CN106800573A - 一种核苷酸膦酸酯一水合物及其制备方法和在医药上的应用 - Google Patents
一种核苷酸膦酸酯一水合物及其制备方法和在医药上的应用 Download PDFInfo
- Publication number
- CN106800573A CN106800573A CN201610973798.7A CN201610973798A CN106800573A CN 106800573 A CN106800573 A CN 106800573A CN 201610973798 A CN201610973798 A CN 201610973798A CN 106800573 A CN106800573 A CN 106800573A
- Authority
- CN
- China
- Prior art keywords
- compound
- monohydrate
- disease
- methyl
- water
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 239000002773 nucleotide Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 150000004682 monohydrates Chemical class 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 208000036142 Viral infection Diseases 0.000 claims abstract description 7
- 230000009385 viral infection Effects 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000013078 crystal Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 208000035473 Communicable disease Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000012916 structural analysis Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- -1 phosphonate ester Chemical class 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 230000003287 optical effect Effects 0.000 description 14
- 229930024421 Adenine Natural products 0.000 description 13
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 229960000643 adenine Drugs 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 10
- 208000002672 hepatitis B Diseases 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 235000004279 alanine Nutrition 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000005864 Sulphur Substances 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 4
- BZCGWAXQDLXLQM-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O.ClP(Cl)(Cl)=O BZCGWAXQDLXLQM-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000004679 31P NMR spectroscopy Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 description 3
- 229960004946 tenofovir alafenamide Drugs 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000037581 Persistent Infection Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 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 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 229960004556 tenofovir Drugs 0.000 description 2
- 229960001355 tenofovir disoproxil Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- BULDYUIJKUQFQX-MJLAEZBCSA-N 9-[(2r)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine Chemical compound O([C@@H](CN1C2=NC=NC(N)=C2N=C1)C)CP(Cl)(=O)OC1=CC=CC=C1 BULDYUIJKUQFQX-MJLAEZBCSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CTWRMZPOOHRGFV-QMMMGPOBSA-N C(C)(C)(C)OC(=O)N[C@H](C(SC(C)C)=O)C Chemical compound C(C)(C)(C)OC(=O)N[C@H](C(SC(C)C)=O)C CTWRMZPOOHRGFV-QMMMGPOBSA-N 0.000 description 1
- CZLZCQPELSAQMC-QMMMGPOBSA-N CC(C)SC([C@H](C)NC(OC(OC(C)(C)C)=O)=O)=O Chemical compound CC(C)SC([C@H](C)NC(OC(OC(C)(C)C)=O)=O)=O CZLZCQPELSAQMC-QMMMGPOBSA-N 0.000 description 1
- 0 CC(C)SC([C@](C)N[P@@](C*[C@](C)C[n]1c(ncnc2N)c2nc1)(Oc1ccccc1)=O)=O Chemical compound CC(C)SC([C@](C)N[P@@](C*[C@](C)C[n]1c(ncnc2N)c2nc1)(Oc1ccccc1)=O)=O 0.000 description 1
- HSEUYPGQAVHSQK-NBYDKSJGSA-N CC(C)[S+]=C([C@H](C)NP(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)(OC1=CC=CC=C1)=O)[O-] Chemical compound CC(C)[S+]=C([C@H](C)NP(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)(OC1=CC=CC=C1)=O)[O-] HSEUYPGQAVHSQK-NBYDKSJGSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- BVMWIXWOIGJRGE-UHFFFAOYSA-N NP(O)=O Chemical compound NP(O)=O BVMWIXWOIGJRGE-UHFFFAOYSA-N 0.000 description 1
- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- KOZSXOSFAQOOMM-YFKPBYRVSA-N S-propan-2-yl (2S)-2-aminopropanethioate Chemical compound N[C@H](C(SC(C)C)=O)C KOZSXOSFAQOOMM-YFKPBYRVSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- ITAMCOCNZJPJDF-LLVKDONJSA-N [(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-phenoxyphosphinic acid Chemical compound O([C@@H](CN1C2=NC=NC(N)=C2N=C1)C)CP(O)(=O)OC1=CC=CC=C1 ITAMCOCNZJPJDF-LLVKDONJSA-N 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate 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
- OSQPUMRCKZAIOZ-UHFFFAOYSA-N carbon dioxide;ethanol Chemical compound CCO.O=C=O OSQPUMRCKZAIOZ-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- ZCIGNRJZKPOIKD-CQXVEOKZSA-N cobicistat Chemical compound S1C(C(C)C)=NC(CN(C)C(=O)N[C@@H](CCN2CCOCC2)C(=O)N[C@H](CC[C@H](CC=2C=CC=CC=2)NC(=O)OCC=2SC=NC=2)CC=2C=CC=CC=2)=C1 ZCIGNRJZKPOIKD-CQXVEOKZSA-N 0.000 description 1
- 229960002402 cobicistat Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- JUZYLCPPVHEVSV-LJQANCHMSA-N elvitegravir Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C=C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F JUZYLCPPVHEVSV-LJQANCHMSA-N 0.000 description 1
- 229960003586 elvitegravir Drugs 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940093097 genvoya Drugs 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000018191 liver inflammation Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000007903 penetration ability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 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
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本本发明涉及一种化合物(I)的一水合物其制备方法、组合物和在制备用于治疗病毒感染性疾病的药物上的应用。
Description
技术领域
本发明涉及一种核苷酸膦酸酯一水合物及其制备方法和在医药上的应用,具体的说,本发明涉及一种化合物(I)的一水合物其制备方法、组合物和在制备用于治疗病毒感染性疾病的药物上的应用。
背景技术
乙肝是世界性的疾病之一,它由乙肝病毒引起。世界上有三分之一的人口均在某种程度上感染了乙肝病毒,其中包括3亿5千万慢性携带者。在一些亚洲和非洲国家,乙肝已经变成流行性疾病,尤其是在中国。乙肝病毒能引起急性和慢性感染,急性感染通常伴随着肝脏发炎,呕吐,黄疸,极个别的还会引起死亡,而慢性感染有可能诱发肝硬化及肝癌。目前虽然可以通过疫苗预防乙肝病毒感染,但仍无有效的方法治疗慢性乙肝疾病。
替诺福韦(tenofovir),化学名称为[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基-乙氧基]甲基磷酸(PMPA),是一种核苷酸类逆转录酶抑制剂,具有抗HBV和HIV;但是由于其含有磷酸基团,具有较大极性,生物膜穿透能力差,在生物体内生物利用度差等缺点。为了克服这一缺点,可制成膦酸酯或者膦酰胺前药形式。2002年由吉利德公司研发上市的药物Viread(富马酸替诺福韦二吡呋酯)为PMPA的一种前药方式,制备成膦酸酯的前药形式大大提高了生物利用度。Viread在治疗HIV和HBV方面发挥了重要的作用。同时,该公司的另一个PMPA的前药tenofoviralafenamide(TAF)与恩曲他滨/cobicistat/elvitegravir组成的复方(商品名Genvoya)已经被FDA批准,用于治疗HIV感染。tenofoviralafenamide单独服用,用于治疗HBV感染目前正处于临床3期。
本发明提供了一种新的PMPA前药的水合物,可用于治疗病毒感染性疾病,其中病毒感染性疾病包括HBV和HIV病毒引起的感染性疾病。
发明内容
本发明提供一种化合物(I)的一水合物:
本发明优选方案,一种化合物(I)的一水合物,该化合物通过单晶衍射结构分析确定属于单斜晶系,空间群为P21,晶胞参数为 α=γ=90°和β=95.086(5)°,晶轴比a/b=0.8391,b/c=0.4076和c/a=2.9237,Z=2,
本发明提供一种制备化合物(I)的一水合物的方法,该方法为将化合物(I)溶于乙腈和水的混合溶剂中,在适宜的温度下,溶剂挥发即可制备得到化合物(I)的一水合物。
本发明优选方案,一种制备化合物(I)的一水合物的方法,该方法为将化合物(I)溶于乙腈和水的混合溶剂中,在适宜的温度下,溶剂挥发即可制备得到化合物(I)的一水合物,所述适宜的温度优选10~30℃。
本发明优选方案,一种制备化合物(I)的一水合物的方法,该方法为将化合物(I)溶于乙腈和水的混合溶剂中,在适宜的温度下,溶剂挥发即可制备得到化合物(I)的一水合物,乙腈和水的体积比为10:1至2:1,优选10:1至1:1,更优选5:1至1:1,进一步优选4:1,适宜的温度优选10~30℃。
本发明提供一种药物组合物,所述药物组合物含有治疗有效剂量的上述任一项所述的化合物(I)的一水合物,以及药学上可接受的载体或者赋形剂。
本发明提供一种上述任一项所述的化合物(I)的一水合物或者其组合物在制备用于治疗病毒感染性疾病的药物上的应用,所述的病毒感染性疾病优选HBV和HIV引起的感染性疾病。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫、氮或卤素均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物,其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
附图说明
图1为化合物(I)的一水合物单晶衍射谱图。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和BrukerAvance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空,充入氢气,反复操作3次。
实施例中无特殊说明,反应在氮气氛下进行。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温。
室温为最适宜的反应温度,为20℃~30℃。
实施例1
(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基-苯氧基-磷酰基]氨基]丙酸硫代异丙酯一水合物(化合物1,光学纯Rp-1)
S-isopropyl
(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino ]propanethioatehydrate
第一步:(S)-2-(叔丁氧基羰基)氨基丙酸硫代异丙酯(1B)
(S)-S-isopropyl 2-((tert-butoxycarbonyl)amino)propanethioate
将N-叔丁氧基羰基-L-丙氨酸(1A)(5g,26.4mmol)溶解于四氢呋喃(40mL)中,加入N,N'-羰基二咪唑(CDI)(4.7g,29.1mmol),室温搅拌2小时。加入硫代异丙醇(6.2g,79.3mmol),室温反应过夜。加入4mol/L的氢氧化钠溶液(30mL),用二氯甲烷(50mL×4)萃取,合并有机层,无水硫酸钠干燥,浓缩,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(v/v)=1:0~9:1),得标题化合物(S)-2-(叔丁氧基羰基)氨基丙酸硫代异丙酯(1B),浅黄色液体(4g,产率61%)。
1H NMR(400MHz,CDCl3)δ3.61(m,1H),2.37–2.16(m,1H),1.46(s,9H),1.36(d,3H),1.30(d,6H)。
第二步:(S)-2-氨基丙酸硫代异丙酯三氟乙酸盐(1C)
(S)-S-isopropyl 2-aminopropanethioate triflouroacetate
将(S)-2-(叔丁氧基羰基)氨基丙酸硫代异丙酯(1B)(4g,16.2mmol)溶于二氯甲烷(10mL)中,加入三氟乙酸(10mL),室温搅拌4小时。减压浓缩至干得粗品(S)-2-氨基丙酸硫代异丙酯三氟乙酸盐(1C)(4g),直接用于下一步。
第三步:[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基次磷酸(1E)
[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphinicacid
氮气保护下将[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]磷酸(即PMPA)(1D)(5g,17.4mmol)加到三颈瓶中,加入乙腈(40mL),三乙胺(3.5g,34.8mmol),4-二甲氨基吡啶(即DMAP)(2.1g,17.4mmol)和亚磷酸三苯酯(8.1g,26.1mmol)加完后,加热至内温80℃反应两天。将反应液减压浓缩除去乙腈,向残留物中加入乙酸乙酯(10mL)和水(15mL),分液,水层用乙酸乙酯(10mL×2)萃取,合并水层,水层用浓盐酸调节pH至3,室温搅拌10分钟,用浓盐酸调节pH至2,冰水冷却至10℃搅拌两小时后静置过夜,过滤,滤饼用水(10mL)洗涤,收集滤饼,烘干标题化合物[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基次磷酸(1E),(3.5g,产率56%)。
1H NMR(400MHz,DMSO)δ8.16(s,1H),8.14(s,1H),7.55(s,2H),7.32–7.25(m,2H),7.09(m,3H),4.30(dd,1H),4.19(dd,1H),3.97(m,1H),3.87–3.69(m,2H),1.05(d,3H)。
31P NMR(400MHz,DMSO)δ16.66。
第四步:[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基磷酰氯(1F)
9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine
将[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基次磷酸(1E)(2g,5.5mmol)悬浮于乙腈(20mL)中,加入氯化亚砜(2.6g,22.0mmol)加热至内温85℃反应4小时,将反应液减压浓缩,得粗品直接用于下一步。
第五步:(2S)-2-[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基磷酰氨基丙酸硫代异丙酯(1G)(光学纯Rp-1)
S-isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanethioate
将(S)-2-氨基丙酸硫代异丙酯三氟乙酸盐(1C)(4g,16.2mmol)溶于干燥的二氯甲烷(20mL)中,氮气保护下,干冰-乙醇冷却至-50℃,滴加三乙胺(5mL,35.8mmol)搅拌10分钟,滴加[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基磷酰氯(1F)(2.1g,5.5mmol)的二氯甲烷(20mL)悬浊液,完成后,自然升温至室温反应1小时。向反应液中加入水(20mL),分液,有机层用水(10mL)洗涤一次,无水硫酸钠干燥,减压浓缩,将残留物溶于乙酸乙酯(50mL)中,冰浴冷却下用4mol/L的盐酸调节pH至2,分液,水层用乙酸乙酯(20mL)萃取,取水层,加入二氯甲烷(50mL),冰浴冷却下滴加饱和碳酸氢钠水溶液调节pH至8,分液,水层用二氯甲烷(20mL)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,减压浓缩,得(2S)-2-[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基磷酰氨基丙酸硫代异丙酯(1G)的两种非对映异构体混合物(300mg,产率11%),将该混合物采用HPLC拆分得到1G(光学纯Rp-1)),化合物1G为HPLC拆分后的峰1。
分离分析方法:仪器,Thar analytical SFC;柱,ChiralPak AS-H,250×4.6mm;流动相,A为CO2以及B为Methanol(0.05%DEA);梯度,B 40%;流量,2.4mL/min;背压,100bar;柱温,35℃;波长,220nm。
制备分离方法:仪器,MGⅡpreparative SFC;柱,ChiralPak AS-H,250×30mmI.D.;流动相,A为CO2以及B为Methanol;梯度,B 40%;流量,40mL/min;背压,100bar;柱温38℃;波长,220nm;周期,5.5min。
样品制备:1G的两种非对映异构体混合物(300mg)溶解于甲醇中,制得样品浓度10mg/mL的溶液,进样3mL/每针,分离后得到两个光学异构体化合物,其中峰1为化合物1G(保留时间:2.21min,106mg,白色固体,ee%=100%),峰2为化合物1G的非对映异构体1G’(保留时间:3.82min,109mg,白色固体,ee%=100%)。
化合物1G
1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.01(s,1H),7.32(t,2H),7.21–7.11(m,3H),6.04(s,2H),4.47(dd,1H),4.21–4.13(m,1H),4.13–4.06(m,1H),4.06–3.96(m,2H),3.69(dd,1H),3.54–3.39(m,2H),1.28–1.17(m,12H)。
31P NMR(162MHz,CDCl3)δ23.15。
LC-MS M/Z(ESI):493.1[M+1]。
化合物1G的非对映异构体1G’
1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.97(s,1H),7.25–7.17(m,2H),7.13–7.05(m,1H),7.03–6.95(m,2H),5.90(s,2H),4.34(dd,1H),4.16–4.03(m,2H),3.99–3.89(m,2H),3.84(t,1H),3.76–3.52(m,2H),1.33–1.20(m,12H)。
31P NMR(162MHz,CDCl3)δ22.12。
LC-MS M/Z(ESI):493.1[M+1]。
第六步:(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基-苯氧基-磷酰基]氨基]丙酸硫代异丙酯一水合物(化合物1,光学纯Rp-1)
S-isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanethioate hydrate
取约5mg(2S)-2-[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基磷酰氨基丙酸硫代异丙酯(1G)(光学纯Rp-1))放于玻璃小瓶中,用乙腈(1.6mL)及水(0.4mL)超声溶清,室温下小孔挥发,得到块状晶体,即为(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基-苯氧基-磷酰基]氨基]丙酸硫代异丙酯一水合物(化合物1,光学纯Rp-1)。
实施例2:化合物1(光学纯Rp-1)单晶X-射线结晶学测量(图1所示)
1.仪器信息和检测方法参数
2单晶结构数据
3.化合物1(光学纯Rp-1)原子坐标(x 104)、等效各向同性位移参数和U(eq)
U(eq)定义为正交化Uij张量轨迹的三分之一(U(eq)is defined as one thirdof the trace of the orthogonalizedUijtensor)
4.化合物1(光学纯Rp-1)氢原子坐标(x 104)、等效各向同性位移参数和U(eq)
5.化合物1(光学纯Rp-1)各向异性位移参数
各项异性位移因子指数采取如下形式:-2π2[h2a*2U11+...+2h k a*b*U12]。
生物测试例
抗乙型肝炎病毒活性筛选
用HepG2.2.15细胞测定化合物的抗乙肝病毒活性。使用的材料与仪器如下:HepG2.2.15细胞,RPMI 1640培养液,胎牛血清,96孔板,DMSO,QIAamp 96DNABlood Kit,Cell-titer blue,酶标仪,Applied Biosystems 7900real-time PCR system。
用DMSO将化合物1(光学纯Rp-1)溶解至20mM,-20℃贮存,将化合物1(光学纯Rp-1)的20mM贮存液用DMSO 3倍梯度稀释,共9个浓度。再用含2.0%FBS的RPMI 1640培养液稀释200倍。化合物的最高测试终浓度为100M。实验步骤参照QIAamp 96DNA Blood Kit(QIAGEN51161)说明书,qPCR法测定化合物抗乙肝病毒活性并计算EC50(半数有效抑制浓度)。分析数据和计算抑制百分比:应用如下公式计算抑制百分比:抑制率(%)=(DMSO对照组的HBV总量-受试样品组的HBV总量)/DMSO对照组的HBV总量×100。最后使用GraphPad Prism软件计算化合物的EC50值。
Cell-titer blue法测定化合物的细胞毒性并计算CC50(致50%细胞毒性浓度)。分析数据和计算相对细胞活力:应用如下公式计算细胞活性百分比:细胞生存率(%)=(受试样品的荧光数值-背景荧光数值)/(DMSO对照组的荧光数值-背景荧光数值)×100。最后使用GraphPad Prism软件计算化合物的CC50值。结果如下表所示:
化合物编号 | ||
化合物1(光学纯Rp-1) | 8 | >100 |
Claims (9)
1.一种化合物(I)的一水合物:
2.根据权利要求1所述的化合物(I)的一水合物,其特征在于,该化合物通过单晶衍射结构分析确定属于单斜晶系,空间群为P21,晶胞参数为 α=γ=90°和β=95.086(5)°,晶轴比a/b=0.8391,b/c=0.4076和c/a=2.9237,Z=2,
3.制备权利要求1所述的化合物(I)的一水合物的方法,其特征在于将化合物(I)溶于乙腈和水的混合溶剂中,在适宜的温度下,溶剂挥发即可制备得到化合物(I)的一水合物。
4.根据权利要求3所述的方法,适宜的温度选自10~30℃。
5.根据权利要求3所述的方法,其特征在于乙腈和水的体积比为10:1至2:1。
6.根据权利要求5所述的方法,其特征在于乙腈和水的体积比为4:1。
7.一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1~2中任一项所述的化合物(I)的一水合物,以及药学上可接受的载体或者赋形剂。
8.权利要求1或2所述的一水合物或7所述的药物组合物在制备用于治疗病毒感染性疾病的药物上的应用。
9.根据权利要求8所述的应用,所述的病毒感染性疾病包括HBV和HIV引起的感染性疾病。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510836885 | 2015-11-25 | ||
CN2015108368853 | 2015-11-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106800573A true CN106800573A (zh) | 2017-06-06 |
CN106800573B CN106800573B (zh) | 2020-03-10 |
Family
ID=58977092
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610973798.7A Expired - Fee Related CN106800573B (zh) | 2015-11-25 | 2016-11-07 | 一种核苷酸膦酸酯一水合物及其制备方法和在医药上的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106800573B (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0481214A1 (en) * | 1990-09-14 | 1992-04-22 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
WO2002008241A2 (en) * | 2000-07-21 | 2002-01-31 | Gilead Sciences, Inc. | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
CN103224530A (zh) * | 2012-08-13 | 2013-07-31 | 洛阳聚慧投资股份有限公司 | 一组替诺福韦酯化合物、制备方法及其在抗病毒方面的应用 |
CN103665043A (zh) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | 一种替诺福韦前药及其在医药上的应用 |
-
2016
- 2016-11-07 CN CN201610973798.7A patent/CN106800573B/zh not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0481214A1 (en) * | 1990-09-14 | 1992-04-22 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
WO2002008241A2 (en) * | 2000-07-21 | 2002-01-31 | Gilead Sciences, Inc. | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
CN103224530A (zh) * | 2012-08-13 | 2013-07-31 | 洛阳聚慧投资股份有限公司 | 一组替诺福韦酯化合物、制备方法及其在抗病毒方面的应用 |
CN103665043A (zh) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | 一种替诺福韦前药及其在医药上的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN106800573B (zh) | 2020-03-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN115175908B (zh) | 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用 | |
CN104672288B (zh) | 一种氘代索菲布韦及其用途 | |
CN107312039B (zh) | 一种替诺福韦前药的制备方法 | |
CN110099912A (zh) | 抗病毒替诺福韦脂肪族酯前药 | |
CN103764653B (zh) | 作为c-Kit激酶抑制剂的化合物和组合物 | |
EP3717465A1 (en) | Compounds | |
CN107849071A (zh) | 抗病毒的β氨基酸酯膦酰二胺化合物 | |
TW201136593A (en) | Nucleoside phosphoramidates | |
AU2011235112A1 (en) | Nucleoside phosphoramidates | |
WO2021053403A1 (en) | Sulfonamide inhibitors as ctps1 inhibitors | |
EP4041723A2 (en) | Sulfonamide derivatives as ctps1 inhibitors | |
IL288822B2 (en) | Phenyl-2-hydroxy-acetylamino-2-methyl-phenyl compounds | |
CN106478753A (zh) | 一种nuc‑1031单一异构体的制备方法和用途 | |
CN105518012B (zh) | 一种取代的氨基酸硫酯类化合物、其组合物及应用 | |
CN105111201A (zh) | 5-甲基-2-(吡啶-2-基氨基)-8H-吡啶并[2,3-d]嘧啶-7-酮化合物 | |
CN104119385A (zh) | 核苷类似物的磷酸酯前药及其应用 | |
CN113105448A (zh) | 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用 | |
ES2564366T3 (es) | Análogos de encefalina | |
CN105001262B (zh) | 芳基取代的磷酰胺类衍生物及其在医学上的应用 | |
CN106800573A (zh) | 一种核苷酸膦酸酯一水合物及其制备方法和在医药上的应用 | |
CN105814068B (zh) | 一种取代的氨基磷酸酯类衍生物、其制备方法及其应用 | |
CN104402833B (zh) | 含有环丁烷取代基的吡嗪类化合物及其组合物及用途 | |
CN114671866A (zh) | 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用 | |
CN112778372A (zh) | 咪唑并喹啉取代磷酸酯类激动剂及其制备方法和应用 | |
CN104447583B (zh) | 含有环丁烷取代基的吡嗪类化合物及其组合物及用途 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200310 |
|
CF01 | Termination of patent right due to non-payment of annual fee |