CN105705508A - Acyclic nucleoside phosphonate derivative and preparation method and use thereof in medical science - Google Patents
Acyclic nucleoside phosphonate derivative and preparation method and use thereof in medical science Download PDFInfo
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- CN105705508A CN105705508A CN201480061359.8A CN201480061359A CN105705508A CN 105705508 A CN105705508 A CN 105705508A CN 201480061359 A CN201480061359 A CN 201480061359A CN 105705508 A CN105705508 A CN 105705508A
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- Prior art keywords
- methyl
- alkyl
- compound
- group
- virus
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- 238000002360 preparation method Methods 0.000 title abstract description 10
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical class NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 title abstract 3
- -1 sulfydryl Chemical group 0.000 claims abstract description 190
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 54
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 32
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 27
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 25
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 23
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 208000002672 hepatitis B Diseases 0.000 claims description 26
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 18
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- 238000006467 substitution reaction Methods 0.000 claims description 17
- 230000009385 viral infection Effects 0.000 claims description 16
- 208000036142 Viral infection Diseases 0.000 claims description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 8
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 208000035473 Communicable disease Diseases 0.000 claims description 7
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 241000711549 Hepacivirus C Species 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 4
- 229950004288 tosilate Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 239000002585 base Substances 0.000 description 103
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 50
- 238000006243 chemical reaction Methods 0.000 description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 46
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 41
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 29
- 125000001424 substituent group Chemical group 0.000 description 29
- 239000000460 chlorine Substances 0.000 description 28
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 24
- 239000007788 liquid Substances 0.000 description 23
- 235000002639 sodium chloride Nutrition 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 125000003118 aryl group Chemical group 0.000 description 20
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000001624 naphthyl group Chemical group 0.000 description 18
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical class NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 17
- 238000001035 drying Methods 0.000 description 17
- 229930024421 Adenine Natural products 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 229960000643 adenine Drugs 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 229940050411 fumarate Drugs 0.000 description 13
- 239000003208 petroleum Substances 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 241000700605 Viruses Species 0.000 description 11
- 125000000753 cycloalkyl group Chemical group 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 238000001819 mass spectrum Methods 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 9
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- HRYQQSALHORBPJ-UHFFFAOYSA-N 1-butan-2-yloxy-2-butoxy-1-[(2-methylpropan-2-yl)oxy]cyclopropane Chemical compound C(CCC)OC1C(C1)(OC(C)(C)C)OC(C)CC HRYQQSALHORBPJ-UHFFFAOYSA-N 0.000 description 8
- 238000004679 31P NMR spectroscopy Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 8
- JTPUMZTWMWIVPA-UHFFFAOYSA-O Isopropamide Chemical compound C=1C=CC=CC=1C(C(N)=O)(CC[N+](C)(C(C)C)C(C)C)C1=CC=CC=C1 JTPUMZTWMWIVPA-UHFFFAOYSA-O 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- 229940126214 compound 3 Drugs 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 229960001737 isopropamide Drugs 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000002777 nucleoside Substances 0.000 description 8
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 8
- 241000700721 Hepatitis B virus Species 0.000 description 7
- 229910019142 PO4 Inorganic materials 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 150000003833 nucleoside derivatives Chemical class 0.000 description 7
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 7
- 235000021317 phosphate Nutrition 0.000 description 7
- 210000002381 plasma Anatomy 0.000 description 7
- 229960004556 tenofovir Drugs 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- KMSZTNIWLJJBMQ-UHFFFAOYSA-N 3-(2-methoxyethoxy)-2,2-dimethylpropanoic acid Chemical compound COCCOCC(C)(C)C(O)=O KMSZTNIWLJJBMQ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000010452 phosphate Substances 0.000 description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000003443 antiviral agent Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
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- 150000001721 carbon Chemical group 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- MTBCHANJJJRWOB-UHFFFAOYSA-N 3-(2-ethoxy-2-methoxyethoxy)-2,2-dimethylpropanoic acid Chemical compound COC(COCC(C(=O)O)(C)C)OCC MTBCHANJJJRWOB-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
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- 108020004414 DNA Proteins 0.000 description 4
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 241001597008 Nomeidae Species 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
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- 125000003282 alkyl amino group Chemical group 0.000 description 4
- BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- PJBIHXWYDMFGCV-UHFFFAOYSA-N chloro(chlorosulfonyloxy)methane Chemical compound ClCOS(Cl)(=O)=O PJBIHXWYDMFGCV-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000001530 fumaric acid Substances 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
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- 125000004545 purin-9-yl group Chemical group N1=CN=C2N(C=NC2=C1)* 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
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- 230000015572 biosynthetic process Effects 0.000 description 3
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- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
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- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 125000006574 non-aromatic ring group Chemical group 0.000 description 3
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- WQADWIOXOXRPLN-UHFFFAOYSA-N 1,3-dithiane Chemical compound C1CSCSC1 WQADWIOXOXRPLN-UHFFFAOYSA-N 0.000 description 2
- LOZWAPSEEHRYPG-UHFFFAOYSA-N 1,4-dithiane Chemical compound C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
- ODTKBCUBSAPRBP-UHFFFAOYSA-N 1-bromo-1-(2-methoxyethoxy)ethane Chemical class COCCOC(C)Br ODTKBCUBSAPRBP-UHFFFAOYSA-N 0.000 description 2
- GOKUDEWVRNZXDZ-UHFFFAOYSA-N 1-bromo-3-(3-bromopropoxy)propane Chemical class BrCCCOCCCBr GOKUDEWVRNZXDZ-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 2
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- RCNJYKSQNKIXBY-UHFFFAOYSA-N chloromethyl 3-(2-methoxyethoxy)-2,2-dimethylpropanoate Chemical compound COCCOCC(C(=O)OCCl)(C)C RCNJYKSQNKIXBY-UHFFFAOYSA-N 0.000 description 1
- RPSLJRYKBMDEQS-UHFFFAOYSA-N chloromethyl 3-hydroxy-2,2-dimethylpropanoate Chemical compound ClCOC(C(CO)(C)C)=O RPSLJRYKBMDEQS-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960005338 clevudine Drugs 0.000 description 1
- GBBJCSTXCAQSSJ-XQXXSGGOSA-N clevudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1[C@H](F)[C@@H](O)[C@H](CO)O1 GBBJCSTXCAQSSJ-XQXXSGGOSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- CHVJITGCYZJHLR-UHFFFAOYSA-N cyclohepta-1,3,5-triene Chemical compound C1C=CC=CC=C1 CHVJITGCYZJHLR-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 208000018191 liver inflammation Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- NYHMZIATOODZJM-UHFFFAOYSA-N methyl 3-(2-ethoxy-2-methoxyethoxy)-2,2-dimethylpropanoate Chemical compound COC(C(COCC(OCC)OC)(C)C)=O NYHMZIATOODZJM-UHFFFAOYSA-N 0.000 description 1
- PZVBRVVKJUAGAS-UHFFFAOYSA-N methyl 3-(2-methoxyethoxy)-2,2-dimethylpropanoate Chemical compound COCCOCC(C)(C)C(=O)OC PZVBRVVKJUAGAS-UHFFFAOYSA-N 0.000 description 1
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229950002366 nafoxidine Drugs 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001915 proofreading effect Effects 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003214 pyranose derivatives Chemical class 0.000 description 1
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical compound C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960005311 telbivudine Drugs 0.000 description 1
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 1
- 229960001355 tenofovir disoproxil Drugs 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000006007 trichloroethoxy group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000010792 warming 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Provided in the present invention are an acyclic nucleoside phosphonate derivative and a preparation method and use thereof in medical science, and the acyclic nucleoside phosphonate derivative is a compound as shown by general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof: R1 is H or methyl; R2 is H, C1-10 alkyl, -(CH2-CH2-O)n-H or -(CH2-CH2-O)n-C1-10 alkyl, wherein the alkyl is optionally further substituted by 0 to 5 R2as; R3 is C1-10 alkyl, -(CH2-CH2-O)n-H or -(CH2-CH2-O)n-C1-10 alkyl, wherein the alkyl is optionally further substituted by 0 to 5 R3as; each of R2a and R3a are independently H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano, carboxyl, C1-4 alkyl or C3-6 cycloalkyl; and n is 1-10.
Description
The present invention relates to the acyclonucleosides phosphate compounds shown in a kind of logical formula (I), its stereoisomer or pharmaceutically acceptable salt, its preparation method and pharmaceutical composition containing them and the purposes in the medicine in preparing treatment disease of viral infection.
Hepatitis B is one of global disease, and it is caused by hepatitis B.The population for having 1/3rd in the world has infected hepatitis B to a certain extent, including 300,000,000 5 thousand ten thousand chronic carriers.In some Asia and African country, hepatitis B has changed into epidemic disease, especially in China.Hepatitis B can cause acute and chronic infection, acute infection generally along with liver inflammation, vomiting, jaundice, extremely it is individual it is other can also cause death, and chronic infection is possible to induce hepatic sclerosis and liver cancer.Although at present can be by vaccine prevention hepatitis B virus infection, but still chronic hepatitis B disease be treated without effective method.
Hepatitis B is a kind of DNA of addicted to liver property (DNA) virus, the dsdna segment genome with ring-type.A shorter chain has 1700 to 2800 nucleotides, and a longer chain has 3020 to 3320 nucleotides, and this long-chain then encodes the archaeal dna polymerase of virus.The genome encoding of hepatitis B four knowns --- C, X, P and S.Gene C encoding nuclear proteins (HBcAg), gene S coded surfaces antigen (HBsAg), gene P then encoding DNA polymerases, and the protein function of gene X codings is unclear, but the generation that it is considered as with liver cancer is relevant, because it have activated the value-added gene of inducing cell, and allow growth regulator to inactivate.
The life cycle of hepatitis B is complicated, is to enter cell by unknown acceptor and endocytosis, its genome is transferred to nucleus by host protein cha petroleum ethers rones.In nucleus, dsdna segment is converted into complete double-stranded DNA by hepatitis B by the archaeal dna polymerase of host cell, and is the cyclic DNA (cccDNA) by Covalent bonding together by morphologic change.CccDNA transcribes four virus mRNA as template.This four transcriptons are transported into cytoplasm as template, are translated into the memebrane protein of virus, nucleoprotein and archaeal dna polymerase.Most long mRNA (3.5kb is longer than viral genome) is used as the new genome copies of template duplicating, transcription nucleocapsid protein and viral dna polymerase.Meanwhile, the RNA of this 3.5kb length goes out reverse transcription the antisense strand of hepatitis B virus DNA, subsequently completes viral plus chain.Double-stranded DNA, which can export as new son virus or come back to nucleus, forms new cccDNA.
Hepatitis B RNA and DNA synthesis depend on hepatitis B virus DNA polymerase, and hepatitis B virus DNA polymerase is necessary for the duplication of virus.The polymerase has four domains：The critically important terminal protein of the assembling of beginning and nucleocapsid for hepatitis B virus duplication, interval albumen, reverse transcriptase and for pregenome RNA template of degrading
RNaseH domains.Nevertheless, lacking the high mutation rate that proofreading function result in hepatitis B virus DNA polymerase.
Using archaeal dna polymerase inhibitor a selection for having much attraction is already known to as anti-hepatic-B virus medicine.Special viral polymerase inhibitors belong to nucleoside analog family.Treatment for chronic hepatitis B patient is improved due to oral anti-hepatitis virus nucleoside analogue drugs.In serum, hepatitis B virus DNA can be down to immesurable level by nucleoside analog rapidly, and the mechanism that works is clear and definite：The nucleoside analog Reverse transcriptase activity of viral dna polymerase.Meanwhile, compared with interferon IFN-α, nucleoside analog shows good tolerance and smaller adverse reaction.Up to the present, there is medicine of five kinds of nucleoside analog hepatitis B virus DNA AG14361s as treatment chronic hepatitis B, in the U.S. and Europe listing, including：Lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir disoproxil fumarate, famciclovir and Clevudine, also have other several medicines to be in the stage of grinding.Meanwhile, because virus is mutated (Substitution for including varial polymerases amino acid) in liver caused by residual and varial polymerases, long-term antiviral therapy may cause the resistance to the action of a drug and selectivity of virus.This proposes requirement for exploitation novel antiviral medicine.
The Antiviral Mechanism and ring-type nucleoside analog of acyclonucleosides phosphine compound are basically identical.The difference is that ring-type nucleoside analog has to pass through three step phosphorylation reactions, and acyclonucleosides phosphine compound contains phosphoryl in itself, eliminates the phosphorylation reaction of first step speed limit, thus activity is higher, and its P-C structure is good to the stability of enzyme.But the phosphonate moiety of acyclonucleosides phosphine compound has two negative electrical charges, not easily passs through the cell membrane of lipid, reduces bioavilability.To solve this problem, the derivative of a large amount of phosphates is synthesized and studied, and is included in phosphonate moiety and connects different lipophilic groups, such as substitution acetyl group, amino acid and aromatic ring etc..
European patent EP 206459 describes 9- (phosphate methoxy alkyl) adenine derivative comprising tenofovir structure, and its purposes for antiviral agent, and its structural formula is as follows：
Wherein R1Select hydrogen, methyl, methylol, R2Selected from substituted or unsubstituted ethylidene, methylene, propylidene etc..It is not considered as that it is a part of the invention to be specifically described in this patent.
EP481214 describes the new oral phosphate nucleoside analog prodrug comprising Aldoforwe ester, and its antiviral medical usage, particularly anti-RNA, DNA virus, can be used for treatment tumour etc., its structure is as follows：
Wherein B is selected from purine, cytimidine, uracil, thymidine, bird pyrimidine etc., R3Selected from substituted or unsubstituted C1-C20Alkyl, R1、R2Independent is selected from substituted or unsubstituted amino, OR4, R4Selected from CH2C(O)N(R5)2,CH2C(O)OR5、CH2OC(O)R5、CH(R5)OC(O)R5、CH2C(R5)2C water H or CH2OR5, R5Selected from C that is unsubstituted or being replaced by hydroxyl, oxygen, nitro, halogen4-C20Alkyl, aryl or aryl-alkyl, R1、R2Can cyclization.It is not considered as that it is a part of the invention to be specifically described in this patent.
WO02057288 describes acyclonucleosides phosphate compounds and its purposes for antiviral agent, and its structural formula is as follows：
Wherein Q is selected from purine or pyrimidine, R4、R5Independent is selected from hydrogen, alkyl, aryl etc., R1、R2、R3、R7、R8Independent is selected from hydroxyl, halogen, hydrogen, amino, alkyl, alkoxy, alkyl amino etc..It is not considered as that it is a part of the invention to be specifically described in this patent.
CN1583769A describes 9- ((phosphate) methoxyalkyl) adenine derivatives and its purposes for antiviral agent, and its structural formula is as follows：
Wherein R1、R2Independent is selected from hydrogen or substituted Biphenylmethyl.It is not considered as that it is a part of the invention to be specifically described in this patent.
CN101066981A describes acyclonucleosides phosphate compounds and its purposes for antiviral agent, and its structural formula is as follows；
Wherein R1Selected from hydrogen, halogen, amino, cyclopropylamino, methoxyl group, ethyoxyl etc., R2Selected from hydrogen or amino, R5Selected from methyl or hydrogen, R3、R4Independent is selected from (substituted amino carbonyl epoxide) alkyl.It is not considered as that it is a part of the invention to be specifically described in this patent.
CN1634943A describes acyclonucleosides phosphate compounds and its purposes for antiviral agent, and its structural formula is as follows：
Wherein R is hydrogen or methyl, R2Selected from hydrogen or camphoryl, R1Aromatic hydrocarbons selected from the cycloalkyl containing 3-8 carbon, the unsaturation chain alkylene of 3-8 carbon, the unsaturation cycloalkyl of 3-8 carbon or 6-10 carbon.It is not considered as that it is a part of the invention to be specifically described in this patent.
WO2011069322 describes acyclonucleosides phosphoric acid ester derivant and its for treating and preventing the medical usage with virus infection relevant disease, and its structural formula is as follows：
Wherein R1Selected from hydrogen or methyl, R2Selected from-R3Or-OR3, R3Selected from C1-8Alkyl, C3-8Cycloalkyl.It is not considered as that it is a part of the invention to be specifically described in this patent.
The content of the invention
The present invention is the compound that design has shown in logical formula (I) on the basis of tenofovir disoproxil, to provide a kind of novel acyclonucleosides phosphoric acid ester derivant of structure, its stereoisomer or pharmaceutically acceptable salt, available for treatment disease of viral infection, wherein disease of viral infection includes infectious diseases caused by hepatitis type B virus and inhibition of HIV.
The invention provides a kind of acyclonucleosides phosphoric acid ester derivant, it is compound shown in logical formula (I), its stereoisomer or pharmaceutically acceptable salt, wherein：
R1Selected from H or methyl；
R2Selected from H, C1-10Alkyl ,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n-C1-10Alkyl, described alkyl is optionally further by 0 to 5 R2aSubstitution；
R3Selected from C1-10Alkyl ,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n-C1-10Alkyl, wherein described alkyl is optionally further by 0 to 5 R3aSubstitution；
R2aAnd R3aIt is independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carboxyl, C1-4Alkyl or C3-6Cycloalkyl；
N is selected from 1,2,3,4,5,6,7,8,9 or 10.
It is preferred that the present invention relates to the compound shown in a kind of logical formula (I), its stereoisomer or pharmaceutically acceptable salt, wherein：
R1Selected from H or methyl；
R2Selected from H, C1-10Alkyl ,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n-C1-10Alkyl, described alkyl is optionally further by 0 to 5 R2aSubstitution；
R3Selected from C1-10Alkyl, wherein described alkyl is optionally further by 0 to 5 R3aSubstitution；
R2aAnd R3aIt is independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carboxyl, C1-4Alkyl or C3-6Cycloalkyl；
N is selected from 1,2,3,4 or 5.
Preferred scheme of the present invention, R2Selected from H, C1-6Alkyl ,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n-C1-6Alkyl, preferably H, C1-4Alkyl ,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n-C1-4Alkyl, described alkyl, cycloalkyl or heterocyclic radical is optionally further by 0 to 5 R2aSubstitution.
Preferred scheme of the present invention, R2Selected from substituted or unsubstituted H, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, isopentyl, neopentyl, pentane -3- bases,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n- methyl, preferably substituted or unsubstituted H, methyl, ethyl, propyl group, isopropyl ,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n- methyl, further preferred H, methyl or-(CH2-CH2-O)n- methyl, when substituted, optionally by 1 to 5 R2aSubstitution.
Preferred scheme of the present invention, R3Selected from C1-6Alkyl ,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n-C1-6Alkyl, preferably C1-4Alkyl ,-(CH2-CH2-O)n-H、-(CH2-CH2-O)n-C1-4Alkyl, described alkyl is optionally further by 0 to 5 R3aSubstitution.
Preferred scheme of the present invention, R3Selected from substituted or unsubstituted methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, isopentyl, neopentyl, pentane -3- bases,-CH2-CH2- OH or-(CH2-CH2-O)2- H, preferably substituted or unsubstituted propyl group, isopropyl, isobutyl group or the tert-butyl group；Further preferred isopropyl, when substituted, optionally by 1 to 5 R3aSubstitution.
Preferred scheme of the present invention, the present invention provides the compound shown in a kind of logical formula (I), wherein：
R1Selected from H or methyl；
R2Selected from substituted or unsubstituted H, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, isopentyl, neopentyl, pentane -3- bases,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n- methyl, preferably substituted or unsubstituted H, methyl, ethyl, propyl group, isopropyl ,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n- methyl, further preferred H, methyl or-(CH2-CH2-O)n- methyl, when substituted, optionally by 1 to 5 R2aSubstitution；
R3Selected from substituted or unsubstituted methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, isopentyl, neopentyl, pentane -3- bases,-CH2-CH2- OH or-(CH2-CH2-O)2- H, preferably substituted or unsubstituted propyl group, isopropyl, isobutyl group or the tert-butyl group, further preferred isopropyl, when substituted, optionally by 1 to 5 R3aSubstitution；
R2aAnd R3aIt is independently selected from H, F, Cl, hydroxyl, amino, methyl or ethyl；
N is selected from 1,2,3,4 or 5.
Preferred scheme of the present invention, R2aAnd R3aIt is independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carboxyl or C1-4Alkyl, preferably H, F, Cl, hydroxyl, amino, methyl or ethyl.
Preferred scheme of the present invention, n is selected from 1,2 or 3.
Preferred scheme of the present invention, the present invention provides compound shown in a kind of logical formula (I), and wherein the compound is selected from compound shown in logical formula (II), its stereoisomer or pharmaceutically acceptable salt, wherein：
R1Selected from H or methyl, preferably methyl；
R2Selected from H, methyl, ethyl, propyl group, isopropyl ,-CH2-CH2-OH、-CH2-CH2-O-CH3、-(CH2-CH2-O)2-H、-(CH2-CH2-O)2-CH3、-(CH2-CH2-O)3-H、-(CH2-CH2-O)3-CH3、-(CH2-CH2-O)4- H or-(CH2-CH2-O)4-CH3, preferably H, methyl, ethyl, propyl group, isopropyl ,-CH2-CH2-OH、-CH2-CH2-O-CH3、-(CH2-CH2-O)2- H or-(CH2-CH2-O)2-CH3。
Preferred scheme of the present invention, a kind of compound selected from shown in logical formula (III), its stereoisomer or pharmaceutically acceptable salt, wherein：
R2Selected from H, methyl, ethyl, propyl group, isopropyl ,-CH2-CH2-O-H、-CH2-CH2-O-CH3、-(CH2-CH2-O)2- H or-(CH2-CH2-O)2-CH3。
Preferred scheme of the present invention, compound of the present invention is selected from, but is not limited to：
The present invention also provides compound shown in logical formula (I), its stereoisomer or its pharmaceutically acceptable salt, wherein described salt is hydrochloride, hydrobromate, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalates, oxyacetate, water
Poplar hydrochlorate, glucuronate salt, galacturonic hydrochlorate, citrate, tartrate, lysine salt, arginine salt, aspartate, glutamate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate, sylvite, sodium salt or combinations thereof, it is preferred that hydrochloride, sulfate, phosphate, acetate, maleate, succinate, fumarate, malate, oxalates, tartrate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, fluoroform sulphonate or combinations thereof, further preferred fumarate, tosilate, fluoroform sulphonate, or mesylate, more preferably fumarate.
The invention further relates to a kind of pharmaceutical composition, described pharmaceutical composition contains compound described in the logical formula (I) of at least one present invention for the treatment of effective dose, or its stereoisomer or pharmaceutically acceptable salt, and pharmaceutically acceptable carrier or excipient.
According to pharmaceutical composition of the present invention, it is preferably used to treat disease of viral infection.Wherein, the disease of viral infection can be specifically to include hepatitis type B virus, hepatitis C virus or infectious diseases caused by AIDS virus.
Further, the present invention relates to compound shown in logical formula (I), its stereoisomer or its pharmaceutically acceptable salt, the application in treatment disease of viral infection related drugs are prepared.
Present invention also offers the method for the treatment of disease of viral infection, the present invention that this method includes giving patient effective amounts leads to compound described in formula (I), or its stereoisomer or pharmaceutically acceptable salt, or pharmaceutical composition of the present invention.
The preferred scheme of the present invention, wherein the disease of viral infection includes hepatitis type B virus, hepatitis C virus or infectious diseases caused by AIDS virus.
The preferred scheme of the present invention, wherein the disease of viral infection includes infectious diseases caused by hepatitis type B virus, such as chronic hepatitis B disease.
The compounds of this invention is compared with marketed drug tenofovir dipivoxil, with higher human plasma stability；The salt of the compounds of this invention possesses suitable pharmacokinetics in rats effect compared with marketed drug tenofovir dipivoxil fumarate.The compounds of this invention is less susceptible to by esterase hydrolyzed in blood plasma, possesses more preferable curative effect, the more potentiality such as low toxicity side effect, with fine DEVELOPMENT PROSPECT.
Unless there are opposite statement, the term used in the specification and in the claims has following implications.
During the present invention relates to being replaced by multiple substituents, each substituent can be with identical or differ.
During the present invention relates to containing multiple hetero atoms, each hetero atom can be with identical or differ.
Involved elemental carbon, hydrogen, oxygen, sulphur, nitrogen or halogen include their isotope situation in group of the present invention and compound, and optionally further by 1 to 5, their corresponding isotopes are substituted elemental carbon, hydrogen, oxygen, sulphur or the nitrogen involved by group of the present invention and compound, the isotope of wherein carbon includes12C、13C and14C, the same position of hydrogen
Element includes protium (H), deuterium (D is called heavy hydrogen), tritium (T is called superheavy hydrogen), and the isotope of oxygen includes16O、17O and18O, the isotope of sulphur includes32S、33S、34S and36S, the isotope of nitrogen includes14N and15N, the isotope of fluorine19F, the isotope of chlorine includes35Cl and37Cl, the isotope of bromine includes79Br and81Br。
Term " alkyl " refers to the aliphatic hydrocarbon groups of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.The alkyl of 1 to 10 carbon atom is preferably comprised, non-limiting example includes, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, n-nonyl, and its various branched chain isomers etc.；Low alkyl group more preferably containing 1 to 4 carbon atom, non-limiting example includes methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group or tert-butyl group etc..Alkyl can be substituted or unsubstituted, and when substituted, substituent is preferably 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C1-10Alkyl, C1-10Alkoxy, C1-4Alkoxy -C1-4Alkoxy, C2-8Alkenyl, C1-4Amide groups ,-C (=O)-O-C1-10Alkyl ,-OC (=O)-C1-10Alkyl, C3-10Carbocyclic ring or C3-10Heterocycle.Preferably, the non-limiting example of substituent includes H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamido, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.
" alkoxy " refers to-O- alkyl, and wherein alkyl is as herein above defined.Alkoxy can be substituted or unsubstituted, and its non-limiting example includes, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy, amoxy or hexyloxy, preferably with 1 to 12 yuan of alkoxy.When substituted, substituent is preferably 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C1-10Alkyl, C1-10Alkoxy, C1-4Alkoxy -C1-4Alkoxy, C2-8Alkenyl, C1-4Amide groups ,-C (=O)-O-C1-10Alkyl ,-OC (=O)-C1-10Alkyl, C3-10Carbocyclic ring or C3-10Heterocycle.Preferably, the non-limiting example of substituent includes H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamido, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.
During " alkenyl " is the alkyl that defines of the present invention, comprising at least one carbon-to-carbon double bond, the alkenyl contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferred 2 to 8 carbon atoms.The non-limiting examples of alkenyl include substituted or unsubstituted vinyl, 2- acrylic, 3- cyclobutenyls, 2- cyclobutenyls, 4- pentenyls, 3- pentenyls, 2- oneself
Alkenyl, 3- hexenyls, 2- heptenyls, 3- heptenyls, 4- heptenyls, 3- octenyls, 3- nonenyls or 4- decene bases etc.; when substituted; substituent is preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid group, carboxylate or Heterocyclylalkyl sulfydryl.
During " alkynyl " is the alkyl that defines of the present invention, comprising at least one carbon-to-carbon triple bond, the alkynyl contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferred 2 to 8 carbon atoms.The non-limiting examples of alkynyl include substituted or unsubstituted acetenyl, 1- propinyls, 2-propynyl, 1- butynyls, 2- butynyls, 3- butynyls, 4- pentynyls, 3- pentynyls, 2- hexin bases, 3- hexin bases, 3- butynyls, 2- heptynyls, 3- heptynyls, 4- heptynyls, 3- octynyls, 3- n-heptylacetylenes base or 4- decynyls etc., when substituted, substituent is preferably 1 to 5, independently selected from F, Cl, Br, I,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or Heterocyclylalkyl sulfydryl.
" cycloalkyl " refers to substituted or unsubstituted 3 to 8 yuan full carbon monocyclic groups, can be connected with bridged ring or loop coil, wherein 1 to 5 can be containing 1 to 5 double bond, but neither one ring has the pi-electron system being completely conjugated.The non-limiting example of cycloalkyl includes, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, two rings [3.2.1] octyl, two rings [5.2.0] nonyl, three rings [5.3.1.1] dodecyl, adamantyl, spiral shell [3.3] heptane base, spiral shell [2.4] heptane base, spiral shell [2.5] octyl or spiral shell [2.3] hexyl etc..When substituted, substituent is preferably 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C1-10Alkyl, C1-10Alkoxy, C1-4Alkoxy -C1-4Alkoxy, C2-8Alkenyl, C1-4Amide groups ,-C (=O)-O-C1-10Alkyl ,-OC (=O)-C1-10Alkyl, C3-10Carbocyclic ring or C3-10Heterocycle.Preferably, the non-limiting example of substituent includes H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamido, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.
" carbocyclic ring " refers to substituted or unsubstituted saturation or undersaturated aromatic rings or non-aromatic ring, aromatic rings or it is non-aromatic can be 3 to 8 yuan monocyclic, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, carbocyclic ring can be connected with bridged ring or loop coil, non-limiting example include cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclohexenyl group, suberyl, cyclopentene, cyclohexadiene, cycloheptatriene, phenyl, naphthyl, benzo cyclopenta, two rings [3.2.1] octyl,
Two rings [5.2.0] nonyl, three rings [5.3.1.1] dodecyl, adamantyl or spiral shell [3.3] heptane base etc..When substituted, substituent is preferably 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C1-10Alkyl, C1-10Alkoxy, C1-4Alkoxy -C1-4Alkoxy, C2-8Alkenyl, C1-4Amide groups ,-C (=O)-O-C1-10Alkyl ,-OC (=O)-C1-10Alkyl, C3-10Carbocyclic ring or C3-10Heterocycle.Preferably, the non-limiting example of substituent includes H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamido, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.
" heterocyclic radical " refers to substituted or unsubstituted saturation or undersaturated aromatic rings, non-aromatic ring, aromatic rings, non-aromatic ring can be 3 to 8 yuan monocyclic, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, and be made up of at least one hetero atom for being selected from N, O or S, it is preferred that N, S for selectively replacing in 3 to 10 circle heterocycles, the ring of heterocycle can be oxidized to various oxidation state.Heterocycle can be connected on hetero atom or carbon atom, and heterocycle can be connected with bridged ring or loop coil.The non-limiting example of heterocyclic radical includes Oxyranyle,Aziridinyl,Oxetanyl,Azetidinyl,Azepine base,Tiacyclopentane base,Oxinane base,Thia cyclohexyl,1,3- dioxolanyls,1,4- dioxolanyls,1,2- diazacyclo pentyls,1,2- oxaza pentyls,1,2- oxathiolane bases,1,3- oxaza pentyls,1,3- oxathiolane bases,1,2- diaza-cyclohexane bases,1,2- morpholine bases,1,2- thioxane bases,1,3- morpholine bases,1,3- sulfur nitrogen heterocycle hexyls,1,3- diaza-cyclohexane bases,1,3- dioxane bases,1,4- dioxane bases,1,3- thioxane bases,1,4- diaza-cyclohexane bases,1,4- thioxane bases,1,4- dithian bases,Spiral shell [3.3] heptane base,Spiral shell [2.3] hexyl,Azepine spiroheptane base,Oxa- spiroheptane base,Azaspiro [2.3] hexyl,Oxaspiro [2.3] hexyl,Spiral shell [2.4] heptane base,Azaspiro [2.4] heptane base,Oxaspiro [2.4] heptane base,Spiral shell [2.5] octyl,Azaspiro [2.5] octyl,Oxaspiro [2.5] octyl,Azabicyclic [3.2.1] octyl,Azabicyclic [5.2.0] nonyl,Oxatricyclo [5.3.1.1] dodecyl,Azaadamantane base,Pyridine radicals,Furyl,Thienyl,Pyridine radicals,Pyranose,N- alkyl pyrrole radicals,Pyrimidine radicals,Pyrazinyl,Pyridazinyl,Imidazole radicals,Piperidyl,Piperazine stings base,Morpholine,Thiomorpholine,1,3- dithiane dihydrofuran,Dihydropyran,The ring of two thiophene penta,Tetrahydrofuran,Nafoxidine,Imidazolidine,Tetrahydro-thiazoles,Hexahydro pyrans,Benzimidazole,Benzo pyridine,Pyrrolopyridine,Coumaran etc..When substituted, substituent is preferably 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C1-10Alkyl, C1-10Alkoxy, C2-8Alkenyl, C1-4Amide groups ,-C (=O)-O-C1-10Alkyl ,-OC (=O)-C1-10Alkyl, C3-10Carbocyclic ring or C3-10Heterocycle.Preferably, the non-limiting example of substituent include H, F, Cl, Br, I, hydroxyl, sulfydryl, amino,
Cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamido, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.
" aryl " refers to that substituted or unsubstituted 6 to 15 yuan full carbon are monocyclic or fused polycycle group, and the polycyclic moiety of the pi-electron system with conjugation, preferably 6 to 10 yuan aromatic rings, its non-limiting example includes, phenyl and naphthyl；The aryl can be with condensed heteroaryl, heterocyclic radical or cycloalkyl, and the part being connected with precursor structure is aryl, and its non-limiting example includes benzofuran, benzocyclopentane base, benzothiazole etc..When substituted, substituent is preferably 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C1-10Alkyl, C1-10Alkoxy, C2-8Alkenyl, C1-4Amide groups ,-C (=O)-O-C1-10Alkyl ,-OC (=O)-C1-10Alkyl, C3-10Carbocyclic ring or C3-10Heterocycle.Preferably, the non-limiting example of substituent includes H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamido, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.
" heteroaryl " refers to substituted or unsubstituted 5 to 15 yuan of aromatic rings, and constituted containing 1 to 3 selected from N, O or S hetero atom, it is preferred that 5 to 10 yuan of aromatic rings, the non-limiting example of heteroaryl includes pyridine radicals, furyl, thienyl, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, benzofuran, benzimidazole, benzo pyridine or pyrrolopyridine etc..When substituted, substituent is preferably 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C1-10Alkyl, C1-10Alkoxy, C1-4Alkoxy -C1-4Alkoxy, C2-8Alkenyl, C1-4Amide groups ,-C (=O)-O-C1-10Alkyl ,-OC (=O)-C1-10Alkyl, C3-10Carbocyclic ring or C3-10Heterocycle.Preferably, the non-limiting example of substituent includes H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamido, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.
" amino " refers to-NH2, can be substituted or unsubstituted, when substituted, substituent is preferably 1 to 2
It is individual, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, hydroxyl, amino, alkyl amino, alkyl acylamino, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, hydroxy alkyl, carboxylic acid group or carboxylic acid ester groups, the non-limiting example of substituent, including hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane, cyclobutane, hexamethylene, pentamethylene, cycloheptane, formamido, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.
The present invention "=O " be this area ordinary practice usage, refer to double bond be connected oxygen atom, the double bond oxygen atom being for example connected in carbonyl with carbon atom.
" stereoisomer " refers to as the isomers produced by the spatially arrangement mode difference of atom in molecule, including cis-trans-isomer, enantiomter and rotamer.
" pharmaceutical composition " represents one or more compounds described herein or its physiology/pharmaceutically acceptable salt or pro-drug and the mixture of other chemical constituents, other components such as physiology/pharmaceutically acceptable carrier and excipient.The purpose of pharmaceutical composition is to promote the administration of compound on organism body.
" prodrug " refers to that the compounds of this invention with bioactivity can be converted into physiological conditions or by solvolysis.The prodrug of the present invention is prepared by modifying the functional group in the compound, operation or be removed in vivo that the modification can be routinely, and obtains parent compound.A hydroxyl, amino or the sulfydryl that prodrug is included in the compounds of this invention are connected to the compound formed on any group, when the prodrug of the compounds of this invention is delivered to mammalian subject, prodrug is isolated and forms free hydroxyl, free amino or free thin base respectively.The example of prodrug includes but is not limited to, the compound that the hydroxyl or amino-functional group in the compounds of this invention are formed with formic acid, acetic acid or benzoic acid.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, including the occasion that the event or environment occur or do not occurred.For example, " aryl is optionally replaced by alkyl " mean alkyl can with but necessarily exist, the explanation include aryl by alkyl-substituted situation and aryl not by alkyl-substituted situation.
" substituted or unsubstituted " refers to the situation that group can be substituted or unsubstituted, if not pointing out in the present invention, group can be substituted, then it represents that the group is unsubstituted situation.
" alternatively " scheme after " alternatively " and the scheme before " alternatively " are referred to for coordination, rather than the further selection situation in the case of front.
" substitution " refers to that one or more hydrogen atoms are by the situation of other substituent groups in group, if described group is replaced by hydrogen atom, the group of formation is identical with the group replaced by hydrogen atom.The substituted situation of group, such as amino, C1-4Alkyl, C1-4Alkoxy, C3-6Carbocyclic ring, 3 to 6 circle heterocycles optionally further by 0 to 4 selected from H, F, Cl,
Br, I, hydroxyl, cyano group, amino, C1-4Alkyl or C1-4The substituent of alkoxy is replaced, and the group of formation includes but is not limited to methyl, chloromethyl, trichloromethyl, hydroxymethyl ,-CH2OCH3、-CH2SH、-CH2CH2CN、-CH2NH2、-NHOH、-NHCH3、-OCH2Cl、-OCH2OCH2CH3、-OCH2CH2NH2、-OCH2CH2SH、-OCH2CH2OH, 1- hydroxycyclopropyl, 2- hydroxycyclopropyls, 2- amino cyclopropyl, 4- methylfurans base, 2- hydroxy phenyls, 4- aminophenyls, phenyl.
The synthetic method of the compounds of this invention：
Wherein
X is selected from F, Cl, Br or I, preferably Cl；
R2、R3Definition is consistent with being defined described in compound of Formula I；
R4Selected from H or C1-4Alkyl, preferably methyl；
R5It is independently selected from H or amino protecting group, wherein described amino protecting group includes but is not limited to tert-butoxycarbonyl, benzyloxycarbonyl, tablet held before the breast by officials methoxycarbonyl group, allyloxy carbonyl, tri-chloroethoxy base carbonyl, trimethyl silicon substrate carbethoxyl group, methoxycarbonyl group, carbethoxyl group, 2- xenyl -2- propylene carbonyl oxygens, tert-butoxy, phthalyl, p-toluenesulfonyl, ortho-nitrophenyl sulfonyl, p-nitrophenyl sulfonyl, pivaloyl group, formoxyl, trifluoroacetyl group, benzoyl, benzyl, trityl, to methoxy-benzyl or 2, 4- dimethoxy-benzyls, it is preferred that H or tert-butoxycarbonyl；
A-1 obtains A-2 with halohydrocarbons reaction in the presence of a base; A-2 reacts in the basic conditions obtains A-3; A-3 obtains A-4 with the reaction of chlorosulfonic acid halo methyl esters in the presence of a phase transfer catalyst; A-4 reacts in the presence of a base with intermediate B obtains A-5, and A-5 deprotections obtain logical formula (I) compound (as two R5When being H, it is not necessary to carry out deprotection steps)；
Intermediate B can be made by conventional synthesis process；
Described halogenated hydrocarbons includes but is not limited to the bromo- 2- methoxyethoxyethanes of 2- bromo-ethyl-methyl ethers, 1- or 2- chloroethyl methyl ethers；
The chlorosulfonic acid halo methyl esters includes but is not limited to chlorosulfonic acid chloromethyl ester；
The alkali includes but is not limited to sodium hydride, hydrofining, lithium hydride, sodium methoxide, caustic alcohol, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or triethylamine；
The phase transfer catalyst includes but is not limited to tetrabutyl hydrogen sulfate ammonia (TBAB), benzyltriethylammoinium chloride (TEBA), TBAB, tetrabutylammonium chloride, tri-n-octyl methyl ammonium chloride, DTAC or tetradecyl trimethyl ammonium chloride；
The deprotection is to use conventional amino protecting group deprotection method, includes but is not limited to Deprotection in acid condition, such as uses trifluoroacetic acid.
Below by way of specific embodiment describe in detail the present invention implementation process and produce beneficial effect, it is intended to help reader more fully understand the present invention essence and feature, not as to this case can practical range restriction.
The structure of compound by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) determines.NMR displacements (δ) are with 10-6(ppm) unit is provided.NMR measure is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, and measure solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS).
MS measure uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC measure uses Agilent 1260DAD high pressure liquid chromatographs (Zorbax SB-C18100 × 4.6mm).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and the specification that the silica gel plate that thin-layered chromatography (TLC) is used is used is 0.15mm~0.20mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.
Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.
Oneself initiation material known of the present invention can be used or synthesized according to methods known in the art, or be can purchase in the smooth science and technology of Thailand, pacified the companies such as silent resistance to Jilin Chemical, Shanghai moral, the imperial chemical industry of Chengdu section, splendid remote chemistry science and technology, lark prestige science and technology.
Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Without specified otherwise in embodiment, reaction is carried out under nitrogen atmosphere.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.
Boc:Tertbutyloxycarbonyl；TMS：Trimethyl silicon substrate.
N：Represent mol/L.
Intermediate：
[(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (1d)
[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-(isopropo xycarbonyloxymethoxy)phosphinic acid
[(1R) -2- [6- [(tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (2b)
[(1R)-2-[6-(tert-butoxycarbonylamino)purin-9-yl]-1-methyl-ethoxy]methyl-(isopropoxycar bonyloxymethoxy)phosphinic acid
The first step：[[(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide isopropyl methyl carbonic ester (1b)
[[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-(isopropo xycarbonyloxymethoxy)phosphoryl]oxymethyl isopropyl carbonate
By [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl]
Epoxide isopropyl methyl carbonic ester fumarate (1a) (100g, 0.157mol) it is suspended in dichloromethane (500mL), 10% sodium hydroxide solution is added dropwise to pH value of solution to 9, divide liquid, tetrahydrofuran (350mL), DMAP (2.0g are added into organic phase, 0.0157mol) with triethylamine (57mL, 0.322mol), di-tert-butyl dicarbonate (90g is added dropwise, 0.322mmol), add rear stirring reaction 30 minutes, be heated to 60 DEG C, continue stirring reaction at such a temperature 2 hours.Reaction solution is concentrated under reduced pressure removing tetrahydrofuran, residue with Ethyl acetate (200mL) dissolves, washed successively with water (50mL × 4), saturated aqueous common salt (50mL × 3), with anhydrous sodium sulfate drying, it is concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (ethyl acetate/petroleum ether (v/v)=1:1~7:10) title compound [[(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide isopropyl methyl carbonic ester (1b) is obtained; light yellow oil (120g, yield 106%).
Second step：[(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (1d)
[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl-ethoxy]methyl-(isopropo xycarbonyloxymethoxy)phosphinic acid
[(1R) -2- [6- [(tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (2b)
[(1R)-2-[6-(tert-butoxycarbonylamino)purin-9-yl]-1-methyl-ethoxy]methyl-(isopropoxycar bonyloxymethoxy)phosphinic acid
By [[(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide isopropyl methyl carbonic ester (1b) (30g; 41.7mmol) it is dissolved in acetonitrile (150mL); add water (150mL); triethylamine (1mL) is added dropwise and adjusts reaction solution pH to 8~9, is heated to 30 DEG C of reactions and stays overnight.Dichloromethane (200mL) is added into reaction solution, divide liquid, water layer is extracted with dichloromethane (100mL × 2), the water layer that is concentrated under reduced pressure at 35 DEG C~40 DEG C obtains [(1R) -2- [6- [(tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (2b), white solid (5.0g, yield 20%)；Merge organic phase, organic phase is washed with saturated aqueous common salt (50mL × 2), and anhydrous sodium sulfate drying is concentrated under reduced pressure, residue silica gel column chromatography separating-purifying (ethyl acetate/petroleum ether (v/v)=1:1~1:0) [(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (1d) is obtained, white solid (4.2g, yield 17%).
Embodiment 1
[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- hydroxyl -2,2- Dimethyl-propionic acids esters (compound 1)
[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(isopropoxycarbonyloxymethoxy)p hosphoryl]oxymethyl 3-hydroxy-2,2-dimethyl-propanoate
The first step：3- hydroxyl -2,2- neopentanoic acids chloromethyl esters (1B)
chloromethyl 3-hydroxy-2,2-dimethyl-propanoate
Successively by 3- hydroxyls -2,2- neopentanoic acids (1A) (5.9g, 50mmol), tetrabutyl hydrogen sulfate ammonia (1.7g, 5mmol), sodium acid carbonate (8.4g, 100mmol) it is dissolved in water (30mL) and dichloromethane (40mL) solution, is cooled to 0 DEG C, chlorosulfonic acid chloromethyl ester (4.95g is added dropwise, 30mmol), it is warmed to room temperature reaction 14 hours.Water (30mL) and dichloromethane (40mL) are added into reaction solution, divide liquid, aqueous phase is extracted with dichloromethane (80mL × 2), merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=3:1) title compound 3- hydroxyls-PA chloromethyl ester (1B), colorless oil (700mg, yield 14%) are obtained.
1H-NMR:(CDCl3):5.74 (s, 2H), 3.62 (s, 2H), 2.40 (s, 1H), 1.23 (s, 6H).
Second step：2,2- dimethyl -3- trimethylsiloxy group propionic acid chloromethyl esters (1C)
chloromethyl 2,2-dimethyl-3-trimethylsilyloxy-propanoate
By 3- hydroxyls -2,2- neopentanoic acids chloromethyl ester (1B) (700mg, 4.20mmol) it is dissolved in dimethylformamide (4mL), add imidazoles (428mg, 6.3mmol), 0 DEG C is cooled to, trim,ethylchlorosilane (547mg is added dropwise, 5.04mmol), it is warmed to room temperature reaction 2 hours.Water (40mL) is added into reaction solution, with ethyl acetate/n-hexane (v/v=1:1) (50mL × 3) are extracted, merges organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (n-hexane:Dichloromethane:Ethyl acetate (v/v/v)=150:10:1) title compound 2,2- dimethyl -3- trimethylsiloxy group propionic acid chloromethyl esters (1C), anhydrous grease (600mg, yield 60%) are obtained.
1H-NMR:(CDCl3):5.71 (s, 2H), 3.57 (s, 2H), 1.18 (s, 6H), 0.08 (s, 9H).
3rd step：[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 2,2- dimethyl -3- trimethylsiloxy groups-propionic ester (1D)
[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(isopropoxycarbonyloxymethoxy)p hosphoryl]oxymethyl 2,2-dimethyl-3-trimethylsilyloxy-propanoate
By [(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl acid phosphate (902mg, 3.145mmol) it is dissolved in 1-METHYLPYRROLIDONE (4mL), add 2,2- dimethyl -3- trimethylsiloxy group propionic acid chloromethyl ester (1C) (1.5g, 6.29mmol), it is warming up to 60 DEG C, add chloromethyl butylperoxyisopropyl carbonate (959mg, 6.29mmol) with triethylamine (1.27g, 12.58mmol), 60 DEG C are maintained to react 5 hours.Reaction solution is cooled down to room temperature, water (40mL) is added, is extracted with ethyl acetate (50mL × 3), merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol:Ammoniacal liquor (v/v/v)=25:1:0.2) title compound [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 2 is obtained; 2- dimethyl -3- trimethylsiloxy groups-propionic ester (1D); anhydrous grease (600mg, yield 32%).
4th step：[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- hydroxyl -2,2- Dimethyl-propionic acids esters (compound 1)
[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(isopropoxycarbonyloxymethoxy)p hosphoryl]oxymethyl 3-hydroxy-2,2-dimethyl-propanoate
By [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 2; 2- dimethyl -3- trimethylsiloxy groups-propionic ester (1D) (600mg; 1mol) it is dissolved in tetrahydrofuran (4mL); add acetic acid (2mL); water (1mL) is added, maintains 15 DEG C to react 30 minutes.Tetrahydrofuran is distilled off in reaction solution, water (10mL) is added into residue, pH value of solution=8 are adjusted with saturated sodium bicarbonate solution, extracted with ethyl acetate (30mL × 2), merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol:Acetone:Ammoniacal liquor (v/v/v/v)=20:1:1.5:0.2~16.5:1:1.5:0.15) title compound [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- hydroxyls -2 are obtained; 2- Dimethyl-propionic acids ester (compound 1); colorless oil (65mg, 12%).
1H-NMR:(CDCl3):8.32 (d, 1H), 8.00 (d, 1H), 6.38 (d, 2H), 5.78-5.55 (m, 4H), 5.36-5.30 (m, 1H), 4.98-4.82 (m, 1H), 4.43-4.37 (m, 1H), 4.06-3.88 (m, 2H), 3.85-3.64 (m, 2H), 3.56-3.50 (m, 2H), 1.34-1.21 (m, 15H).
MS M/Z(ESI)：534.2(M+1).
Embodiment 2
[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl]
Epoxide methyl 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids ester (compound 2)
[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(isopropoxycarbonyloxymethoxy)phosp horyl]oxymethyl 3-(methoxyethoxy)-2,2-dimethyl-propanoate
The first step：3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids methyl esters (2B)
methyl 3-(methoxy-ethoxy)-2,2-dimethyl-propanoate
By sodium hydride (10g, 0.42mol, wt=60%) it is added in tetrahydrofuran (800mL), ice-water bath is cooled to 0 DEG C, it is slowly added to 3- hydroxyls -2,2,-dimethylated methyl propionate (2A) (50g, 0.38mol), reaction 1 hour, 2- bromo-ethyl-methyl ethers (63.2g, 0.46mol) are added, is warmed to room temperature and is stirred overnight.Saturated aqueous ammonium chloride is added into reaction solution reaction is quenched, divide liquid, aqueous layer with ethyl acetate (800mL × 2) is extracted, merge organic phase, organic phase is washed with saturated aqueous common salt (1000mL × 2), anhydrous sodium sulfate drying, concentration, residue composes separating-purifying (petroleum ether with silicagel column:Ethyl acetate (v/v)=25:1) title compound 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids methyl esters (2B), colourless liquid (9.8g, yield 14%) are obtained.
MS M/Z(ESI)：191.1(M+1).
Second step：3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids (2C)
3-(methoxy-ethoxy)-2,2-dimethyl-propionic acid
3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids methyl esters (2B) (4.7g, 24.7mmol) is dissolved in methanol/water
(v/v=1:Isosorbide-5-Nitrae 0mL) in the mixed solvent, potassium hydroxide (5.5g, 98.8mmol) is added, stirring reaction is stayed overnight at 35 DEG C.Hydrochloric acid (4N) aqueous solution is added into reaction solution and adjusts solution to acidity, vacuum distillation removes methanol, add water (10mL) dilution, extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase is washed with saturated aqueous common salt (100mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=50:1) title compound 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids (2C), colourless liquid (0.9g, yield 21%) are obtained；
1H-NMR:(CDCl3):9.17 (s, 1H), 3.65-3.63 (m, 2H), 3.56-3.53 (m, 2H), 3.51 (s, 2H), 3.38 (s, 3H), 1.22 (s, 6H).
MS M/Z(ESI)：177.2(M+1).
3rd step：3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids chloromethyl ester (2D)
chloromethyl 3-(methoxy-ethoxy)-2,2-dimethyl-propanoate
3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids (2C) (2.6g, 14.8mmol) are dissolved in methylene chloride/water (v/v=1：1,10mL) in the mixed solvent, ice-water bath is cooled to 0 DEG C, adds tetrabutyl hydrogen sulfate ammonia (1.0g, 2.96mmol),
Sodium acid carbonate (5.0g, 59.2mmol), stirring reaction 10 minutes adds chlorosulfonic acid chloromethyl ester (2.42g, 14.8mmol), is warmed to room temperature and is stirred overnight.By reaction solution point liquid, water layer is extracted with dichloromethane (10mL), merges organic phase, organic phase saturated common salt water washing (20mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (ethyl acetate:Methanol (v/v)=10:1) title compound 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids chloromethyl ester (2D), colourless liquid (0.91g, yield 27%) are obtained.
1H-NMR:(CDCl3):5.65(s,2H),3.54-3.51(m,2H),3.45-3.43(m,4H),3.29(s,3H),1.16(s,6H)。
4th step：[[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids ester (2E)
[[(1R)-2-(bis(tert-butoxycarbonyl)amino]purin-9-yl)-1-methyl-ethoxy]methyl-(isopropoxy carbonyloxymethoxy)phosphoryl]oxymethyl 3-(methoxy-ethoxy)-2,2-dimethyl-propanoate
By [(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (1d) (0.448g, 0.743mmol) it is dissolved in N, in dinethylformamide (1mL), add triethylamine (0.226g, 2.23mmol), rise to 70 DEG C of stirring reactions 10 minutes, add 3- (methoxy ethoxy) -2, 2- Dimethyl-propionic acids chloromethyl ester (2D) (0.5g, N 2.23mmol), dinethylformamide (1mL) solution, 70 DEG C are stirred 2 hours.Dichloromethane (10mL) and water (1mL) are added into reaction solution, divide liquid, water layer is extracted with dichloromethane (10mL), merge organic phase, organic phase is washed with saturated aqueous common salt (20mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=3:1) title compound [[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2 is obtained; 2- Dimethyl-propionic acids ester (2E); colourless liquid (0.143g, 24%).
1H-NMR:(CDCl3):8.85(s,1H),8.27(s,1H),5.70-5.52(m,4H),4.95-4.91(m,1H),4.45(d,1H),4.26(dd,1H),4.00-3.92(m,2H),3.77-3.71(m,1H),3.59-3.57(m,2H),3.50(m,4H),3.34(s,3H),1.45(s,18H),1.32(d,6H),1.21(m,9H)。
MS M/Z(ESI)：792.3(M+1).
5th step：[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids ester (compound 2)
[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(isopropoxycarbonyloxymethoxy)p
hosphoryl]oxymethyl 3-(methoxyethoxy)-2,2-dimethyl-propanoate
By [[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2; 2- Dimethyl-propionic acids ester (2E) (0.143g; 0.18mmol) it is dissolved in dichloromethane (2mL); ice-water bath is cooled to 0 DEG C; stirring reaction 5 minutes; add trifluoroacetic acid (2mL); stirring reaction 5 minutes, is warmed to room temperature reaction 1 hour.Reaction solution is adjusted into pH to neutrality with saturated sodium bicarbonate aqueous solution, divide liquid, water layer is extracted with dichloromethane (10mL × 2), merge organic phase, organic phase uses saturated sodium bicarbonate aqueous solution (20mL × 2) successively, saturated aqueous common salt (20mL × 2) is washed, anhydrous sodium sulfate drying, concentration, residue obtains title compound [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2 with silica gel column chromatography separating-purifying (ethyl acetate), 2- Dimethyl-propionic acids ester (compound 2), colourless liquid (0.09g, yield 85%).
1H-NMR:(CDCl3):8.33(s,1H),7.99(s,1H),6.01(s,2H),5.70-5.62(m,4H),4.95-4.88(m,1H),4.36(d,1H),4.18-4.12(m,1H),3.97-3.90(m,2H),3.73-3.67(m,1H),3.59-3.56(m,2H),3.50-3.48(m,4H),3.34(s,3H),1.32-1.29(m,6H),1.23-1.20(m,9H)。
MS M/Z(ESI)：592.3(M+1).
The fractionation of compound 2
Take [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2; 2- Dimethyl-propionic acids ester (compound 2) (4.5g) is used to split, method for separating and analyzing：Instrument:Thar analytical SFC；Post:ChiraPak AD-3,150×4.6mm；Mobile phase:A for CO2and B for ETOH (0.05%DEA)；Gradient:B 20%；Flow:2.4mL/min；Back pressure:100bar；Column temperature:35℃；Wavelength:220nm；Preparative separation method：Instrument:The preparative SFC of MG II, post:ChiralPak AD-H, 250 × 30mmI.D., mobile phase:A for CO2and B for ETOH, gradient:B 20%, flow:60mL/min, back pressure:100bar, column temperature:38 DEG C, wavelength:220nm, cycle:~4.0min；Sample preparation：Compound 2 dissolves the solution that sample concentration 160mg/ml is made in ethanol, sample introduction:0.5mL is per pin.
Two optical isomer compound 2-1 (retention times are obtained after separation：2.85min, 2.18g, colorless viscous thing, ee%=100%), compound 2-2 (retention times：3.28min, 2.04g, colorless viscous thing, ee%=98.3%).
Compound 2-1
1H NMR(400MHz,CDCl3)δ8.33(s,1H),8.05(s,1H),6.42(s,2H),5.69–5.54(m,
4H),4.96–4.86(m,1H),4.38(dd,1H),4.16(dd,1H),3.99–3.90(m,2H),3.69(dd,1H),3.58(m,,2H),3.49(m,4H),3.34(s,3H),1.31(s,3H),1.30(s,3H),1.24–1.20(m,9H)。
31P NMR(162MHz,CDCl3)δ22.47。
LC-MS M/Z(ESI):592.3(M+1)。
Compound 2-2
1H NMR(400MHz,CDCl3)δ8.33(s,1H),8.02(s,1H),6.19(s,2H),5.68–5.57(m,4H),4.92(m,1H),4.37(dd,1H),4.15(dd,1H),3.99–3.90(m,2H),3.70(m,1H),3.57(m,2H),3.52–3.47(m,4H),3.34(s,3H),1.32(s,3H),1.30(s,3H),1.24–1.19(m,9H)。
31P NMR(162MHz,CDCl3)δ22.47。
LC-MS M/Z(ESI):592.4(M+1)。
Embodiment 3
[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids ester (compound 3)
[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(isopropoxycarbonyloxymethoxy)p hosphoryl]oxymethyl 3-(methoxy-ethoxy-ethoxy)-2,2-dimethyl-propanoate
The first step：3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids methyl esters (3B)
methyl 3-(methoxy-ethoxy-ethoxy)-2,2-dimethyl-propanoate
Weigh sodium hydride (8.2g, 0.204mol, wt=60%) it is added in tetrahydrofuran (200mL), ice-water bath is cooled to 0 DEG C, is slowly added to 3- hydroxyls -2,2- dimethylated methyl propionates (3A) (22.44g, 0.170mol), stirring reaction 0.5 hour, adds the bromo- 2- methoxyethoxyethanes (62g of 1-, 0.339mol), stirring reaction is warmed to room temperature to stay overnight.By reaction solution
Reaction is quenched with saturated aqueous ammonium chloride (300mL), divide liquid, aqueous layer with ethyl acetate (500mL × 2) is extracted, merge organic phase, organic phase is washed with saturated aqueous common salt (1000mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=25:1) title compound 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids methyl esters (3B), colourless liquid (9.73g, yield 25%) are obtained.
1H-NMR:(CDCl3):3.65(s,3H),3.62-3.56(m,6H),3.52-3.50(m,2H),3.45(s,2H),3.36(s,3H),1.16(s,6H)。
MS M/Z(ESI)：235.2(M+1).
Second step：3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids (3C)
3-(methoxy-ethoxy-ethoxy)-2,2-dimethyl-propionic acid
3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids methyl esters (3B) (40g, 0.171mol) is dissolved in methanol/water (v/v=1:Isosorbide-5-Nitrae 00mL) in the mixed solvent, potassium hydroxide (38.3g, 0.684mol) is added, 35 DEG C of stirring reactions are stayed overnight.Reaction solution is adjusted into pH=3 or so with hydrochloric acid (6N) aqueous solution, vacuum distillation removes most of methanol, aqueous layer with ethyl acetate (200mL × 2) is extracted, merge organic phase, organic phase is washed with saturated aqueous common salt (400mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=60:1) title compound 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids (3C), colourless liquid (24.0g, 64%) are obtained.
3rd step：3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids chloromethyl ester (3D)
chloromethyl 3-(methoxy-ethoxy-ethoxy)-2,2-dimethyl-propanoate
3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids (3C) (20.0g, 0.091mol) are dissolved in methylene chloride/water (v/v=1:1,200mL) in the mixed solvent, ice-water bath is cooled to 0 DEG C, adds tetrabutyl hydrogen sulfate ammonia (3.09g, 0.0091mol), sodium acid carbonate (22.9g, 0.273mol), stirring reaction 30 minutes, add chlorosulfonic acid chloromethyl ester (15g, 0.091mol), stirring reaction is warmed to room temperature to stay overnight.By reaction solution point liquid, water layer is washed with dichloromethane (100mL × 2), merges organic phase, organic phase is washed with saturated aqueous common salt (200mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (ethyl acetate:Methanol (v/v)=10:1) title compound 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids chloromethyl ester (3D), colourless liquid (14.0g, yield 57%) are obtained.
1H-NMR:(CDCl3):5.73(s,2H),3.64-3.61(m,6H),3.54-3.52(m,2H),3.50(s,2H),3.38(s,3H),1.24(s,6H)。
4th step：[[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids ester (3E)
[[(1R)-2-(bis(tert-butoxycarbonyl)amino]purin-9-yl)-1-methyl-ethoxy]methyl-(isopropoxy carbonyloxymethoxy)phosphoryl]oxymethyl 3-(methoxy-ethoxy-ethoxy)-2,2-dimethyl-propanoate
By [(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (1d) (7.0g, 11.6mmol) it is dissolved in N, in dinethylformamide (20mL), add triethylamine (5.3g, 52.2mmol), rise to 70 DEG C of stirring reactions 20 minutes, add 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids chloromethyl ester (3D) (14.0g, 52.2mmol), stirring reaction 2 hours at 70 DEG C.Dichloromethane (20mL) and water (20mL) are added into reaction solution, divide liquid, water layer is extracted with dichloromethane (20mL), merge organic layer, organic layer is washed with saturated aqueous common salt (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=3:1) title compound [[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2 is obtained; 2- Dimethyl-propionic acids ester (3E); colourless liquid (1.4g, yield 15%).
1H-NMR:(CDCl3):8.80(s,1H),8.23(s,1H),5.63-5.46(m,4H),4.90-4.86(m,1H),4.40(d,1H),4.22(dd,1H),3.96-3.88(m,2H),3.73-3.67(m,1H),3.55(s,6H),3.48-3.45(m,4H),3.32(s,3H),1.40(m,18H),1.26(d,6H),1.17(d,9H)。
MS M/Z(ESI)：836.2(M+1).
5th step：[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids ester (compound 3)
[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(isopropoxycarbonyloxymethoxy)p hosphoryl]oxymethyl 3-(methoxy-ethoxy-ethoxy)-2,2-dimethyl-propanoate
By [[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2; 2- Dimethyl-propionic acids ester (3E) (1.4g; 1.68mmol) it is dissolved in dichloromethane (6mL); ice-water bath is cooled to 0 DEG C; stirring reaction 5 minutes; add trifluoroacetic acid (6mL); stirring reaction 5 minutes, is warmed to room temperature reaction 3 hours.Reaction solution is adjusted into pH to neutrality with saturated sodium bicarbonate aqueous solution, divide liquid, water layer is extracted with dichloromethane (20mL × 3), merge organic phase, organic phase is washed with saturated sodium bicarbonate aqueous solution (20mL × 2), the saturated common salt aqueous solution (20mL × 2) successively, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (dichloromethane:Methanol (v/v)=30:1) title compound [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2 is obtained; 2- Dimethyl-propionic acids ester (compound 3); colourless liquid (0.37g, yield 35%).
1H-NMR:(CDCl3):8.30(s,1H),7.98(s,1H),6.38(s,2H),5.64-5.53(m,4H),4.91-4.85(m,1H),4.34(d,1H),4.12(m 1H),3.94-3.88(m,2H),3.70-3.65(m,1H),3.62-3.60(m,6H),3.53-3.48(m,4H),3.31(s,3H),1.28-1.27(m,6H),1.23-1.17(m,9H)。
MS M/Z(ESI):636.2(M+1)。
The fractionation of compound 3
Take [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2; 2- Dimethyl-propionic acids ester (compound 3) (8.6g) is used to split, method for separating and analyzing：Instrument:Thar analytical SFC, post:ChiralPak AD-3,150 × 4.6mm, 3um, mobile phase:A for CO2And B for Ethanol (0.05%DEA), gradient:B 25%, flow:2.4mL/min, back pressure:100bar, column temperature:35 DEG C, wavelength:220nm；Preparative separation method：Instrument:Thar 350preparative SFC, post:ChiralPak AD-10u, 300 × 50mmI.D., mobile phase:A for CO2And B for Ethanol, gradient:B 25%, flow:200mL/min, back pressure:100bar, column temperature:38 DEG C, wavelength:220nm, cycle:~3min, sample preparation：Compound 3 dissolves the solution sample introduction that sample concentration 20mg/ml is made in ethanol:2.5mL is per pin.
Two optical isomer compound 3-1 (retention times are obtained after separation：2.67min, 3.2g, colorless viscous thing, ee%=100%), compound 3-2 (retention times：3.07min, 3g, colorless viscous thing, ee%=98%).
Compound 3-1
1H NMR(400MHz,CDCl3)δ8.34(s,1H),7.98(s,1H),5.97(s,2H),5.73-5.53(m,4H),4.91(m,1H),4.36(dd,1H),4.15(dd,1H),4.01-3.88(m,2H),3.70(m,1H),3.64-3.56(m,6H),3.51(m,4H),3.37(s,3H),1.30(d,6H),1.21(m,9H)。
31P NMR(162MHz,CDCl3)δ22.58。
LC-MS M/Z(ESI):636.2(M+1)。
Compound 3-2
1H NMR(400MHz,CDCl3)δ8.34(s,1H),7.98(s,1H),5.97(s,2H),5.72-5.53(m,4H),4.91(m,1H),4.36(dd,1H),4.15(dd,1H),4.02-3.87(m,2H),3.70(dd,1H),3.65-3.55(m,6H),3.51(m,4H),3.37(s,3H),1.30(d,6H),1.21(m,9H)。
31P NMR(162MHz,CDCl3)δ22.55。
LC-MS M/Z(ESI):636.2(M+1)。
The preparation of the compound 2-1 of embodiment 4 fumarate
By compound 2-1 (1.95g, 3.29mmol) it is dissolved in ethyl acetate (18mL), add fumaric acid (0.382g, 3.29mmol) and absolute methanol (2mL), it is heated to being cooled to room temperature again after 50 DEG C of stirrings are clarified completely to solution, adds petroleum ether (20mL), stirring and crystallizing 3 hours, filtering, collects filter cake and is dried under reduced pressure to obtain title compound (1.5g, yield 65.2%).
1H NMR(400MHz,DMSO)δ13.13(s,2H),8.14(s,1H),8.04(s,1H),7.20(s,2H),6.64(s,2H),5.67-5.47(m,4H),4.89-4.76(m,1H),4.27(d,1H),4.18(dd,1H),3.98(m,3H),3.49(s,2H),3.46-3.35(m,4H),3.22(s,3H),1.24(d,6H),1.12(s,6H),1.08(d,3H)。
31P NMR(162MHz,DMSO)δ23.13。
LC-MS M/Z(ESI):592.2(M+1)。
The preparation of the compound 2-2 of embodiment 5 fumarate
By compound 2-2 (1.61g, 2.73mmol) it is dissolved in ethyl acetate (14.5mL), add fumaric acid (0.316g, 2.73mmol) and absolute methanol (1.5mL), it is heated to being cooled to room temperature again after 50 DEG C of stirrings are clarified completely to solution, adds petroleum ether (16ml), stirring and crystallizing 3 hours, filtering, collects filter cake and is dried under reduced pressure to obtain title compound (1.3g, yield 67.7%).
1H NMR(400MHz,DMSO)δ13.12(s,2H),8.14(s,1H),8.04(s,1H),7.19(s,2H),6.63(s,2H),5.61-5.49(m,4H),4.83(m,1H),4.26(m,1H),4.17(m,1H),4.00-3.89(m,3H),3.49(m,2H),3.45-3.37(m,4H),3.22(s,3H),1.24(m,,6H),1.11(s,6H),1.08(d,3H)。
31P NMR(162MHz,DMSO)δ23.14。
LC-MS M/Z(ESI):592.2(M+1)。
The preparation of the compound 3-1 of embodiment 6 fumarate
By compound 3-1 (1.8g, 2.83mmol) it is dissolved in ethyl acetate (16mL), add fumaric acid (0.328g, 2.83mmol) and absolute methanol (2mL), it is heated to being down to room temperature again after 50 DEG C of stirrings are clarified completely to solution, adds petroleum ether (18mL), stirring and crystallizing 3 hours, filtering, collects filter cake and is dried under reduced pressure to obtain title compound (1.3g, yield
61.9%).
1H NMR(400MHz,DMSO)δ13.11(s,2H),8.14(s,1H),8.03(s,1H),7.19(s,2H),6.63(s,2H),5.67-5.46(m,4H),4.82(m,1H),4.26(dd,1H),4.17(dd,1H),4.05-3.88(m,3H),3.48(s,6H),3.41(m,4H),3.23(s,3H),1.24(d,6H),1.12(s,6H),1.07(d,3H)。
31P NMR(162MHz,DMSO)δ23.12。
LC-MS M/Z(ESI):636.2(M+1)。
The preparation of the compound 3-2 of embodiment 7 fumarate
By compound 3-2 (1.8g, 2.83mmol) it is dissolved in ethyl acetate (16mL), add fumaric acid (0.328g, 2.83mmol) and absolute methanol (2mL), it is heated to being down to room temperature again after 50 DEG C of stirrings are clarified completely to solution, adds petroleum ether (18mL), stirring and crystallizing 3 hours, filtering, collects filter cake and is dried under reduced pressure to obtain title compound (1.2g, yield 57.1%).
1H NMR(400MHz,DMSO)δ13.09(s,2H),8.14(s,1H),8.04(s,1H),6.63(s,2H),4.88-4.77(m,1H),4.26(dd,1H),4.17(dd,1H),4.04-3.87(m,3H),3.53-3.44(m,6H),3.44-3.35(m,4H),3.27-3.19(m,3H),1.23(m,6H),1.15-1.03(m,9H)。
31P NMR(162MHz,DMSO)δ23.14。
LC-MS M/Z(ESI):636.2(M+1)。
Study on the stability in test case 1, human plasma
People's whole blood and 3.8% sodium citrate anticoagulant are taken by 9:1 mixing anti-freezing, in 4 DEG C, centrifuged 15 minutes under the conditions of 2000g, take supernatant to be placed in constant incubator or water-bath to be incubated 5 minutes, take tenofovir dipivoxil, compound 2, compound 2-1, each 250 μ l of compound 2-2 and compound 3 DMSO/TBS mixed liquors (0.2mg/mL) are mixed with the μ l of pre-temperature human plasma 1000, fully mix, labeled as mixture 1, 2, 3, by mixture 1, 2, 3 are placed in incubation in constant incubator or water-bath, respectively 0, 5 seconds, 10 seconds, 15 seconds, 25 seconds, 45 seconds, 1 minute, 2 minutes, the μ l of reaction mixture 200 are taken at 5 minutes and 10 minutes and are mixed with 600 μ l methanol solutions, after fully mixing, centrifuged 5 minutes under the conditions of 15000g, take supernatant, with being analyzed after 0.22 μm of membrane filtration with HPLC, analysis result is as shown in table 1.
Table 1：Human plasma internal stability experimental result
| Numbering | Human plasma stability (t1/2) |
| Tenofovir dipivoxil | 77.5s |
| Compound 2 | 189s |
| Compound 2-1 | 189s |
| Compound 2-2 | 189s |
| Compound 3 | 140.8s |
Conclusion：Compared with tenofovir dipivoxil, the compounds of this invention has higher human plasma stability.
Test case 2, anti-hepatitis B virus activity screening
With the anti-hepatitis B activity of HepG2.2.15 raji cell assay Raji compounds.The material used and instrument are as follows：HepG2.2.15 cells, RPMI 1640 culture mediums, hyclone, 96 orifice plates, DMSO, QIAamp 96DNA Blood Kit, Cell-titer blue, ELIASA, Applied Biosystems 7900real-time PCR system.
Each compound is dissolved to 20mM with DMSO, the 20mM of each compound is stored liquid 3 times of gradient dilutions of DMSO, totally 9 concentration by -20 DEG C of storages.Again 200 times are diluted with the RPMI 1640 culture mediums containing 2.0%FBS.Final concentration of 100 μM of the highest test of compound.Experimental procedure is with reference to QIAamp 96DNA Blood Kit (QIAGEN 51161) specification.
QPCR methods determine compound anti-hepatitis B activity and calculate EC50(half effective inhibition concentration).Analyze data and calculating suppression percentage：Suppression percentage is calculated using equation below：%Inh.=【(HBV quantity of DMSO control-HBV quantity of sample)/HBV quantity of DMSO control】×100.The EC of compound is finally calculated using GraphPad Prism softwares50Value.
Cell-titer blue methods determine the cytotoxicity of compound and calculate CC50(causing 50% cytotoxic concentration).Analyze data and calculating versus cell vigor：Cytoactive percentage is calculated using equation below：%cell viability=(fluorescence of sample-fluorescence of medium control)/(fluorescence of DMSO control-fluorescence of medium control) × 100.The CC of compound is finally calculated using GraphPad Prism softwares50Value.As a result it is as shown in table 2.
Table 2：Each compound EC50Value and CC50Value
| Sequence number | Compound number | EC<sub>50</sub>(μM) | CC<sub>50</sub>(μM) |
| Control | Tenofovir dipivoxil | 0.00182 | >100 |
| 1 | 2 | <0.0152 | 50.50 |
| 2 | 2-1 | 0.00065 | ＞ 100 |
| 3 | 2-2 | 0.00079 | ＞ 100 |
| 4 | 3 | <0.0152 | 82.75 |
| 5 | 3-1 | 0.01068 | ＞ 100 |
| 6 | 3-2 | 0.01592 | ＞ 100 |
Conclusion：Test compound shows preferable anti-hepatitis B activity, and (0.0152-100 μM) does not show cytotoxicity in the concentration range of test.
Test case 3, Pharmacokinetic Evaluation
Male SD rat (is purchased from Vital River Laboratory Animal Technology Co.LTD, credit number：1400700005540) 200-240g, overnight fasting.3 SD rats difference gavage 15mgkg-1 of experimental day (are pressed
Active compound PMPA is counted), 5,15,30min, 1,2,4,8,12 and 24h before being administered and after administration, by jugular vein blood collection 0.20mL, is placed in EDTA test tubes.2 times of volumes of acetonitrile, whirlpool mixing 1min, 13000rpm centrifugation 8min are added after blood sample collection.The μ L of supernatant 100 are taken, are added after 50 μ L acetonitriles and internal standard (Verapamil, 5.00ngmL-1and glibenclamides, 50.0ngmL-1), whirlpool mixing 1min, N2 dryings.Residue adds 100 μ L deionized water dissolvings, takes 5 μ L to carry out LC-MS/MS detections.Pharmacokinetic parameter is calculated using the non-compartment model in Pharsight Phoenix 6.3, and evaluates oral administration biaavailability of the prodrug compound relative to active compound PMPA.Experimental result is as shown in table 3.
Table 3：Pharmacokinetics in rats evaluation result
Conclusion：Compound 2-1 fumarate and compound 2-2 fumarate are compared with control drug tenofovir dipivoxil fumarate, with suitable effect.
Claims (12)
- Compound, its stereoisomer shown in a kind of logical formula (I) or pharmaceutically acceptable salt,Wherein：R1Selected from H or methyl；R2Selected from H, C1-10Alkyl ,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n-C1-10Alkyl, described alkyl is optionally further by 0 to 5 R2aSubstitution；R3Selected from C1-10Alkyl ,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n-C1-10Alkyl, wherein described alkyl is optionally further by 0 to 5 R3aSubstitution；R2aAnd R3aIt is independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carboxyl, C1-4Alkyl or C3-6Cycloalkyl；N is selected from 1,2,3,4,5,6,7,8,9 or 10.
- Compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein：R1Selected from H or methyl；R2Selected from substituted or unsubstituted H, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, isopentyl, neopentyl, pentane -3- bases,-(CH2-CH2-O)n- H or-(CH2-CH2-O)n- methyl, when substituted, optionally by 1 to 5 R2aSubstitution；R3Selected from substituted or unsubstituted methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, isopentyl, neopentyl, pentane -3- bases,-CH2-CH2- OH or-(CH2-CH2-O)2- H, when substituted, optionally by 1 to 5 R3aSubstitution；R2aAnd R3aIt is independently selected from H, F, Cl, hydroxyl, amino, methyl or ethyl；N is selected from 1,2,3,4 or 5.
- Compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt, the wherein compound are selected from compound shown in logical formula (II), its stereoisomer or pharmaceutically acceptable salt, wherein：R1Selected from H or methyl；R2Selected from H, methyl, ethyl, propyl group, isopropyl ,-CH2-CH2-O-CH3、-CH2-CH2-OH、-(CH2-CH2-O)2- H or-(CH2-CH2-O)2-CH3。
- Compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein compound are selected from one of following structure：
- According to compound according to any one of claims 1 to 4, its stereoisomer or pharmaceutically acceptable salt, wherein described salt is tosilate, fluoroform sulphonate, mesylate or fumarate.
- A kind of pharmaceutical composition, described pharmaceutical composition contains：Compound, its stereoisomer or the pharmaceutically acceptable salt, and pharmaceutically acceptable carrier or excipient according to any one of profit requires 1~5 for the treatment of effective dose.
- Pharmaceutical composition according to claim 6, the pharmaceutical composition is to be used to treat disease of viral infection.
- Pharmaceutical composition according to claim 7, wherein, the disease of viral infection includes hepatitis type B virus, hepatitis C virus or infectious diseases caused by AIDS virus.
- Compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically application of the acceptable salt in preparing for treating the related drugs of disease of viral infection.
- Application according to claim 9, wherein the disease of viral infection includes hepatitis type B virus, hepatitis C virus or infectious diseases caused by AIDS virus.
- A kind of method for treating disease of viral infection, the profit that this method includes giving patient effective amounts requires compound, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition described in claim 6 any one of 1~5.
- Method according to claim 11, wherein, the disease of viral infection includes hepatitis type B virus, hepatitis C virus or infectious diseases caused by AIDS virus.
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| US5663159A (en) * | 1990-09-14 | 1997-09-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| CN1986553A (en) * | 2005-12-19 | 2007-06-27 | 北京美倍他药物研究有限公司 | Precursor medicine of acyclic nucleoside phosphonic acid |
| CN102977146A (en) * | 2012-11-20 | 2013-03-20 | 广东肇庆星湖生物科技股份有限公司 | Adenine derivative and inclusion compound thereof |
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| US5663159A (en) * | 1990-09-14 | 1997-09-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| CN1986553A (en) * | 2005-12-19 | 2007-06-27 | 北京美倍他药物研究有限公司 | Precursor medicine of acyclic nucleoside phosphonic acid |
| CN102977146A (en) * | 2012-11-20 | 2013-03-20 | 广东肇庆星湖生物科技股份有限公司 | Adenine derivative and inclusion compound thereof |
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