CN105732748B - 一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用 - Google Patents
一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用 Download PDFInfo
- Publication number
- CN105732748B CN105732748B CN201410767141.6A CN201410767141A CN105732748B CN 105732748 B CN105732748 B CN 105732748B CN 201410767141 A CN201410767141 A CN 201410767141A CN 105732748 B CN105732748 B CN 105732748B
- Authority
- CN
- China
- Prior art keywords
- base
- nucleotide analog
- pharmaceutical composition
- amide
- pyrazine
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 125000003729 nucleotide group Chemical group 0.000 title claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- -1 Nucleoside compound Chemical class 0.000 claims abstract description 23
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 31
- 241000790917 Dioxys <bee> Species 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 13
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 6
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 6
- 239000006187 pill Substances 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 5
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 3
- SZPBAPFUXAADQV-UHFFFAOYSA-N 2-oxo-1h-pyrazine-3-carboxamide Chemical compound NC(=O)C1=NC=CN=C1O SZPBAPFUXAADQV-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 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
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 150000004996 alkyl benzenes Chemical class 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
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 208000037797 influenza A Diseases 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 150000003891 oxalate salts Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 229950004288 tosilate Drugs 0.000 claims description 2
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 claims 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 1
- 210000000936 intestine Anatomy 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 241000700605 Viruses Species 0.000 abstract description 7
- 206010022000 influenza Diseases 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 239000002777 nucleoside Substances 0.000 abstract description 2
- 230000001717 pathogenic effect Effects 0.000 abstract description 2
- 229910052717 sulfur Inorganic materials 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 239000002585 base Substances 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 229940023488 pill Drugs 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 150000001447 alkali salts Chemical class 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 241000712461 unidentified influenza virus Species 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000000022 bacteriostatic agent Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002019 doping agent Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 235000015110 jellies Nutrition 0.000 description 2
- 239000008274 jelly Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 229940040145 liniment Drugs 0.000 description 2
- 239000000865 liniment Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003340 retarding agent Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 229940061367 tamiflu Drugs 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical group CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- NDVMCQUOSYOQMZ-UHFFFAOYSA-N 2,2-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)C(C(N)=O)[Si](C)(C)C NDVMCQUOSYOQMZ-UHFFFAOYSA-N 0.000 description 1
- WBDGLSGKTWAWHK-UHFFFAOYSA-N 2,3-dibutylbenzoic acid Chemical compound CCCCC1=CC=CC(C(O)=O)=C1CCCC WBDGLSGKTWAWHK-UHFFFAOYSA-N 0.000 description 1
- OQUFOZNPBIIJTN-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;sodium Chemical compound [Na].OC(=O)CC(O)(C(O)=O)CC(O)=O OQUFOZNPBIIJTN-UHFFFAOYSA-N 0.000 description 1
- LAQJGAKLLZAETL-UHFFFAOYSA-N 2h-pyrazin-3-one Chemical compound O=C1CN=CC=N1 LAQJGAKLLZAETL-UHFFFAOYSA-N 0.000 description 1
- QFWKQBKWGOPRCC-UHFFFAOYSA-N 3-oxo-2h-pyrazine-2-carboxamide Chemical compound NC(=O)C1N=CC=NC1=O QFWKQBKWGOPRCC-UHFFFAOYSA-N 0.000 description 1
- XFZZDIHCNHYESF-UHFFFAOYSA-N 7-amino-1-bromo-4-phenyl-5,7,8,9-tetrahydrobenzo[7]annulen-6-one Chemical compound C=12CC(=O)C(N)CCC2=C(Br)C=CC=1C1=CC=CC=C1 XFZZDIHCNHYESF-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241001500351 Influenzavirus A Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- AQLLBJAXUCIJSR-UHFFFAOYSA-N OC(=O)C[Na] Chemical compound OC(=O)C[Na] AQLLBJAXUCIJSR-UHFFFAOYSA-N 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000220324 Pyrus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 241000218636 Thuja Species 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229940017687 beta-d-ribose Drugs 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000001664 diethylamino group Chemical class [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical class [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007948 fast release tablet Substances 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000003205 fragrance Chemical group 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 159000000003 magnesium salts Chemical group 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000015091 medicinal tea Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000021017 pears Nutrition 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 239000008342 pharmaceutical dispersion Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940098458 powder spray Drugs 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- 239000002994 raw material Substances 0.000 description 1
- 239000012047 saturated solution Substances 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
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 125000005270 trialkylamine group Chemical group 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
- 210000001215 vagina Anatomy 0.000 description 1
- 239000000003 vaginal tablet Substances 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
目前急需开发新型特效治疗药物，降低致病性A型流感病毒的危害。本发明公开了一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用，本发明核苷酸类似物的结构式如式(I)所示：其中，X为O、S或NH，R1为H、OH、RO或卤素，R2为OH、RO或卤素，所述的R为烷基或芳香基。本发明的核苷类化合物具有优良的抗流感病毒活性，并具有较低的毒性和很高的安全性。
Description
技术领域
本发明属于药物领域，具体地说是一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用。
背景技术
由病毒引起的传染病在世界范围内时有发生，特别是近些年出现的H1N1、H3N1、H5N1、H7N9等致病性A型流感病毒在全球范围引起的致命性疾病，由于没有特效药物引起了整个社会的恐慌，目前急需开发新型特效治疗药物，降低该种病毒的危害。
US20030130213公布了一种化合物，其结构式如下：
其具有抗流感病毒性能，到目前为止，该类化合物还没有上市。
发明内容
本发明的目的在于提供一种具有优良抗流感病毒活性，并具有较低毒性和很高安全性的核苷酸类似物。
为此，本发明采用如下的技术方案：一种核苷酸类似物，其结构式如式(I)所示：
其中，X为O、S或NH，R1为H、OH、RO或卤素，R2为OH、RO或卤素，所述的R为烷基或芳香基。
进一步，所述的烷基为C1～C6脂肪烷基、三元环的环烷基、四元环的环烷基、五元环的环烷基或六元环的环烷基；所述的芳香基为苯基、烷基苯或卤代苯基。
进一步，式(I)所示的化合物优选为下列化合物中的一种：
(1)(1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；
(2)(1S,3R,4R,7R)-1-羟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；
(3)(1S,3R,4R,7S)-1-氟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；
(4)(1S,3R,4R,7R)-1-氟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷。
本发明的另一个目的在于提供上述核苷酸类似物的制备方法，其步骤如下：
3-氧基吡嗪-2-酰胺与1,2-二-O-乙酰基-3-O-苄基-4-C-甲磺酰基甲基-5-O-甲磺酰基-D-核糖或1,2-二-O-乙酰基-3-O-苄基-4-C-甲磺酰基甲基-5-O-甲磺酰基-L-核糖缩合，再经过Vorbruggen偶合反应在1’-C处引入3-羟基-2-吡嗪酰胺，经过闭环、脱除甲磺酰基和脱除苄基得到目标化合物。
本发明的又一个目的在于提供一种抗A型流感病毒的药物组合物，其含有治疗有效量的核苷酸类似物或其药学上可接受的盐，以及一种或多种药学上可接受的载体。
进一步，所述的药物组合物包含5-75重量％的式(I)所示结构的化合物或其药学上可接受的盐的任一种或其组合，余量为药学上可接受的载体。
进一步，所述药学上可接受的盐为无机酸盐、有机酸盐、无机碱盐或有机碱盐；所述的无机酸盐选用盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐、磷酸盐、高氯酸盐中的任一种或其组合；所述的有机酸盐选用对甲苯磺酸盐、甲磺酸盐、乙酸盐、三氟乙酸盐、丙酸盐、枸橼酸盐、丙二酸盐、琥珀酸盐、乳酸盐、草酸盐、酒石酸盐、苯甲酸盐中的任一种或其组合；所述的无机碱盐为碱土金属盐；所述的有机碱盐为有机胺盐。本发明的更优选方案中，所述的碱土金属盐为镁盐或钙盐；所述的有机胺盐为吗啉盐、哌啶盐、三烷基胺盐、吡啶盐、二甲胺盐或二乙胺盐。
本发明的再一个目的在于提供一种上述含有核苷酸类似物的药物组合物在制备抗由A型流感病毒导致的疾病药物中的应用。
本发明的优选方案中，所述药物组合物适用于肠内(例如口服或直肠给药)、局部或肠胃外给药，例如，口服、注射、植入、外用、喷雾、吸入等。
进一步，所述的药物组合物为片剂、胶囊剂、丸剂、颗粒剂、口服液体制剂、注射剂或外用制剂。
本发明的优选方案中，所述口服药物组合物选自片剂(普通片、含片、舌下片、口腔贴片、咀嚼片、分散片、可溶片、泡腾片、阴道片或阴道泡腾片、缓释片、控释片、肠溶片、口腔速释片等)、胶囊剂(硬胶囊、软胶囊、缓释胶囊、控释胶囊、肠溶胶囊等)、丸剂(滴丸、糖丸、小丸)、口服液体制剂(糖浆剂、混悬剂、口服溶液剂、口服混悬剂、口服乳剂、糖浆剂、合剂、露剂或茶剂)、颗粒剂(混悬颗粒、泡腾颗粒、肠溶颗粒、缓释颗粒、控释颗粒等)、散剂的任一种。
本发明的优选方案中，所述注射剂包括注射液、注射用无菌粉末或无菌块状物(包括采用溶剂结晶法、喷雾干燥法或冷冻干燥法等工艺制备)、输液、注射用浓溶液的任一种。
本发明的优选方案中，所述外用制剂选自栓剂、气雾剂、粉雾剂、喷雾剂、膜剂、凝胶剂、贴剂、胶剂、贴膏剂、膏药、软膏剂、搽剂、洗剂、涂抹剂、凝膏剂的任一种。
本发明的优选方案中，可采用本领域熟知的制剂技术手段来制备本发明组合物。
本发明的优选方案中，所述药物组合物选自包合制剂或分散制剂。
本发明的优选方案中，所述的药学上可接受的载体为本领域熟知用于制备上述制剂的常用赋形剂或辅料，其中，口服制剂或外用制剂常用的赋形剂或辅料包括但不仅限于填充剂或稀释剂、润滑剂或助流剂或抗粘着剂、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂等。粘合剂，例如糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮，优选的纤维素衍生物为微晶纤维素、羧甲基纤维素钠、乙基纤维素、羟丙甲基纤维素；填充剂，例如乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐、山梨醇或甘氨酸，优选无机钙盐为硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙；润滑剂，例如微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇；崩解剂，例如淀粉及其衍生物、聚乙烯吡咯烷酮或微晶纤维素，优选的淀粉衍生物为羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉；湿润剂，例如十二烷基硫酸钠、水或醇等，优选药学上可接受的载体为环糊精(α-环糊精、β-环糊精或γ-环糊精)、Celldone 102 CG、Polyplasdone XL-10、滑石粉、硬脂酸镁或乙醇等。
本发明的优选方案中，所述注射剂常用的赋形剂或辅料包括但不仅限于：抗氧剂，例如硫代硫酸钠、亚硫酸钠、亚硫酸氢钠、二丁基苯酸或焦亚硫酸钠等；抑菌剂，例如0.5％苯酚、0.3％甲酚、0.5％三氯叔丁醇；pH调节剂，例如盐酸、枸橼酸、氢氧化钾(钠)、枸橼酸钠、缓冲剂(如磷酸二氧钠和磷酸氢二钠组成的缓冲剂)；乳化剂，例如聚山梨酯-80、没酸山梨坦、普流罗尼克F-68，卵磷酯、豆磷脂；增溶剂，例如吐温-80、甘油等。
本发明的优选方案中，还可将活性成分与药学上可接受的缓控释载体按其制备要求加以混合，再按照本领域熟知的缓控释制剂的制备方法，如加入阻滞剂包衣或将活性成分微囊化后再制成微丸，如缓释微丸或控释微丸；所述的缓控释载体包括但不仅限于油脂性掺入剂、亲水胶体或包衣阻滞剂等，所述的油脂性掺入剂为单硬脂酸甘油酯、氢化蓖麻油、矿油、聚硅氧烷、二甲基硅氧烷；所述的亲水胶体为羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素等纤维素衍生物，或PVP、阿拉伯胶、西黄耆胶或卡波普等；所述的包衣阻滞剂为乙基纤维素(EC)、羟丙甲基纤维素(HMPC)、聚乙烯吡咯烷酮(PVP)、邻苯二甲酸醋酸纤维素(CAP)、丙烯酸类树脂等。
本发明的核苷类化合物具有优良的抗流感病毒活性，并具有较低的毒性和很高的安全性。
附图说明
图1为化合物I2的1HNMR图。
图2为化合物2的1HNMR图。
具体实施方式
下面，通过以下实例来对本发明作进一步具体说明，但并不仅限于以下实施例和实施例中的工艺参数范围。
本发明的化合物可以通过以下路线制备目标化合物：
参考已经发表的文献方法(J.Org.Chem.1979,44,1301‐1309；The Journal oforganic chemistry,2001,66(25):8504‐8512)制备中间体I。
然后以上述中间体I为原料按照下列路线制备目标化合物。
实施例1 化合物4-(2-O-乙酰基-3-O-苄基-4-C-甲磺酰基氧甲基-5-O-甲磺酰基-β-D-核糖)-3-氧-吡嗪-2-酰胺(I1)的制备
称取1.08g(7.8mmol)3-氧基吡嗪-2-酰胺溶于50mL乙腈中，滴加3.835mL N,O-双三甲硅基乙酰胺，升温至80℃，加热回流反应2个小时，体系为浅红色溶液，降至室温，加入3.32g中间体I，滴加1.9mL四氯化锡，加热回流，搅拌反应2个小时，降至室温，加入75mL冰饱和碳酸氢钠溶液，用乙酸乙酯萃取后，柱层析分离得到2.89g白色絮状固体，收率62.8％。
产品结构鉴定1H NMR(DMSO,400MHz)：δppm,1.95,2.36,2.38(9H.s),4.05(1H,d,J＝6.8Hz),4.15(1H,d,J＝10.8),4.20(1H，d,J＝3.6Hz),4.33(3H，m),4.44(1H,d,J＝6.4Hz),5.46(1H,d,J＝5.6Hz),5.67(1H,s),7.30(7H,m),7.60(1H,d,J＝4.4Hz),8.14(1H，br s)。
实施例2 (1S,3R,4R,7S)-1-甲磺酰基氧甲基-3-[4-(3-氧代吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I2)的制备
取上述实施例1制得的化合物(I1)(2.7g，4.58mmol)溶于30mL CH3OH和H2O，加入3.8g无水碳酸钾(27.48mmol)，室温下搅拌反应8个小时。反应完毕后加入醋酸中和，二氯甲烷萃取，蒸除溶剂，柱色谱纯化得到白色粉末1.4g，产率68％。结构鉴定1H NMR(DMSO,400MHz)：δ2.38(1H,s),3.82(2H,m),3.91(1H,s),4.43(2H,m),4.48(1H,d,J＝12Hz),4.59(1H,s),4.66(1H,d,J＝12Hz),5.7(1H,s),7.27(5H,m),7.57(1H,d,J＝4.4Hz),7.62(1H,d,J＝4.4Hz),7.75,8.32(2H,s)。
实施例3 (1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I3)的制备
将实施例2制得的化合物(I2)1.3g(2.88mmol)溶于30mL 1,4-二氧六环中，加入醋酸钾(1.23g，14.4mmol)和18-冠醚-6(1.52g，5.76mmol)，加热回流15个小时，反应完毕后直接蒸除溶剂，用二氯甲烷溶解过滤，干燥后得到(1S,3R,4R,7S)-1-乙酰基氧甲基-3-[4-(3-氧代吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷945mg，然后溶于10mL甲醇氨的饱和溶液，室温搅拌3小时，减压蒸除溶剂，柱层析分离得到浅黄色固体粉末530mg，产率62.5％。
产品结构鉴定1H NMR(CDCl3,400)：δ3.93-3.95(1H,d),4.00-4.0(1H,d),4.17-4.19(1H，d),4.65-4.68(1H，d),4.74-4.77(1H，d),4.85(1H，s),6.00(1H，br s),6.09(1H，s),7.36(5H，m),7.85(2H,s)9.04(1H，br s)。
实施例4 (1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(1)的制备
取500mg上述实施例3制得的化合物(I3)制备的化合物溶于无水甲醇中，加入20％的Pd/C(100mg)，向反应体系中通入氢气，加热回流2个小时，冷却至室温，过滤，减压蒸出溶剂得到浅黄色固体粉末139mg，产率36.9％。
产品结构鉴定1H NMR(CDCl3,400MHz)：δppm3.96(1H,d),4.10(1H,s),4.30(1H,m),4.21(1H,m),4.47(1H,d),4.67(1H,m),5.34(1H,m),5.68(1H,s)6.97(1H,m),7.12(1H,d),7.22(1H,s),7.61(1H,m),7.79(1H,d,J＝4Hz).IR vmax:3340,2929,1680,1452,1105,963,826,741cm-1。
实施例5 4-(2-O-乙酰基-3-O-苄基-4-C-甲磺酰基氧甲基-5-O-甲磺酰基-β-L-核糖基)-3-氧代吡嗪-2-酰胺(I4)的制备
参照实施例1化合物4-(2-O-乙酰基-3-O-苄基-4-C-甲磺酰基氧甲基-5-O-甲磺酰基-β-D-核糖)-3-氧-吡嗪-2-酰胺(I1)的合成方法，可以制备化合物4-(2-O-乙酰基-3-O-苄基-4-C-甲磺酰基氧甲基-5-O-甲磺酰基-β-L-核糖基)-3-氧代吡嗪-2-酰胺(I4)。
产品的结构鉴定1H NMR(DMSO,400MHz)δ2.05,3.22,3.26(9H,s),4.38(1H,d,J＝4Hz),4.42(2H,d,J＝2.4Hz),4.47(1H,d,J＝10.8Hz),4.64(3H,m),5.52(1H,t),6.29(1H,d,J＝4.4Hz),7.27(5H,m),7.49(1H,d,J＝4.4Hz),7.84(1H,d,J＝4Hz),7.74,8.17(2H,brs)。
实施例6 (1S,3R,4R,7R)-1-甲磺酰基氧甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I5)的制备
参照实施例2化合物(1S,3R,4R,7S)-1-甲磺酰基氧甲基-3-[4-(3-氧代吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I2)的合成方法，可以制备化合物(1S,3R,4R,7R)-1-甲磺酰基氧甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I5)。
产品的结构鉴定1H NMR(DMSO,400MHz)：δppm 2.40(3H,s),3.77(1H,d,J＝8.4Hz),3.88(2H,d,J＝8.4Hz),4.08(1H,d,J＝12Hz),4.18(1H,d,J＝2Hz),4.32(2H,m),4.56(1H,d,J＝11.2Hz),4.69(1H,d,J＝11.6Hz),5.64(1H,s),6.89(2H,m),7.22(2H,m),7.34(1H,d,J＝4Hz),7.66(1H,d,J＝4.4Hz),7.75,8.32(2H,br s)。
实施例7 (1S,3R,4R,7R)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I6)的制备
参照实施例3化合物(1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I3)的合成方法，可以制备化合物(1S,3R,4R,7R)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-O-苄基-2,5-二氧二环[2.2.1]庚烷(I6)。
产品的结构鉴定1H NMR(DMSO,400)：δ3.80-3.82(1H,d,J＝8.4Hz),3.92(2H,d,J＝5.2Hz)3.97(1H,d,J＝5.6Hz),4.03(1H,d,J＝8.4Hz),4.11(1H,dJ＝2.4Hz),4.16(1H,d,J＝12Hz),4.35(1H,d,J＝2Hz),4.44(1H,dJ＝11.6Hz),5.20(3H,t),5.68(1H,s),6.97(2H,m),7.24(3H,m),7.45(2H,d，J＝4.4Hz),7.77(1H，br s),7.80(2H,d，J＝4.4Hz),8.40(1H，br s)。
实施例8 (1S,3R,4R,7R)-1-羟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(2)的制备
参照实施例4化合物(1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(1)的合成方法可以得到化合物(1S,3R,4R,7R)-1-羟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(2)。
产品的结构鉴定1H NMR(CDCl3,400MHz)：δppm 3.66(3H,s),4.3(4H,t),5.34(1H,t),7.51(2H,m),7.70(2H,m)。IR Vmax:3360,2931,1664,1420,1080,878,752cm-1。
实施例9 (1S,3R,4R,7S)-1-氟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(3)和(1S,3R,4R,7R)-1-氟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷(4)的制备
分别将0.1mol化合物I3和I6溶解在二氯甲烷中，加入0.12mol二乙氨基三氟化硫，搅拌反应10小时后，蒸出溶剂后，用纯洁水洗涤烘干。将柱色谱分离得到的固体参照实施例4的方法制备目标化合物3和4。
产品3的结构鉴定1H NMR(CDCl3,400MHz)：δppm 3.97(1H，d)，4.08(1H，s)，4.32(1H，m)，4.21(1H，m)，4.47(1H，d)，4.67(1H，m),5.34(1H，m),5.68(1H，s)6.97(1H，m)，7.12(1H，d)，7.22(1H，s)，7.79(1H，d，J＝4Hz)。
产品4的结构鉴定1H NMR(CDCl3,400MHz)：δppm 3.76(3H,s),4.35(4H,t),5.44(1H,t),7.70(2H,m)。
本发明的化合物抗流感病毒实验
本实验采用的病毒株：流感病毒A/天津津南/15/2009,以MDCK(狗肾)细胞为病毒宿主，测定样品抑制病毒引起细胞病变程度，结果如表1所示。
从实验结果可以看出本发明的系列化合物在对达菲没有活性的病毒株而具有明显的抗流感病毒性能，相对于已经上市的产品(达菲)具有更加优异的性能。
Claims (9)
1.一种核苷酸类似物，其结构式如式(I)所示：
其中，X为O，R1为H、OH、RO或卤素，R2为OH、RO或卤素，所述的R为烷基或芳香基；
所述的烷基为C1～C6脂肪烷基、三元环的环烷基、四元环的环烷基、五元环的环烷基或六元环的环烷基；所述的芳香基为苯基、烷基苯或卤代苯基。
2.根据权利要求1所述的核苷酸类似物，其特征在于，式(I)所示的化合物为下列化合物中的一种：(1S,3R,4R,7S)-1-羟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；(1S,3R,4R,7R)-1-羟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；(1S,3R,4R,7S)-1-氟甲基-3-[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷；(1S,3R,4R,7R)-1-氟甲基-3[4-(3-氧-吡嗪-2-酰胺)基]-7-羟基-2,5-二氧二环[2.2.1]庚烷。
3.权利要求1-2任一项所述核苷酸类似物的制备方法，其步骤如下：
3-氧基吡嗪-2-酰胺与1,2-二-O-乙酰基-3-O-苄基-4-C-甲磺酰基甲基-5-O-甲磺酰基-D-核糖或1,2-二-O-乙酰基-3-O-苄基-4-C-甲磺酰基甲基-5-O-甲磺酰基-L-核糖，经过Vorbruggen偶合反应在1’-C处引入3-羟基-2-吡嗪酰胺，经过闭环、脱除甲磺酰基和脱除苄基得到目标化合物。
4.含有权利要求1-2任一项所述核苷酸类似物或其药学上可接受的盐的药物组合物，其特征在于，其含有治疗有效量的核苷酸类似物或其药学上可接受的盐，以及一种或多种药学上可接受的载体。
5.根据权利要求4所述的药物组合物，其特征在于，其包含5-75重量％的式(I)所示结构的化合物或其药学上可接受的盐的任一种或其组合，余量为药学上可接受的载体。
6.根据权利要求4所述的药物组合物，其特征在于，所述药学上可接受的盐为无机酸盐或有机酸盐；所述的无机酸盐选用盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐、磷酸盐、高氯酸盐中的任一种或其组合；所述的有机酸盐选用对甲苯磺酸盐、甲磺酸盐、乙酸盐、三氟乙酸盐、丙酸盐、枸橼酸盐、丙二酸盐、琥珀酸盐、乳酸盐、草酸盐、酒石酸盐、苯甲酸盐中的任一种或其组合。
7.权利要求4所述药物组合物在制备抗由A型流感病毒导致的疾病药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述的药物组合物适用于肠内、局部或肠胃外给药。
9.根据权利要求8所述的应用，其特征在于，所述的药物组合物为片剂、胶囊剂、丸剂、颗粒剂、口服液体制剂、注射剂或外用制剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410767141.6A CN105732748B (zh) | 2014-12-12 | 2014-12-12 | 一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410767141.6A CN105732748B (zh) | 2014-12-12 | 2014-12-12 | 一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105732748A CN105732748A (zh) | 2016-07-06 |
| CN105732748B true CN105732748B (zh) | 2019-01-01 |
Family
ID=56240679
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410767141.6A Active CN105732748B (zh) | 2014-12-12 | 2014-12-12 | 一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105732748B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1418220A (zh) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | 新的吡嗪衍生物或其盐、含有该衍生物或盐的药物组合物和制备二者的中间体 |
| CN1551777A (zh) * | 2001-08-14 | 2004-12-01 | 富山化学工业株式会社 | 新的病毒增殖抑制剂/杀病毒方法,以及新的吡嗪核苷酸/吡嗪核苷类似物 |
| CN101072570A (zh) * | 2004-09-24 | 2007-11-14 | 埃迪尼克斯(开曼)有限公司 | 用于治疗黄病毒、瘟病毒和肝炎病毒的方法和组合物 |
-
2014
- 2014-12-12 CN CN201410767141.6A patent/CN105732748B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1418220A (zh) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | 新的吡嗪衍生物或其盐、含有该衍生物或盐的药物组合物和制备二者的中间体 |
| CN1551777A (zh) * | 2001-08-14 | 2004-12-01 | 富山化学工业株式会社 | 新的病毒增殖抑制剂/杀病毒方法,以及新的吡嗪核苷酸/吡嗪核苷类似物 |
| CN101072570A (zh) * | 2004-09-24 | 2007-11-14 | 埃迪尼克斯(开曼)有限公司 | 用于治疗黄病毒、瘟病毒和肝炎病毒的方法和组合物 |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis and Biological Evaluation of 2-oxo-pyrazine-3-carboxamide-yl Nucleoside Analogues and Their Epimers as Inhibitors of Influenza A Viruses;GAO,Jingjing等;《Chemical Biology & Drug Design》;20140712;第85卷(第3期);245-252 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105732748A (zh) | 2016-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2017128605A (ja) | 抗ウイルス化合物の固体形態 | |
| US7446116B2 (en) | Montelukast amantadine salt | |
| US9309201B2 (en) | Process for preparating ivabradine hydrochloride form IV and methods of treatment of disease using ivabradine hydrochloride form IV | |
| CN102952062B (zh) | 取代苯并杂环类化合物及其制备方法和应用 | |
| KR20080055990A (ko) | 시나칼셋 ＨＣｌ의 결정형 및 이의 제조 방법 | |
| TWI579277B (zh) | 取代桂皮醯胺衍生物、其製備方法、其應用及醫藥組成物 | |
| JPH0136819B2 (zh) | ||
| WO2015139386A1 (zh) | 坎格列净一水合物及其晶型、它们的制备方法和用途 | |
| US20080234323A1 (en) | Amorphous and Three Crystalline Forms of Rimonabant Hydrochloride | |
| JP2008546719A (ja) | 結晶形のｏ−デスメチルベンラファキシン | |
| EP1896439B1 (en) | Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base | |
| WO2017153958A1 (en) | Novel polymorphic forms and amorphous form of olaparib | |
| CN102471273B (zh) | 2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫代]-n-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺苯磺酸盐、其晶体、其多晶型物以及用于制备其的方法 | |
| JP2008539278A (ja) | 結晶性ロスバスタチンカルシウム | |
| WO2009017813A1 (en) | O-desmethyl venlafaxine saccharinate | |
| KR102276281B1 (ko) | 의약으로 사용하기 위한 펄린돌 광학이성질체의 약학적으로 허용가능한 염 | |
| CN105732748B (zh) | 一种核苷酸类似物及其制备方法、以及含有核苷酸类似物的药物组合物及其应用 | |
| JP2004526706A (ja) | オクスカルバゼピンの新しい結晶形態及びそれらの調製方法 | |
| CN102453020A (zh) | 一种来那度胺的新晶型及其制备方法 | |
| WO2008140302A1 (en) | Polymorphic forms of tenofovir disoproxil fumarate | |
| KR20140114406A (ko) | 안정한 비정질 랄테그라빌 포타슘 프리믹스 및 이의 제조 방법 | |
| CN101781300B (zh) | 一种恩替卡韦的盐化合物，其制备方法和药物应用 | |
| US7649008B2 (en) | Crystal of benzimidazole derivative and process for producing the same | |
| CA2938387C (en) | Processes for the preparation of intermediates of raltegravir | |
| CN108530439A (zh) | 呋喃甲酰胺衍生物及其制备方法与应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20210111 Address after: 2 / F, auxiliary building, environmental protection center, 58 Changhe Road, Binhai New Town, Shaoxing City, Zhejiang Province, 312000 Patentee after: Zhejiang New Code Biomedical Co.,Ltd. Address before: 312500 No. 59 Huancheng East Road, Chengguan Town, Xinchang County, Shaoxing City, Zhejiang Province Patentee before: Zhejiang Medicine Co.,Ltd. Xinchang Pharmaceutical Factory |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20231227 Address after: No.168 Zhiyuan middle Avenue, Binhai New Town, Shaoxing City, Zhejiang Province Patentee after: ZHEJIANG MEDICINE Co.,Ltd. Address before: 2 / F, auxiliary building, environmental protection center, 58 Changhe Road, Binhai New Town, Shaoxing City, Zhejiang Province, 312000 Patentee before: Zhejiang New Code Biomedical Co.,Ltd. |