CN106800573B - Nucleotide phosphonate monohydrate, preparation method and medical application thereof - Google Patents
Nucleotide phosphonate monohydrate, preparation method and medical application thereof Download PDFInfo
- Publication number
- CN106800573B CN106800573B CN201610973798.7A CN201610973798A CN106800573B CN 106800573 B CN106800573 B CN 106800573B CN 201610973798 A CN201610973798 A CN 201610973798A CN 106800573 B CN106800573 B CN 106800573B
- Authority
- CN
- China
- Prior art keywords
- compound
- monohydrate
- acetonitrile
- preparation
- methyl
- 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.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- QWZRZYWLWTWVLF-UHFFFAOYSA-N O.OP(O)=O Chemical compound O.OP(O)=O QWZRZYWLWTWVLF-UHFFFAOYSA-N 0.000 title description 3
- 239000002773 nucleotide Substances 0.000 title description 3
- 125000003729 nucleotide group Chemical group 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 150000004682 monohydrates Chemical class 0.000 claims abstract description 18
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 11
- 230000003612 virological effect 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 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 238000004458 analytical method Methods 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- -1 protium (H) Chemical compound 0.000 description 12
- 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 11
- 229940125904 compound 1 Drugs 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KTYVHLCLTPLSGC-UHFFFAOYSA-N amino propanoate Chemical compound CCC(=O)ON KTYVHLCLTPLSGC-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000010410 layer Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 208000002672 hepatitis B Diseases 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 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 5
- 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 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 125000004035 thiopropyl group Chemical group [H]SC([H])([H])C([H])([H])C([H])([H])* 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
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- 241000701076 Macacine alphaherpesvirus 1 Species 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 229910052805 deuterium Inorganic materials 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000005764 inhibitory process Effects 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
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 229960001355 tenofovir disoproxil Drugs 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-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
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-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
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229960004556 tenofovir Drugs 0.000 description 2
- 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 2
- 229960004946 tenofovir alafenamide 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
- 238000005406 washing Methods 0.000 description 2
- OMQFSBUUJBSXDN-UHFFFAOYSA-N 2-amino-3-(oxo-$l^{5}-phosphanylidyne)propanoic acid Chemical compound OC(=O)C(N)C#P=O OMQFSBUUJBSXDN-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 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
- 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [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
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 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
- 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
- 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
- 241000700605 Viruses Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- DSLSVPYCKGQEMT-ZCFIWIBFSA-N [(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl dihydrogen phosphate Chemical compound NC1=C2N=CN(C2=NC=N1)C[C@H](OCOP(O)(O)=O)C DSLSVPYCKGQEMT-ZCFIWIBFSA-N 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000011230 binding agent Substances 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
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-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
- 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
- 239000012043 crude product 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
- 238000007405 data analysis Methods 0.000 description 1
- 238000001514 detection method Methods 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
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 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
- 239000011521 glass Substances 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
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 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
- 230000007903 penetration ability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 125000005541 phosphonamide group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 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
- 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
Images
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
The invention relates to a monohydrate of a compound (I), a preparation method and a composition thereof, and application of the monohydrate of the compound (I) in preparation of medicaments for treating viral infectious diseases.
Description
Technical Field
The invention relates to a nucleotide phosphonate monohydrate, a preparation method and a medical application thereof, in particular to a monohydrate of a compound (I), a preparation method and a composition thereof and an application thereof in preparing a medicament for treating virus infectious diseases.
Background
Hepatitis B is one of the worldwide diseases, and is caused by hepatitis B virus. One third of the world's population is infected to some extent with hepatitis B virus, including 3 billion to 5 million chronic carriers. In some asian and african countries, hepatitis b has become an epidemic disease, especially in china. Hepatitis b virus causes acute and chronic infections, with acute infections usually accompanied by liver inflammation, vomiting, jaundice, and very individually death, while chronic infections may induce cirrhosis and liver cancer. Although hepatitis B virus infection can be prevented by vaccines at present, there is no effective method for treating chronic hepatitis B disease.
Tenofovir (tenofovir), chemical name [ (1R) -2- (6-aminopurine-9-yl) -1-methyl-ethoxy ] methylphosphonic acid (PMPA), is a nucleotide reverse transcriptase inhibitor, and has anti-HBV and anti-HIV activity; but because it contains phosphate group, it has large polarity, poor biological membrane penetration ability, poor bioavailability in vivo and other disadvantages. To overcome this disadvantage, phosphonate or phosphonamide prodrug forms can be prepared. In 2002, Viread (tenofovir disoproxil fumarate) which is a marketed drug is developed by Gilidde corporation and is used as a prodrug mode of PMPA, and the phosphonate prepared by the Viread mode greatly improves the bioavailability. Viread plays an important role in the treatment of HIV and HBV. Meanwhile, another PMPA prodrug of this company, tenofoviralafenamide (taf), has been FDA approved for use in treating HIV infection in combination with emtricitabine/cobicistat/elvitegravir (trade name Genvoya). Tenofovir alafenamide, taken alone, is currently in clinical phase 3 for the treatment of HBV infection.
The invention provides a novel PMPA prodrug hydrate, which can be used for treating viral infectious diseases, wherein the viral infectious diseases comprise infectious diseases caused by HBV and HIV viruses.
Disclosure of Invention
The present invention provides a monohydrate of compound (I):
in a preferred embodiment of the present invention, the monohydrate of compound (I) is a monoclinic compound determined by single crystal diffraction structure analysis, and has a space group of P21Cell parameter of
α γ 90 ° and β 95.086(5 °), the ratio of crystal axes a/b 0.8391, b/c 0.4076 and c/a 2.9237, Z2,
the invention provides a method for preparing a monohydrate of a compound (I), which is to dissolve the compound (I) in a mixed solvent of acetonitrile and water, and volatilize the solvent at a proper temperature to prepare the monohydrate of the compound (I).
In a preferred embodiment of the present invention, the method for preparing the monohydrate of the compound (I) is to dissolve the compound (I) in a mixed solvent of acetonitrile and water, and volatilize the solvent at a suitable temperature, wherein the suitable temperature is preferably 10 to 30 ℃.
In a preferred embodiment of the present invention, the monohydrate of the compound (I) is prepared by dissolving the compound (I) in a mixed solvent of acetonitrile and water, and volatilizing the solvent at a suitable temperature, wherein the volume ratio of acetonitrile to water is 10:1 to 2:1, preferably 10:1 to 1:1, more preferably 5:1 to 1:1, further preferably 4:1, and the suitable temperature is preferably 10 to 30 ℃.
The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a monohydrate of compound (I) as defined in any one of the above, together with a pharmaceutically acceptable carrier or excipient.
The invention provides an application of the monohydrate of the compound (I) or the composition thereof in preparing a medicament for treating viral infectious diseases, wherein the viral infectious diseases are preferably infectious diseases caused by HBV and HIV.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The elemental carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the invention all include their isotopes, and the elemental carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include12C、13C and14c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including16O、17O and18isotopes of O, sulfur including32S、33S、34S and36isotopes of S, nitrogen include14N and15isotopes of N, F19Isotopes of F, chlorine including35Cl and37cl, isotopes of bromine including79Br and81Br。
"pharmaceutical composition" means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt thereof with other ingredients, wherein the other ingredients comprise physiologically/pharmaceutically acceptable carriers and excipients.
"carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like.
Drawings
FIG. 1 is a single crystal diffraction pattern of monohydrate of Compound (I).
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.
The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is room temperature, unless otherwise specified.
The room temperature is the most suitable reaction temperature and is 20-30 ℃.
Example 1
Thiopropyl (2S) -2- [ [ [ (1R) -2- (6-aminopurine-9-yl) -1-methylethoxy ] methyl-phenoxy-phosphoryl ] amino ] propanoate monohydrate (Compound 1, optically pure Rp-1)
S-isopropyl
(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanethioatehydrate
The first step is as follows: (S) -Thioisopropyl 2- (tert-Butoxycarbonyl) aminopropionate (1B)
(S)-S-isopropyl 2-((tert-butoxycarbonyl)amino)propanethioate
N-tert-butoxycarbonyl-L-alanine (1A) (5g,26.4mmol) was dissolved in tetrahydrofuran (40mL), and N, N' -Carbonyldiimidazole (CDI) (4.7g, 29.1mmol) was added and stirred at room temperature for 2 hours. Thioisopropanol (6.2g,79.3mmol) was added and the reaction was allowed to proceed overnight at room temperature. 4mol/L sodium hydroxide solution (30mL) was added, extraction was performed with dichloromethane (50 mL. times.4), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified with a silica gel column (petroleum ether: ethyl acetate (v/v) ═ 1:0 to 9:1) to give the title compound (S) -thioisopropyl 2- (tert-butoxycarbonyl) aminopropionate (1B) as a pale yellow liquid (4g, 61% yield).
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)。
The second step is that: (S) -2-Aminopropionic acid Thioisopropyl trifluoroacetate (1C)
(S)-S-isopropyl 2-aminopropanethioate triflouroacetate
Thiopropyl (S) -2- (tert-butoxycarbonyl) aminopropionate (1B) (4g,16.2mmol) was dissolved in methylene chloride (10mL), and trifluoroacetic acid (10mL) was added and the mixture was stirred at room temperature for 4 hours. Concentration under reduced pressure to dryness gave crude (S) -2-aminopropionic acid thioisopropyl ester trifluoroacetate (1C) (4g) which was used directly in the next step.
The third step: [ [ (1R) -2- (6-aminopurin-9-yl) -1-methylethoxy ] methyl ] phenoxyphosphinic acid (1E)
[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphinicacid
[ [ (1R) -2- (6-aminopurine-9-yl) -1-methylethoxy ] methyl ] phosphoric acid (i.e., PMPA) (1D) (5g,17.4mmol) was added to a three-necked flask under nitrogen, and after addition of acetonitrile (40mL), triethylamine (3.5g,34.8mmol), 4-dimethylaminopyridine (i.e., DMAP) (2.1g, 17.4mmol) and triphenyl phosphite (8.1g, 26.1mmol), the flask was heated to an internal temperature of 80 ℃ for two days. The reaction mixture was concentrated under reduced pressure to remove acetonitrile, ethyl acetate (10mL) and water (15mL) were added to the residue, the layers were separated, the aqueous layer was extracted with ethyl acetate (10 mL. times.2), the aqueous layers were combined, the pH of the aqueous layer was adjusted to 3 with concentrated hydrochloric acid, stirred at room temperature for 10 minutes, adjusted to 2 with concentrated hydrochloric acid, cooled to 10 ℃ with ice water, stirred for two hours, allowed to stand overnight, filtered, the filter cake was washed with water (10mL), the filter cake was collected, and the title compound [ [ (1R) -2- (6-aminopurine-9-yl) -1-methylethoxy ] methyl ] phenoxy hypophosphorous acid (1E), (3.5g, 56% yield) was oven dried.
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。
The fourth step: [ [ (1R) -2- (6-aminopurin-9-yl) -1-methylethoxy ] methyl ] phenoxyphosphoryl chloride (1F)
9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine
[ [ (1R) -2- (6-aminopurine-9-yl) -1-methylethoxy ] methyl ] phenoxy-phosphinic acid (1E) (2g, 5.5mmol) was suspended in acetonitrile (20mL), thionyl chloride (2.6g, 22.0mmol) was added, the reaction was heated to an internal temperature of 85 ℃ for 4 hours, and the reaction was concentrated under reduced pressure to give a crude product which was used directly in the next step.
The fifth step: thiopropyl (1G) (optically pure Rp-1) of (2S) -2- [ [ (1R) -2- (6-aminopurine-9-yl) -1-methylethoxy ] methyl ] phenoxyphosphorylaminopropionate
S-isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanethioate
(S) -2-Aminopropionic acid thioisopropyl ester trifluoroacetate (1C) (4g,16.2mmol) was dissolved in dry dichloromethane (20mL), cooled to-50 ℃ under nitrogen, triethylamine (5mL, 35.8mmol) was added dropwise, the mixture was stirred for 10 minutes, a suspension of [ [ (1R) -2- (6-aminopurine-9-yl) -1-methylethoxy ] methyl ] phenoxyphosphoryl chloride (1F) (2.1g, 5.5mmol) in dichloromethane (20mL) was added dropwise, and after completion, the temperature was naturally raised to room temperature for 1 hour. Adding water (20mL) to the reaction solution, separating, washing the organic layer once with water (10mL), drying over anhydrous sodium sulfate, concentrating under reduced pressure, dissolving the residue in ethyl acetate (50mL), adjusting the pH to 2 with 4mol/L hydrochloric acid under ice-bath cooling, separating, extracting the aqueous layer with ethyl acetate (20mL), collecting the aqueous layer, adding dichloromethane (50mL), adding saturated aqueous sodium bicarbonate solution under ice-bath cooling to adjust the pH to 8, separating, extracting the aqueous layer with dichloromethane (20mL), combining the organic layers, washing with saturated sodium chloride (10mL), drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain a mixture of two diastereomers of (2S) -2- [ [ (1R) -2- (6-aminopurine-9-yl) -1-methylethoxy ] methyl ] phenoxy ] phosphoryl amino propionic acid thioisopropyl ester (1G) (300mg, yield 11%), the mixture was resolved by HPLC to give 1G (optically pure Rp-1)), compound 1G being peak 1 after HPLC resolution.
The separation and analysis method comprises the following steps: instrument, Thar analytical SFC; column, ChiralPak AS-H, 250X 4.6 mm; mobile phase, A is CO2And B is Methanol (0.05% DEA); gradient, B40%; flow rate, 2.4 mL/min; back pressure, 100 bar; column temperature, 35 ℃; wavelength, 220 nm.
The preparation and separation method comprises the following steps: instrument, MG ii preparatory SFC; column, ChiralPak AS-H,250 × 30 mmi.d.; mobile phase, A is CO2And B is Methanol; gradient, B40%; flow rate, 40 mL/min; back pressure, 100 bar; the column temperature is 38 ℃; wavelength, 220 nm; cycle, 5.5 min.
Sample preparation 1G of a mixture of two diastereomers (300mg) was dissolved in methanol to prepare a solution having a sample concentration of 10mg/mL, and 3 mL/needle was injected, and two optical isomer compounds were obtained after separation, wherein peak 1 was compound 1G (retention time: 2.21min, 106mg, white solid, ee%: 100%) and peak 2 was diastereoisomer 1G' of compound 1G (retention time: 3.82min, 109mg, white solid, ee%: 100%).
Compound 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]。
Diastereomer 1G 'of Compound 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]。
And a sixth step: thiopropyl (2S) -2- [ [ [ (1R) -2- (6-aminopurine-9-yl) -1-methylethoxy ] methyl-phenoxy-phosphoryl ] amino ] propanoate monohydrate (Compound 1, optically pure Rp-1)
S-isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanethioate hydrate
About 5mg of thioisopropyl (2S) -2- [ [ (1R) -2- (6-aminopurine-9-yl) -1-methylethoxy ] methyl ] phenoxy phosphoryl ] aminopropionate (1G) (optically pure Rp-1)) was placed in a glass vial, sonicated with acetonitrile (1.6mL) and water (0.4mL) and evaporated in a small well at room temperature to give a bulk crystal, i.e., (2S) -2- [ [ [ (1R) -2- (6-aminopurine-9-yl) -1-methylethoxy ] methyl-phenoxy-phosphoryl ] amino ] propionate monohydrate (compound 1, optically pure Rp-1).
Example 2: single crystal X-ray crystallography measurements of Compound 1 (optically pure Rp-1) (shown in FIG. 1)
1. Instrument information and detection method parameters
2 data of single crystal structure
3. Compound 1 (optically pure Rp-1) atomic coordinate (x 10)4) Equivalent isotropic displacement parameter
And U (eq)
U (eq) is defined as one third (U (eq) of the orthogonal Uij tensor track of the orthogonal as one third of the orthogonal as of the orthogonal Uijtensor)
4. Compound 1 (optically pure Rp-1) Hydrogen atom coordinate (x 10)4) Equivalent isotropic displacement parameter
And U (eq)
5. Anisotropy shift parameter of Compound 1 (optically pure Rp-1)
The anisotropy displacement factor index takes the form-2 π2[h2a*2U11+...+2h k a*b*U12]。
Biological test example
Screening for anti-hepatitis B Virus Activity
The anti-hepatitis B virus activity of the compounds was determined using HepG2.2.15 cells. The materials and instruments used were as follows: HepG2.2.15 cells, RPMI 1640 medium, fetal bovine serum, 96-well plates, DMSO, QIAamp 96DNAblood Kit, Cell-titer blue, microplate reader, Applied Biosystems 7900real-time PCR system.
Compound 1 (optically pure Rp-1) was dissolved in DMSO to 20mM, stored at-20 ℃ and a 20mM stock solution of compound 1 (optically pure Rp-1) was diluted in DMSO in a 3-fold gradient for a total of 9 concentrations. Then diluted 200-fold with 2.0% FBS-containing RPMI 1640 medium. The highest final concentration tested for the compound was 100M. Experimental procedures referring to the QIAamp 96DNA Blood Kit (QIAGEN51161) instructions, the qpCR method was used to determine the anti-hepatitis B virus activity of the compounds and to calculate the EC50(half the effective inhibitory concentration). Data analysis and calculation of percent inhibition: percent inhibition was calculated using the following formula: inhibition (%) - (total amount of HBV in DMSO control group-total amount of HBV in test sample group)/total amount of HBV in DMSO control group × 100. Finally, EC of the compound was calculated using GraphPad Prism software50The value is obtained.
Cell-titer blue method for determining cytotoxicity of compounds and calculating CC50(resulting in a 50% cytotoxic concentration). Analysis of data and calculation of relative cell viability: the percentage of cell activity was calculated using the following formula: cell viability (%) × (fluorescence value of test sample-background fluorescence value)/(fluorescence value of DMSO control group-background fluorescence value) × 100. Finally CC of the compound was calculated using GraphPad Prism software50The value is obtained. The results are shown in the following table:
| compound numbering | EC50(nM) | CC50(μM) |
| Compound 1 (optical purity Rp-1) | 8 | >100 |
Claims (8)
1. A monohydrate of Compound (I):
2. compound (I) monohydrate according to claim 1, characterized in that it belongs to the monoclinic system, determined by single crystal diffraction structure analysis, as space group P21Cell parameter of
α γ 90 ° and β 95.086(5 °), the ratio of crystal axes a/b 0.8391, b/c 0.4076 and c/a 2.9237, Z2,
3. the method for preparing the monohydrate of the compound (I) according to claim 1, which is characterized in that the monohydrate of the compound (I) is prepared by dissolving the compound (I) in a mixed solvent of acetonitrile and water and volatilizing the solvent at 10-30 ℃.
4. A process according to claim 3, characterized in that the volume ratio of acetonitrile to water is from 10:1 to 2: 1.
5. The process according to claim 4, characterized in that the volume ratio of acetonitrile to water is 4: 1.
6. A pharmaceutical composition comprising a therapeutically effective amount of a monohydrate of compound (I) according to any one of claims 1 to 2, together with a pharmaceutically acceptable carrier or excipient.
7. Use of the monohydrate of claim 1 or 2 or the pharmaceutical composition of 6 for the preparation of a medicament for the treatment of a viral infectious disease.
8. The use according to claim 7, wherein the viral infectious diseases include infectious diseases caused by HBV and HIV.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015108368853 | 2015-11-25 | ||
| CN201510836885 | 2015-11-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106800573A CN106800573A (en) | 2017-06-06 |
| CN106800573B true CN106800573B (en) | 2020-03-10 |
Family
ID=58977092
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610973798.7A Expired - Fee Related CN106800573B (en) | 2015-11-25 | 2016-11-07 | Nucleotide phosphonate monohydrate, preparation method and medical application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106800573B (en) |
Citations (3)
| 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 |
| CN103224530A (en) * | 2012-08-13 | 2013-07-31 | 洛阳聚慧投资股份有限公司 | Tenofovir disoproxil compounds, and preparation method and application thereof in anti-virus aspects |
| CN103665043A (en) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | Tenofovir prodrug and medical application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2001282941C1 (en) * | 2000-07-21 | 2016-12-22 | Gilead Sciences, Inc. | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
-
2016
- 2016-11-07 CN CN201610973798.7A patent/CN106800573B/en not_active Expired - Fee Related
Patent Citations (3)
| 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 |
| CN103224530A (en) * | 2012-08-13 | 2013-07-31 | 洛阳聚慧投资股份有限公司 | Tenofovir disoproxil compounds, and preparation method and application thereof in anti-virus aspects |
| CN103665043A (en) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | Tenofovir prodrug and medical application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106800573A (en) | 2017-06-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7470151B2 (en) | Use of chloroquine and clemizole compounds to treat inflammatory and cancerous conditions | |
| KR20160007651A (en) | Phosphoric acid/phosphonic acid derivatives and medicinal uses thereof | |
| CN106167504A (en) | Acyclonucleosides phosphamide D amino acid ester derivative and the preparation of salt thereof and in the application of anti-virus aspect | |
| EP2970184A1 (en) | Compounds and uses thereof for the modulaton of hemoglobin | |
| JP2013082717A (en) | Process for preparation of hiv protease inhbitors | |
| CN105518012B (en) | A kind of substituted amino acid sulfur ester, its composition and application | |
| CN108947949B (en) | Anxiolytic deuterated compounds and medical application thereof | |
| CN114380864B (en) | Dihydroartemisinin derivative, preparation method, pharmaceutical composition and application thereof in preparation of antitumor drugs | |
| JP7305198B2 (en) | Nucleoside Cyclic Phosphate Ester Compounds and Applications of Entecavir Prodrugs Based on Hepatic Delivery | |
| CN108350007B (en) | Substituted adenine compound and pharmaceutical composition thereof | |
| CN106800573B (en) | Nucleotide phosphonate monohydrate, preparation method and medical application thereof | |
| TWI718990B (en) | A novel polymorphic form of tenofovir prodrug and its preparation as well as the use thereof | |
| CN111909204B (en) | Tenofovir dipivoxil phenylpropionate phosphoramidate compound, and pharmaceutical composition and application thereof | |
| CN102633796B (en) | New preparation method of sophora flavescens acid derivative | |
| TWI616453B (en) | Substituted amino acid thioester compounds, materials and uses thereof | |
| CN111909205B (en) | Tenofovir dipivoxil base phosphoramidate compound, and pharmaceutical composition and application thereof | |
| CN110092799B (en) | Cyclic compound, preparation method and application thereof | |
| CN113501847B (en) | High-efficiency anti-hepatitis B virus compound and preparation method and application thereof | |
| CN117126161A (en) | Benzopyridine compound and preparation method and application thereof | |
| CN114591322A (en) | Alkynyl pyridine compound, and pharmaceutical composition, preparation method and application thereof | |
| CN106674320B (en) | HCV (hepatitis C virus) treatment medicine | |
| CN106674319B (en) | Compound for treating hepatitis C | |
| TWI654198B (en) | Aryl substituted phosphonium derivatives and their application in medicine | |
| CN117126163A (en) | Benzo heterocyclic compound, and preparation method and application thereof | |
| CN108218940A (en) | Nucleoside phosphoramidate class compound, preparation method and the usage |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200310 |