.2077。
原料9：1'-二苯甲基-5'-(苄氧基)-3'-(2-甲氧基乙基)-1'H，3'H-螺[环己烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮
将3'-(2-甲氧基乙基)-5'-(苄氧基)-1'H，3'H-螺[环己烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮(1.19g，3mmol)与(溴亚甲基)二苯(1.1g，4.5mmol)溶于10ml二氯甲烷中，再加入无水碳酸钾(621mg，4.5mmol)于室温下搅拌约12小时，反应结束后，加入水，并加二氯甲烷萃取，有机层经饱和食盐水洗涤，干燥，减压旋干过柱(流动相为DCM/MeOH＝60:1)得化合物9(675mg，收率40％)。1H NMR(500MHz,CDCl3)δ7.52-7.51(m,5H),7.40-7.37(m,2H),7.31-7.22(m,5H),7.16-7.13(m,3H),6.95(s,1H),6.25(d,J＝8.0Hz,1H),5.81(s,1H),5.17(d,J＝10.0Hz,1H),4.85(d,J＝10.0Hz,1H),3.81-3.76(m,2H),3.69-3.63(m,1H),3.57-3.52(m,1H),3.43(s,3H),2.17-2.15(m,1H),2.05-1.99(m,1H),1.68-1.64(m,1H),1.56-1.30(m,6H),1.20-1.14(m,1H).HRMS(ESI):m/zcalcd for(C35H37N3O4+H)+:564.2857；found:564.2858。
终产物I：1'-二苯甲基-5'-羟基-3'-(2-甲氧基乙基)-1'H，3'H-螺[环己烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮盐酸盐
将1'-二苯甲基-5'-(苄氧基)-3'-(2-甲氧基乙基)-1'H，3'H-螺[环己烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮(563mg，1mmol)溶于8ml四氢呋喃中，再加入氯化锂(210mg，5mmol)于回流状态下反应12小时，反应完成后，减压旋干溶剂，加入水，乙酸乙酯萃取，有机层饱和食盐水洗涤，干燥，减压旋干后加入盐酸乙醚析出固体，抽滤得终产物I(412mg，收率87％)。m.p.:204.8-205.3℃；1H NMR(500MHz,DMSO)δ8.67(d,J＝7.0Hz,1H),7.72(d,J＝7.5Hz,2H),7.43(t,J＝7.5Hz,2H),7.31(t,J＝7.5Hz,1H),7.12(s,3H),6.96(s,2H),6.74(d,J＝7.0Hz,1H),6.07(s,1H),3.94-3.85(m,2H),3.80-3.75(m,1H),3.64-3.60(m,1H),3.41(s,3H),2.28(d,J＝13.5Hz,1H),2.17-2.11(m,1H),1.74-1.41(m,5H),1.17(s,3H).HRMS(ESI):m/z calcd for(C28H31N3O4+H)+:474.2387；found:474.2389。
实施例2 1'-二苯甲基-5'-羟基-3'-(2-甲氧基乙基)-1'H，3'H-螺[环丁烷-1,2'-吡啶基[2,1-f][1,2,4]三嗪]-4'，6'-二酮盐酸盐
参照实施例1的方法，只是将环己酮替换成环丁酮，收率为88％。m.p.:144.3-144.8℃；1H NMR(500MHz,CDCl3)δ8.04(s,1H),7.95(s,1H),7.57(d,J＝7.5Hz,2H),7.46(t,J＝7.5Hz,2H),7.38(t,J＝7.5Hz,1H),7.20(t,J＝7.5Hz,1H),7.14(t,J＝7.5Hz,2H),6.80(d,J＝7.5Hz,2H),5.88(s,1H),4.19–4.15(m,1H),3.87–3.67(m,3H),3.49(s,3H),2.93–2.86(m,1H),2.32–2.15(m,4H),1.95–1.91(m,1H).HRMS(ESI):m/z calcd for(C26H27N3O4+H)+:446.2074；found:446.2075。
实施例3 1'-二苯甲基-5'-羟基-3'-(2-甲氧基乙基)-2,3,5,6-四氢-1'H，3'H-螺[吡喃-4,2'-吡啶[2，1-f][1,2,4]三嗪]-4'，6'-二酮盐酸盐
参照实施例1的方法，只是将环己酮替换成四氢吡喃酮，收率为83％。m.p.:>250℃；1H NMR(500MHz,DMSO)δ8.58(d,J＝7.0Hz,1H),7.77(d,J＝7.5Hz,2H),7.44(t,J＝7.5Hz,2H),7.32(t,J＝7.5Hz,1H),7.12(s,3H),6.98(s,2H),6.49(d,J＝7.0Hz,1H),6.04(s,1H),3.97–3.89(m,2H),3.81–3.74(m,2H),3.64–3.59(m,2H),3.42(s,3H),3.36(dd,J＝11.5,4.5Hz,1H),3.21(t,J＝11.5Hz,1H),2.45–2.39(m,1H),2.10(d,J＝14.0Hz,1H),1.99–1.93(m,1H),1.57(d,J＝14.0Hz,1H).HRMS(ESI):m/z calcd for(C27H29N3O5+H)+:476.2180；found:476.2183。
实施例4 1'-二苯甲基-3'-苄基-5'-羟基-1'H，3'H-螺[环戊烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮
参照实施例1的方法，只是将环己酮替换成环戊酮，2-甲氧基乙胺替换成苄胺，收率为89％。m.p.:155.3-155.9℃；1H NMR(500MHz,DMSO)δ8.30(d,J＝7.5Hz,1H),7.56–7.24(m,11H),7.12–7.11(m,3H),6.96–6.95(m,2H),6.34(d,J＝7.0Hz,1H),5.49(s,1H),5.16(d,J＝15.5Hz,1H),4.86(d,J＝15.5Hz,1H),2.20–2.13(m,1H),1.81–1.30(m,7H).HRMS(ESI):m/z calcd for(C31H29N3O3+H)+:492.2282；found:492.2285。
实施例5 1'-二苯甲基-3'-(环己基甲基)-5'-羟基-1'H，3'H-螺[环戊烷-1,2'-吡啶[2,1-f][1,2,4]三嗪]-4'，6'-二酮
参照实施例1的方法，只是将环己酮替换成环戊酮，2-甲氧基乙胺替换成环己甲胺，收率为86％。m.p.:156.8-157.5℃；1H NMR(500MHz,DMSO)δ8.22(d,J＝7.5Hz,1H),7.68(d,J＝7.5Hz,2H),7.43(t,J＝7.5Hz,2H),7.32(t,J＝7.5Hz,1H),7.11–7.09(m,3H),6.93(s,2H),6.23(d,J＝7.5Hz,1H),5.80(s,1H),3.63–3.54(m,2H),2.14–2.07(m,1H),1.95–1.57(m,13H),1.43–1.29(m,2H),1.23–1.12(m,3H).HRMS(ESI):m/z calcd for(C31H35N3O3+H)+:498.2751；found:498.2755。
实施例6.MDCK细胞感染甲型流感病毒后的CPE抑制效果和病毒RNA聚合酶抑制效果
MDCK细胞铺24孔板，置于37℃、5％二氧化碳培养箱内，培养24小时。将待筛选药物配置成一系列浓度梯度，分别加入24孔板孔内，与细胞共同孵育6小时。按MOI＝0.1在每个孔内加入A型流感病毒(A/WSN/33(H1N1))。48h后收取每个孔内的病毒上清液样本。检测每个孔内病毒在不同药物不同浓度处理下的滴度(TCID50/mL)验证药物作用后上清液中病毒滴度。首先MDCK细胞铺96孔板，置于37℃、5％二氧化碳培养箱内，培养24小时。将每个收取的病毒上清液样本按照1:1000稀释，分别加入96孔板第一列，依次倍比稀释，72小时后计数每个96孔板的病变孔数，计算得出每个样本的病毒滴度(TCID50/mL)。根据待筛选药物每个浓度作用下病毒的病毒滴度(TCID50/mL)，通过回归分析得出回归曲线和回归方程，计算得出待筛选药物的IC50值。
构建了位于A/WSN/33NP片段的非编码区两端的firefly luciferase质粒，firefly luciferase蛋白的表达受到fluA/WSN/33聚合酶(PB2,PB1,PA)数量、功能的调控。因此，通过检测firefly luciferase蛋白酶促反应降解底物产生的荧光强度，可以定量检测流感病毒RNA聚合酶被药物抑制的情况。
实施例1-3均能有效地降低病毒的滴度，IC50值在0.23～1.70μM。且在RNA聚合酶抑制实验中，10μM浓度下，实施例1-3的抑制百分比达到了95％以上，结果见表1。
表1
| 实施例 | CPE_IC<sub>50</sub>(μM) | Inhibition at 10μM(Polymerase WT) |
| 实施例1 | 0.23 | 96.66％ |
| 实施例2 | 0.97 | 99.76％ |
| 实施例3 | 1.70 | 97.30％ |
| 实施例4 | — | 38.51％ |
| 实施例5 | — | 29.21％ |
Claims (2)
1.一种螺环吡啶酮衍生物，其特征在于，选自如下化合物：
1'-二苯甲基-5'-羟基-3'-（2-甲氧基乙基）-1'H，3'H-螺[环丁烷-1,2'-吡啶[2,1-f][1,2,4 ]三嗪] -4'，6'-二酮盐酸盐，
1'-二苯甲基-5'-羟基-3'-（2-甲氧基乙基）-1'H，3'H-螺[环戊烷-1,2'-吡啶[2,1-f][1,2,4 ]三嗪] -4'，6'-二酮盐酸盐，
1'-二苯甲基-5'-羟基-3'-（2-甲氧基乙基）-2,3,5,6-四氢-1'H，3'H-螺[吡喃-4,2'-吡啶[2,1-f] [1,2,4]三嗪] -4'，6'-二酮盐酸盐。
2.根据权利要求1所述的螺环吡啶酮衍生物在制备抑制甲型流感病毒RNA聚合酶活性和抗甲型流感药物中的应用。
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| CN103228653A (zh) * | 2010-09-24 | 2013-07-31 | 盐野义制药株式会社 | 被取代的多环性氨基甲酰基吡啶酮衍生物的前药 |
| WO2015089847A1 (en) * | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | Spirocyclic heterocycle compounds useful as hiv integrase inhibitors |
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