CN108137630A - 氟化无环核苷膦酸酯的前药 - Google Patents
氟化无环核苷膦酸酯的前药 Download PDFInfo
- Publication number
- CN108137630A CN108137630A CN201780001997.4A CN201780001997A CN108137630A CN 108137630 A CN108137630 A CN 108137630A CN 201780001997 A CN201780001997 A CN 201780001997A CN 108137630 A CN108137630 A CN 108137630A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- virus
- nmr
- compound
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 acyclic nucleoside phosphate ester Chemical class 0.000 title claims abstract description 158
- 239000002777 nucleoside Substances 0.000 title abstract description 19
- 229940002612 prodrug Drugs 0.000 title abstract description 15
- 239000000651 prodrug Substances 0.000 title abstract description 15
- 229910019142 PO4 Inorganic materials 0.000 title abstract description 10
- 239000010452 phosphate Substances 0.000 title abstract description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 69
- 239000003814 drug Substances 0.000 claims abstract description 22
- 241000701085 Human alphaherpesvirus 3 Species 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 230000009385 viral infection Effects 0.000 claims abstract description 10
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 claims abstract description 8
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 127
- 239000000203 mixture Substances 0.000 claims description 59
- 238000000034 method Methods 0.000 claims description 55
- 241000700605 Viruses Species 0.000 claims description 51
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 50
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 37
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 37
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 36
- 201000010099 disease Diseases 0.000 claims description 36
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 24
- 229930024421 Adenine Natural products 0.000 claims description 23
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims description 23
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims description 23
- 229960000643 adenine Drugs 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 17
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 claims description 17
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims description 17
- 229940104230 thymidine Drugs 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 241000124008 Mammalia Species 0.000 claims description 15
- 241001465754 Metazoa Species 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 208000015181 infectious disease Diseases 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
- 241000701022 Cytomegalovirus Species 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 10
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 10
- 241000725643 Respiratory syncytial virus Species 0.000 claims description 9
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 230000004048 modification Effects 0.000 claims description 8
- 238000012986 modification Methods 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 230000003612 virological effect Effects 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000002574 poison Substances 0.000 claims description 7
- 231100000614 poison Toxicity 0.000 claims description 7
- 230000002062 proliferating effect Effects 0.000 claims description 7
- 241001631646 Papillomaviridae Species 0.000 claims description 6
- 241000700618 Vaccinia virus Species 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000002837 carbocyclic group Chemical group 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 150000003254 radicals Chemical class 0.000 claims description 6
- 241000829111 Human polyomavirus 1 Species 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 208000002606 Paramyxoviridae Infections Diseases 0.000 claims description 5
- 125000001821 azanediyl group Chemical group [H]N(*)* 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 241000725619 Dengue virus Species 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
- 241000701161 unidentified adenovirus Species 0.000 claims description 4
- 241000712461 unidentified influenza virus Species 0.000 claims description 3
- 208000010201 Exanthema Diseases 0.000 claims description 2
- 201000005884 exanthem Diseases 0.000 claims description 2
- 206010037844 rash Diseases 0.000 claims description 2
- 230000029305 taxis Effects 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 2
- 208000005176 Hepatitis C Diseases 0.000 claims 1
- 206010061598 Immunodeficiency Diseases 0.000 claims 1
- 208000029462 Immunodeficiency disease Diseases 0.000 claims 1
- 241000700627 Monkeypox virus Species 0.000 claims 1
- 150000001350 alkyl halides Chemical class 0.000 claims 1
- 210000004907 gland Anatomy 0.000 claims 1
- 230000007813 immunodeficiency Effects 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001384 succinic acid Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 abstract description 14
- 239000011737 fluorine Substances 0.000 abstract description 13
- 241000701024 Human betaherpesvirus 5 Species 0.000 abstract description 11
- 125000003835 nucleoside group Chemical group 0.000 abstract description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract description 6
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 abstract description 6
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 4
- 208000036142 Viral infection Diseases 0.000 abstract 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 230
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 212
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 141
- 239000002585 base Substances 0.000 description 103
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 94
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 74
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 68
- 238000005160 1H NMR spectroscopy Methods 0.000 description 68
- 238000010898 silica gel chromatography Methods 0.000 description 68
- 238000004679 31P NMR spectroscopy Methods 0.000 description 67
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- 238000003786 synthesis reaction Methods 0.000 description 53
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 52
- 230000015572 biosynthetic process Effects 0.000 description 52
- 239000000243 solution Substances 0.000 description 48
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 48
- BBHJTCADCKZYSO-UHFFFAOYSA-N 4-(4-ethylcyclohexyl)benzonitrile Chemical compound C1CC(CC)CCC1C1=CC=C(C#N)C=C1 BBHJTCADCKZYSO-UHFFFAOYSA-N 0.000 description 46
- 229910001868 water Inorganic materials 0.000 description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 42
- 239000012230 colorless oil Substances 0.000 description 39
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 38
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 38
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 37
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 31
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 30
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 26
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 26
- 239000006260 foam Substances 0.000 description 25
- 238000002360 preparation method Methods 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 22
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 22
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 21
- 239000003153 chemical reaction reagent Substances 0.000 description 17
- BVXLLZBMCZWPGZ-UHFFFAOYSA-N [SiH4].[Br-].C[NH+](C)C Chemical compound [SiH4].[Br-].C[NH+](C)C BVXLLZBMCZWPGZ-UHFFFAOYSA-N 0.000 description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 230000000840 anti-viral effect Effects 0.000 description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 239000012973 diazabicyclooctane Substances 0.000 description 12
- 238000003682 fluorination reaction Methods 0.000 description 12
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 12
- 229960005261 aspartic acid Drugs 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 241000723848 Tobamovirus Species 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 229940009098 aspartate Drugs 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 241000711549 Hepacivirus C Species 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 150000003230 pyrimidines Chemical class 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 241001529453 unidentified herpesvirus Species 0.000 description 8
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 7
- 241000709661 Enterovirus Species 0.000 description 7
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 7
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 230000006698 induction Effects 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 241001505332 Polyomavirus sp. Species 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 241000700584 Simplexvirus Species 0.000 description 6
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000004113 cell culture Methods 0.000 description 6
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- 238000004611 spectroscopical analysis Methods 0.000 description 6
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 208000032839 leukemia Diseases 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 150000003009 phosphonic acids Chemical class 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 241000271566 Aves Species 0.000 description 4
- 206010011703 Cyanosis Diseases 0.000 description 4
- 241000175212 Herpesvirales Species 0.000 description 4
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 4
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 4
- 230000010261 cell growth Effects 0.000 description 4
- 239000003610 charcoal Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 241001430294 unidentified retrovirus Species 0.000 description 4
- 230000029812 viral genome replication Effects 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- WGABOZPQOOZAOI-UHFFFAOYSA-N 2-[4-[[(3,5-dimethoxy-4-methylbenzoyl)-(3-phenylpropyl)amino]methyl]phenyl]acetic acid Chemical compound COC1=C(C)C(OC)=CC(C(=O)N(CCCC=2C=CC=CC=2)CC=2C=CC(CC(O)=O)=CC=2)=C1 WGABOZPQOOZAOI-UHFFFAOYSA-N 0.000 description 3
- NIFAOMSJMGEFTQ-UHFFFAOYSA-N 4-methoxybenzenethiol Chemical class COC1=CC=C(S)C=C1 NIFAOMSJMGEFTQ-UHFFFAOYSA-N 0.000 description 3
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
- 0 CC1=*=C2N=CN(C[C@@](CF)OC*)C2=CCNC=N1 Chemical compound CC1=*=C2N=CN(C[C@@](CF)OC*)C2=CCNC=N1 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 3
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 3
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 3
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 3
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 125000004442 acylamino group Chemical group 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940126212 compound 17a Drugs 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229940029575 guanosine Drugs 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000010839 reverse transcription Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 210000001541 thymus gland Anatomy 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 229940035893 uracil Drugs 0.000 description 3
- DAAXYQZSKBPJOX-FQEVSTJZSA-N (2S)-2-amino-3-[4-[5-[3-(4-hydroxyphenyl)-4-methoxyphenyl]-1,2,4-oxadiazol-3-yl]phenyl]propanoic acid Chemical compound COC1=C(C=C(C=C1)C2=NC(=NO2)C3=CC=C(C=C3)C[C@@H](C(=O)O)N)C4=CC=C(C=C4)O DAAXYQZSKBPJOX-FQEVSTJZSA-N 0.000 description 2
- SLTBMTIRYMGWLX-XMMPIXPASA-N (2r)-2-[(4-chloroanilino)carbamoylamino]-3-(1h-indol-3-yl)-n-(2-phenylethyl)propanamide Chemical compound C1=CC(Cl)=CC=C1NNC(=O)N[C@@H](C(=O)NCCC=1C=CC=CC=1)CC1=CNC2=CC=CC=C12 SLTBMTIRYMGWLX-XMMPIXPASA-N 0.000 description 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- AEVBPXDFDKBGLT-YOUFYPILSA-N (2s,3s,4r,5r)-n-[2-[4-(diethoxyphosphorylmethyl)anilino]-2-oxoethyl]-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolane-2-carboxamide Chemical compound C1=CC(CP(=O)(OCC)OCC)=CC=C1NC(=O)CNC(=O)[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 AEVBPXDFDKBGLT-YOUFYPILSA-N 0.000 description 2
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 2
- LENAVORGWBTPJR-UHFFFAOYSA-N (5-pyridin-3-ylfuran-2-yl)methanamine Chemical compound O1C(CN)=CC=C1C1=CC=CN=C1 LENAVORGWBTPJR-UHFFFAOYSA-N 0.000 description 2
- JHLIGYPHPBLDDL-UHFFFAOYSA-N (5-pyridin-3-ylthiophen-2-yl)methanamine Chemical compound S1C(CN)=CC=C1C1=CC=CN=C1 JHLIGYPHPBLDDL-UHFFFAOYSA-N 0.000 description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 2
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 2
- YCGQPIRMLGEWMW-UHFFFAOYSA-N 1-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-3-[4-[(dimethylamino)methyl]-2,6-di(propan-2-yl)phenyl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN(C)C)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 YCGQPIRMLGEWMW-UHFFFAOYSA-N 0.000 description 2
- SZCBDIVMCGFVPW-UHFFFAOYSA-N 1-[4-(aminomethyl)-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 SZCBDIVMCGFVPW-UHFFFAOYSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- HNFMVVHMKGFCMB-UHFFFAOYSA-N 3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine Chemical compound NC1=NC=CC=C1C1=NC2=CC=C(C=3C=CC=CC=3)N=C2N1C1=CC=C(C2(N)CCC2)C=C1 HNFMVVHMKGFCMB-UHFFFAOYSA-N 0.000 description 2
- TXEBWPPWSVMYOA-UHFFFAOYSA-N 4-[3-[(1-amino-2-chloroethyl)amino]propyl]-1-[[3-(2-chlorophenyl)phenyl]methyl]-5-hydroxyimidazolidin-2-one Chemical compound NC(CCl)NCCCC1NC(=O)N(Cc2cccc(c2)-c2ccccc2Cl)C1O TXEBWPPWSVMYOA-UHFFFAOYSA-N 0.000 description 2
- KUZSBKJSGSKPJH-VXGBXAGGSA-N 5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2,4,6-trien-4-yl]pyrazin-2-amine Chemical compound C[C@@H]1COCCN1c1nc(nc2N3CCOC[C@H]3Cc12)-c1cnc(N)cn1 KUZSBKJSGSKPJH-VXGBXAGGSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241001118702 Border disease virus Species 0.000 description 2
- 241000710780 Bovine viral diarrhea virus 1 Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- WUZBOJXXYMKMMF-UHFFFAOYSA-N COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F Chemical compound COC1=CC2=NC=3N(C(N(C(C=3N2C=C1)=O)CCC)=O)CCCCNC(=O)C1=CC=C(C=C1)S(=O)(=O)F WUZBOJXXYMKMMF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010012310 Dengue fever Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 241000710781 Flaviviridae Species 0.000 description 2
- 241000710831 Flavivirus Species 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 241000700739 Hepadnaviridae Species 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 241000709715 Hepatovirus Species 0.000 description 2
- 241000701806 Human papillomavirus Species 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 201000008197 Laryngitis Diseases 0.000 description 2
- 241000701043 Lymphocryptovirus Species 0.000 description 2
- 208000006758 Marek Disease Diseases 0.000 description 2
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000701034 Muromegalovirus Species 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- ZNSPHKJFQDEABI-NZQKXSOJSA-N Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(n1)N1CCC2(CN[C@@H](C2)C(O)=O)CC1 Chemical compound Nc1nc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)cc(n1)N1CCC2(CN[C@@H](C2)C(O)=O)CC1 ZNSPHKJFQDEABI-NZQKXSOJSA-N 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- 241000175217 Percavirus Species 0.000 description 2
- 241000710778 Pestivirus Species 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 241001474791 Proboscis Species 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 241000701037 Rhadinovirus Species 0.000 description 2
- 241000122129 Roseolovirus Species 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- KZUGHQWNFSZLLP-UHFFFAOYSA-N [1-(2-amino-6-oxo-3h-purin-9-yl)-3-fluoropropan-2-yl]oxymethylphosphonic acid Chemical compound N1C(N)=NC(=O)C2=C1N(CC(CF)OCP(O)(O)=O)C=N2 KZUGHQWNFSZLLP-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 208000013593 acute megakaryoblastic leukemia Diseases 0.000 description 2
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 2
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 2
- 229960000724 cidofovir Drugs 0.000 description 2
- 229940125876 compound 15a Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000000120 cytopathologic effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 208000025729 dengue disease Diseases 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 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 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 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 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- TZSZZENYCISATO-WIOPSUGQSA-N rodatristat Chemical compound CCOC(=O)[C@@H]1CC2(CN1)CCN(CC2)c1cc(O[C@H](c2ccc(Cl)cc2-c2ccccc2)C(F)(F)F)nc(N)n1 TZSZZENYCISATO-WIOPSUGQSA-N 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 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 2
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- ITHPEWAHFNDNIO-UHFFFAOYSA-N triphosphane Chemical compound PPP ITHPEWAHFNDNIO-UHFFFAOYSA-N 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 210000002845 virion Anatomy 0.000 description 2
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- TWYYFYNJOJGNFP-CUXYNZQBSA-N (2s,4r,5s,6s)-2-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-2-carbamoyl-4-[[(e,4s,6s)-4,6-dimethyloct-2-enoyl]oxymethyl]-5-hydroxy-1,3-dioxane-4,5,6-tricarboxylic acid Chemical compound O1[C@H](C(O)=O)[C@](C(O)=O)(O)[C@](COC(=O)/C=C/[C@@H](C)C[C@@H](C)CC)(C(O)=O)O[C@]1(C(N)=O)CCC(=C)[C@@H](OC(C)=O)[C@H](C)CC1=CC=CC=C1 TWYYFYNJOJGNFP-CUXYNZQBSA-N 0.000 description 1
- OGQVROWWFUXRST-FNORWQNLSA-N (3e)-hepta-1,3-diene Chemical compound CCC\C=C\C=C OGQVROWWFUXRST-FNORWQNLSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 1
- RXNPEQZHMGFNAY-GEALJGNFSA-N (5R)-4-[(1S,6R)-5-[(2S)-2-(4-chlorophenyl)-3-(propan-2-ylamino)propanoyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-5-methyl-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one Chemical compound C[C@@H]1CC(=O)NC2=C1C(=NC=N2)N3CCN([C@H]4[C@@H]3C4)C(=O)[C@H](CNC(C)C)C5=CC=C(C=C5)Cl RXNPEQZHMGFNAY-GEALJGNFSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical class C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 1
- IIQSIMDTVOZMQN-UHFFFAOYSA-N 2,3-dipentylpyridine Chemical compound CCCCCC1=CC=CN=C1CCCCC IIQSIMDTVOZMQN-UHFFFAOYSA-N 0.000 description 1
- LBYJICCOHIHLOJ-UHFFFAOYSA-N 2,4-diamino-1h-pyrimidin-4-ol Chemical class NC1=NC(N)(O)C=CN1 LBYJICCOHIHLOJ-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- JBMBVWROWJGFMG-UHFFFAOYSA-N 2-chloro-7h-purine Chemical compound ClC1=NC=C2NC=NC2=N1 JBMBVWROWJGFMG-UHFFFAOYSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical group OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 1
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 1
- LQOBMKYCRQDMTN-UHFFFAOYSA-N 3-(2-ethylphenyl)pentan-3-amine;hydrochloride Chemical compound Cl.CCC1=CC=CC=C1C(N)(CC)CC LQOBMKYCRQDMTN-UHFFFAOYSA-N 0.000 description 1
- VGOALPIDEXVYQI-UHFFFAOYSA-N 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-n-[3-imidazol-1-yl-5-(trifluoromethyl)phenyl]-4-methylbenzamide Chemical compound C1=C(C#CC=2N3N=CC=CC3=NC=2)C(C)=CC=C1C(=O)NC(C=C(C=1)C(F)(F)F)=CC=1N1C=CN=C1 VGOALPIDEXVYQI-UHFFFAOYSA-N 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- UWSONZCNXUSTKW-UHFFFAOYSA-N 4,5-Dimethylthiazole Chemical compound CC=1N=CSC=1C UWSONZCNXUSTKW-UHFFFAOYSA-N 0.000 description 1
- JOFDSYLCZIHGGO-UHFFFAOYSA-N 4-[(4-cyclohexylphenyl)methyl-[2-[[5-(dimethylamino)naphthalen-1-yl]sulfonyl-methylamino]acetyl]amino]-2-hydroxybenzoic acid Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)N(C)CC(=O)N(C=1C=C(O)C(C(O)=O)=CC=1)CC(C=C1)=CC=C1C1CCCCC1 JOFDSYLCZIHGGO-UHFFFAOYSA-N 0.000 description 1
- MVXAKOGJWVQPKC-UHFFFAOYSA-N 5-(3-ethynyl-5-fluorophenyl)-2-pyridin-2-yl-4,6,7,8-tetrahydro-[1,3]oxazolo[4,5-c]azepine Chemical compound FC1=CC(C#C)=CC(N2CC=3N=C(OC=3CCC2)C=2N=CC=CC=2)=C1 MVXAKOGJWVQPKC-UHFFFAOYSA-N 0.000 description 1
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 description 1
- VKKXEIQIGGPMHT-UHFFFAOYSA-N 7h-purine-2,8-diamine Chemical compound NC1=NC=C2NC(N)=NC2=N1 VKKXEIQIGGPMHT-UHFFFAOYSA-N 0.000 description 1
- LPWKFUVWWQYLOD-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-methylphenyl)pyrido[2,3]thieno[2,4-d]pyrimidin-4-one Chemical compound C1=2C(N(C)C)=CN=CC=2SC(C2=O)=C1N=CN2C1=CC=C(C)C=C1 LPWKFUVWWQYLOD-UHFFFAOYSA-N 0.000 description 1
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000010370 Adenoviridae Infections Diseases 0.000 description 1
- 206010060931 Adenovirus infection Diseases 0.000 description 1
- 241001492267 Alcelaphine gammaherpesvirus 1 Species 0.000 description 1
- 241000700587 Alphaherpesvirinae Species 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- PEMQXWCOMFJRLS-UHFFFAOYSA-N Archaeosine Natural products C1=2NC(N)=NC(=O)C=2C(C(=N)N)=CN1C1OC(CO)C(O)C1O PEMQXWCOMFJRLS-UHFFFAOYSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 206010055181 BK virus infection Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 241000282817 Bovidae Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- KOMXKNSMXQUBRT-UHFFFAOYSA-N C1(=CC=CC=C1)OC.[S] Chemical compound C1(=CC=CC=C1)OC.[S] KOMXKNSMXQUBRT-UHFFFAOYSA-N 0.000 description 1
- OYGXAWKSXUUNPG-IDPUCBEOSA-N CCCCCOC(C[C@@H](C(OCCCCC)=O)NP(CO[C@H](CN(C=CC(N)=N1)C1=O)CF)(Oc1ccccc1)=O)=O Chemical compound CCCCCOC(C[C@@H](C(OCCCCC)=O)NP(CO[C@H](CN(C=CC(N)=N1)C1=O)CF)(Oc1ccccc1)=O)=O OYGXAWKSXUUNPG-IDPUCBEOSA-N 0.000 description 1
- DVOYUBKJIFKTEB-CYBMUJFWSA-N CCCCCOC(C[C@H](C(OCCCCC)=O)NC)=O Chemical compound CCCCCOC(C[C@H](C(OCCCCC)=O)NC)=O DVOYUBKJIFKTEB-CYBMUJFWSA-N 0.000 description 1
- LPSKCENXVZIQTM-GCKASKAXSA-N CCOP(CO[C@@H](C[N](C)(C=CC(N)N1)C1=O)CF)([O](C)(C)CC)=O Chemical compound CCOP(CO[C@@H](C[N](C)(C=CC(N)N1)C1=O)CF)([O](C)(C)CC)=O LPSKCENXVZIQTM-GCKASKAXSA-N 0.000 description 1
- QCMHGCDOZLWPOT-FMNCTDSISA-N COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 Chemical compound COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 QCMHGCDOZLWPOT-FMNCTDSISA-N 0.000 description 1
- SSFLIOUDIAJHHT-LLVKDONJSA-N COc(cc1)ccc1Sc1c2nc[n](C[C@@H](CF)OCP(O)(O)=O)c2nc(N)n1 Chemical compound COc(cc1)ccc1Sc1c2nc[n](C[C@@H](CF)OCP(O)(O)=O)c2nc(N)n1 SSFLIOUDIAJHHT-LLVKDONJSA-N 0.000 description 1
- CPAZSFYQHFPYCS-SNVBAGLBSA-N C[C@](CN(C=C(C)C(N1)=O)C1=O)(CF)OCP(O)(O)=O Chemical compound C[C@](CN(C=C(C)C(N1)=O)C1=O)(CF)OCP(O)(O)=O CPAZSFYQHFPYCS-SNVBAGLBSA-N 0.000 description 1
- 241000680578 Canid alphaherpesvirus 1 Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000710190 Cardiovirus Species 0.000 description 1
- 241000282994 Cervidae Species 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- 241000710777 Classical swine fever virus Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241001466953 Echovirus Species 0.000 description 1
- 241001316389 Elephantid betaherpesvirus 1 Species 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 241000725578 Equid gammaherpesvirus 2 Species 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000710198 Foot-and-mouth disease virus Species 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 206010019773 Hepatitis G Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241001455657 Human betaherpesvirus 6A Species 0.000 description 1
- 241001455656 Human betaherpesvirus 6B Species 0.000 description 1
- 241000701041 Human betaherpesvirus 7 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 241000829106 Human polyomavirus 3 Species 0.000 description 1
- 241000714192 Human spumaretrovirus Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 241000701460 JC polyomavirus Species 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 241001468006 Kobuvirus Species 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 108010022337 Leucine Enkephalin Proteins 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 101150113681 MALT1 gene Proteins 0.000 description 1
- 241000969460 MW polyomavirus Species 0.000 description 1
- 241000283923 Marmota monax Species 0.000 description 1
- 241000579048 Merkel cell polyomavirus Species 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 102000057613 Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Human genes 0.000 description 1
- 108700026676 Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Proteins 0.000 description 1
- 241000701029 Murid betaherpesvirus 1 Species 0.000 description 1
- 208000002231 Muscle Neoplasms Diseases 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 1
- WDZSBBQIFWIRCR-UHFFFAOYSA-N NOP(=O)ON Chemical compound NOP(=O)ON WDZSBBQIFWIRCR-UHFFFAOYSA-N 0.000 description 1
- BVMWIXWOIGJRGE-UHFFFAOYSA-N NP(O)=O Chemical compound NP(O)=O BVMWIXWOIGJRGE-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241000991583 Parechovirus Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 241000175215 Proboscivirus Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 241000712907 Retroviridae Species 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 206010061494 Rhinovirus infection Diseases 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- 241000216886 STL polyomavirus Species 0.000 description 1
- 241000701062 Saimiriine gammaherpesvirus 2 Species 0.000 description 1
- 241001333897 Sapelovirus Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 241000351085 Scutavirus Species 0.000 description 1
- 241001632234 Senecavirus Species 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 241000249096 Teschovirus Species 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 241000933101 Tragelaphus scriptus Species 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 241001365589 Tremovirus Species 0.000 description 1
- 206010072358 Trichodysplasia spinulosa Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 241000379754 WU Polyomavirus Species 0.000 description 1
- 241000710886 West Nile virus Species 0.000 description 1
- 208000003152 Yellow Fever Diseases 0.000 description 1
- NPUXORBZRBIOMQ-RUZDIDTESA-N [(2R)-1-[[4-[[3-(benzenesulfonylmethyl)-5-methylphenoxy]methyl]phenyl]methyl]-2-pyrrolidinyl]methanol Chemical compound C=1C(OCC=2C=CC(CN3[C@H](CCC3)CO)=CC=2)=CC(C)=CC=1CS(=O)(=O)C1=CC=CC=C1 NPUXORBZRBIOMQ-RUZDIDTESA-N 0.000 description 1
- BFZJTDBFUROXJA-LURJTMIESA-N [(2r)-1-(6-aminopurin-9-yl)-3-fluoropropan-2-yl]oxymethylphosphonic acid Chemical compound NC1=NC=NC2=C1N=CN2C[C@H](CF)OCP(O)(O)=O BFZJTDBFUROXJA-LURJTMIESA-N 0.000 description 1
- BFZJTDBFUROXJA-ZCFIWIBFSA-N [(2s)-1-(6-aminopurin-9-yl)-3-fluoropropan-2-yl]oxymethylphosphonic acid Chemical compound NC1=NC=NC2=C1N=CN2C[C@@H](CF)OCP(O)(O)=O BFZJTDBFUROXJA-ZCFIWIBFSA-N 0.000 description 1
- BFZJTDBFUROXJA-UHFFFAOYSA-N [1-(6-aminopurin-9-yl)-3-fluoropropan-2-yl]oxymethylphosphonic acid Chemical compound NC1=NC=NC2=C1N=CN2CC(CF)OCP(O)(O)=O BFZJTDBFUROXJA-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- 208000011589 adenoviridae infectious disease Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000006323 alkenyl amino group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000006319 alkynyl amino group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- XQJHRCVXRAJIDY-UHFFFAOYSA-N aminophosphine Chemical class PN XQJHRCVXRAJIDY-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000000631 analytical pyrolysis Methods 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- PEMQXWCOMFJRLS-RPKMEZRRSA-N archaeosine Chemical compound C1=2NC(N)=NC(=O)C=2C(C(=N)N)=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O PEMQXWCOMFJRLS-RPKMEZRRSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000001691 aryl alkyl amino group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229960001169 brivudine Drugs 0.000 description 1
- 125000004799 bromophenyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 125000006310 cycloalkyl amino group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 208000001763 cytomegalovirus retinitis Diseases 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- UOEFFQWLRUBDME-UHFFFAOYSA-N diethoxyphosphorylmethyl 4-methylbenzenesulfonate Chemical compound CCOP(=O)(OCC)COS(=O)(=O)C1=CC=C(C)C=C1 UOEFFQWLRUBDME-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003937 drug carrier Substances 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
- 239000004210 ether based solvent Substances 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 230000001036 exonucleolytic effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 210000002768 hair cell Anatomy 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000005570 heteronuclear single quantum coherence Methods 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
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000005191 hydroxyalkylamino group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- URLZCHNOLZSCCA-UHFFFAOYSA-N leu-enkephalin Chemical compound C=1C=C(O)C=CC=1CC(N)C(=O)NCC(=O)NCC(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=CC=C1 URLZCHNOLZSCCA-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 201000010453 lymph node cancer Diseases 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 208000021937 marginal zone lymphoma Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 208000000516 mast-cell leukemia Diseases 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000005497 microtitration Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000005871 monkeypox Diseases 0.000 description 1
- 201000002077 muscle cancer Diseases 0.000 description 1
- 210000003887 myelocyte Anatomy 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical group CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000003003 phosphines Chemical class 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 150000003008 phosphonic acid esters Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000001394 phosphorus-31 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- 239000002718 pyrimidine nucleoside Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 150000003566 thiocarboxylic acids Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 description 1
- 238000005866 tritylation reaction Methods 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000025247 virus-associated trichodysplasia spinulosa Diseases 0.000 description 1
- 239000003643 water by type Substances 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及具有3‑氟‑2‑(膦酰甲氧基)丙基侧链的无环核苷膦酸酯的新型氨基膦酸酯前药。本发明还涉及这些新型膦酸酯修饰的核苷用于治疗或预防病毒感染的用途及它们制造用于治疗或预防病毒感染,特别是诸如乙型肝炎病毒、人类免疫缺陷病毒、人巨细胞病毒和水痘带状疱疹病毒的病毒感染的药物的用途。
Description
技术领域
本发明涉及具有3-氟-2-(膦酰甲氧基)丙基侧链的无环核苷膦酸酯(acyclicnucleoside phosphonates)的新型氨基膦酸酯(phosphonoamidate)前药。本发明还涉及这些新型膦酸酯修饰的核苷用于治疗或预防病毒感染的用途及它们用于制造药物用于治疗或预防病毒感染,特别是由诸如乙型肝炎病毒、人类免疫缺陷病毒、人巨细胞病毒和水痘带状疱疹病毒的病毒的感染。
背景技术
无环核苷膦酸酯(ANP)是一类重要的抗病毒药物。它们的主要结构特征是:(1)代替环状糖部分的脂肪族侧链和(2)存在连接到该无环核苷部分的膦酸酯基团。
存在于ANP中的膦酰基甲氧基官能团(P-C-O)可被认为是核苷单膦酸酯中的天然存在的膦酸-氧基甲基(P-O-C)部分的等排物。与磷酸酯基相反,膦酸酯不易受膦酸二酯酶和磷酸酶水解的影响,因此是酶促稳定的。这个模序(motif)的成功是由于它与磷酸酯基团等极和等排的事实。因此,它们可以进行酶促磷酸化,其将它们转化为相应的二磷酸膦酸酯,其充当天然核苷三磷酸酯的类似物。由于这种膦酸酯部分是磷酸酯模拟基团,因此ANP只需要两个(而不是三个用于正规的核苷类似物)磷酸化步骤以达到它们的生物活性阶段。这是有利的,因为第一磷酸化在核苷三磷酸酯的形成中经常是低效率和限速的。在无环糖侧链中的柔韧性允许这些化合物在去磷酸化时采取适合于与DNA聚合酶或逆转录酶的活性位点相互作用的构象。
对ANP的合成和抗病毒评估的广泛研究导致了三种ANP的销售(图1)。西多福韦(HPMPC,(S)-1-(3-羟基-2-膦酰甲氧基丙基)胞嘧啶)获得上市许可,用于治疗AIDS患者的CMV视网膜炎。阿德福韦(PMEA,9-(2-膦酰基甲氧基乙基)腺嘌呤)被许可用于治疗乙型肝炎病毒感染的患者,且替诺福韦(PMPA,(R)-9-(2-膦酰基甲氧基丙基)腺嘌呤)被用作抗HIV和抗HBV药物。后两者以口服生物可利用的前药形式销售。
将氟原子引入到生物活性分子常常导致它们的物理、生物和药代动力学性质的显著变化。已经合成并测试具有氟化侧链的ANP的抗病毒活性。氟化ANP的最佳研究的种类是3-氟-2-(膦酰基甲氧基)丙基(FPMP)衍生物。FPMPA和FPMPG的两种对映异构体(图2)完全没有针对广泛的DNA病毒(HSV-1、HSV-2、CMV、VZV、VV)的抗病毒活性。另一方面,(S)-FPMPA显示对HIV-1和HIV-2强效和选择性抗病毒活性,其中EC50值在8μM的范围内。相应的(R)-FPMPA完全缺乏抗HIV活性(Antimicrob.Agents Chemother.1993,37,332-338)。对于含鸟苷的同源物(FPMPG),两种对映异构体对HIV-1和HIV-2具有相等的活性,其中两种异构体的EC50值在5μM的范围内。此外,已经合成了核碱基修饰的FPMP衍生物并评估了抗病毒活性。二氨基嘌呤同源物(FPMPDAP)表现出对一组DNA病毒没有活性,而(R)-FPMPDAP分别对HIV-1和HIV-2显示4.3μM和4.6μM的EC50值。
膦酸酯在生理pH下带负电,并且因此不能穿透富含脂质的细胞膜,这阻碍了它们的抗病毒活性。已经研究了各种前药或“前核苷酸”方法来促进通过亲脂性细胞膜的被动扩散并在细胞内释放母体核苷酸,其中它可以被进一步磷酸化成药理活性品种。
本发明基于意想不到的发现,即具有3-氟-2-(膦酰基甲氧基)丙基(FPMP)侧链的氟化ANP的氨基膦酸酯前药显示出意想不到的生物学性质,特别是对乙型肝炎病毒、人类免疫缺陷病毒、人巨细胞病毒和水痘带状疱疹病毒具有显著的抗病毒活性。
发明内容
本发明涉及无环核苷膦酸酯(ANP)的新型氨基膦酸酯和二氨基膦酸酯前药,以及它们作为用于治疗病毒性疾病的药剂的用途。它基于意想不到的发现,即某些核苷前药显示出意想不到的生物学性质,特别是对乙型肝炎病毒、人类免疫缺陷病毒、人巨细胞病毒和水痘带状疱疹病毒具有显著活性。
本发明编号声明项如下:
1.一种式I的化合物:
其中
-B是任何天然或修饰的核碱基
-R1具有通式II
其中
-R3选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8-环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基和烷氧基烷基组成的组;
-R4选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基、烷氧基烷基、X-COOR5、X-O(C=O)-R5组成的组;
其中X是芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基或C3-C8-环烷基,并且其中所述芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C8-环烷基任选地包含一个或多个独立地选自由卤素、卤代烷基、氰基、C1-C7烷氧基组成的组的官能团、原子或自由基;且
其中R5选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基和烷氧基烷基组成的组;
-R2是O-Ar,其中Ar是稠合二环芳基部分或单环芳基部分,其中任何一个芳基部分是碳环或杂环并且任选地被卤素、C1-C6烷基、C1-C6烷氧基取代;
或者R2具有通式II
其中R1和R2可以相同或不同;
和/或其药学上可接受的加成盐和/或其立体异构体和/或其溶剂化物。
2.根据声明项1所述的化合物,其中B选自由腺嘌呤、胸腺嘧啶、胞嘧啶和鸟嘌呤组成的组。
3.根据声明项1或2的化合物,其中R2是O-Ph。
4.根据声明项1至3中任一项的化合物,其中R3选自C1-C10烷基。
5.根据声明项1至4中任一项的化合物,其中R4是X-COOR5且其中X是芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基或C3-C8-环烷基,且其中所述芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C8-环烷基任选地包含一个或多个独立地选自由卤素、卤代烷基、氰基、C1-C7烷氧基组成的组的官能团、原子或自由基;且其中R5选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基和烷氧基烷基组成的组。
6.根据声明项1至5中任一项的化合物,其中X是C1-C10烷基且R5是C1-C10烷基。
7.根据声明项1至6中任一项的化合物,其中R2是O-Ph且其中R1是
8.一种化合物,其选由自:(S)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胸腺嘧啶;(R)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胸腺嘧啶;(S)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}腺嘌呤;(R)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}腺嘌呤;(S)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胞嘧啶;(R)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胞嘧啶;(S)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}鸟嘌呤;(R)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}鸟嘌呤;(S)-O2-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胞嘧啶;(R)-O2-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胞嘧啶;二戊基(((((R)-1-(2-氨基-4-氧代-3,4-二氢-7H-吡咯并[2,3-d]嘧啶-7-基)-3-氟丙烷-2-基)氧基)甲基)(苯氧基)磷酰基)-L-天门冬氨酸酯(二戊基(((((R)-1-(2-氨基-4-氧代-3,4-二氢-7H-吡咯并[2,3-d]嘧啶-7-基)-3-氟丙烷-2-基)氧基)甲基)(苯氧基)磷酰基)-L-天门冬氨酸盐,Diamyl(((((R)-1-(2-amino-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluo ropropan-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-aspartate);四戊基2,2’-((((((R)-1-(2-氨基-4-氧代-3,4-二氢-7H-吡咯并[2,3-d]嘧啶-7-基)-3-氟丙烷-2-基)氧基)甲基)磷酰基)双(氮烷二基))(2S,2’S)-丁二酸氢酯(四戊基2,2’-((((((R)-1-(2-氨基-4-氧代-3,4-二氢-7H-吡咯并[2,3-d]嘧啶-7-基)-3-氟丙烷-2-基)氧基)甲基)磷酰基)双(氮烷二基))(2S,2’S)-丁二酸氢盐,Tetraamyl2,2'-((((((R)-1-(2-amino-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoropropan-2-yl)oxy)methyl)phosphoryl)bis(azanediyl))(2S,2'S)-disuccinat e)组成的组。
9.根据声明项1至8中任一项的化合物,用于作为药物的用途。
10.根据声明项1至8中任一项的化合物,用于作为预防或治疗动物、哺乳动物或人类中的病毒感染的药物的用途。
11.根据声明项10的化合物,其中病毒感染是乙型肝炎病毒(HBV)感染、人类免疫缺陷病毒(HIV)感染、水痘带状疱疹病毒(VZV)感染、巨细胞病毒(CMV)感染、牛痘病毒(VV)感染、单纯性疱疹病毒(HSV)感染、BK病毒感染、埃博斯坦-巴病毒(EBV)感染、乳头瘤病毒感染、猴痘病毒感染、牛痘病毒感染、丙型肝炎病毒(HCV)感染、呼吸道合胞体病毒(RSV)感染、登革病毒感染、流感病毒感染、腺病毒感染、副流感病毒感染和/或鼻病毒感染。
12.根据声明项1至8中任一项的化合物,用于作为预防或治疗动物、哺乳动物或人类中的诸如癌症的增殖性疾病的药物的用途。
13.一种药物组合物,包含治疗有效量的根据声明项1至8中任一项的化合物和一种或多种药学上可接受的赋形剂。
14.根据声明项13所述的药物组合物,还包含一种或多种选自抗病毒药物和/或抗增殖药物的生物活性药物。
15.一种预防或治疗动物、哺乳动物或人类中的病毒感染的方法,其包括施用治疗有效量的根据声明项1至8中任一项的化合物,任选地结合一种或多种药学上可接受的赋形剂。
16.一种预防或治疗动物、哺乳动物或人类中的增殖性疾病的方法,其包括施用治疗有效量的根据声明项1至8中任一项的化合物,任选地结合一种或多种药学上可接受的赋形剂。
现在将进一步描述本发明。在下面的段落中,更详细地定义了本发明的不同方面。如此定义的各个方面可以与任何其它方面或多个方面组合,除非明确地规定相反的情况。特别地,可将被指示为优选的或有利的任何特征与被指示为优选的或有利的任何其它特征或多个特征组合。
具体实施方式
方案1示意性地示出了用于合成无环氟化膦酸酯4a/b的方法,其是用于制备带有3-氟-2-(膦酰基甲氧基)丙基侧链的ANP的重要结构单元(building blocks)。根据修改的文献报告制备它们(Baszczynski,O.;Jansa,P.;Dracinsky,M.;Klepetarova,B.;Holy,A.;Votruba,I.;Clerck,E,D.;Balzarini,J.;Janeba,Z.Bioorg.Med.Chem.2011,19,2114-2124),从可商购的对映体O-三苯甲基化缩水甘油1a/b开始,并使用甲苯磺酰氧基甲基膦酸二乙酯代替甲苯磺酰氧基甲基膦酸二异丙酯1。
试剂和条件:(a)KHF2、PhCl、催化剂(cat.)Bu4NH2F3,135℃,15h;(b)甲苯磺酰氧基甲基膦酸二乙酯、NaH、THF,0℃到室温,5h;(c)80%AcOH,90℃,1h。
方案1:(S)/(R)-氟化膦酸酯4a/b的合成。
方案2示出了用胸苷作为核碱基合成3-氟-2-(膦酰基甲氧基)丙基ANP的方法。4a/b与N3-Bom-胸腺嘧啶的缩合以高产率提供化合物6a/b。通过使用10%的钯碳的催化氢化除去N3-Bom基团提供化合物7a/b,随后是用TMSBr在干燥乙腈中水解二酯基团过夜以形成相应的膦酸酯酸8a/b。
试剂和条件:(a)Ph3P、DIAD、THF,室温,12h;(b)Pd/C、H2、EtOH,室温,24h;(c)TMSBr、2,6-二甲基吡啶、CH3CN,室温,12h。
方案2:(S)/(R)-无环氟化胸腺嘧啶膦酸酯酸8a/8b的合成
方案3示出了用腺嘌呤作为核碱基合成3-氟-2-(膦酰基甲氧基)丙基ANP的方法。在6-氯嘌呤存在下的光延反应(Mitsunobu reaction)顺利进行,分别以60%和65%的产率得到化合物10a/b。然后,通过用NH3的EtOH溶液在加压下处理将氯嘌呤部分转化成腺嘌呤,最后用TMSBr断裂膦酸酯,分别以65%和70%的产率得到的化合物12a/b。
试剂和条件:(a)Ph3P、DIAD、THF,室温,12h;(b)NH3/EtOH,50℃,24h;(c)TMSBr、2,6-二甲基吡啶、CH3CN,室温,12h。
方案3:(S)/(R)-无环氟化腺嘌呤膦酸酯酸12a/12b的合成。
方案4示出了用胞嘧啶作为核碱基合成3-氟-2-(膦酰基甲氧基)丙基ANP的方法。用N4-异丁酰基胞嘧啶获得中等产率以及出乎意料的形成O-2-烷基化产物15a/b(比例1:1,O-2:N-1烷基化)。在NH3/MeOH中除去N4-异丁酰基保护基并断裂膦酸酯后,获得化合物17a/b和19a/b。
试剂和条件:(a)Ph3P、DIAD、THF,室温,12h;(b)NH3/MeOH,45℃,15h;(c)TMSBr、2,6-二甲基吡啶、CH3CN,室温,12h。
方案4:(S)/(R)-无环氟化胞嘧啶和O2-胞嘧啶膦酸酯酸17a/b和19a/b的合成。
方案5示出了用鸟苷作为核碱基合成3-氟-2-(膦酰基甲氧基)丙基ANP的方法。6-O-苄基鸟嘌呤20与化合物4a/b之间的反应得到化合物21a/b和相应的三苯基膦加合物(未示出)的混合物。然后,将该粗混合物残余物在THF/H2O中回流几小时以除去不期望的三苯基膦加合物。使用10%的钯碳依次除去6-O-苄基保护基并用TMSBr处理,得到期望产物。
试剂和条件:(a)Ph3P、DIAD、THF,室温,12h;(b)Pd/C、H2、EtOAc,10h.;(c)TMSBr、2,6-二甲基吡啶、CH3CN,室温,12h。
方案5:(S)/(R)-无环氟化鸟嘌呤膦酸酯酸23a/b的合成。
方案6和7示出将游离膦酸转化成相应的芳基氧基氨基膦酸酯的方法。在三乙胺存在下,2,2’-二硫代二吡啶和三苯基膦在吡啶中过夜成功地获得氨基膦酸酯24a/b-27a/b。然而,对于鸟嘌呤氨基膦酸酯29a/b的合成,只形成了意想不到的三苯基膦加合物28a/b(方案7)。在腺嘌呤和胞嘧啶的情况下,仅形成少量的三苯基膦加合物。可以通过在室温下用1MHCl处理而成功地断裂这些三苯膦加合物。
试剂和条件:(a)L-天冬氨酸戊二酯HCl盐、PhOH,2,2’-二硫代二吡啶、PPh3、Et3N、吡啶,60℃,12h。
方案6:(S)/(R)-无环氟化核苷氨基膦酸酯24a/b-27a/b的合成。
试剂和条件:(a)L-天冬氨酸戊二酯HCl盐、PhOH、2,2’-二硫代二吡啶、PPh3、Et3N、吡啶,60℃,12h;(b)1M HCl,0℃至室温,1h。
方案7:(S)/(R)-无环氟化鸟嘌呤氨基膦酸酯29a/b的合成。
方案8示出了使用2-氨基-6-(4-甲氧基-苯硫酚)嘌呤作为核碱基合成3-氟-2-(膦酰基甲氧基)丙基ANP的方法。在光延反应条件下(Ph3P、DIAD),2-氨基-6-氯嘌呤30与前体4a/b缩合,得到化合物31a/b,伴随形成相应的三苯基膦加合物。通过回流粗反应混合物24小时,成功分解这些加合物。用三乙胺存在下,在DMF中加热化合物31a/b与4-甲氧基苯硫酚,得到32a/b,产率分别为87%和67%。路易斯酸介导的膦酸酯脱保护得到化合物33a/b。
试剂和条件:(a)(i)Ph3P、DIAD、THF,室温,24h;(ii)THF/H2O,回流,24h;(b)Et3N、DMF,100℃,4h;(c)TMSBr、2,6-二甲基吡啶、CH3CN,室温,12h。
方案8:(R)/(S)-氟化无环膦酸酯33a/b的合成。
方案9示出了具有7-脱氮鸟嘌呤和7-脱氮-7-氟-鸟嘌呤作为核碱基合成3-氟-2-(膦酰基甲氧基)丙基ANP的方法。从可商购的30开始4-氯-5-氟-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶35的制备。按照文献方案选择选择性氟试剂(Selectfluor)作为氟化试剂(参见la,F.;Xu,K.;Chittepu,P.氟化吡咯并[2,3-d]嘧啶核苷:7-氟-7-脱氮嘌呤2’-脱氧呋喃核糖苷和2’-脱氧-2’-氟阿糖呋喃衍生物。Synthesis 2006,12,2005-2012)。使用标准光延条件(Ph3P、DIAD)制备膦酸二乙酯36a/b和37a/b。分别通过DABCO/K2CO3和NH3/MeOH实现用羟基顺序置换氯和新戊酰基的脱保护,得到化合物38a/b和39a/b。膦酸酯基团的水解产生化合物40a/b和41a/b。
试剂和条件:(a)PivCl、吡啶,室温,3h;(b)选择性氟试剂、MeCN,50℃,30分钟。(c)Ph3P、DIAD、THF,室温,24h;(d)(i)DABCO、K2CO3、二氧六环/H2O,90℃,3h;(ii)NH3/MeOH,室温,12h;(e)TMSBr、2,6-二甲基吡啶、CH3CN,室温,12h。
方案9:(R)/(S)-氟化无环膦酸酯40a/b和41a/b的合成。
方案10示出了用7-脱氮-7-氰基-鸟嘌呤作为核碱基合成3-氟-2-(膦酰基甲氧基)丙基ANP的方法。通过用甲酸甲酯甲酰化氯乙腈42开始杂环结构单元46的合成(Llona-Minguez,S.;Mackay,S.P.核苷Q前体(PreQ0)的碳环类似物的立体选择性合成.BeilsteinJ.Org.Chem.2014,10,1333-1338)。所得不稳定的氯醛43立即用于下一步骤而无需进一步纯化,得到环缩合化合物44。然后,将环外胺保护为新戊酰基,且使用POCl3在相转移催化剂的存在下完成随后的氯化步骤,以提供期望的氯中间体46。通过用Ph3P和DIAD处理,成功地进行了使用46烷基化4a/b,得到化合物47a/b。由于对于48a使用DABCO/K2CO3将4-氯转化为4-氧代只获得低产率,因此在47b上应用通过使用DABCO/NaOAc处理的替代方法(Brückl,T.;Klepper,F.;Gutsmiedl,K.;Carell,T.A short and efficient synthesis of thetRNA nucleosides PreQ0and archaeosine.Org.Biomol.Chem.2007,5,3821-3825)。因此,以良好产率分离期望的产物48b(60%通过两个步骤)。最后,断裂膦酸酯,得到化合物49a/b。
试剂和条件:(a)甲酸甲酯、NaH、THF,0℃,5h;(b)2,6-二氨基-6-羟基嘧啶、NaOAc、H2O,100℃,24h;(c)PivCl、吡啶,85℃,2h;(d)POCl3、DMA、BnEt3NCl、MeCN,90℃,1h.(e)Ph3P、DIAD、THF,室温,24h;(f)(i)DABCO、K2CO3、二氧六环/H2O,90℃,3h或DABCO、NaOAc、DMF,室温,48h;(ii)NH3/MeOH,室温,12h;(g)TMSBr、2,6-二甲基吡啶、CH3CN,室温,12h。
方案10:(R)/(S)-氟化无环膦酸酯49a/b的合成。
方案11示出了从相应的游离膦酸40a合成芳基氧基氨基膦酸酯前药50和双氨基膦酸酯前药51的方法。使用2,2’-二硫代二吡啶和三苯基膦作为活化剂并使用苯酚和适当的氨基酸酯的混合物,从母体膦酸核苷类40a制备化合物51。以类似的方式,使用期望的氨基酸酯制备双氨基膦酸酯前药51。
试剂和条件:(a)对于50,L-天冬氨酸戊二酯HCl盐、PhOH、2,2’-二硫代二吡啶、PPh3、Et3N、吡啶,60℃,12h;对于51,L-天冬氨酸戊二酯HCl盐、2,2’-二硫代二吡啶、PPh3、Et3N、吡啶,60℃,12h。
方案11:(R)-氟化无环氨基膦酸酯50和51的合成
根据一个实施方案中,本发明包括通式I的化合物:
其中
-B是任何天然或修饰的核碱基
-R1具有通式II
其中
-R3选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8-环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基和烷氧基烷基组成的组;
-R4选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基、烷氧基烷基、X-COOR5、X-O(C=O)-R5组成的组;
其中X是芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基或C3-C8-环烷基,并且其中所述芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C8-环烷基任选地包含一个或多个独立地选自由卤素、卤代烷基、氰基、C1-C7烷氧基组成的组的官能团、原子或自由基;且
其中R5选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基和烷氧基烷基组成的组;
-R2是O-Ar,其中Ar是稠合二环芳基部分或单环芳基部分,其中任何一个芳基部分是碳环或杂环并且任选地被卤素、C1-C6烷基、C1-C6烷氧基取代;
或者R2具有通式II
其中R1和R2可以相同或不同;
和/或其药学上可接受的加成盐和/或其立体异构体和/或其溶剂化物。
所述碱(B)选自嘧啶和嘌呤碱基的组。这样的碱基包括天然碱基如腺嘌呤、胸腺嘧啶、胞嘧啶、尿嘧啶,鸟嘌呤和修饰的碱基或所述天然碱基的修饰。在本发明的某些实施方案中,所述碱基是鸟嘌呤、胞嘧啶、腺嘌呤、胸腺嘧啶、胞嘧啶或尿嘧啶。在本发明的更具体的实施方案中,所述碱基是腺嘌呤或鸟嘌呤。在本发明的另一个具体的实施方案中,所述碱基是胞嘧啶。在本发明的另一个具体的实施方案中,所述碱基是胸腺嘧啶。在本发明的另一个具体的实施方案中,所述碱基是尿嘧啶.在本发明的某些实施方案中,所述碱基通过它的氮原子与化合物的其余部分连接,例如在实施例31、32、33、34、35、36、39、40、67和68中。在本发明的其它实施方案中,所述碱基通过氧原子与化合物的其余部分连接,例如在实施例37和38中。在其更具体的实施方案中,所述碱基(通过其氧原子与式I的其余部分连接)选自由以下项组成的列表:
其中R选自由H、卤素和甲基组成的组。在其更具体的实施方案中,所述碱基是
因此所述实施方案包括式Ib的化合物:
其中R1和R2可具有如本文所述的任何值。
在另一个实施方案中,本发明涉及根据本发明的化合物,包括式I、Ib或其任何亚组的化合物,其中Ar是稠合二环芳基部分或单环芳基部分,其中任何一个芳基部分是碳环或杂环并且任选地被卤素、C1-C6烷基、C1-C6烷氧基取代。在更具体的实施方案中,所述Ar是苯基。在本发明的具体的实施方案中,式I、Ib或其任何亚组的化合物可具有本文所述的R1的任何值,其中Ar为苯基。
在更具体的实施方案中,所述R3是C1-C10烷基。在另一具体的实施方案中,所述R3是C3-C10烷基。在另一具体的实施方案中,所述R3是C1-C5烷基。在另一具体的实施方案中,所述R3是C3-C5烷基。在另一具体的实施方案中,所述R3是C5烷基。
在另一具体的实施方案中,所述R4选自由C1-C10烷基或X-COOR5组成的组,其中R5可以具有如本文所述的任何值。在更具体的实施方案中,所述R5选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基和烷氧基烷基组成的组。在更具体的实施方案中,R5是C1-C7烷基或C3-C8环烷基;在更具体的实施方案中,R5是C1-C5烷基,并且在另一更具体的实施方案中,R5是C3-C7烷基,在甚至更具体的实施方案中,R5是C3-C5烷基。在更具体的实施方案中,R5是C5烷基。在另一具体的实施方案中,R5是芳基-(C1-C2)烷基;在另一更具体的实施方案中,R5是苄基或苯基-甲基。
在另一具体的实施方案中,X选自由芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基或C3-C8-环烷基组成的组,且其中所述芳基、杂芳基、C1-C10烷基和C3-C8-环烷基任选地包含一个或多个独立地选自由卤素、羰基、硫代羰基、羟基、硫醇、醚、硫醚、缩醛、硫缩醛、氨基、亚氨基、肟基、烷基肟基、氨基酸、氰基、酰基氨基、硫代酰基氨基、氨基甲酰基、硫代氨基甲酰基、脲基、硫脲基、羧酸酯或卤化物或酸酐或酰胺、硫代羧酸或酯或硫酯或卤化物或酸酐或酰胺、硝基、硫代C1-7烷基、硫代C3-C10环烷基、羟基氨基、巯基氨基,烷基-氨基、环烷基氨基、烯基氨基、环烯基氨基、炔基氨基、芳基氨基、芳基烷基氨基、羟基烷基氨基、巯基烷基氨基、杂环取代的烷基氨基、杂环氨基、杂环取代的芳基氨基、肼、烷基肼基、苯基肼基、磺酰基、亚磺酰基和磺酰胺组成的组的官能团、原子或自由基。在更具体的实施方案中,X选自由芳基、杂芳基、C1-C10烷基或C3-C8-环烷基组成的组,更具体地所述X是C1-C6烷基,甚至更具体地所述X是C1-C3烷基或C1-C2烷基或-CH2-。
根据本发明的特别的新化合物包括其制备在所附实施例中描述的各个化合物及其药学上可接受的盐和溶剂合物。
本发明还涉及用于作为药物的用途的式I、Ib或其任何亚组或其立体异构形式的化合物。
本发明还涉及用作用于预防或治疗动物,优选为哺乳动物中的病毒疾病和肿瘤疾病的药物的具有式I、Ib或其任何亚组或其立体异构形式的化合物。在一个实施方案中,所述疾病是病毒疾病,包括由病毒感染引起的疾病,例如由HBV、HIV、HCV、RSV、登革病毒、流感病毒、VZV、CMV、腺病毒、副流感病毒、鼻病毒、BK病毒和/或HSV的感染;在另一个实施方案中,所述疾病是肿瘤疾病,其可以是急性的或慢性的,包括增殖性疾病,尤其是癌症。在一个实施方案中,所述哺乳动物是人类。在具体的实施方案中,用于作为药物的用途,特别是用于预防或治疗病毒疾病的所述化合物是式I和Ib的化合物,包括其任何亚组。在其更具体的实施方案中,所述式I的化合物具有作为碱基B嘧啶碱基,更具体地,具有由结构式(IV)表示的嘧啶碱基:
或
嘌呤碱基,更具体地为由结构式(V)表示的嘌呤碱基:
其中:
R7和R9独立地选自由H、–OH、-SH、-NH2和-NH-Me组成的组;
R8和R10独立地选自由H、甲基、乙基、异丙基、羟基、氨基、乙基氨基、三氟甲基、氰基和卤素组成的组;且
X1和Y1独立地选自CR11和N,其中R11选自由H、卤素和氰基组成的组。
本发明还涉及式I、Ib或其任何亚组的化合物或其立体异构形式在制备用于预防或治疗动物中的病毒疾病和/或肿瘤疾病的药物中的用途。在一个实施方案中,所述动物是哺乳动物,优选地所述哺乳动物是人类。
在进一步具体的实施方案中,所述病毒疾病是由病毒感染引起的疾病,例如由HBV、HIV、HCV、RSV、登革病毒、流感病毒、CMV、VZV、腺病毒、副流感病毒、鼻病毒、BK病毒和/或HSV的感染。在甚至更具体的实施方案中,所述病毒疾病是由HBV和/或HIV病毒感染引起的疾病。在具体的实施方案中,所述病毒疾病是由HBV病毒感染引起的疾病。在另一个具体的实施方案中,所述病毒疾病是由HIV1病毒感染引起的疾病。
本发明还涉及一种药物组合物,其包含治疗有效量的具有式I、Ib或其任何亚组的化合物或其立体异构形式和一种或多种药学上可接受的赋形剂。所述组合物还可包含一种或多种选自抗病毒药物和抗肿瘤药物的生物活性药物。
本发明还涉及一种预防或治疗动物的病毒疾病的方法,其包括施用治疗有效量的具有式I、Ib或其任何亚组或其立体异构形式的化合物,任选地结合一种或多种药学上可接受的赋形剂。
本发明还涉及一种预防或治疗动物的肿瘤疾病的方法,其包括施用治疗有效量的具有式I、Ib或其任何亚组或其立体异构形式的化合物,任选地结合一种或多种药学上可接受的赋形剂。
为了用于药物,式I或Ib化合物的盐将是药学上可接受的盐。然而,其它盐可用于制备本发明的化合物或它们的药学上可接受的盐。本发明的化合物的合适的药学上可接受的盐包括酸加成盐,其可以是例如通过将本发明的化合物的溶液与药学上可接受的酸如盐酸、硫酸、甲磺酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、柠檬酸、酒石酸或磷酸的溶液混合而形成。此外,在本发明的化合物携带酸性部分如羧基的情况下,其合适的药学上可接受的盐可以包括碱金属盐,例如钠或钾盐;碱土金属盐,例如钙盐或镁盐;以及与合适的有机配体形成的盐,例如季铵盐。
本发明在其范围内包括上述式I和Ib的化合物的溶剂化物。这种溶剂化物可以用常见的有机溶剂形成,例如,烃溶剂如苯或甲苯;氯化溶剂如氯仿或二氯甲烷;醇溶剂如甲醇、乙醇或异丙醇;醚溶剂如乙醚或四氢呋喃;或酯溶剂如乙酸乙酯。或者,可以与水形成式I和Ib的化合物的溶剂合物,在这种情况下它们将是水合物。
根据本发明的化合物有益于治疗和/或预防各种动物、哺乳动物或人类小病或疾病。这些包括病毒疾病,例如由病毒感染引起的疾病,例如由HBV、HIV、HCV、RSV、登革病毒、流感病毒、单纯性疱疹病毒1和2(HSV-1和HSV-2)、水痘带状疱疹病毒(VZV)、埃博斯坦-巴病毒(EBV或HHV-4)、人巨细胞病毒(HCMV或HHV-5)、人疱疹病毒6A和6B(HHV-6A和HHV-6B)、人疱疹病毒7(HHV-7)和卡波济肉瘤相关疱疹病毒(KSHV,还称为HHV-8)、腺病毒、副流感病毒、鼻病毒和/或BK病毒的感染;和肿瘤疾病如增殖性疾病(例如,癌症)。
病毒疾病包括由各种病毒科引起的感染,包括肝脱氧核糖核酸病毒科、逆转录病毒科、疱疹病毒科、乳多瘤病毒科、乳头瘤病毒科或乳头瘤病毒、黄病毒科、小核糖核酸病毒科。肝脱氧核糖核酸病毒科内的各种属包括正肝脱氧核糖核酸病毒属和鸟类肝脱氧核糖核酸病毒属;正肝脱氧核糖核酸病毒属成员包括乙型肝炎病毒(HBV)和土拨鼠肝炎病毒。鸟类肝脱氧核糖核酸病毒属的成员包括鸭乙肝病毒。逆转录病毒科内的各种属包括α逆转录病毒、β逆转录病毒、γ逆转录病毒、δ逆转录病毒、ε逆转录病毒、慢病毒和泡沫病毒。慢病毒属的成员包括人类免疫缺陷病毒1(HIV-1)和人类免疫缺陷病毒2(HIV-2)。疱疹病毒科内的各种属包括(i)在α疱疹病毒亚科的亚科内的:水痘病毒、盾板病毒属(Scutavirus)、传喉炎病毒属、马立克病毒属、单纯性疱疹病毒属;(ii)在β-疱疹病毒亚科的亚科内的:巨细胞病毒、鼠巨细胞病毒属、长鼻动物病毒属(Proboscivirus)、玫瑰疹病毒属;和(iii)在γ疱疹病毒亚科的亚科内的:淋巴隐病毒属、玛卡病毒属、Percavirus、细长病毒属。水痘病毒属的成员包括水痘带状疱疹病毒(VZV);猿猴带状疱疹病毒;海豹疱疹病毒1型;猪疱疹病毒1型;猫疱疹病毒1型;马疱疹病毒1、3、4、8和9型;鹿疱疹病毒1和2型;猕猴疱疹病毒9型;山羊疱疹病毒1型;牛疱疹病毒1和5;非洲羚羊属疱疹病毒1;犬疱疹病毒1型。单纯性疱疹病毒属的成员包括人疱疹病毒1和2型。盾板病毒属的成员包括蛇疱疹病毒5型。传喉炎病毒属的成员包括禽疱疹病毒1型。马立克病毒属的成员包括禽疱疹病毒2型。巨细胞病毒属的成员包括人巨细胞病毒(CMV)。长鼻动物病毒属的成员包括象疱疹病毒1型。鼠巨细胞病毒属的成员包括鼠疱疹病毒1型。玫瑰疹病毒属的成员包括人类疱疹病毒6A、6B和7型。淋巴隐病毒属的成员包括人类疱疹病毒4型。玛卡病毒属的成员包括狷羚疱疹病毒1型。马疱疹病毒(Percavirus)属的成员包括马疱疹病毒2型。细长病毒属的成员包括松鼠猴疱疹病毒2型、卡波济肉瘤相关病毒。黄病毒科内的各种属包括黄病毒、瘟病毒属、肝炎病毒和庚型肝炎病毒。乳多空病毒科包括多瘤病毒属(例如JC病毒;BK病毒;梅克尔细胞多瘤病毒;Trichodysplasia spinulosa多瘤病毒;人类多瘤病毒6、7、和12型;以及人类多瘤病毒6、7、9和12;新泽西多瘤病毒;KI多瘤病毒;WU多瘤病毒;MW多瘤病毒;STL多瘤病毒)。乳头瘤病毒科或乳头瘤病毒包括人类乳头瘤病毒(HPV)。黄病毒属的成员包括登革热病毒、黄热病病毒、西尼罗河脑炎病毒和日本脑炎病毒。瘟病毒属的成员包括牛病毒性腹泻病毒(BVDV)、古典猪瘟病毒和边界病病毒2型(BDV-2)。肝炎病毒属的成员包括丙型肝炎病毒(HCV)。庚型肝炎病毒属的成员包括庚型肝炎病毒。微小核糖核酸病毒科中的各种属包括口蹄疫病毒、禽肝病毒属、心病毒属、肠道病毒、马鼻病毒属、肝病毒属、嵴病毒(Kobuvirus)、双埃可病毒(Parechovirus)、萨佩罗病毒(sapelovirus)、塞尼卡病毒属(Senecavirus),捷申病毒属(Teschovirus)和震颤病毒属(Tremovirus)。肠道病毒属的成员包括脊髓灰质炎病毒、柯萨奇A病毒、柯萨奇B病毒和鼻病毒。
可能是急性或慢性的肿瘤疾病包括动物包括哺乳动物,特别是人中的增殖性疾病,尤其是癌症。癌症的具体种类包括血液系统恶性肿瘤(包括白血病和淋巴瘤)和非血液系统恶性肿瘤(包括实体瘤癌、肉瘤、脑膜瘤、多形性成胶质细胞瘤、成神经细胞瘤、黑素瘤、胃癌和肾细胞癌)。慢性白血病可以是髓样或淋巴样的。白血病的种类包括淋巴母细胞性T细胞白血病、慢性粒细胞性白血病(CML)、慢性淋巴细胞性/淋巴样白血病(CLL)、毛细胞白血病、急性淋巴细胞白血病(ALL)、急性骨髓性白血病(AML)、骨髓增生异常综合征、慢性中性粒细胞白血病、急性淋巴母细胞性T细胞白血病、浆细胞瘤、免疫母细胞性大细胞白血病、套细胞白血病、多发性骨髓瘤、急性成巨核细胞白血病,急性巨核细胞白血病、早幼粒细胞白血病和红白血病。淋巴瘤的种类包括恶性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、淋巴母细胞性T细胞淋巴瘤、伯基特淋巴瘤、滤泡性淋巴瘤、MALT1淋巴瘤和边缘区淋巴瘤。非血液恶性肿瘤包括前列腺癌、肺癌、乳腺癌、直肠癌、结肠癌、淋巴结癌、膀胱癌、肾癌、胰腺癌、肝癌、卵巢癌、子宫癌、子宫颈癌、脑癌、皮肤癌、骨癌、胃癌和肌肉癌。
本发明还提供了一种药物组合物,其包含根据如上所述的本发明的化合物或其药学上可接受的盐或溶剂化物结合一种或多种药学上可接受的载体。
根据本发明的药物组合物可以采取适于口服、颊、肠胃外、鼻、局部、眼部或直肠给药的形式,或适于通过吸入或吹入给药的形式。
用于预防或治疗特定疾病状况或疾病所需的本发明中使用的化合物的量将根据所选择的化合物和待治疗的动物、哺乳动物或人类患者的疾病状况而变化。然而,一般而言,每日剂量可以在约10ng/kg至1000mg/kg的范围内,对于口服或颊给药通常为100ng/kg至100mg/kg,例如约0.01mg/kg至40mg/kg体重,对于肠胃外给药为约10ng/kg至50mg/kg体重,并且对于鼻给药或通过吸入或吹入给药为约0.05mg至约1000mg,例如为约0.5mg至约1000mg。
定义
如本文所用,术语“嘧啶和嘌呤碱基”包括但不限于:腺嘌呤、胸腺嘧啶、胞嘧啶、尿嘧啶、鸟嘌呤、2,6-二氨基嘌呤、5-氟胞嘧啶、5-氟尿嘧啶、7-脱氮鸟苷、7-脱氮腺嘌呤及其类似物。如本文所用,嘌呤或嘧啶碱基包括如上所述在天然存在的核苷中发现的嘌呤或嘧啶碱基。其类似物是以使得它们的结构(原子种类和它们的排列)与天然存在的碱基类似,但可以具有另外的或缺乏天然存在的碱基的某些功能性质的方式模拟这种天然存在的碱基的碱基。这种类似物包括通过用氮原子取代CH部分(例如,5-氮杂嘧啶类如5-氮杂胞嘧啶)或反之亦然(例如,7-脱氮嘌呤,例如7-脱氮腺嘌呤或7-脱氮鸟嘌呤)或二者(例如,7-脱氮,8-脱氮嘌呤类)衍生的那些。这种碱基或类似物的衍生物是指其中的环取代基被本领域已知的常规取代基如,卤素、羟基、氨基、(C1-C6)烷基等结合、去除或修饰的那些碱基。这样的嘌呤或嘧啶碱基及其类似物是本领域技术人员熟知的,例如,如WO 03/093290的第20-38页所示。
特别地,用于本发明的目的的嘌呤和嘧啶类似物B可以选自包括由结构式(IV)表示的嘧啶碱基的组:
和由结构式(V)表示的嘌呤碱基:
其中:
R7和R9独立地选自由H、-OH、-SH、-NH2和-NH-Me组成的组;
R8和R10独立地选自由H、甲基、乙基、异丙基、羟基、氨基、乙基氨基、三氟甲基、氰基和卤素组成的组;且
X1和Y1独立地选自CR11和N,其中R11选自由H、卤素和氰基组成的组。
正如嘧啶类似物的一些非限制性实例,可以被命名为具有式(IV)的取代的尿嘧啶,其中X1是CH,R7是羟基,且R8选自由甲基、乙基、异丙基、氨基、乙基氨基、三氟甲基、氰基、氟、氯、溴和碘组成的组。
如本文所用,术语“烷基”是指具有所示碳原子数的直链(正常)或支链(例如,仲或叔)烃链(或在未指出的情况下,优选具有1-20个,更优选为1-6个碳原子)。术语“C1-C6烷基”是指具有1至6个碳原子的这种烃链。其实例为甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丙基(异丁基)、2-丁基(仲丁基)2-甲基-2-丙基(叔丁基)、1-戊基(正戊基)、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正戊基、正己基。
如本文关于取代基所使用的,除非另有说明,否则术语"C2-C10烯基”是指具有一个或多个烯属不饱和度且具有2至10个碳原子的直链和支链无环烃单价自由基,如例如乙烯基、1-丙烯基、2-丙烯基(烯丙基)、1-丁烯基、2-丁烯基、2-戊烯基、3-戊烯基、3-甲基-2-丁烯基、3-己烯基、2-己烯基、2-庚烯基、1,3-丁二烯基、戊二烯基、己二烯基、庚二烯基、庚三烯基、2-辛烯基等,包括其所有可能的异构体。
如本文关于取代基所使用的,除非另有说明,否则术语"C2-C10炔基"定义了含有一个或多个三键和任选的至少一个双键并具有2至10个碳原子的直链和支链烃基,例如像乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、2-戊炔基、1-戊炔基、3-甲基-2-丁炔基、3-己炔基、2-己炔基、1-戊烯-4-炔基、3-戊烯-1-炔基、1,3-己二烯-1-炔基等。
如本文所用并且除非另有说明,否则术语“环烷基”是指具有所示碳原子数的单环饱和烃单价基团(或在未指明的情况下,优选具有3-20个,更优选3-10个碳原子,更优选3-8或3-6个碳原子)。“C3-C8环烷基”指具有3至8个碳原子的这种单环饱和烃单价基团,例如像环丙基、环丁基、环戊基、环己基、环庚基、环辛基。
术语“烷氧基”指基团烷基-O-,其中烷基如上所定义。如本文所用,“(C1-C6)烷氧基”包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、戊氧基、3-戊氧基或己氧基。
如本文所用并且除非另有说明,术语“卤素”或“卤代”是指选自氟(F)、氯(Cl)、溴(Br)和碘(I)的任何原子。
如本文所用并且除非另有说明,术语“Ar”或“芳基”是指具有1、2、3、4、5或6个环,优选为1、2或3个环的一价不饱和芳族碳环基团,其可以是融合或双环。关于可存在于基团Ar或芳基上的任选取代基,芳基基团可任选地被一个、两个、三个或更多个如本发明所述的取代基所取代。优选的芳基基团是:含有6个碳原子的芳族单环;含有7、8、9或10个碳原子的芳族双环或稠环体系;或含有10、11、12、13或14个碳原子的芳族三环环体系。芳基的非限制性实例包括苯基和萘基。Ar的优选取代基独立地选自卤素、C1-C6烷基、C1-C6烷氧基、羟基(-OH)、酰基(R’-C(=O)-、酰氧基(R’-C(=O)-O-)、硝基(-NO2)、氨基(-NH2)、-SO3H、-SH、-SR’,其中R’是烷基。优选的Ar是苯基、溴苯基和萘基。
如本文所用并且除非另有说明,术语“立体异构体”是指式I和Ib的化合物可具有的所有可能的不同异构体以及构象形式,特别是所有可能的立体化学和构象异构体形式,所有非对映异构体,对映异构体和/或基本分子结构的构象。本发明的一些化合物可以不同的互变异构形式存在,所有后者都包括在本发明的范围内。
如本文所用并且除非另有说明,术语“对映异构体”是指本发明的化合物的每个单独的光学活性形式,其光学纯度或对映异构体过量(如通过本领域方法标准测定的)为至少80%(即,至少90%的一种对映异构体和至多10%的另一种对映异构体),优选为至少90%,且更优选为至少98%。
实施例
实验部分
对于反应来说,所有试剂和溶剂都购自商业来源并按原样使用。水分敏感的反应在烘箱干燥的玻璃器皿中在氮气或氩气气氛下进行。在Bruker Avance 300、500或600MHz光谱仪上记录1H、13C和31P NMR光谱,使用四甲基硅烷作为内标或参考残余溶剂信号,以及85%的H3PO4进行31P NMR实验。通过使用2D NMR(H-COSY、HSQC和HMBC)光谱技术表征中间体和最终化合物。在四重正交加速度飞行时间质谱仪(Synapt G2HDMS,Waters,Milford,MA)上获得高分辨率质谱(HRMS)。以3μL/min输注样品,并且使用亮氨酸脑啡肽作为锁定质量以15000(fwhm)的分辨率以正(或负)电离模式获得光谱。预涂铝片(254nm)用于TLC。产物通过硅胶柱层析(0.035-0.070mm,Acros Organics)纯化。使用含50mmol的TEAB或H2O/CH3CN的H2O/CH3CN作为洗脱液梯度,在Phenomenex Gemini 110A柱(C18,10μm,21.2mm×250mm)上进行制备RP-HPLC纯化。
实施例1:(S)-1-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}-N3-(苄氧基甲基)胸腺嘧啶(6a)的合成
在室温下,将DIAD(0.32mL,1.64mmol)的无水THF(1mL)的溶液滴加到化合物4a1(200mg,0.82mmol)、化合物5(240mg,0.98mmol)和Ph3P(430mg,1.64mmol)的无水THF(5mL)的混合物中。将反应混合物搅拌12小时,然后将它减压浓缩。通过硅胶柱色谱法(梯度为DCM/MeOH,80:1,v/v;DCM/MeOH,50:1,v/v)纯化粗残余物,得到无色油形式的6a(310mg,80%)。1H NMR(300MHz,CDCl3):δ7.39-7.25(m,5H,ArH),7.14-7.12(m,1H,H-6),5.50(s,2H,OCH2N),4.73-4.33(m,4H,CH2-Ar,H-3’),4.17-3.92(m,7H,H-1’,H-2’,2x CH2CH3),3.84-3.66(m,2H,PCH2),1.93(d,J=1.2Hz,3H,CH3-5),1.34-1.28(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ163.8(C-4),151.8(C-2),140.5(C-6),138.1(Ar-C),128.3(Ar-C),127.7(Ar-C),109.7(C-5),82.3(d,1JC,F=173.4Hz,C-3’),78.6(dd,2JC,F=18.5Hz,3JC,P=9.8Hz,C-2’),72.3(OCH2N),70.8(CH2-Ar),64.6(d,1JC,P=167.4Hz,CH2P),62.6,62.5(2×d,2JC,P=3.8Hz,CH2CH3),62.5(d,2JC,P=3.7Hz,CH2CH3),49.3(d,3JC,F=8.6Hz,C-1’),16.6,16.5(CH2CH3),13.0(CH3-5);31P NMR(121MHz,CDCl3):δ20.8;HRMS对于C21H30FN2O7P[M+H]+计算值:473.1847,发现值:473.1848。
实施例2:(R)-1-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}-N3-(苄氧基甲基)胸腺嘧啶(6b)的合成
根据用于制备6a的程序,从化合物4b1(300mg,1.23mmol)、化合物5(360mg,1.47mmol)、Ph3P(640mg,2.46mmol)和DIAD(0.48mL,2.46mmol)的无水THF(8mL)溶液开始得到无色油状物形式的化合物6b(460mg,70%)。通过硅胶柱色谱法纯化粗残余物(梯度为DCM/MeOH,80:1,v/v;DCM/MeOH,50:1,v/v)。1H NMR(300MHz,CDCl3):δ7.39-7.25(m,5H,ArH),7.13(t,J=1.3Hz,1H,H-6),5.50(s,2H,OCH2N),4.73-4.33(m,4H,CH2-Ar,H-3’),4.17-3.91(m,7H,H-1’,H-2’,2x CH2CH3),3.84-3.66(m,2H,PCH2),1.93(d,J=1.1Hz,3H,CH3-5),1.34-1.28(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ163.8(C-4),151.8(C-2),140.5(C-6),138.0(Ar-C),128.3(Ar-C),127.7(Ar-C),109.7(C-5),82.3(d,1JC,F=173.5Hz,C-3’),78.6(dd,2JC,F=18.5Hz,3JC,P=9.7Hz,C-2’),72.3(OCH2N),70.7(CH2-Ar),64.6(d,1JC,P=167.3Hz,CH2P),62.6,62.5(2×d,2JC,P=3.5Hz,CH2CH3),49.3(d,3JC,F=8.8Hz,C-1’),16.6,16.5(CH2CH3),13.0(CH3-5);31P NMR(121MHz,CDCl3):δ20.8;HRMS对于C21H30FN2O7P[M+H]+计算值:473.1847,发现值:473.1841。
实施例3:(S)-1-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}胸腺嘧啶(7a)
用氮气然后用氢气吹扫化合物6a(240mg,0.51mmol)和木炭上的Pd/C(10%w/w,120mg)的EtOH(10mL)中的悬浮液,然后使其在氢气气氛下搅拌。在24小时后,通过硅藻土垫过滤混合物,并减压蒸发滤液,得到粗产物。然后,将残余物重新溶于MeOH(10mL)和Et3N(1mL)中,并将溶液在室温下搅拌3小时。将反应混合物减压浓缩并通过硅胶柱色谱法(梯度为DCM/MeOH,30:1,v/v;DCM/MeOH,20:1,v/v)纯化所得粗残余物,得到无色油状物形式的7a(160mg,90%)。1H NMR(300MHz,CDCl3):δ9.63(s,1H,NHCO),7.16(t,J=1.3Hz,1H,H-6),4.72-4.33(m,2H,H-3’),4.17-3.90(m,7H,H-1’,H-2’,2x CH2CH3),3.83-3.63(m,2H,PCH2),1.89(d,J=1.2Hz,3H,CH3-5),1.33-1.28(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ164.5(C-4),151.3(C-2),141.9(C-6),110.4(C-5),82.3(d,1JC,F=173.4Hz,C-3’),78.7(dd,2JC,F=18.5Hz,3JC,P=9.5Hz,C-2’),64.6(d,1JC,P=167.3Hz,CH2P),62.7,62.6(CH2CH3),48.6(d,3JC,F=8.8Hz,C-1’),16.6,16.5(CH2CH3),12.3(CH3-5);31P NMR(121MHz,CDCl3):δ21.0;HRMS对于C9H14FN2O6P[M+H]+计算值:353.1272,发现值:353.1262。
实施例4:(R)-1-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}胸腺嘧啶(7b)的合成。
根据用于7a的制备程序,从化合物6b(400mg,0.85mmol)、木炭上的Pd/C(10%w/w,200mg)的EtOH(20mL)和Et3N(1mL)的MeOH(20mL)溶液开始,得到无色油状物形式的化合物7b(270mg,90%)。通过硅胶柱色谱法纯化粗残余物(梯度为DCM/MeOH,30:1,v/v;DCM/MeOH,20:1,v/v)。1H NMR(300MHz,CDCl3):δ9.67(s,1H,NHCO),7.18(d,J=1.4Hz,1H,H-6),4.75-4.35(m,2H,H-3’),4.19-3.93(m,7H,H-1’,H-2’,2x CH2CH3),3.86-3.66(m,2H,PCH2),1.92(d,J=1.2Hz,3H,CH3-5),1.35-1.31(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ164.5(C-4),151.3(C-2),141.9(C-6),110.4(C-5),82.3(d,1JC,F=173.4Hz,C-3’),78.7(dd,2JC,F=18.5Hz,3JC,P=9.5Hz,C-2’),64.6(d,1JC,P=167.4Hz,CH2P),62.7,62.6(2×d,2JC,P=5.5Hz,CH2CH3),48.5(d,3JC,F=8.8Hz,C-1’),16.6,16.5(CH2CH3),12.3(CH3-5);31P NMR(121MHz,CDCl3):δ21.0;HRMS对于C9H14FN2O6P[M+H]+计算值:353.1272,发现值:353.1278。
实施例5:(S)-1-[3-氟-2-(膦酰基甲氧基)丙基]胸腺嘧啶三乙铵盐(8a)的合成
在0℃下,将溴代三甲基硅烷(0.15mL,1.14mmol)滴加到二乙基膦酸酯7a(100mg,0.28mmol)和2,6-二甲基吡啶(0.26mL,2.27mmol)的无水乙腈(5mL)的溶液中。在完成添加后,将混合物缓慢升温至室温,并在黑暗中放置12小时。反应用0.1M TEAB淬灭,然后减压浓缩。通过硅胶柱色谱法(梯度为DCM/MeOH/Et3N,10:5:1,v/v/v;7.5:5:1,v/v/v)纯化粗残余物。将收集的洗脱液反复冷冻干燥至恒重,得到白色泡沫形式的期望的膦酸三乙铵盐8a(59mg,70%)。1H NMR(300MHz,D2O):δ7.52(s,1H,H-6),4.77-4.48(m,2H,H-3’,与H2O重叠),3.93-3.79(m,3H,H-1’,H-2’),3.58-3.46(m,2H,PCH2),1.80(s,3H,CH3-5);13C NMR(75MHz,D2O):δ166.8(C-4),152.2(C-2),143.5(C-6),110.3(C-5),82.1(d,1JC,F=167.3Hz,C-3’),77.1(dd,2JC,F=18.1Hz,3JC,P=10.4Hz,C-2’),67.7(d,1JC,P=150.9Hz,CH2P),47.3(d,3JC,F=6.9Hz,C-1’),11.0(CH3-5);31P NMR(121MHz,D2O):δ12.9;HRMS对于C9H14FN2O6P[M-H]-计算值:295.0501,发现值:295.0499。
光谱数据符合文献数据(Pomeisl,K.;Pohl,R.;Holy,A.;Votruba,I.Collect.Czech.Chem.Commun.2005,70,1465–1481)。
实施例6:(R)-1-[3-氟-2-(膦酰基甲氧基)丙基]胸腺嘧啶三乙铵盐(8b)的合成
根据用于8a的制备程序,从化合物7b(300mg,0.85mmol)、溴三甲基硅烷(0.45mL,3.41mmol)和2,6-二甲基吡啶(0.79mL,6.81mmol)的无水乙腈(10mL)开始,得到白色泡沫形式的化合物8b(176mg,70%)。通过硅胶柱色谱(梯度为DCM/MeOH/Et3N,10:5:1,v/v/v;7.5:5:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ7.55-7.54(m,1H,H-6),4.80-4.43(m,2H,H-3’,与H2O重叠),4.09-3.88(m,3H,H-1’,H-2’),3.79-3.60(m,2H,PCH2),1.87(d,J=1.1Hz,3H,CH3);13C NMR(75MHz,D2O):δ166.7(C-4),152.0(C-2),143.5(C-6),110.2(C-5),82.0(d,1JC,F=168.0Hz,C-3’),77.5(dd,2JC,F=18.2Hz,3JC,P=11.5Hz,C-2’),66.4(d,1JC,P=156.3Hz,CH2P),47.6(d,3JC,F=7.6Hz,C-1’),11.0(CH3);31P NMR(121MHz,D2O):δ14.7;HRMS对于C9H14FN2O6P[M-H]-计算值:295.0501,发现值:295.0498。
光谱数据符合文献数据(Pomeisl,K.;Pohl,R.;Holy,A.;Votruba,I.Collect.Czech.Chem.Commun.2005,70,1465–1481)。
实施例7:(S)-6-氯-9-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}嘌呤(10a)的合成
根据用于制备6a的程序,从化合物4a(200mg,0.82mmol)、化合物9(150mg,0.98mmol)、Ph3P(430mg,1.64mmol)和DIAD(0.32mL,1.64mmol)的无水THF(6mL)溶液开始得到无色油状物形式的化合物10a(190mg,60%)。通过硅胶柱色谱法纯化粗残余物(梯度为DCM/MeOH,50:1,v/v;DCM/MeOH,30:1,v/v)。1H NMR(300MHz,CDCl3):δ8.75(s,1H,H-2),8.32(s,1H,H-8),4.74-4.40(m,4H,H-3’,H-1’),4.22-3.94(m,6H,H-2’,2x CH2CH3,PCH2a),3.78(dd,J=14.0,8.5Hz,1H,PCH2b),1.34-1.24(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ152.0(C-2,C-4),151.1(C-6),146.5(C-8),131.4(C-5),81.6(d,1JC,F=174.3Hz,C-3’),78.0(dd,2JC,F=19.6Hz,3JC,P=9.0Hz,C-2’),64.4(d,1JC,P=167.1Hz,CH2P),62.7,62.5(2×d,2JC,P=6.7Hz,CH2CH3),44.2(d,3JC,F=8.0Hz,C-1’),16.5,16.4(2×d,3JC,P=3.8Hz,CH2CH3);31P NMR(121MHz,CDCl3):δ20.3;HRMS对于C13H19ClFN4O4P[M+H]+计算值:381.0889,发现值:381.0884。
实施例8:(R)-6-氯-9-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}嘌呤(10b)的合成
根据用于制备6a的程序,从化合物4b(300mg,1.23mmol)、化合物9(230mg,1.50mmol)、Ph3P(640mg,2.46mmol)和DIAD(0.48mL,2.46mmol)的无水THF(10mL)溶液开始得到无色油状物形式的化合物10b(300mg,65%)。通过硅胶柱色谱法纯化粗残余物(梯度为DCM/MeOH,50:1,v/v;DCM/MeOH,30:1,v/v)。1H NMR(300MHz,CDCl3):δ8.71(s,1H,H-2),8.26(s,1H,H-8),4.69-4.35(m,4H,H-3’,H-1’),4.17-3.89(m,6H,H-2’,2x CH2CH3,PCH2a),3.73(dd,J=14.0,8.4Hz,1H,PCH2b),1.30-1.19(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ152.0(C-2,C-4),151.1(C-6),146.5(C-8),131.5(C-5),81.6(d,1JC,F=174.3Hz,C-3’),78.1(dd,2JC,F=19.6Hz,3JC,P=8.9Hz,C-2’),64.5(d,1JC,P=167.0Hz,CH2P),62.7,62.6(2×d,2JC,P=6.6Hz,CH2CH3),44.2(d,3JC,F=8.2Hz,C-1’),16.5,16.4(2×d,3JC,P=4.5Hz,CH2CH3);31P NMR(121MHz,CDCl3):δ20.6;HRMS对于C13H19ClFN4O4P[M+H]+计算值:381.0889,发现值:381.0883。
实施例9:(S)-9-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}腺嘌呤(11a)的合成
将10a(150mg,0.40mmol)的10%的乙醇氨(20mL)的溶液在50℃下搅拌24小时。在除去所有挥发物后,通过硅胶柱色谱(梯度为DCM/MeOH,20:1,v/v;15:1,v/v)纯化残余物,得到无色油状物形式的11a(110mg,80%)。1H NMR(300MHz,CDCl3):δ8.30(s,1H,H-2),8.00(s,1H,H-8),6.75(s,2H,NH2),4.71-4.27(m,4H,H-3’,H-1’),4.14-3.90(m,6H,H-2’,2xCH2CH3,PCH2a),3.76(dd,J=13.9,8.9Hz,1H,PCH2b),1.30-1.22(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ155.0(C-6),151.6(C-2),159.9(C-4),142.1(C-8),119.2(C-5),82.0(d,1JC,F=173.8Hz,C-3’),78.5(dd,2JC,F=19.3Hz,3JC,P=10.0Hz,C-2’),64.6(d,1JC,P=167.3Hz,CH2P),62.7,62.6(CH2CH3),43.6(d,3JC,F=8.3Hz,C-1’),16.5,16.4(CH2CH3);31PNMR(121MHz,CDCl3):δ20.5;HRMS对于C13H21FN5O4P[M+H]+计算值:362.1389,发现值:362.1386。
实施例10:(R)-9-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}腺嘌呤(11b)的合成
根据用于11a的制备程序,从化合物10b(300mg,0.80mmol)的10%的乙醇氨(30mL)开始,得到无色油状物形式的化合物11b(260mg,90%)。通过硅胶柱色谱法(梯度为DCM/MeOH,20:1,v/v;15:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ8.35(s,1H,H-2),7.95(s,1H,H-8),5.86(s,2H,NH2),4.74-4.28(m,4H,H-3’,H-1’),4.18-3.91(m,6H,H-2’,2xCH2CH3,PCH2a),3.78(dd,J=13.9,8.9Hz,1H,PCH2b),1.34-1.25(m,6H,2x CH2CH3);13C NMR(150MHz,CDCl3):δ155.4(C-6),153.1(C-2),150.2(C-4),141.6(C-8),119.4(C-5),82.0(d,1JC,F=173.8Hz,C-3’),78.5(dd,2JC,F=19.4Hz,3JC,P=9.4Hz,C-2’),64.6(d,1JC,P=167.3Hz,CH2P),62.5,62.4(d,2JC,P=6.5Hz,CH2CH3),43.6(d,3JC,F=8.1Hz,C-1’),16.4,16.3(CH2CH3);31P NMR(121MHz,CDCl3):δ20.6;HRMS对于C13H21FN5O4P[M+H]+计算值:362.1389,发现值:362.1390。
实施例11:(S)-9-[3-氟-2-(膦酰基甲氧基)丙基]腺嘌呤(12a)的合成
根据用于8a的制备程序,从化合物11a(70mg,0.19mmol)、溴三甲基硅烷(0.10mL,0.77mmol)和2,6-二甲基吡啶(0.18mL,1.59mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物12a(38mg,65%)。通过硅胶柱色谱法(梯度为丙酮/H2O/Et3N,6:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ8.23(s,1H,H-2),8.14(s,1H,H-8),4.97-4.27(m,4H,H-3’,H-1’),4.05-3.95(m,1H,H-2’),3.55-3.40(m,2H,PCH2);13C NMR(75MHz,D2O):δ154.2(C-6),150.7(C-2),148.7(C-4),143.4(C-8),117.8(C-5),81.7(d,1JC,F=168.0Hz,C-3’),77.6(dd,2JC,F=18.9Hz,3JC,P=11.4Hz,C-2’),66.1(d,1JC,P=157.0Hz,CH2P),43.3(d,3JC,F=7.5Hz,C-1’);31P NMR(121MHz,D2O):δ12.7;HRMS对于C9H13FN5O4P[M-H]-计算值:304.0616,发现值:304.0603。
光谱数据符合文献数据(Jindrich,J.;Holy,A.;Dvorakova,H.Collect.Czech.Chem.Commun.1993,58,1645-1667)。
实施例12:(R)-9-[3-氟-2-(膦酰基甲氧基)丙基]腺嘌呤(12b)的合成
根据用于8a的制备程序,从化合物11b(250mg,0.67mmol)、溴三甲基硅烷(0.37mL,2.77mmol)和2,6-二甲基吡啶(0.64mL,5.54mmol)的无水乙腈(10mL)开始,得到白色泡沫形式的化合物12b(148mg,70%)。通过硅胶柱色谱法(梯度为丙酮/H2O/Et3N,6:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ8.01(d,J=1.0Hz,1H,H-2),7.89(d,J=1.0Hz,1H,H-8),4.71-4.18(m,4H,H-3’,H-1’),3.96-3.85(m,1H,H-2’),3.62-3.40(m,2H,PCH2);13C NMR(75MHz,D2O):δ154.6(C-6),151.6(C-2),148.2(C-4),142.6(C-8),117.3(C-5),81.7(d,1JC,F=168.1Hz,C-3’),77.3(dd,2JC,F=18.9Hz,3JC,P=11.4Hz,C-2’),66.4(d,1JC,P=155.5Hz,CH2P),43.0(d,3JC,F=7.4Hz,C-1’);31P NMR(121MHz,D2O):δ14.2;HRMS对于C9H13FN5O4P[M-H]-计算值:304.0616,发现值:304.0609。
光谱数据符合文献数据(Jindrich,J.;Holy,A.;Dvorakova,H.Collect.Czech.Chem.Commun.1993,58,1645-1667)。
实施例13:(S)-1-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}-N4-异丁酰基胞嘧啶(14a)的合成
根据用于制备6a的程序,从化合物4a(200mg,0.82mmol)、化合物13(180mg,0.98mmol)、Ph3P(430mg,1.63mmol)和DIAD(0.33mL,1.63mmol)的无水THF(6mL)溶液开始得到无色油状物形式的化合物14a(130mg,40%)。通过硅胶柱色谱法纯化粗残余物(梯度为DCM/MeOH,30:1,v/v;DCM/MeOH,25:1,v/v)。1H NMR(300MHz,CDCl3):δ9.14(s,1H,NHCO),7.71(d,J=7.3Hz,1H,H-6),7.41(d,J=7.3Hz,1H,H-5),4.82-4.31(m,3H,H-3’,H-1’a),4.22-3.95(m,7H,H-1’b,H-2’,2x CH2CH3,PCH2a),3.70(dd,J=13.6,8.3Hz,1H,PCH2b),2.72-2.63(m,1H,CH(CH3)2),1.36-1.20(m,12H,2x CH2CH3,CH(CH3)2);13C NMR(75MHz,CDCl3):δ177.4(CONH),163.0(C-4),156.1(C-2),150.4(C-6),96.3(C-5),82.3(d,1JC,F=173.4Hz,C-3’),78.3(dd,2JC,F=18.3Hz,3JC,P=11.9Hz,C-2’),64.4(d,1JC,P=166.9Hz,CH2P),62.7,62.5(2×d,2JC,P=6.6Hz,CH2CH3),51.0(d,3JC,F=8.7Hz,C-1’),36.7(CH(CH3)2),19.3,19.1(CH(CH3)2),16.6,16.5(CH2CH3);31P NMR(121MHz,CDCl3):δ20.7;HRMS对于C16H27FN3O6P[M+H]+计算值:408.1694,发现值:408.1690。
实施例14:(R)-1-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}-N4-异丁酰基胞嘧啶(14b)的合成
根据用于制备6a的程序,从化合物4a(400mg,1.64mmol)、化合物9(360mg,1.96mmol)、Ph3P(860mg,3.26mmol)和DIAD(0.66mL,3.26mmol)的无水THF(10mL)溶液开始得到无色油状物形式的化合物14b(260mg,40%)。通过硅胶柱色谱法纯化粗残余物(梯度为DCM/MeOH,30:1,v/v;DCM/MeOH,25:1,v/v)。1H NMR(300MHz,CDCl3):δ8.89(s,1H,NHCO),7.71(d,J=7.3Hz,1H,H-6),7.40(d,J=7.4Hz,1H,H-5),4.82-4.31(m,3H,H-3’,H-1’a),4.24-3.95(m,7H,H-1’b,H-2’,2x CH2CH3,PCH2a),3.70(dd,J=13.4,8.2Hz,1H,PCH2b),2.69-2.60(m,1H,CH(CH3)2),1.35-1.20(m,12H,2x CH2CH3,CH(CH3)2);13C NMR(75MHz,CDCl3):δ177.2(CONH),162.9(C-4),156.1(C-2),150.4(C-6),96.3(C-5),82.3(d,1JC,F=173.3Hz,C-3’),78.3(dd,2JC,F=18.4Hz,3JC,P=11.8Hz,C-2’),64.4(d,1JC,P=166.9Hz,CH2P),62.7,62.5(2×d,2JC,P=6.6Hz,CH2CH3),51.0(d,3JC,F=9.1Hz,C-1’),36.7(CH(CH3)2),19.3,19.1(CH(CH3)2),16.6,16.5(CH2CH3);31P NMR(121MHz,CDCl3):δ21.4;HRMS对于C16H27FN3O6P[M+H]+计算值:408.1694,发现值:408.1691。
实施例15:(S)-O2-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}-N4-异丁酰基胞嘧啶(15a)的合成
根据用于制备6a的程序,从化合物4a(200mg,0.82mmol)、化合物13(180mg,0.98mmol)、Ph3P(430mg,1.63mmol)和DIAD(0.33mL,1.63mmol)的无水THF(6mL)溶液开始得到无色油状物形式的化合物15a(150mg,45%)。通过硅胶柱色谱法纯化粗残余物(梯度为DCM/MeOH,80:1,v/v;DCM/MeOH,50:1,v/v)。1H NMR(600MHz,CDCl3):δ8.83(s,1H,NHCO),8.38(dd,J=5.6,0.6Hz,1H,H-6),7.84(d,J=5.7Hz,1H,H-5),4.72-4.50(m,3H,H-3’,H-1’a),4.38-4.35(m,1H,H-1’b),4.23-4.15(m,5H,H-2’,2x CH2CH3),4.08(d,J=8.1Hz,2H,PCH2),2.68-2.61(m,1H,CH(CH3)2),1.36-1.33(m,6H,2x CH2CH3),1.26-1.25(m,6H,CH(CH3)2);13C NMR(150MHz,CDCl3):δ176.8(CONH),164.1(C-2),160.6(C-6),159.5(C-4),104.4(C-5),82.9(d,1JC,F=172.0Hz,C-3’),78.1(dd,2JC,F=19.1Hz,3JC,P=8.9Hz,C-2’),65.0(d,3JC,F=8.1Hz,C-1’),64.9(d,1JC,P=195Hz,CH2P),62.8,62.6(2×d,2JC,P=6.5Hz,CH2CH3),36.6(CH(CH3)2),19.2,19.1(CH(CH3)2),16.5,16.4(CH2CH3);31P NMR(121MHz,CDCl3):δ20.7;HRMS对于C16H27FN3O6P[M+H]+计算值:408.1694,发现值:408.1699。
实施例16:(R)-O2-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}-N4-异丁酰基胞嘧啶(15b)的合成
根据用于制备6a的程序,从化合物4b(300mg,1.64mmol)、化合物13(360mg,1.96mmol)、Ph3P(860mg,3.26mmol)和DIAD(0.66mL,3.26mmol)的无水THF(10mL)溶液开始得到无色油状物形式的化合物15b(400mg,45%)。通过硅胶柱色谱法纯化粗残余物(梯度为DCM/MeOH,80:1,v/v;DCM/MeOH,50:1,v/v)。1H NMR(300MHz,CDCl3):δ8.94(s,1H,NHCO),8.38(d,J=5.6Hz,1H,H-6),7.84(d,J=5.6Hz,1H,H-5),4.77-4.48(m,3H,H-3’,H-1’a),4.39-4.33(m,1H,H-1’b),4.25-4.07(m,7H,H-2’,2x CH2CH3,PCH2),2.73-2.63(m,1H,CH(CH3)2),1.37-1.24(m,12H,2x CH2CH3,CH(CH3)2);13C NMR(75MHz,CDCl3):δ176.9(CONH),164.1(C-2),160.5(C-6),159.5(C-4),104.4(C-5),82.8(d,1JC,F=172.3Hz,C-3’),78.1(dd,2JC,F=18.8Hz,3JC,P=9.1Hz,C-2’),64.9(d,3JC,F=8.2Hz,C-1’),64.8(d,1JC,P=165Hz,CH2P),62.8,62.5(d,2JC,P=6.6Hz,CH2CH3),36.4(CH(CH3)2),19.2,19.1(CH(CH3)2),16.5,16.4(CH2CH3);31P NMR(121MHz,CDCl3):δ20.9;HRMS对于C16H27FN3O6P[M+H]+计算值:408.1694,发现值:408.1693。
实施例17:(S)-1-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}胞嘧啶(16a)的合成
将14a(120mg,0.31mmol)的30%甲醇氨(20mL)的溶液在45℃下搅拌15小时。在除去所有挥发物后,通过硅胶柱色谱(梯度为DCM/MeOH,10:1,v/v;DCM/MeOH,8:1,v/v)纯化残余物,得到无色泡沫形式的16a(90mg,90%)。1H NMR(300MHz,CDCl3):δ7.40(d,J=7.2Hz,1H,H-6),5.92(d,J=7.2Hz,1H,H-5),4.77-4.35(m,2H,H-3’),4.18-3.95(m,7H,H-1’,H-2’,2x CH2CH3),3.83(dd,J=13.8,9.0Hz,1H,PCH2a),3.70(dd,J=13.4,7.2Hz,1H,PCH2b),1.36-1.30(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ165.8(C-4),156.3(C-2),147.1(C-6),94.7(C-5),82.6(d,1JC,F=172.9Hz,C-3’),78.7(dd,2JC,F=18.4Hz,3JC,P=10.8Hz,C-2’),64.6(d,1JC,P=167.6Hz,CH2P),62.8,62.6(2×d,2JC,P=6.6Hz,CH2CH3),50.1(d,3JC,F=8.7Hz,C-1’),16.6,16.5(CH2CH3);31P NMR(121MHz,CDCl3):δ20.4;HRMS对于C12H21FN3O5P[M-H]+计算值:338.1275,发现值:338.1280。
实施例18:(R)-1-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}胞嘧啶(16b)的合成
根据用于16a的制备程序,从化合物14b(200mg,0.49mmol)的30%的甲醇氨(20mL)开始,得到白色泡沫形式的化合物16b(140mg,82%)。通过硅胶柱色谱(梯度为DCM/MeOH,10:1,v/v;DCM/MeOH,8:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ7.35(d,J=7.2Hz,1H,H-6),5.81(m,d,J=7.2Hz,1H,H-5),4.76-4.34(m,2H,H-3’),4.18-3.93(m,7H,H-1’,H-2’,2x CH2CH3),3.87-3.66(m,2H,PCH2),1.36-1.30(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ166.5(C-4),156.8(C-2),146.8(C-6),94.5(C-5),82.7(d,1JC,F=172.9Hz,C-3’),78.8(dd,2JC,F=18.6Hz,3JC,P=10.6Hz,C-2’),64.7(d,1JC,P=167.1Hz,CH2P),62.7,62.6(2×d,2JC,P=6.4Hz,CH2CH3),50.1(d,3JC,F=8.4Hz,C-1’),16.6,16.5(CH2CH3);31P NMR(121MHz,CDCl3):δ20.9;HRMS对于C12H21FN3O5P[M+H]+计算值:338.1275,发现值:338.1278。
实施例19:(S)-1-[3-氟-2-(膦酰基甲氧基)丙基]胞嘧啶(17a)的合成
根据用于8a的制备程序,从化合物16a(100mg,0.30mmol)、溴三甲基硅烷(0.16mL,1.19mmol)和2,6-二甲基吡啶(0.27mL,2.37mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物17a(58mg,70%)。通过硅胶柱色谱(梯度为丙酮/H2O/Et3N,6:1:1,v/v/v;丙酮/H2O/Et3N,5:1:1,v/v/v)纯化粗残余物。1H NMR(600MHz,D2O):δ7.75-7.74(m,1H,H-6),6.07-6.06(m,1H,H-5),4.80-4.48(m,1H,H-3’,与H2O重叠),4.14(dd,J=14.1,3.4Hz,1H,H-1’a),3.98-3.88(m,2H,H-2’,H-1’b),3.77(dd,J=13.1,9.1Hz,1H,PCH2a),3.59(dd,J=13.1,9.6Hz,1H,PCH2b);13C NMR(75MHz,D2O):δ162.4(C-4),153.0(C-2),149.0(C-6),94.5(C-5),82.0(d,1JC,F=167.9Hz,C-3’),77.4(dd,2JC,F=18.4Hz,3JC,P=11.5Hz,C-2’),66.1(d,1JC,P=157.2Hz,CH2P),49.1(d,3JC,F=7.9Hz,C-1’);31P NMR(121MHz,D2O):δ14.9;HRMS对于C8H13FN3O5P[M-H]-计算值:280.0504,发现值:280.0501。
光谱数据符合文献数据(Yu,K.L.;Bronson,J.J.;Yang,H.;Patick,A.;Alam,M.;Brankovan,V.;Datema,R.;Hitchcock,M.J.M.;Martin,J.C.J.Med.Chem.1993,36,2726-2738)。
实施例20:(R)-1-[3-氟-2-(膦酰基甲氧基)丙基]胞嘧啶(17b)的合成
根据用于8a的制备程序,从化合物16b(140mg,0.42mmol)、溴三甲基硅烷(0.22mL,1.66mmol)和2,6-二甲基吡啶(0.38mL,3.32mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物17b(82mg,70%)。通过硅胶柱色谱(梯度为丙酮/H2O/Et3N,6:1:1,v/v/v;丙酮/H2O/Et3N,5:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ7.72(d,J=7.6Hz,1H,H-6),6.05(d,J=7.5Hz,1H,H-5),4.82-4.45(m,1H,H-3’,与H2O重叠),4.18-4.12(m,1H,H-1’a),4.02-3.75(m,3H,H-2’,H-1’b,PCH2a),3.64-3.57(m,1H,PCH2b);13C NMR(75MHz,D2O):δ163.9(C-4),155.0(C-2),148.4(C-6),94.7(C-5),82.1(d,1JC,F=167.7Hz,C-3’),77.6(dd,2JC,F=18.3Hz,3JC,P=11.6Hz,C-2’),66.2(d,1JC,P=157.1Hz,CH2P),49.2(d,3JC,F=7.9Hz,C-1’);31P NMR(121MHz,D2O):δ14.9;HRMS对于C8H13FN3O5P[M-H]-计算值:280.0504,发现值:280.0507。
光谱数据符合文献数据(Yu,K.L.;Bronson,J.J.;Yang,H.;Patick,A.;Alam,M.;Brankovan,V.;Datema,R.;Hitchcock,M.J.M.;Martin,J.C.J.Med.Chem.1993,36,2726-2738)。
实施例21:(S)-O2-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}胞嘧啶(18a)的合成
根据用于16a的制备程序,从化合物15a(150mg,0.37mmol)的30%的甲醇氨(15mL)开始,得到白色泡沫形式的化合物18a(100mg,82%)。通过硅胶柱色谱(梯度为DCM/MeOH,25:1,v/v;DCM/MeOH,20:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ7.92(dd,J=5.7Hz,1H,H-6),6.11(d,J=5.7Hz,1H,H-5),5.71(s,2H,NH2),4.71-4.60(m,1H,H-3’a),4.56-4.44(m,1H,H-3’b),4.41-4.31(m,2H,H-1’),4.19-3.96(m,7H,2x CH2CH3,H-2’,PCH2),1.32-1.27(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ165.3(C-4),164.7(C-2),157.1(C-6),100.1(C-5),83.0(d,1JC,F=172.2Hz,C-3’),78.8(dd,2JC,F=19.0Hz,3JC,P=11.3Hz,C-2’),64.8(d,1JC,P=165.0Hz,CH2P),64.6(d,3JC,F=8.3Hz,C-1’),62.9,62.7(2×d,2JC,P=6.4Hz,CH2CH3),16.5,16.4(CH2CH3);31P NMR(121MHz,CDCl3):δ20.5;HRMS对于C12H21FN3O5P[M+H]+计算值:338.1276,发现值:338.1292。
实施例22:(R)-O2-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}胞嘧啶(18b)的合成
根据用于16a的制备程序,从化合物15b(250mg,0.60mmol)的30%的甲醇氨(20mL)开始,得到白色泡沫形式的化合物18b(190mg,90%)。通过硅胶柱色谱(梯度为DCM/MeOH,25:1,v/v;DCM/MeOH,20:1,v/v)纯化粗残余物。1H NMR(500MHz,CDCl3):δ7.92(dd,J=5.7Hz,1H,H-6),6.11(d,J=5.7Hz,1H,H-5),5.71(s,2H,NH2),4.67-4.48(m,2H,H-3’),4.39-4.32(m,1H,H-1’),4.17-4.11(m,4H,2x CH2CH3),4.06-3.98(m,3H,H-2’,PCH2),1.31-1.28(m,6H,2x CH2CH3);13C NMR(125MHz,CDCl3):δ165.3(C-4),164.7(C-2),157.0(C-6),100.1(C-5),83.0(d,1JC,F=172.2Hz,C-3’),78.8(dd,2JC,F=18.9Hz,3JC,P=11.3Hz,C-2’),64.8(d,1JC,P=162.5Hz,CH2P),64.6(d,3JC,F=8.5Hz,C-1’),62.9,62.7(2×d,2JC,P=6.6Hz,CH2CH3),16.5,16.4(CH2CH3);31P NMR(202MHz,CDCl3):δ20.5;HRMS对于C12H21FN3O5P[M+H]+计算值:338.1276,发现值:338.1271。
实施例23:(S)-O2-[3-氟-2-(膦酰基甲氧基)丙基]胞嘧啶(19a)的合成
根据用于8a的制备程序,从化合物18a(100mg,0.30mmol)、溴三甲基硅烷(0.16mL,1.20mmol)和2,6-二甲基吡啶(0.27mL,2.37mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物19a(82mg,70%)。通过硅胶柱色谱(梯度为丙酮/H2O/Et3N,5:1:1,v/v/v;丙酮/H2O/Et3N,4:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ7.75(d,J=6.0Hz,1H,H-6),6.16(d,J=6.0Hz,1H,H-5),4.75-4.46(m,2H,H-3’),4.27(d,J=5.0Hz,2H,H-1’),3.98-3.87(m,1H,H-2’),3.53(d,J=9.1Hz,2H,PCH2);13C NMR(75MHz,D2O):δ165.3(C-4),163.7(C-2),155.6(C-6),100.2(C-5),82.3(d,1JC,F=165.9Hz,C-3’),78.9(dd,2JC,F=18.6Hz,3JC,P=10.9Hz,C-2’),67.8(d,1JC,P=149.9Hz,CH2P),64.2(d,3JC,F=7.6Hz,C-1’);31P NMR(121MHz,D2O):δ12.7;HRMS对于C8H13FN3O5P[M-H]-计算值:280.0504,发现值:280.0505。
实施例24:(R)-O2-[3-氟-2-(膦酰基甲氧基)丙基]胞嘧啶(19b)的合成
根据用于8a的制备程序,从化合物18b(200mg,0.60mmol)、溴三甲基硅烷(0.32mL,2.20mmol)和2,6-二甲基吡啶(0.54mL,4.80mmol)的无水乙腈(10mL)开始,得到白色泡沫形式的化合物19b(160mg,70%)。通过硅胶柱色谱(梯度为丙酮/H2O/Et3N,5:1:1,v/v/v;丙酮/H2O/Et3N,4:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ7.74(d,J=6.1Hz,1H,H-6),6.15(dd,J=6.0,1.0Hz,1H,H-5),4.75-4.46(m,2H,H-3’),4.33-4.23(m,2H,H-1’),4.03-3.91(m,1H,H-2’),3.65(d,J=9.2Hz,2H,PCH2);13C NMR(75MHz,D2O):δ165.2(C-4),163.4(C-2),155.1(C-6),100.2(C-5),82.3(d,1JC,F=166.5Hz,C-3’),77.2(dd,2JC,F=18.6Hz,3JC,P=10.9Hz,C-2’),66.7(d,1JC,P=154.2Hz,CH2P),64.3(d,3JC,F=7.7Hz,C-1’);31P NMR(121MHz,D2O):δ14.2;HRMS对于C8H13FN3O5P[M-H]-计算值:280.0504,发现值:280.0513。
实施例25:(S)-9-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}-O6-苄基鸟嘌呤(21a)的合成
根据用于制备6a的程序,从化合物4a(300mg,1.23mmol)、化合物20(360mg,1.47mmol)、Ph3P(650mg,2.46mmol)和DIAD(0.48mL,2.46mmol)的无水THF(8mL)溶液开始得到无色油状物形式的化合物21a(290mg,50%)。通过硅胶柱色谱法纯化粗残余物(梯度为DCM/MeOH,40:1,v/v;DCM/MeOH,30:1,v/v)。1H NMR(300MHz,CDCl3):δ7.70(s,1H,H-8),7.51-7.29(m,5H,ArH),5.56(s,2H,CH2-Ar),5.01(s,2H,NH2),4.69-4.28(m,3H,H-3’,H-1’a),4.20-4.01(m,6H,H-1’b,H-2’,2x CH2CH3),3.95-3.77(m,2H,PCH2),1.34-1.23(m,6H,2xCH2CH3);13C NMR(75MHz,CDCl3):δ161.1(C-6),159.4(C-2),154.2(C-4),140.3(C-8),136.5(Ar-C),128.4(Ar-C),128.3(Ar-C),128.0(Ar-C),115.4(C-5),82.1(d,1JC,F=173.5Hz,C-3’),78.6(dd,2JC,F=19.3Hz,3JC,P=10.3Hz,C-2’),68.1(CH2-Ar),64.6(d,1JC,P=166.9Hz,CH2P),62.7,62.6(2×d,2JC,P=7.0Hz,CH2CH3),44.3(d,3JC,F=7.9Hz,C-1’),16.5,16.4(CH2CH3);31P NMR(121MHz,CDCl3):δ19.9;HRMS对于C20H27FN5O5P[M+H]+计算值:468.1806,发现值:468.1801。
实施例26:(R)-9-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}-O6-苄基鸟嘌呤(21b)的合成
根据用于制备6a的程序,从化合物4b(300mg,1.23mmol)、化合物20(360mg,1.47mmol)、Ph3P(650mg,2.46mmol)和DIAD(0.48mL,2.46mmol)的无水THF(8mL)溶液开始得到无色油状物形式的化合物21b(250mg,44%)。通过硅胶柱色谱法纯化粗残余物(梯度为DCM/MeOH,40:1,v/v;DCM/MeOH,30:1,v/v)。1H NMR(300MHz,CDCl3):δ7.70(s,1H,H-8),7.52-7.28(m,5H,ArH),5.57(s,2H,CH2-Ar),4.94(s,2H,NH2),4.64-4.28(m,3H,H-3’,H-1’a),4.21-4.00(m,6H,H-1’b,H-2’,2x CH2CH3),3.95-3.77(m,2H,PCH2),1.34-1.24(m,6H,2xCH2CH3);13C NMR(75MHz,CDCl3):δ161.2(C-6),159.4(C-2),154.3(C-4),140.4(C-8),136.5(Ar-C),128.4(d,J=8.2Hz,Ar-C),128.1(Ar-C),115.4(C-5),82.2(d,1JC,F=173.5Hz,C-3’),78.6(dd,2JC,F=19.3Hz,3JC,P=10.1Hz,C-2’),68.2(CH2-Ar),64.7(d,1JC,P=167.0Hz,CH2P),62.7,62.6(2×d,2JC,P=7.0Hz,CH2CH3),44.3(d,3JC,F=8.1Hz,C-1’),16.5,16.4(2×d,3JC,P=2.9Hz,CH2CH3);31P NMR(121MHz,CDCl3):δ20.5;HRMS对于C20H27FN5O5P[M+H]+计算值:468.1806,发现值:468.1811。
实施例27:(S)-9-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}鸟嘌呤(22a)的合成
将化合物21a(300mg,0.64mmol)和木炭上的Pd/C(10%w/w,150mg)悬浮于EtOAc(20mL)中,并且首先用氮气然后用氢气吹扫溶液,并使其在氢气气氛下搅拌。在10小时后,通过硅藻土垫过滤混合物,并减压蒸发滤液,得到粗产物。通过硅胶柱色谱(梯度为DCM/MeOH,10:1,v/v;7:1,v/v)纯化残余物,得到无色泡沫形式的22a(170mg,70%)。1H NMR(300MHz,MeOD):δ7.74(s,1H,H-8),4.77-4.37(m,2H,H-3’),4.33-3.85(m,9H,H-1’,H-2’,2x CH2CH3,PCH2),1.31-1.23(m,6H,2x CH2CH3);13C NMR(75MHz,MeOD):δ159.5(C-6),155.3(C-2),153.4(C-4),140.4(C-8),117.3(C-5),83.2(d,1JC,F=171.7Hz,C-3’),79.9(dd,2JC,F=19.1Hz,3JC,P=11.9Hz,C-2’),64.5(d,1JC,P=165.0Hz,CH2P),64.3,64.1(2×d,2JC,P=6.6Hz,CH2CH3),44.3(d,3JC,F=8.6Hz,C-1’),16.7,16.6(CH2CH3);31P NMR(121MHz,MeOD):δ21.1;HRMS对于C13H21FN5O5P[M+H]+计算值:378.1337,发现值:378.1329。
实施例28:(R)-9-{3-氟-2-[(二乙基磷酰基)甲氧基]丙基}鸟嘌呤(22b)的合成
根据用于22a的制备的一般程序,从化合物21b(250mg,0.54mmol)和木炭上的Pd/C(10%w/w,120mg)的EtOAc(30mL)开始,得到无色泡沫形式的化合物23b(160mg,80%)。通过硅胶柱色谱(梯度为DCM/MeOH,10:1,v/v;7:1,v/v)纯化粗残余物。1H NMR(300MHz,MeOD):δ7.74(s,1H,H-8),4.76-4.37(m,2H,H-3’),4.33-3.85(m,9H,H-1’,H-2’,2x CH2CH3,PCH2),1.31-1.23(m,6H,2x CH2CH3);13C NMR(75MHz,MeOD):δ159.5(C-6),155.4(C-2),153.4(C-4),140.4(C-8),117.3(C-5),83.2(d,1JC,F=171.6Hz,C-3’),79.9(dd,2JC,F=19.0Hz,3JC,P=11.9Hz,C-2’),64.5(d,1JC,P=165.0Hz,CH2P),64.3,64.1(2×d,2JC,P=6.6Hz,CH2CH3),44.3(d,3JC,F=8.6Hz,C-1’),16.7,16.6(CH2CH3);31P NMR(121MHz,MeOD):δ21.1;HRMS对于C13H21FN5O5P[M+H]+计算值:378.1337,发现值:378.1329。
实施例29:(S)-9-[3-氟-2-(膦酰基甲氧基)丙基]鸟嘌呤(23a)的合成
根据用于8a的制备程序,从化合物22a(170mg,0.45mmol)、溴三甲基硅烷(0.24mL,1.80mmol)和2,6-二甲基吡啶(0.42mL,3.60mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物23a(87mg,60%)。通过硅胶柱色谱(梯度为丙酮/H2O/Et3N,5:1:1,v/v/v;丙酮/H2O/Et3N,4:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ7.74(s,1H,H-8),4.79-4.59(m,4H,H-3’,H-1’),3.97-3.88(m,1H,H-2’),3.51-3.39(m,2H,PCH2);13C NMR(75MHz,D2O):δ166.8(C-6),160.0(C-2),151.2(C-4),138.8(C-8),116.7(C-5),81.9(d,1JC,F=167.4Hz,C-3’),77.2(dd,2JC,F=18.7Hz,3JC,P=10.6Hz,C-2’),68.0(d,1JC,P=150.0Hz,CH2P),42.2(d,3JC,F=7.1Hz,C-1’);31P NMR(121MHz,D2O):δ13.6;HRMS对于C9H13FN5O5P[M-H]-计算值:320.0565,发现值:320.0565。
光谱数据符合文献数据(Baszczynski,O.;Hockova,D.;Janeba,Z.;Holy,A.;Jansa,P.;Dracinsky,M.;Keough,D.T.;Guddat,L.W.Eur.J.Med.Chem.2013,67,81-89)。
实施例30:(R)-9-[3-氟-2-(膦酰基甲氧基)丙基]鸟嘌呤(23b)的合成
根据用于8a的制备程序,从化合物22b(160mg,0.42mmol)、溴三甲基硅烷(0.22mL,1.70mmol)和2,6-二甲基吡啶(0.39mL,3.40mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物23b(87mg,60%)。通过硅胶柱色谱(梯度为丙酮/H2O/Et3N,5:1:1,v/v/v;丙酮/H2O/Et3N,4:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ7.76(s,1H,H-8),4.70-4.29(m,2H,H-3’),4.25-4.09(m,2H,H-1’),4.02-3.88(m,1H,H-2’),3.65-3.47(m,2H,PCH2);13CNMR(75MHz,D2O):δ158.4(C-6),153.3(C-2),151.2(C-4),140.3(C-8),115.2(C-5),81.9(d,1JC,F=167.9Hz,C-3’),77.5(dd,2JC,F=18.7Hz,3JC,P=11.3Hz,C-2’),66.4(d,1JC,P=156.0Hz,CH2P),42.7(d,1JC,F=7.6Hz,C-1’);31P NMR(121MHz,D2O):δ14.5;HRMS对于C9H13FN5O5P[M-H]-计算值:320.0565,发现值:320.0571。
光谱数据符合文献数据(Baszczynski,O.;Hockova,D.;Janeba,Z.;Holy,A.;Jansa,P.;Dracinsky,M.;Keough,D.T.;Guddat,L.W.Eur.J.Med.Chem.2013,67,81-89)。
实施例31-40:游离磷酸酯8a-b、12a-b、17a-b、19a-b和23a-b的芳基氧基氨基膦酸酯前药的合成。
一般程序
将相关膦酸(1当量)与L-天冬氨酸酯HCl盐(1.7当量.)和苯酚(4.4当量)的无水吡啶溶液混合。然后,加入Et3N(10当量),并将混合物在60℃下在氮气气氛下搅拌15-20分钟。在单独的烧瓶中将2,2’-二硫代二吡啶(7当量)与PPh3(7当量)在无水吡啶中混合,并将所得的混合物搅拌10-15分钟,得到澄清的淡黄色溶液。然后,将该溶液加入到上述溶液中,并将合并的混合物在60℃下搅拌12小时。然后,将混合物减压浓缩得到残余物,将其重新溶于EtOAc中。该溶液用饱和NaHCO3水溶液和盐水洗涤,分离有机层,用Na2SO4干燥,过滤,并减压浓缩。通过硅胶色谱纯化粗残余物,得到期望的氨基膦酸酯。
根据该程序制备以下化合物:
实施例31:(S)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]
丙基}胸腺嘧啶(24a)
根据一般程序,从化合物8a(50mg,0.17mmol)、天冬氨酸酯HCl盐(90mg,0.29mmol)、PhOH(70mg,0.75mmol)、Et3N(0.24mL,1.7mmol)、2,2’-二硫代二吡啶(260mg,1.20mmol)和PPh3(310mg,1.20mmol)的无水吡啶(5mL)开始,得到无色油状物形式的化合物24a(45mg,45%)。通过硅胶柱色谱(梯度为DCM/MeOH,60:1,v/v;50:1,v/v)纯化粗残余物。1H NMR(300MHz,CD3CN):δ9.35(s,1H,NHCO),7.36-7.13(m,6H,H-6,ArH),4.72-3.65(m,13H,H-3’,H-2’,H-1’,2x OCH2(CH2)3CH3,PCH2,H-α-Asp,NHPO),2.77-2.49(m,2H,H-β-Asp),1.74(d,J=1.2Hz,3H,CH3-5),1.71(d,J=1.2Hz,3H,CH3-5),1.60-1.50(m,4H,2x OCH2CH2(CH2)2CH3),1.35-1.26(m,8H,2x O(CH2)2(CH2)2CH3),0.91-0.85(m,6H,2x O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ172.9(d,3JC,P=4.7Hz,CO-α),172.6(d,3JC,P=4.6Hz,CO-α),171.5(CO-β),165.3(C-4),152.3,152.2(C-2),151.3(Ar-C),143.0(C-6),130.7(Ar-C),125.9,125.8(Ar-C),121.9(d,3JC,P=4.3Hz,Ar-C),121.7(d,3JC,P=4.5Hz,Ar-C),110.4,110.3(C-5),83.5(d,1JC,F=172.5Hz,C-3’),83.2(d,1JC,F=165.0Hz,C-3’),79.9,79.8,79.7,79.6,79.5,79.4,79.2(C-2’),66.9(d,1JC,P=157.5Hz,CH2P),66.5,66.4,65.8,65.7(OCH2(CH2)3CH3),51.5,51.4(C-1’),49.0,48.8(C-α-Asp),39.8(d,3JC,P=4.0Hz,C-β-Asp),39.6(d,3JC,P=4.1Hz,C-β-Asp),29.0,28.9,28.7,28.6(OCH2(CH2)2CH2CH3),23.0,22.9(O(CH2)3CH2CH3),14.3(O(CH2)4CH3),12.3(CH3-5);31P NMR(121MHz,CD3CN):δ22.3,21.3;HRMS对于C29H43FN3O9P[M+Na]+计算值:650.2613,发现值:650.2629。
实施例32:(R)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]
丙基}胸腺嘧啶(24b)
根据一般程序,从化合物8b(80mg,0.27mmol)、天冬氨酸酯HCl盐(142mg,0.46mmol)、PhOH(112mg,1.20mmol)、Et3N(0.38mL,2.70mmol)、2,2’-二硫代二吡啶(420mg,1.90mmol)和PPh3(500mg,1.90mmol)的无水吡啶(5mL)开始,得到无色油状物形式的化合物24b(80mg,50%)。通过硅胶柱色谱(梯度为DCM/MeOH,60:1,v/v;50:1,v/v)纯化粗残余物。1H NMR(300MHz,CD3CN):δ9.59(s,1H,NHCO),7.39-7.13(m,6H,H-6,ArH),4.77-3.71(m,13H,H-3’,H-2’,H-1’,2x OCH2(CH2)3CH3,PCH2,H-α-Asp,NHPO),2.82-2.53(m,2H,H-β-Asp),1.79(s,3H,CH3-5),1.73(s,3H,CH3-5),1.64-1.55(m,4H,2x OCH2CH2(CH2)2CH3),1.41-1.28(m,8H,2x O(CH2)2(CH2)2CH3),0.97-0.88(m,6H,2x O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ172.8(d,3JC,P=5.0Hz,CO-α),172.6(d,3JC,P=4.5Hz,CO-α),171.6,171.5(CO-β),165.4(C-4),152.3(C-2),151.4,151.3(Ar-C),143.1,143.0(C-6),130.7,130.6(Ar-C),125.8(Ar-C),121.8(d,3JC,P=4.0Hz,Ar-C),121.7(d,3JC,P=4.4Hz,Ar-C),110.4,110.3(C-5),83.4(d,J=172.5Hz,C-3’),82.2(d,1JC,F=165.0Hz,C-3’),79.8,79.6,79.5,79.4,79.2(C-2’),66.9(d,1JC,P=157.5Hz,CH2P),66.5,66.4,65.7(OCH2(CH2)3CH3),51.5(C-1’),49.0(d,2JC,P=8.3Hz,C-α-Asp),48.8(d,2JC,P=8.0Hz,C-α-Asp),39.7(d,3JC,P=4.0Hz,C-β-Asp),39.6(d,3JC,P=4.6Hz,C-β-Asp),29.0,28.9,28.7,28.6(OCH2(CH2)2CH2CH3),23.0,22.9(O(CH2)3CH2CH3),14.3(O(CH2)4CH3),12.3(CH3-5);31P NMR(121MHz,CD3CN):δ22.2,21.5;HRMS对于C29H43FN3O9P[M-H]-计算值:626.2648,发现值:626.2648。
实施例33:(S)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]
丙基}腺嘌呤(25a)
根据一般程序,从化合物12a(30mg,0.10mmol)、天冬氨酸酯HCl盐(52mg,0.17mmol)、PhOH(40mg,0.43mmol)、Et3N(0.14mL,1.00mmol)、2,2’-二硫代二吡啶(150mg,0.69mmol)和PPh3(180mg,0.69mmol)的无水吡啶(3mL)开始,得到无色油状物形式的化合物25a(26mg,40%)。通过硅胶柱色谱(梯度为DCM/MeOH,25:1,v/v;20:1,v/v)纯化粗残余物。1H NMR(300MHz,CD3CN):δ8.25(s,1H,H-2),8.22(s,1H,H-2),7.99(s,1H,H-8),7.97(s,1H,H-8),7.37-7.05(m,6H,ArH),6.02(s,2H,NH2),4.75-3.83(m,13H,H-3’,H-2’,H-1’,2x OCH2(CH2)3CH3,PCH2,H-α-Asp,NHPO),2.79-2.53(m,2H,H-β-Asp),1.61-1.53(m,4H,2x OCH2CH2(CH2)2CH3),1.36-1.28(m,8H,2x O(CH2)2(CH2)2CH3),0.93-0.87(m,6H,O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ172.9(d,3JC,P=4.4Hz,CO-α),172.6(d,3JC,P=4.7Hz,CO-α),171.5,171.4(CO-β),156.9(C-6),153.8,153.7(C-2),151.4,151.2,151.1(Ar-C,C-4),142.9,142.8(C-8),130.6(Ar-C),125.8,125.7(Ar-C),121.9(d,3JC,P=4.4Hz,Ar-C),121.7(d,3JC,P=4.4Hz,Ar-C),120.1,120.0(C-5),83.3(d,1JC,F=165.0Hz,C-3’),83.1(d,1JC,F=172.5Hz,C-3’),79.9,79.8,79.7,79.5,79.4,79.3(C-2’),67.0(d,1JC,P=157.5Hz,CH2P),66.7(d,1JC,P=157.5Hz,CH2P),66.5,66.4,65.8,65.7(OCH2(CH2)3CH3),51.6,51.5(C-1’),44.3(d,2JC,P=2.4Hz,C-α-Asp),44.2(d,2JC,P=2.4Hz,C-α-Asp),39.8(d,3JC,P=3.9Hz,C-β-Asp),39.6(d,3JC,P=4.2Hz,C-β-Asp),29.0,28.9,28.7,28.6(OCH2(CH2)2CH2CH3),23.0,22.9(O(CH2)3CH2CH3),14.3(O(CH2)4CH3);31P NMR(121MHz,CD3CN):δ22.2,21.2;HRMS对于C29H42FN6O7P[M+H]+计算值:637.2909,发现值:637.2913。
实施例34:(R)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]
丙基}腺嘌呤(25b)
根据一般程序,从化合物12b(80mg,0.26mmol)、天冬氨酸酯HCl盐(140mg,0.45mmol)、PhOH(110mg,1.15mmol)、Et3N(0.36mL,2.60mmol)、2,2’-二硫代二吡啶(400mg,1.83mmol)和PPh3(480mg,1.83mmol)的无水吡啶(5mL)开始,得到无色油状物形式的化合物25b(110mg,55%)。通过硅胶柱色谱(梯度为DCM/MeOH,25:1,v/v;20:1,v/v)纯化粗残余物。1H NMR(300MHz,CD3CN):δ8.26(s,1H,H-2),8.05(s,1H,H-8),8.03(s,1H,H-8),7.35-7.01(m,5H,ArH),6.02(s,2H,NH2),4.87-3.90(m,13H,H-3’,H-2’,H-1’,2x OCH2(CH2)3CH3,PCH2,H-α-Asp,NHPO),2.82-2.56(m,2H,H-β-Asp),1.57-1.48(m,4H,OCH2CH2(CH2)2CH3),1.32-1.24(m,8H,2x O(CH2)2(CH2)2CH3),0.90-0.81(m,6H,2x O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ172.8(d,3JC,P=5.0Hz,CO-α),172.7(d,3JC,P=4.4Hz,CO-α),171.5,171.4(CO-β),157.0(C-6),153.8(C-2),151.3,151.2,151.1,151.0(Ar-C,C-4),142.8(C-8),130.6,130.5(Ar-C),125.7(Ar-C),121.7(d,3JC,P=4.6Hz,Ar-C),119.9(C-5),83.3(d,1JC,F=172.5Hz,C-3’),83.1(d,1JC,F=172.5Hz,C-3’),79.7,79.6,79.5,79.4,79.3(C-2’),66.8(d,1JC,P=150.0Hz,CH2P),66.6(d,1JC,P=157.5Hz,CH2P),66.4,65.7(OCH2(CH2)3CH3),51.5(C-1’),44.2(d,2JC,P=8.2Hz,C-α-Asp),44.0(d,2JC,P=7.8Hz,C-α-Asp),39.7(d,3JC,P=3.9Hz,C-β-Asp),39.6(d,3JC,P=3.8Hz,C-β-Asp),28.9,28.8,28.7,28.6(OCH2(CH2)2CH2CH3),23.0,22.9(O(CH2)3CH2CH3),14.2(O(CH2)4CH3);31P NMR(121MHz,CD3CN):δ22.1,21.5;HRMS对于C29H42FN6O7P[M-H]-计算值:635.2764,发现值:635.2775。
实施例35:(S)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]
丙基}胞嘧啶(26a)
根据一般程序,从化合物17a(40mg,0.14mmol)、天冬氨酸酯HCl盐(75mg,0.24mmol)、PhOH(59mg,0.63mmol)、Et3N(0.20mL,1.40mmol)、2,2’-二硫代二吡啶(220mg,1.00mmol)和PPh3(260mg,1.00mmol)的无水吡啶(3mL)开始,得到无色油状物形式的化合物26a(23mg,26%)。通过硅胶柱色谱(梯度为DCM/MeOH,20:1,v/v;10:1,v/v)纯化粗残余物。1H NMR(300MHz,CD3CN):δ7.45-7.16(m,6H,ArH,H-6),5.95(s,2H,NH2),5.70(s,1H,H-5),5.68(s,1H,H-5),4.75-3.66(m,13H,H-3’,H-2’,H-1’,2x OCH2(CH2)3CH3,PCH2,H-α-Asp,NHPO),2.82-2.56(m,2H,H-β-Asp),1.63-1.55(m,4H,2x OCH2CH2(CH2)2CH3),1.35-1.27(m,8H,2x O(CH2)2(CH2)2CH3),0.94-0.88(m,6H,O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ172.9(d,3JC,P=4.7Hz,CO-α),172.7(d,3JC,P=4.5Hz,CO-α),171.5(CO-β),167.5(C-4),157.5,157.4(C-2),151.5,151.4,151.3,151.2(Ar-C),148.2(C-6),130.7,130.6(Ar-C),125.8,125.7(Ar-C),122.0(d,3JC,P=4.4Hz,Ar-C),121.8(d,3JC,P=4.4Hz,Ar-C),94.2,94.1(C-5),83.8(d,1JC,F=172.5Hz,C-3’),83.4(d,1JC,F=165.0Hz,C-3’),80.0,79.8,79.7,79.6,79.5,79.4,79.3(C-2’),66.9(d,J=150.0Hz,CH2P),66.8(d,1JC,P=150.0Hz,CH2P),66.5,66.4,65.8,65.7(OCH2(CH2)3CH3),51.6,51.5(C-1’),50.6,50.5,50.4(C-α-Asp),39.8(d,3JC,P=4.0Hz,C-β-Asp),39.5(d,3JC,P=4.2Hz,C-β-Asp),29.0,28.9,28.8,28.7(OCH2(CH2)2CH2CH3),23.0,22.9(O(CH2)3CH2CH3),14.3(O(CH2)4CH3);31P NMR(121MHz,CD3CN):δ22.4,21.4;HRMS对于C28H42FN4O8P[M+H]+计算值:613.2797,发现值:613.2802。
实施例36:(R)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]
丙基}胞嘧啶(26b)
根据一般程序,从化合物17b(40mg,0.14mmol)、天冬氨酸酯HCl盐(75mg,0.24mmol)、PhOH(59mg,0.63mmol)、Et3N(0.20mL,1.40mmol)、2,2’-二硫代二吡啶(220mg,1.00mmol)和PPh3(260mg,1.00mmol)的无水吡啶(3mL)开始,得到无色油状物形式的化合物26b(20mg,20%)。通过硅胶柱色谱(梯度为DCM/MeOH,20:1,v/v;10:1,v/v)纯化粗残余物。1H NMR(300MHz,CD3CN):δ7.45-7.13(m,6H,ArH,H-6),5.74-5.69(m,1H,H-5),4.78-3.70(m,13H,H-3’,H-2’,H-1’,2x OCH2(CH2)3CH3,PCH2,H-α-Asp,NHPO),2.82-2.56(m,2H,H-β-Asp),1.64-1.52(m,4H,2x OCH2CH2(CH2)2CH3),1.40-1.24(m,8H,2x O(CH2)2(CH2)2CH3),0.93-0.87(m,6H,2x O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ172.8(d,3JC,P=5.1Hz,CO-α),172.7(d,3JC,P=4.4Hz,CO-α),171.6,171.5(CO-β),167.5(C-4),157.5,157.4(C-2),151.5,151.3,151.2(Ar-C),148.2,148.1(C-6),130.6(Ar-C),125.8,125.7(Ar-C),121.9(d,3JC,P=4.4Hz,Ar-C),121.8(d,3JC,P=4.4Hz,Ar-C),94.3,94.2(C-5),88.7(d,1JC,F=172.5Hz,C-3’),83.5(d,1JC,F=165Hz,C-3’),79.8,79.7,79.6,79.4,79.3(C-2’),66.9(d,1JC,P=157.5Hz,CH2P),66.7(d,1JC,P=150.0Hz,CH2P),66.5,66.4,65.7(OCH2(CH2)3CH3),51.5(C-1’),50.5(d,2JC,P=8.3Hz,C-α-Asp),50.4(d,2JC,P=8.3Hz,C-α-Asp),39.8(d,3JC,P=4.2Hz,C-β-Asp),39.6(d,3JC,P=3.8Hz,C-β-Asp),29.0,28.9,28.8,28.7(OCH2(CH2)2CH2CH3),23.0,22.9(O(CH2)3CH2CH3),14.3(O(CH2)4CH3);31P NMR(121MHz,CD3CN):δ22.4,21.7;HRMS对于C28H42FN4O8P[M-H]-计算值:611.2651,发现值:611.2655。
实施例37:(S)-O2-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]
丙基}胞嘧啶(27a)
根据一般程序,从化合物19a(20mg,0.07mmol)、天冬氨酸酯HCl盐(38mg,0.12mmol)、PhOH(30mg,0.32mmol)、Et3N(0.10mL,0.70mmol)、2,2’-二硫代二吡啶(110mg,0.50mmol)和PPh3(130mg,0.50mmol)的无水吡啶(3mL)开始,得到无色油状物形式的化合物27a(12mg,28%)。通过硅胶柱色谱(梯度为DCM/MeOH,40:1,v/v;30:1,v/v)纯化粗残余物。1H NMR(300MHz,CD3CN):δ7.95-7.93(m,1H,H-6),7.38-7.16(m,5H,ArH),6.19(s,1H,H-5),6.17(s,1H,H-5),5.61(s,2H,NH2),4.75-3.93(m,13H,H-3’,H-2’,H-1’,2x OCH2(CH2)3CH3,PCH2,H-α-Asp,NHPO),2.86-2.63(m,2H,H-β-Asp),1.64-1.52(m,4H,2x OCH2CH2(CH2)2CH3),1.34-1.27(m,8H,2x O(CH2)2(CH2)2CH3),0.93-0.87(m,6H,2x O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ173.0(d,3JC,P=4.4Hz,CO-α),172.8(d,3JC,P=4.5Hz,CO-α),171.5(CO-β),166.6(C-4),165.9(C-2),158.0(C-6),151.3(Ar-C),130.6(Ar-C),125.8(Ar-C),122.0(d,3JC,P=4.0Hz,Ar-C),121.9(d,3JC,P=4.3Hz,Ar-C),100.6(C-5),83.9(d,1JC,F=168.0Hz,C-3’),82.7(d,1JC,F=168.0Hz,C-3’),80.1,80.0,79.9,79.7,79.6,79.5,79.3(C-2’),66.9(d,1JC,P=152.3Hz,CH2P),66.7(d,1JC,P=150.0Hz,CH2P),66.5,66.4,65.7,65.4,65.3,65.2(OCH2(CH2)3CH3,C-1’),51.7,51.5(C-α-Asp),39.8(d,3JC,P=3.9Hz,C-β-Asp),39.6(d,3JC,P=4.2Hz,C-β-Asp),29.0,28.9,28.8,28.7(OCH2(CH2)2CH2CH3),23.0,22.9(O(CH2)3CH2CH3),14.3(O(CH2)4CH3);31P NMR(121MHz,CD3CN):δ22.5,21.9;HRMS对于C28H42FN4O8P[M-H]-计算值:611.2651,发现值:611.2642。
实施例38:(R)-O2-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]
丙基}胞嘧啶(27b)
根据一般程序,从化合物19b(60mg,0.21mmol)、天冬氨酸酯HCl盐(114mg,0.36mmol)、PhOH(90mg,0.96mmol)、Et3N(0.30mL,2.10mmol)、2,2’-二硫代二吡啶(330mg,1.50mmol)和PPh3(390mg,1.50mmol)的无水吡啶(5mL)开始,得到无色油状物形式的化合物27b(31mg,24%)。通过硅胶柱色谱(梯度为DCM/MeOH,40:1,v/v;30:1,v/v)纯化粗残余物。1H NMR(300MHz,CD3CN):δ7.94(s,1H,H-6),7.92(s,1H,H-6),7.39-7.19(m,5H,ArH),6.18(s,1H,H-5),6.16(s,1H,H-5),5.73(s,2H,NH2),4.75-3.93(m,13H,H-3’,H-2’,H-1’,2xOCH2(CH2)3CH3,PCH2,H-α-Asp,NHPO),2.86-2.59(m,2H,H-β-Asp),1.63-1.51(m,4H,2xOCH2CH2(CH2)2CH3),1.39-1.24(m,8H,2x O(CH2)2(CH2)2CH3),0.95-0.87(m,6H,2x O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ172.8,172.7(CO-α),171.6,171.5(CO-β),166.6(C-4),165.9(C-2),157.9(C-6),151.4(Ar-C),130.6(Ar-C),125.8,125.7(Ar-C),122.0(d,3JC,P=4.1Hz,Ar-C),121.9(d,3JC,P=4.4Hz,Ar-C),100.7,100.6(C-5),83.8(d,1JC,F=165.0Hz,C-3’),80.2,80.0,79.9,79.7,79.6,79.5,79.3(C-2’),67.0(d,1JC,P=157.5Hz,CH2P),66.6(d,1JC,P=150.0Hz,CH2P),66.5,66.4,65.7,65.6(OCH2(CH2)3CH3),65.3(d,3JC,F=7.5Hz,C-1’),51.5(C-α-Asp),39.8(d,3JC,P=4.0Hz,C-β-Asp),39.6(d,3JC,P=3.9Hz,C-β-Asp),29.0,28.9,28.8,28.7(OCH2(CH2)2CH2CH3),23.0,22.9(O(CH2)3CH2CH3),14.3(O(CH2)4CH3);31P NMR(121MHz,CD3CN):δ22.8,21.8;HRMS对于C28H42FN4O8P[M-H]-计算值:611.2651,发现值:611.2650。
实施例39:(S)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]
丙基}鸟嘌呤(29a)
根据一般程序,从化合物23a(30mg,0.09mmol)、天冬氨酸酯HCl盐(50mg,0.16mmol)、PhOH(40mg,0.41mmol)、Et3N(0.13mL,0.90mmol)、2,2’-二硫代二吡啶(145mg,0.65mmol)和PPh3(170mg,0.65mmol)的无水吡啶(3mL)开始。通过硅胶柱色谱法(梯度为DCM/MeOH,40:1,v/v;30:1,v/v)纯化粗残余物,得到化合物29a的三膦加合物。将收集的洗脱液蒸发并重新溶解在CH3CN/H2O(1:1,v/v,10mL)中。在0℃下加入1滴1M HCl溶液,然后将混合物在室温下搅拌另外1小时。用2M的TEAB中和该溶液。在除去所有挥发物后,将所得残余物通过RP-HPLC(CH3CN,H2O)纯化,得到无色油状物形式的化合物29a(3mg,5%)。1H NMR(300MHz,CD3CN):δ7.64(s,1H,H-8),7.61(s,1H,H-8),7.38-7.13(m,5H,ArH),4.74-3.92(m,13H,H-3’,H-2’,H-1’,2x OCH2(CH2)3CH3,PCH2,H-α-Asp,NHPO),2.82-2.54(m,2H,H-β-Asp),1.61-1.52(m,4H,2x OCH2CH2(CH2)2CH3),1.33-1.26(m,8H,2x O(CH2)2(CH2)2CH3),0.92-0.85(m,6H,O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ172.8,172.7(CO-α),171.6,171.5(CO-β),154.7,154.6(C-2),152.8(C-4),151.2(Ar-C),139.3(C-8),130.6(Ar-C),125.9,125.8(Ar-C),121.9(d,3JC,P=4.3Hz,Ar-C),121.7(d,3JC,P=4.4Hz,Ar-C),118.3(C-5,与CD3CN重叠),83.5(d,1JC,F=172.5Hz,C-3’),83.2(d,1JC,F=165.0Hz,C-3’),79.7,79.6,79.5(C-2’),66.7(d,1JC,P=157.5Hz,CH2P),66.6,66.5,65.8,65.7(OCH2(CH2)3CH3),51.6,51.5(C-1’),43.8(C-α-Asp),39.8,39.6(C-β-Asp),29.0,28.9,28.8,28.7(OCH2(CH2)2CH2CH3),23.0,22.9(O(CH2)3CH2CH3),14.3(O(CH2)4CH3);31P NMR(121MHz,CD3CN):δ22.3,21.5;HRMS对于C29H42FN6O8P[M-H]-计算值:651.2713,发现值:651.2733。
实施例40:(R)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]
丙基}鸟嘌呤(29b)
根据一般程序,从化合物23b(60mg,0.18mmol)、天冬氨酸酯HCl盐(100mg,0.32mmol)、PhOH(80mg,0.82mmol)、Et3N(0.26mL,1.80mmol)、2,2’-二硫代二吡啶(290mg,1.30mmol)和PPh3(340mg,1.30mmol)的无水吡啶(5mL)开始。通过硅胶柱色谱法(梯度为DCM/MeOH,40:1,v/v;30:1,v/v)纯化粗残余物,得到化合物28b的三膦加合物。将收集的洗脱液蒸发并重新溶解在CH3CN/H2O(1:1,v/v,10mL)中。在0℃下加入1滴1M HCl溶液,然后将混合物在室温下搅拌另外1小时。用2M的TEAB中和该溶液。在除去所有挥发物后,将所得残余物通过RP-HPLC(CH3CN,H2O)纯化,得到无色油状物形式的化合物29b(5mg,4%)。1H NMR(300MHz,CD3CN):δ7.67(s,1H,H-8),7.65(s,1H,H-8),7.38-7.09(m,5H,ArH),4.76-3.94(m,13H,H-3’,H-2’,H-1’,2x OCH2(CH2)3CH3,PCH2,H-α-Asp,NHPO),2.81-2.56(m,2H,H-β-Asp),1.59-1.52(m,4H,2x OCH2CH2(CH2)2CH3),1.32-1.28(m,8H,2x O(CH2)2(CH2)2CH3),0.92-0.86(m,6H,2x O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ172.8(CO-α),171.6(CO-β),158.6(C-6),154.6(C-2),152.7(C-4),151.4(Ar-C),139.3(C-8),130.7,130.6(Ar-C),125.9(Ar-C),121.8(t,3JC,P=4.7Hz,Ar-C),118.3(C-5,与CD3CN重叠),83.4(d,1JC,F=172.5Hz,C-3’),83.2(d,1JC,F=165.0Hz,C-3’),79.8,79.6,79.5,79.4(C-2’),66.9(d,1JC,P=150.0Hz,CH2P),66.6(d,1JC,P=157.5Hz,CH2P),66.5,65.8(OCH2(CH2)3CH3),51.5(C-1’),43.8(C-α-Asp),39.8,39.6(C-β-Asp),29.0,28.9,28.8,28.7(OCH2(CH2)2CH2CH3),23.0,22.9(O(CH2)3CH2CH3),14.3(O(CH2)4CH3);31P NMR(121MHz,CD3CN):δ22.3,21.7;HRMS对于C29H42FN6O8P[M-H]-计算值:651.2726,发现值:651.2733。
实施例41:(R)-2-氨基-6-氯-9-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}嘌呤(31a)
在室温下,将DIAD(0.24mL,1.20mmol)的无水THF(1mL)的溶液滴加到30(120mg,0.74mmol)、4a(150mg,0.61mmol)和Ph3P(300mg,1.20mmol)的无水THF(5mL)的混合物中。将反应混合物搅拌24小时,然后加入H2O(5mL)。将所得混合物回流24小时(以除去三苯基膦加合物)。在除去所有挥发物后,通过硅胶柱色谱(梯度为DCM/MeOH,50:1,v/v;30:1,v/v;25:1,v/v)纯化粗残余物,得到无色油状物形式的31a(200mg,83%)。1H NMR(300MHz,CDCl3):δ7.91(s,1H,H-8),5.50(s,1H,NH2),4.71-4.35(m,3H,H-3’,H-1’a),4.26-3.92(m,7H,H-1’b,H-2’,2x CH2CH3,PCH2a),3.83(dd,J=13.9,8.8Hz,1H,PCH2b),1.35-1.26(m,6H,2xCH2CH3);13C NMR(75MHz,CDCl3):δ159.5(C-2),154.1(C-4),151.5(C-6),143.5(C-8),125.1(C-5),82.0(d,1JC,P=173.9Hz,C-3’),78.4(dd,2JC,F=19.5Hz,3JC,P=9.6Hz,C-2’),64.7(d,1JC,P=167.1Hz,CH2P),62.9,62.8(CH2CH3),43.8(d,3JC,F=8.0Hz,C-1’),16.7,16.6(CH2CH3);31P NMR(121MHz,CDCl3):δ20.5;HRMS对于C13H20ClFN5O4P[M+H]+计算值:396.0998,发现值:396.1002。
实施例42:3.2.2(S)-2-氨基-6-氯-9-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}嘌呤(31b)
根据用于制备31a的程序,从30(250mg,1.47mmol)、4b(300mg,1.47mmol)、Ph3P(640mg,2.46mmol)和DIAD(0.48mL,2.46mmol)的无水THF(10mL)溶液开始得到无色油状物形式的化合物31b(300mg,70%)。通过硅胶柱色谱法(梯度为DCM/MeOH,50:1,v/v;30:1,v/v;25:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ7.90(s,1H,H-8),5.40(s,1H,NH2),4.71-4.34(m,3H,H-3’,H-1’a),4.25-3.79(m,8H,H-1’b,H-2’,2x CH2CH3,PCH2),1.35-1.24(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ159.5(C-2),154.2(C-4),151.5(C-6),143.6(C-8),125.1(C-5),82.0(d,1JC,P=173.7Hz,C-3’),78.4(dd,2JC,F=19.7Hz,3JC,P=9.5Hz,C-2’),64.8(d,1JC,P=167.0Hz,CH2P),62.9,62.8(CH2CH3),43.8(d,3JC,F=7.8Hz,C-1’),16.7,16.6(CH2CH3);31P NMR(121MHz,CDCl3):δ20.5;HRMS对于C13H20ClFN5O4P[M+H]+计算值:396.0998,发现值:396.0998。
实施例43:(R)-2-氨基-6-(4-甲氧基苯基硫代)-9-{2-[(二乙基磷酰基)甲氧基]-3-氟丙基}嘌呤(32a)
在室温下,将4-甲氧基硫代苯酚(0.12mL,0.96mmol)加入到31a(190mg,0.48mmol)和三乙胺(0.07mL,0.48mmol)的无水DMF(10mL)的混合物中,并将混合物在100℃下搅拌另外4小时。将溶液用EtOAc(100mL)稀释并用饱和NaHCO3(50mL)水溶液和盐水(50mL)洗涤。有机层用Na2SO4干燥、过滤并减压浓缩。然后,通过硅胶柱色谱(梯度为DCM/MeOH,60:1,v/v;50:1,v/v;40:1,v/v)纯化残余物,得到无色油状物形式的32a(210mg,87%)。1H NMR(600MHz,CDCl3):δ7.76(s,1H,H-8),7.52(d,J=8.9Hz,2H,ArH),6.94(d,J=8.9Hz,2H,ArH),4.88(s,2H,NH2),4.64-4.38(m,2H,H-3’),4.33-4.28(m,1H,H-1’a),4.19-4.04(m,6H,H-1’b,H-2’,2x CH2CH3),3.91(dd,J=13.9,8.7Hz,1H,PCH2a),3.85-3.77(m,4H,OCH3,PCH2b),1.34-1.27(m,6H,2x CH2CH3);13C NMR(150MHz,CDCl3):δ161.7(C-2),160.4(Ar-C),159.1(C-6),150.9(C-4),141.0(C-8),137.1(Ar-C),124.6(C-5),118.0(Ar-C),114.5(Ar-C),82.0(d,1JC,P=173.6Hz,C-3’),78.3(dd,2JC,F=19.2Hz,3JC,P=9.9Hz,C-2’),64.5(d,1JC,P=166.9Hz,CH2P),62.5,62.4(d,2JC,P=6.4Hz,CH2CH3),55.3(OCH3),43.1(d,3JC,F=7.9Hz,C-1’),16.4,16.3(CH2CH3);31P NMR(121MHz,CDCl3):δ19.9;HRMS对于C20H27FN5O5PS[M+H]+计算值:500.1527,发现值:500.1526。
实施例44:(S)-2-氨基-6-(4-甲氧基苯基硫代)-9-{2-[(二乙基磷酰基)甲氧基l]-3-氟丙基}嘌呤(32b)
根据用于32a的制备程序,从31b(190mg,0.48mmol)、4-甲氧基硫代苯酚(0.12mL,0.96mmol)和三乙胺(0.07mL,0.48mmol)的无水DMF(10mL)开始,得到无色油状物形式的化合物32b(160mg,67%)。通过硅胶柱色谱(梯度为DCM/MeOH,60:1,v/v;50:1,v/v;40:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ7.77(s,1H,H-8),7.53(d,J=8.8Hz,2H,ArH),6.95(d,J=8.8Hz,2H,ArH),5.03(s,1H,NH2),4.70-4.30(m,3H,H-3’,H-1’a),4.22-3.98(m,6H,H-1’b,H-2’,2x CH2CH3),3.93-3.77(m,5H,PCH2,OCH3),1.35-1.26(m,6H,2x CH2CH3);13CNMR(75MHz,CDCl3):δ162.1(C-2),160.9(Ar-C),159.0(C-6),151.0(C-4),141.7(C-8),137.5(Ar-C),124.9(C-5),118.0(Ar-C),115.0(Ar-C),82.3(d,1JC,P=173.7Hz,C-3’),78.7(dd,2JC,F=19.5Hz,3JC,P=9.9Hz,C-2’),64.9(d,1JC,P=166.9Hz,CH2P),62.9,62.8(CH2CH3),55.6(OCH3),43.6(d,3JC,F=8.1Hz,C-1’),16.8,16.7(CH2CH3);31P NMR(121MHz,CDCl3):δ20.5;HRMS对于C20H27FN5O5PS[M+H]+计算值:500.1527,发现值:500.1518。
实施例45:4-氯-5-氟-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶(35)
将4-氯-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶34(150mg,0.59mmol)和选择性氟试剂(320mg,0.90mmol)置于圆底烧瓶中,然后加入无水MeCN(6mL)和AcOH(0.6mL)。然后,将混合物在N2下在50℃下加热30分钟。然后,将混合物用冰水冷却并用CH2Cl2(50mL)稀释。有机层用饱和NaHCO3(50mL)洗涤。将无机层分离并用CH2Cl2(2×20ml)提取。将合并的有机层用Na2SO4干燥、过滤并减压浓缩。然后,通过硅胶柱色谱法(梯度为DCM/MeOH,200:1)纯化残余物,得到无色泡沫形式的35(48mg,30%)。1H NMR(300MHz,CDCl3):δ11.79(s,1H,NHCO),8.25(s,1H,H-6),1.39(s,9H,(CH3)3C);13C NMR(75MHz,CDCl3):176.5(NHCO),151.3(C-2),150.8(C-4),147.8(C-7a),141.4(d,1JC,F=248.8Hz,C-5),111.2(d,2JC,F=26.0Hz,C-6),103.6(d,2JC,F=14.9Hz,C-4a),40.5(C(CH3)3),27.7(C(CH3)3)。
实施例46:(R)-4-氯-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶(36a)
在室温下,将DIAD(0.24mL,1.20mmol)的无水THF(1mL)的溶液滴加到34(180mg,0.74mmol)、4a(150mg,0.61mmol)和Ph3P(300mg,1.20mmol)的无水THF(10mL)的混合物中。将反应混合物搅拌24小时,然后将它减压浓缩。通过硅胶柱色谱(梯度为DCM/MeOH,60:1,v/v;40:1,v/v;30:1,v/v)纯化粗残余物,得到无色油状物形式的36a(220mg,78%)。1H NMR(300MHz,CDCl3):δ8.16(s,1H,NHCO),7.29(dd,J=0.9Hz,1H,H-6),6.53(dd,J=3.6,0.9Hz,1H,H-6),4.74-4.31(m,4H,H-3’,H-1’),4.18-3.86(m,7H,H-2’,2x CH2CH3,PCH2),1.36-1.27(m,15H,(CH3)3C,2x CH2CH3);13C NMR(150MHz,CDCl3):δ175.7(NHCO),152.3(C-4,C-7a),151.6(C-2),130.1(C-6),114.2(C-4a),100.1(C-5),82.9(d,1JC,P=173.2Hz,C-3’),79.4(dd,2JC,F=19.1Hz,3JC,P=10.9Hz,C-2’),64.9(d,1JC,P=166.9Hz,CH2P),62.7,62.6(CH2CH3),44.9(d,3JC,F=8.5Hz,C-1’),40.5(C(CH3)3),27.7(C(CH3)3),16.7,16.6(CH2CH3);31P NMR(121MHz,CDCl3):δ20.9;HRMS对于C19H29ClFN4O5P[M+H]+计算值:479.1621,发现值:479.1617。
实施例47:(S)-4-氯-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶(36b)
根据用于制备36a的程序,从34(180mg,0.74mmol)、4b(230mg,1.47mmol)、Ph3P(300mg,1.20mmol)和DIAD(0.24mL,1.20mmol)的无水THF(10mL)溶液开始得到无色油状物形式的化合物36b(230mg,79%)。通过硅胶柱色谱(梯度为DCM/MeOH,60:1,v/v;40:1,v/v;30:1,v/v)纯化粗残余物。1H NMR(600MHz,CDCl3):δ8.13(s,1H,NHCO),7.30(dd,J=3.6,2.0Hz,1H,H-6),6.53(dd,J=3.6,2.5Hz,1H,H-6),4.69-4.59(m,1H,H-3’a),4.55-4.51(m,H-1’a),4.46-4.33(m,2H,H-3’b,H-1’b),4.15-4.08(m,5H,H-2’,2x CH2CH3),4.00-3.96(m,1H,PCH2a),3.92-3.88(m,1H,PCH2b),1.35-1.29(m,15H,(CH3)3C,2x CH2CH3);13C NMR(150MHz,CDCl3):δ175.5(NHCO),152.1(C-4,C-7a),151.3(C-2),129.8(C-6),113.9(C-4a),99.8(C-5),82.5(d,1JC,P=173.0Hz,C-3’),79.1(dd,2JC,F=19.0Hz,3JC,P=11.1Hz,C-2’),64.5(d,1JC,P=167.2Hz,CH2P),62.5,62.4(CH2CH3),44.5(d,3JC,F=8.5Hz,C-1’),40.2(C(CH3)3),27.4(C(CH3)3),16.4(CH2CH3);31P NMR(121MHz,CDCl3):δ20.9;HRMS对于C19H29ClFN4O5P[M+H]+计算值:479.1621,发现值:479.1624。
实施例48:(R)-4-氯-5-氟-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶(37a)
根据用于制备36a的程序,从35(200mg,0.74mmol)、4a(150mg,0.61mmol)、Ph3P(300mg,1.20mmol)和DIAD(0.24mL,1.20mmol)的无水THF(10mL)溶液开始得到无色油状物形式的化合物37a(70mg,25%)。通过硅胶柱色谱法(梯度为DCM/MeOH,80:1,v/v;60:1,v/v;40:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ8.13(s,1H,NHCO),7.10(d,J=2.6Hz,1H,H-6),4.72-3.96(m,9H,H-3’,H-1’,H-2’,2x CH2CH3),4.00(dd,J=13.8,8.7Hz,1H,PCH2a),3.88(dd,J=13.8,9.2Hz,1H,PCH2b),1.34-1.28(m,15H,(CH3)3C,2x CH2CH3);13CNMR(125MHz,CDCl3):δ175.6(NHCO),152.0(C-2),150.9(d,3JC,F=4.2Hz,C-4),147.9(C-7a),141.6(d,1JC,F=252.5Hz,C-5),112.5(d,2JC,F=26.5Hz,C-6),103.6(d,2JC,F=14.9Hz,C-4a),82.6(d,1JC,P=173.3Hz,C-3’),79.5,79.4,79.2,79.1(C-2’),64.8(d,1JC,P=166.9Hz,CH2P),62.7,62.6(CH2CH3),44.4(d,3JC,F=8.5Hz,C-1’),40.5(C(CH3)3),27.6(C(CH3)3),16.6,16.5(CH2CH3);31P NMR(121MHz,CDCl3):δ20.9;HRMS对于C19H28ClF2N4O5P[M+H]+计算值:497.1527,发现值:497.1523。
实施例49:(S)-4-氯-5-氟-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶(37b)
根据用于制备36a的程序,从35(200mg,0.74mmol)、4b(100mg,1.47mmol)、Ph3P(300mg,1.20mmol)和DIAD(0.24mL,1.20mmol)的无水THF(10mL)溶液开始得到无色油状物形式的化合物37b(100mg,33%)。通过硅胶柱色谱(梯度为DCM/MeOH,80:1,v/v;60:1,v/v;40:1,v/v)纯化粗残余物。1H NMR(600MHz,CDCl3):δ8.13(s,1H,NHCO),7.10(d,J=2.5Hz,1H,H-6),4.67-4.25(m,4H,H-3’,H-1’),4.18-4.02(m,5H,H-2’,2x CH2CH3),4.00(dd,J=13.8,8.7Hz,1H,PCH2a),3.89(dd,J=13.8,9.2Hz,1H,PCH2b),1.34-1.30(m,15H,(CH3)3C,2x CH2CH3);13C NMR(125MHz,CDCl3):δ175.5(NHCO),151.8(C-2),150.7(C-4),147.6(C-7a),141.3(d,1JC,F=252.3Hz,C-5),112.4(d,2JC,F=26.3Hz,C-6),103.4(d,2JC,F=14.9Hz,C-4a),82.4(d,1JC,P=173.3Hz,C-3’),79.2,79.0(C-2’),64.5(d,1JC,P=167.0Hz,CH2P),62.5(CH2CH3),44.1(d,3JC,F=8.5Hz,C-1’),40.3(C(CH3)3),27.4(C(CH3)3),16.4(CH2CH3);31P NMR(121MHz,CDCl3):δ20.8;HRMS对于C19H28ClF2N4O5P[M+H]+计算值:497.1527,发现值:497.1521。
实施例50:(R)-2-氨基-3,4-二氢-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-7H-吡咯并[2,3-d]嘧啶-4-酮(38a)
将36a(200mg,0.42mmol)、DABCO(46mg,0.42mmol)和K2CO3(58mg,0.42mmol)在二氧六环和H2O(6mL,5:1,v/v)的混合物溶剂中的混合物在90℃下搅拌3小时。然后,将反应减压浓缩,得到残余物,将其重新溶于30%的甲醇氨(20mL)中并在室温下搅拌12小时。在除去所有挥发物后,通过硅胶柱色谱(梯度为DCM/MeOH,20:1,v/v;15:1,v/v;10:1,v/v)纯化残余物,得到无色油状物形式的38a(100mg,64%)。1H NMR(300MHz,CDCl3):δ11.01(s,1H,NHCO),6.59(dd,J=3.5,0.9Hz,1H,H-6),6.50(dd,J=3.5,0.9Hz,1H,H-5),6.23(s,2H,NH2),4.67-4.28(m,2H,H-3’),4.23-4.10(m,6H,H-1’,2x CH2CH3),4.05-3.91(m,2H,H-2’,PCH2a),3.85-3.77(m,1H,PCH2b),1.37-1.31(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ160.7(C-4),152.8(C-2),151.1(C-7a),121.6(C-6),102.6(C-4a),101.3(C-5),82.2(d,1JC,P=173.4Hz,C-3’),79.6(dd,2JC,F=18.7Hz,3JC,P=11.5Hz,C-2’),64.7(d,1JC,P=168.3Hz,CH2P),62.3,62.2(CH2CH3),44.5(d,3JC,F=8.0Hz,C-1’),16.7,16.6(CH2CH3);31PNMR(121MHz,CDCl3):δ21.0;HRMS对于C14H22FN4O5P[M+H]+计算值:377.1384,发现值:377.1387。
实施例51:(S)-2-氨基-3,4-二氢-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-7H-吡咯并[2,3-d]嘧啶-4-酮(38b)
根据用于制备38a的程序,从在二氧六环和H2O(6mL,5:1,v/v)以及NH3/MeOH(20mL)的混合物溶剂中的36b(100mg,0.21mmol)、DABCO(23mg,0.21mmol)和K2CO3(29mg,0.21mmol)开始,得到无色油状物形式的化合物38b(50mg,64%)。通过硅胶柱色谱(梯度为DCM/MeOH,20:1,v/v;15:1,v/v;10:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ11.04(s,1H,NHCO),6.60(d,J=3.4Hz,1H,H-6),6.49(d,J=3.5Hz,1H,H-5),6.21(s,2H,NH2),4.67-4.29(m,2H,H-3’),4.22-4.11(m,6H,H-1’,2x CH2CH3),4.04-3.93(m,2H,H-2’,PCH2a),3.86-3.78(m,1H,PCH2b),1.36-1.30(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ160.6(C-4),152.7(C-2),150.7(C-7a),121.6(C-6),102.6(C-4a),101.2(C-5),82.2(d,1JC,P=173.6Hz,C-3’),79.6(C-2’),64.7(d,1JC,P=168.3Hz,CH2P),62.3,62.2(CH2CH3),44.6(d,3JC,F=8.0Hz,C-1’),16.7,16.6(CH2CH3);31P NMR(121MHz,CDCl3):δ21.0;HRMS对于C14H22FN4O5P[M+H]+计算值:377.1384,发现值:377.1384。
实施例52:(R)-2-氨基-5-氟-3,4-二氢-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-7H-吡咯并[2,3-d]嘧啶-4-酮(39a)
根据用于制备38a的程序,从37a(60mg,0.12mmol)、DABCO(14mg,0.12mmol)和K2CO3(17mg,0.12mmol)在二氧六环和H2O(6mL,5:1,v/v)以及NH3/MeOH(20mL)的混合物溶剂开始,得到无色油状物形式的化合物39a(20mg,30%)。通过硅胶柱色谱法(梯度为DCM/MeOH,18:1,v/v;15:1,v/v;10:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ6.42(d,J=2.3Hz,1H,H-6),5.99(s,2H,NH2),4.66-3.83(m,11H,H-3’,H-1’,H-2’,2x CH2CH3,PCH2),1.37-1.32(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ158.4(d,2JC,F=2.6Hz,C-4),152.3(C-2),146.7(C-7a),145.4(d,1JC,F=248.6Hz,C-5),103.6(d,2JC,F=26.7Hz,C-6),90.6(d,2JC,F=13.9Hz,C-4a),81.9(d,1JC,P=173.2Hz,C-3’),79.0(dd,2JC,F=19.0Hz,3JC,P=10.8Hz,C-2’),64.2(d,1JC,P=167.5Hz,CH2P),62.4,62.3(CH2CH3),43.5(d,3JC,F=7.9Hz,C-1’),16.1,16.0(CH2CH3);31P NMR(121MHz,CDCl3):δ20.3;HRMS对于C14H21F2N4O5P[M+H]+计算值:395.1290,发现值:395.1284。
实施例53:(S)-2-氨基-5-氟-3,4-二氢-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-7H-吡咯并[2,3-d]嘧啶-4-酮(39b)
根据用于制备38a的程序,从在二氧六环和H2O(6mL,5:1,v/v)以及NH3/MeOH(20mL)的混合物溶剂中的37b(90mg,0.18mmol)、DABCO(20mg,0.18mmol)和K2CO3(25mg,0.18mmol)开始,得到无色油状物形式的化合物39b(25mg,35%)。通过硅胶柱色谱法(梯度为DCM/MeOH,18:1,v/v;15:1,v/v;10:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ6.41(d,J=2.4Hz,1H,H-6),6.00(s,2H,NH2),4.66-3.82(m,11H,H-3’,H-1’,H-2’,2x CH2CH3,PCH2),1.36-1.31(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ159.0(C-4),152.9(C-2),147.3(C-7a),146.1(d,1JC,F=248.6Hz,C-5),104.2(d,2JC,F=26.5Hz,C-6),91.2(d,2JC,F=13.7Hz,C-4a),82.5(d,1JC,P=173.1Hz,C-3’),79.6(dd,2JC,F=19.2Hz,3JC,P=11.1Hz,C-2’),64.8(d,1JC,P=167.6Hz,CH2P),63.0,62.9(CH2CH3),44.2(d,3JC,F=7.9Hz,C-1’),16.7,16.6(CH2CH3);31P NMR(121MHz,CDCl3):δ20.9;HRMS对于C14H21F2N4O5P[M+H]+计算值:395.1290,发现值:395.1286。
实施例54:4-氯-5-氰基-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶(46)
使用POCl3(2.95g,19.30mmol)逐滴处理干燥MeCN(3mL)中的5-氰基-3,4-二氢-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶-4-酮45(500mg,1.93mmol)、N,N-二甲基苯胺(980mg,8.10mmol)和三乙基苄基氯化铵(220mg,0.96mmol)。将反应混合物回流1小时,使其冷却并真空浓缩。用冰小心地处理所得的黑色油,并使用33%的H2O中的氨将其设定为pH=5。水层用EtOAc(2×50mL)提取。将合并的有机层用Na2SO4干燥、过滤并减压浓缩。然后,通过硅胶柱色谱(梯度为己烷:EtOAc,3:1,v/v;1:1,v/v)纯化残余物,得到白色粉末形式的46(350mg,65%)。1H NMR(300MHz,CDCl3):δ10.30(s,1H,NHCO),8.52(s,1H,H-6),1.24(s,9H,(CH3)3C);13C NMR(75MHz,CDCl3):δ176.0(NHCO),153.2,152.9,150.8(C-4,C-7a,C-2),137.7(C-6),114.6(C-5),111.3(C-4a),83.5(CN),40.5-38.8(C(CH3)3,与DMSO重叠),26.9(C(CH3)3)。
实施例55:(R)-4-氯-5-氰基-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶(47a)
根据用于制备36a的程序,从46(150mg,0.54mmol)、4a(120mg,0.49mmol)、Ph3P(260mg,0.98mmol)和DIAD(0.19mL,0.98mmol)的无水THF(10mL)溶液开始得到无色油状物形式的化合物47a(220mg,80%)。通过硅胶柱色谱法(梯度为DCM/MeOH,50:1,v/v;40:1,v/v;30:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ8.24(s,1H,NHCO),7.91(s,1H,H-6),4.74-4.29(m,4H,H-3’,H-1’),4.17-3.96(m,6H,H-2’,2x CH2CH3,PCH2a),3.81(dd,J=13.9,9.0Hz,1H,PCH2b),1.34-1.25(m,15H,(CH3)3C,2x CH2CH3);13C NMR(75MHz,CDCl3):δ175.8(NHCO),153.4,153.2,152.3(C-4,C-7a,C-2),138.2(C-6),113.5(C-5),112.1(C-4a),86.0(CN),82.3(d,1JC,P=174.0Hz,C-3’),78.7(dd,2JC,F=19.2Hz,3JC,P=9.8Hz,C-2’),64.7(d,1JC,P=167.1Hz,CH2P),62.9,62.8(CH2CH3),45.6(d,3JC,F=8.4Hz,C-1’),40.6(C(CH3)3),27.6(C(CH3)3),16.7(CH2CH3);31P NMR(121MHz,CDCl3):δ20.7;HRMS对于C20H28ClFN5O5P[M+H]+计算值:504.1573,发现值:504.1567。
实施例56:(S)-4-氯-5-氰基-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-2-新戊酰基氨基-7H-吡咯并[2,3-d]嘧啶(47b)
根据用于制备36a的程序,从46(150mg,0.54mmol)、4b(120mg,0.49mmol)、Ph3P(260mg,0.98mmol)和DIAD(0.19mL,0.98mmol)的无水THF(10mL)溶液开始得到无色油状物形式的化合物47b(150mg,60%)。通过硅胶柱色谱(梯度为DCM/MeOH,50:1,v/v;40:1,v/v;30:1,v/v)纯化粗残余物。1H NMR(300MHz,CDCl3):δ8.24(s,1H,NHCO),7.92(s,1H,H-6),4.74-4.30(m,4H,H-3’,H-1’),4.15-3.96(m,6H,H-2’,2x CH2CH3,PCH2a),3.81(dd,J=13.9,9.0Hz,1H,PCH2b),1.35-1.26(m,15H,(CH3)3C,2x CH2CH3);13C NMR(75MHz,CDCl3):δ175.7(NHCO),153.2,153.0,152.1(C-4,C-7a,C-2),138.1(C-6),113.4(C-5),111.9(C-4a),85.8(CN),82.1(d,1JC,P=174.0Hz,C-3’),78.5(dd,2JC,F=19.2Hz,3JC,P=9.9Hz,C-2’),64.5(d,1JC,P=167.0Hz,CH2P),62.8-62.6(CH2CH3),45.4(d,3JC,F=8.6Hz,C-1’),40.5(C(CH3)3),27.5(C(CH3)3),16.6,16.5(CH2CH3);31P NMR(121MHz,CDCl3):δ20.7;HRMS对于C20H28ClFN5O5P[M+H]+计算值:504.1573,发现值:504.1578。
实施例57:(R)-2-氨基-5-氰基-3,4-二氢-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-7H-吡咯并[2,3-d]嘧啶-4-酮(48a)
根据用于制备38a的程序,从在二氧六环和H2O(6mL,5:1,v/v)以及NH3/MeOH(20mL)的混合物溶剂中的47a(220mg,0.44mmol)、DABCO(33mg,0.30mmol)和K2CO3(61mg,0.44mmol)开始,得到无色油状物形式的化合物48a(50mg,30%)。通过硅胶柱色谱法(梯度为DCM/MeOH,20:1,v/v;15:1,v/v;10:1,v/v)纯化残余物。1H NMR(300MHz,CDCl3):δ10.89(s,1H,NHCO),7.30(d,J=1.1Hz,1H,H-6),6.16(s,2H,NH2),4.71-4.29(m,3H,H-3’,H-1’a),4.21-3.93(m,7H,H-1’b,H-2’,2x CH2CH3,PCH2a),3.83(dd,J=13.8,9.1Hz,1H,PCH2b),1.38-1.32(m,6H,2x CH2CH3);13C NMR(75MHz,CDCl3):δ159.2(C-4),154.0(C-2),152.2(C-7a),130.9(C-6),115.5(C-5),99.6(C-4a),86.7(CN),82.4(d,1JC,P=173.6Hz,C-3’),79.1(dd,2JC,F=19.1Hz,3JC,P=10.4Hz,C-2’),64.8(d,1JC,P=167.7Hz,CH2P),62.9,62.8(CH2CH3),45.2(d,3JC,F=8.1Hz,C-1’),16.8,16.7(CH2CH3);31P NMR(121MHz,CDCl3):δ20.7;HRMS对于C15H21FN5O5P[M+H]+计算值:402.1336,发现值:402.1324。
实施例58:(S)-2-氨基-5-氰基-3,4-二氢-7-{2-[(二乙基磷酰基)-甲氧基]-3-氟丙基}-7H-吡咯并[2,3-d]嘧啶-4-酮(48b)
在室温下将DMF(5mL)中的47b(150mg,0.30mmol)、Et3N(0.12mL,0.89mmol)、NaOAc(73mg,0.89mmol)和DABCO(33mg,0.30mmol)的混合物搅拌40小时。然后,将H2O(5mL)加入到反应中并搅拌另外1小时。用EtOAc(2x 25mL)提取混合物。将合并的有机相用Na2SO4干燥,过滤并减压浓缩,得到粗产物。然后,将残余物溶解在30%的甲醇氨(20mL)中并在室温下搅拌12小时。在除去所有挥发物后,通过硅胶柱色谱(梯度为DCM/MeOH,20:1,v/v;15:1,v/v;10:1,v/v)纯化残余物,得到无色油状物形式的48b(80mg,67%)。1H NMR(300MHz,CDCl3):δ10.89(s,1H,NHCO),7.30(d,J=1.1Hz,1H,H-6),4.71-4.28(m,3H,H-3’,H-1’a),4.21-3.93(m,7H,H-1’b,H-2’,2x CH2CH3,PCH2a),3.87-3.80(m,1H,PCH2b),1.38-1.32(m,6H,2xCH2CH3);13C NMR(75MHz,CDCl3):δ159.2(C-4),154.0(C-2),152.2(C-7a),130.9(C-6),115.5(C-5),99.5(C-4a),86.6(CN),82.4(d,1JC,P=173.5Hz,C-3’),79.1(dd,2JC,F=19.2Hz,3JC,P=10.4Hz,C-2’),64.8(d,1JC,P=167.2Hz,CH2P),63.0,62.9(CH2CH3),45.2(d,3JC,F=8.2Hz,C-1’),16.8,16.7(CH2CH3);31P NMR(121MHz,CDCl3):δ20.7;HRMS对于C15H21FN5O5P[M+H]+计算值:402.1336,发现值:402.1329。
实施例59:(R)-2-氨基-6-(4-甲氧基苯基硫代)-9-[2-(膦酰基甲氧基)-3-氟丙基]嘌呤(33a)
在0℃下,将溴代三甲基硅烷(0.43mL,3.20mmol)滴加到二乙基膦酸酯32a(200mg,0.40mmol)和2,6-二甲基吡啶(0.74mL,6.40mmol)的无水乙腈(10mL)的溶液中。在完成添加后,将混合物缓慢升温至室温,并在黑暗中放置12小时。反应用0.1M TEAB淬灭,然后减压浓缩。通过硅胶柱色谱(梯度为丙酮/Et3N/H2O,6:1:1,v/v/v),随后RP-HPLC(线性梯度,2-98%CH3CN的0.05M TEAB溶液)纯化粗残余物,得到白色泡沫形式的期望的膦酸三乙铵盐33a(120mg,70%)。1H NMR(300MHz,D2O):δ7.93(s,1H,H-8),7.19(d,J=8.8Hz,2H,ArH),6.73-6.70(m,2H,ArH),4.60-4.21(m,2H,H-3’),4.18-4.08(m,2H,H-1’),3.89-3.81(m,1H,H-2’),3.61(s,3H,OCH3),3.59-3.41(m,2H,PCH2);13C NMR(75MHz,D2O):δ161.1(C-2),160.0(Ar-C),159.3(C-6),150.1(C-4),142.8(C-8),136.8(Ar-C),123.0(C-5),116.8(Ar-C),114.8(Ar-C),82.1(d,1JC,P=168.0Hz,C-3’),77.4(dd,2JC,F=18.9Hz,3JC,P=11.2Hz,C-2’),66.9(d,1JC,P=154.8Hz,CH2P),55.3(OCH3),42.7(d,3JC,F=7.1Hz,C-1’);31P NMR(121MHz,D2O):δ14.1;HRMS对于C16H19FN5O5PS[M-H]-计算值:442.0756,发现值:442.0752。
实施例60:(S)-2-氨基-6-(4-甲氧基苯基硫代)-9-[2-(膦酰基甲氧基)-3-氟丙基]嘌呤(33b)
根据用于33a的制备程序,从化合物32b(150mg,0.30mmol)、溴三甲基硅烷(0.32mL,2.40mmol)和2,6-二甲基吡啶(0.56mL,4.80mmol)的无水乙腈(10mL)开始,得到白色泡沫形式的化合物33b(86mg,65%)。通过硅胶柱色谱法(梯度为丙酮/Et3N/H2O,6:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ7.95(s,1H,H-8),7.22(d,J=8.4Hz,2H,ArH),6.82-6.65(m,2H,ArH),4.63-4.24(m,2H,H-3’),4.20-4.10(m,2H,H-1’),3.93-3.85(m,1H,H-2’),3.64(s,3H,OCH3),3.61-3.45(m,2H,PCH2);13C NMR(75MHz,D2O):δ161.1(C-2),160.0(Ar-C),159.3(C-6),150.1(C-4),142.8(C-8),136.8(Ar-C),123.0(C-5),116.8(Ar-C),114.8(Ar-C),82.1(d,1JC,P=168.1Hz,C-3’),77.5(dd,2JC,F=18.9Hz,3JC,P=11.1Hz,C-2’),66.7(d,1JC,P=155.5Hz,CH2P),55.3(OCH3),42.8(d,3JC,F=7.1Hz,C-1’);31P NMR(121MHz,D2O):δ14.3;HRMS对于C16H19FN5O5PS[M-H]-计算值:442.0756,发现值:442.0734。
实施例61:(R)-2-氨基-3,4-二氢-7-(2-膦酰基甲氧基-3-氟丙基)-7H-吡咯并[2,3-d]嘧啶-4-酮(40a)
根据用于33a的制备程序,从化合物38a(100mg,0.26mmol)、溴三甲基硅烷(0.28mL,2.12mmol)和2,6-二甲基吡啶(0.50mL,4.24mmol)的无水乙腈(10mL)开始,得到白色泡沫形式的化合物40a(59mg,70%)。通过硅胶柱色谱(梯度为丙酮/Et3N/H2O,4:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ6.65(d,J=3.7Hz,1H,H-6),6.17(d,J=3.6Hz,1H,H-5),4.50-4.04(m,2H,H-3’),4.95-3.93(m,2H,H-1’),3.83-3.70(m,1H,H-2’),3.41(d,J=9.2Hz,2H,PCH2);13C NMR(75MHz,D2O):δ160.8(C-4),152.0(C-2),150.3(C-7a),123.1(C-6),100.9(C-5),99.5(C-4a),82.3(d,1JC,P=167.3Hz,C-3’),78.0(dd,2JC,F=18.4Hz,3JC,P=10.7Hz,C-2’),67.6(d,1JC,P=151.9Hz,CH2P),43.4(d,3JC,F=7.3Hz,C-1’);31P NMR(121MHz,D2O):δ12.3;HRMS对于C10H14FN4O5P[M-H]-计算值:319.0612,发现值:319.0611。
实施例62:(S)-2-氨基-3,4-二氢-7-(2-膦酰基甲氧基l-3-氟丙基)-7H-吡咯并[2,3-d]嘧啶-4-酮(40b)
根据用于33a的制备程序,从化合物38b(50mg,0.13mmol)、溴三甲基硅烷(0.14mL,1.06mmol)和2,6-二甲基吡啶(0.25mL,2.12mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物40b(30mg,70%)。通过硅胶柱色谱法(梯度为丙酮/Et3N/H2O,4:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ6.73(d,J=3.5Hz,1H,H-6),6.25(d,J=3.5Hz,1H,H-5),4.56-4.11(m,2H,H-3’),4.09-3.98(m,2H,H-1’),3.90-3.78(m,1H,H-2’),3.42(d,J=9.2Hz,2H,PCH2);13C NMR(75MHz,D2O):δ166.0(C-4),156.5(C-2),151.1(C-7a),122.3(C-6),100.6(C-4a,C-5),82.4(d,1JC,P=167.0Hz,C-3’),78.0(dd,2JC,F=18.2Hz,3JC,P=10.4Hz,C-2’),68.1(d,1JC,P=150.0Hz,CH2P),43.2(d,3JC,F=7.2Hz,C-1’);31P NMR(121MHz,D2O):δ12.6;HRMS对于C10H14FN4O5P[M-H]-计算值:319.0612,发现值:319.0598。
实施例63:(R)-2-氨基-5-氟-3,4-二氢-7-{2-膦酰基甲氧基-3-氟丙基}-7H-吡咯并[2,3-d]嘧啶-4-酮(41a)
根据用于33a的制备程序,从化合物39a(20mg,0.05mmol)、溴三甲基硅烷(0.05mL,0.40mmol)和2,6-二甲基吡啶(0.09mL,0.81mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物41a(9mg,50%)。通过硅胶柱色谱(梯度为丙酮/Et3N/H2O,4:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ6.56(d,J=2.1Hz,1H,H-6),4.59-4.16(m,2H,H-3’),4.00-3.98(m,2H,H-1’),3.90-3.81(m,1H,H-2’),3.49(d,J=9.1Hz,2H,PCH2);13C NMR(75MHz,D2O):δ159.5(d,3JC,F=2.8Hz,C-4),152.3(C-2),146.0(d,3JC,F=3.0Hz,C-7a),144.6(d,1JC,F=246.3Hz,C-5),105.1(d,1JC,F=26.6Hz,C-6),90.0(d,1JC,F=14.4Hz,C-4a),82.4(d,1JC,P=167.2Hz,C-3’),78.1(dd,2JC,F=18.3Hz,3JC,P=10.4Hz,C-2’),67.2(d,1JC,P=153.2Hz,CH2P),43.2(d,3JC,F=7.4Hz,C-1’);31P NMR(121MHz,D2O):δ13.8;HRMS对于C10H13F2N4O5P[M-H]-计算值:337.0519,发现值:337.0503。
实施例64:(S)-2-氨基-5-氟-3,4-二氢-7-{2-膦酰基甲氧基-3-氟丙基}-7H-吡咯并[2,3-d]嘧啶-4-酮(41b)
根据用于33a的制备程序,从化合物39b(20mg,0.05mmol)、溴三甲基硅烷(0.05mL,0.40mmol)和2,6-二甲基吡啶(0.09mL,0.81mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物41b(10mg,60%)。通过硅胶柱色谱法(梯度为丙酮/Et3N/H2O,4:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ6.52(d,J=2.2Hz,1H,H-6),4.57-4.09(m,2H,H-3’),4.07-3.92(m,2H,H-1’),3.89-3.77(m,1H,H-2’),3.43(d,J=9.1Hz,2H,PCH2);13C NMR(75MHz,D2O):δ167.1(C-4),159.1(C-2),147.4(C-7a),144.6(d,1JC,F=244.3Hz,C-5),103.5(d,2JC,F=27.2Hz,C-6),91.2(d,2JC,F=14.4Hz,C-4a),82.4(d,1JC,P=166.9Hz,C-3’),77.9(dd,2JC,F=18.2Hz,3JC,P=10.3Hz,C-2’),68.1(d,1JC,P=150.1Hz,CH2P),42.7(d,3JC,F=7.2Hz,C-1’);31P NMR(121MHz,D2O):δ12.7;HRMS对于C10H13F2N4O5P[M-H]-计算值:337.0519,发现值:337.0522。
实施例65:(R)-2-氨基-5-氰基-3,4-二氢-7-{2-膦酰基甲氧基-3-氟丙基}-7H-吡咯并[2,3-d]嘧啶-4-酮(49a)
根据用于33a的制备程序,从化合物48a(50mg,0.13mmol)、溴三甲基硅烷(0.13mL,1.00mmol)和2,6-二甲基吡啶(0.23mL,2.00mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物49a(30mg,70%)。通过硅胶柱色谱(梯度为丙酮/Et3N/H2O,5:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ7.51(s,1H,H-6),4.60-4.21(m,2H,H-3’),4.10-4.08(m,2H,H-1’),3.90-3.83(m,1H,H-2’),3.44(d,J=9.1Hz,2H,PCH2);13C NMR(75MHz,D2O):δ162.0(C-4),155.6(C-2),151.1(C-7a),132.6(C-6),116.2(C-5),99.3(C-4a),84.3(CN),82.2(d,1JC,P=167.1Hz,C-3’),77.3(dd,2JC,F=18.6Hz,3JC,P=10.5Hz,C-2’),68.0(d,1JC,P=149.9Hz,CH2P),44.1(d,3JC,F=7.0Hz,C-1’);31P NMR(121MHz,D2O):δ12.5;HRMS对于C11H13FN5O5P[M-H]-计算值:344.0565,发现值:344.0573。
实施例66:(S)-2-氨基-5-氰基-3,4-二氢-7-{2-膦酰基甲氧基-3-氟丙基}-7H-吡咯并[2,3-d]嘧啶-4-酮(49b)
根据用于33a的制备程序,从化合物48b(80mg,0.20mmol)、溴三甲基硅烷(0.21mL,1.60mmol)和2,6-二甲基吡啶(0.37mL,3.20mmol)的无水乙腈(5mL)开始,得到白色泡沫形式的化合物49b(51mg,75%)。通过硅胶柱色谱(梯度为丙酮/Et3N/H2O,5:1:1,v/v/v)纯化粗残余物。1H NMR(300MHz,D2O):δ7.40(d,J=1.1Hz,1H,H-6),4.70-4.20(m,2H,H-3’),4.08-3.93(m,2H,H-1’),3.90-3.78(m,1H,H-2’),3.58-3.42(m,2H,PCH2);13C NMR(75MHz,D2O):δ159.0(C-4),153.3(C-2),150.7(C-7a),132.7(C-6),115.7(C-5),98.7(C-4a),84.6(CN),82.2(d,1JC,P=167.7Hz,C-3’),77.7(dd,2JC,F=18.5Hz,3JC,P=11.3Hz,C-2’),66.7(d,1JC,P=155.2Hz,CH2P),44.3(d,3JC,F=7.6Hz,C-1’);31P NMR(121MHz,D2O):δ14.3;HRMS对于C11H13FN5O5P[M-H]-计算值:344.0565,发现值:344.0557。
实施例67:二戊基(((((R)-1-(2-氨基-4-氧代-3,4-二氢-7H-吡咯并[2,3-d]嘧啶-7-基)-3-氟丙烷-2-基)氧基)甲基)(苯氧基)磷酰基)-L-天门冬氨酸酯(50)
将化合物40a(40mg,0.09mmol,Et3N盐)与L-天冬氨酸戊二酯HCl盐(Maiti,M.;Maiti,M.;Rozenski,J.;De Jonghe,S.;Herdewijn,P.Aspartic acid based nucleosidephosphoramidate prodrugs as potent inhibitors of hepatitis C virusreplication.Org.Biomol.Chem.2015,13,5158-5174)(50mg,0.16mmol)以及苯酚(40mg,0.42mmol)的无水吡啶(53mL)混合。然后,加入Et3N(0.13mL,0.95mmol),并将混合物在60℃下在氮气气氛下搅拌15-20分钟。在单独的烧瓶中将2,2’-二硫代二吡啶(150mg,0.66mmol)与PPh3(180mg,0.66mmol)的无水吡啶(2mL)溶液混合,并将所得的混合物搅拌10-15分钟,得到澄清的淡黄色溶液。然后,将该溶液加入到上述溶液中,并将合并的混合物在60℃下搅拌12小时。然后,将混合物减压浓缩得到残余物,将其重新溶于EtOAc(50mL)中。该溶液用饱和NaHCO3(25mL)水溶液和盐水(25mL)洗涤,分离有机层,用Na2SO4干燥,过滤,并减压浓缩。通过硅胶色谱(梯度为DCM/MeOH,30:1,v/v;20:1,v/v),然后通过RP-HPLC(线性梯度,5-95%CH3CN的水溶液)纯化粗残余物,得到白色粉末形式的化合物50(60mg,40%)。1H NMR(300MHz,CD3CN):δ10.08(s,1H,NHCO),7.37-7.08(m,5H,ArH),6.72-6.69(m,1H,H-6),6.40-6.38(m,1H,H-5),5.80,5.78(s,2H,NH2),4.70-4.25(m,4H,H-3’,NHPO,H-α-Asp),4.16-3.89(m,9H,H-1’,H-2’,2x OCH2(CH2)3CH3,PCH2),2.84-2.57(m,2H,H-β-Asp),1.58-1.52(m,4H,2x OCH2CH2(CH2)2CH3),1.32-1.24(m,8H,2x O(CH2)2(CH2)2CH3),0.91-0.84(m,6H,2x O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ172.9,172.8,172.7(CO-α),171.6(CO-β),160.5(C-4),153.5,153.4(C-2),152.0,151.9(C-7a),130.7(Ar-C),125.9(Ar-C),122.4(C-6),121.9,121.8(Ar-C),102.7(C-5),101.7(C-4a),83.6(d,1JC,F=170.3Hz,C-3’),83.5(d,1JC,F=170.0Hz,C-3’),80.7,80.5,80.4,80.3,80.1(C-2’),66.8(d,1JC,P=156.2Hz,CH2P),66.6(d,1JC,P=154.2Hz,CH2P),66.6,65.9,65.8(OCH2(CH2)3CH3),51.7,51.6(C-α-Asp),45.1,45.0,44.9(C-1’),39.9(d,3JC,P=3.9Hz,C-β-Asp),39.7(d,3JC,P=3.9Hz,C-β-Asp),29.1,29.0,28.8,28.7(OCH2(CH2)2CH2CH3),23.1,23.0(O(CH2)3CH2CH3),14.3(O(CH2)4CH3);31P NMR(121MHz,CD3CN):δ23.0,22.2;HRMS对于C30H43FN5O8P[M+H]+计算值:652.2905,发现值:652.2923。
实施例68:四戊基2,2’-((((((R)-1-(2-氨基-4-氧代-3,4-二氢-7H-吡咯并[2,3-d]嘧啶-7-基)-3-氟丙烷-2-基)氧基)甲基)磷酰基)双(氮烷二基))(2S,2’S)-丁二酸氢酯(51)
将化合物40a(15mg,0.04mmol,Et3N盐)与L-天冬氨酸戊二酯HCl盐(Maiti,M.;Maiti,M.;Rozenski,J.;De Jonghe,S.;Herdewijn,P.Aspartic acid based nucleosidephosphoramidate prodrugs as potent inhibitors of hepatitis C virusreplication.Org.Biomol.Chem.2015,13,5158-5174)(44mg,0.14mmol)的无水吡啶(3mL)混合。然后,加入Et3N(0.04mL,0.40mmol),并将混合物在60℃下在氮气气氛下搅拌15-20分钟。在单独的烧瓶中将2,2’-二硫代二吡啶(55mg,0.25mmol)与PPh3(65mg,0.25mmol)的无水吡啶(2mL)溶液混合,并将所得的混合物搅拌10-15分钟,得到澄清的淡黄色溶液。然后,将该溶液加入到上述溶液中,并将合并的混合物在60℃下搅拌12小时。然后,将混合物减压浓缩得到残余物,将其重新溶于EtOAc(50mL)中。该溶液用饱和NaHCO3(25mL)水溶液和盐水(25mL)洗涤,分离有机层,用Na2SO4干燥,过滤,并减压浓缩。通过硅胶色谱(梯度为DCM/MeOH,30:1,v/v;20:1,v/v),然后通过RP-HPLC(线性梯度,5-95%的CH3CN的水溶液)纯化粗残余物,得到白色粉末形式的化合物51(5mg,20%)。1H NMR(300MHz,CD3CN):δ9.87(s,1H,NHCO),6.63(d,J=3.5Hz,1H,H-6),6.32(d,J=3.5Hz,1H,H-5),6.06(s,2H,NH2),4.68,3.74(m,19H,H-3’,2x NHPO,2x H-α-Asp,H-1’,H-2’,4x OCH2(CH2)3CH3,PCH2),2.89-2.73(m,4H,2x H-β-Asp),1.61-1.53(m,8H,4x OCH2CH2(CH2)2CH3),1.33-1.24(m,16H,4x O(CH2)2(CH2)2CH3),0.91-0.84(m,12H,4x O(CH2)4CH3);13C NMR(75MHz,CD3CN):δ173.3,173.2(CO-α),171.9,171.8(CO-β),160.0(C-4),153.7(C-2),151.6(C-7a),122.1(C-6),102.8(C-5),101.8(C-4a),83.1(d,1JC,F=170.2Hz,C-3’),80.13(dd,2JC,F=18.7Hz,3JC,P=11.5Hz,C-2’),68.1(d,1JC,P=136.9Hz,CH2P),66.6,66.5,65.8(OCH2(CH2)3CH3),51.1,50.5(C-α-Asp),44.86(d,J=8.1Hz,C-1’),40.0,39.9,39.8(d,3JC,P=3.9Hz,C-β-Asp),29.1,29.0,28.8(OCH2(CH2)2CH2CH3),23.1,23.0(O(CH2)3CH2CH3),14.3(O(CH2)4CH3);31P NMR(121MHz,CD3CN):δ21.5;HRMS对于C38H64FN6O11P[M-H]-计算值:829.4282,发现值:829.4298。
实施例69:HepG2 2.2.15细胞中的HBV抗病毒测定
如前所述进行初级抗HBV测定(Korba,BF和Milman,G.A cell culture assay forcompound which inhibit hepatitis B virus replication.Antiviral Res.1991,15,217-228;以及Korba,BF和Gerin,JL.Use of a standardized cell culture assay toassess activities of nucleoside analogs again hepatitis B virusreplication.Antiviral Res.1992,19,55-70),其中修改为使用实时qPCR(TaqMan)来测量与从HepG2 2.2.15细胞释放的病毒粒子相关的细胞外HBV DNA拷贝数。HepG2 2.2.15细胞系是稳定的人类肝母细胞瘤细胞系,其含有HBV野生型菌株ayw1基因组的两个拷贝,并且组成性地产生高水平的HBV。可使用该细胞系鉴定和表征阻断病毒复制的任何后期步骤如转录、转译、前基因组衣壳化、逆转录、病毒颗粒组装和释放的抗病毒化合物。
简言之,在补充有2%的FBS,380μg/mL的G418,2.0mM的L-谷氨酰胺,100单位/mL的青霉素,100μg/mL的链霉素和0.1mM的非必需氨基酸的达尔伯克改良伊格尔培养基中将HepG2 2.2.15细胞以1.5×104个细胞/孔在96孔微量滴定板中制板。只有内部孔用来减少在细胞培养期间观察到的“边缘效应”;将外部孔充满完全培养基以帮助最小化样品蒸发。在16-24小时后,洗涤HepG2 2.2.15细胞的融合单层,并用含有不同浓度的测试化合物的完全培养基一式三份地更换培养基。拉米夫定(3Tc)和恩替卡韦用作阳性对照,而将单独的培养基加入到细胞中作为阴性对照(病毒对照,VC)。三天后,用含有适当稀释的测试化合物的新鲜培养基更换该培养基。在测试化合物的初始给药6天后,收集细胞培养上清液,用链霉蛋白酶处理,然后用于实时定量TaqMan qPCR测定。通过监测与扩增的HBV DNA杂交的猝灭荧光探针分子的核酸外切降解产生的荧光信号的增加,实时检测PCR扩增的HBV DNA。对于各个PCR扩增,使用纯化的HBVDNA的稀释物同时产生标准曲线。从HBV DNA水平的降低计算抗病毒活性(测定的EC50和EC90值)。然后,将四唑染料(MTS;3-(4,5-二甲基噻唑-2-基)-5-(3-羧基-甲氧基苯基)-2-(4-磺基苯基)-2H-四唑;试剂,Promega)摄取测定法用于测量细胞活力,其用于计算毒性(CC50)。将选择性指数(SI50)计算为CC50/IC50。数据显示在表1中。
a将HBV诱导的细胞病变减少50%所需的有效浓度(以μM表示)。
b将HBV诱导的细胞病变减少90%所需的有效浓度(以μM表示)。
c将细胞生长降低50%所需的细胞毒性浓度(以μM表示)。
表1
实施例70:针对HIV-1X4菌株NL4.3和HIV-1R5菌株BaL的抗病毒活性
将TZM-bl细胞(Montefiori,D.C.Methods Mol.Biol.2009,485,395-405)以每孔1×104个细胞在含有10%胎牛血清(FBS)和10mM HEPES的DMEM中(达尔伯克改良伊格尔培养基;Life Technologies,Waltham,MA,USA)接种在透明的96孔板中。随后,加入化合物并将细胞/化合物混合物在37℃下温育。在30分钟后,以100pg p-24每孔加入病毒。在温育48小时后,分析测定板。为了分析,将steadylite plus底物溶液(PerkinElmer,Waltham,MA,USA)加入到测定板中。在黑暗中10分钟温育期后,在SpectraMax L发光酶标仪(分子器件,Sunnyvale,CA,USA)上的白色96孔板中分析裂解的细胞悬浮液的发光信号。测量HIV-1Tat蛋白表达诱导的萤光素酶活性作为HIV复制的量的评估。数据显示在表2中。
a将HIV诱导的细胞病变减少50%所需的有效浓度(以μM表示)。
b将细胞生长降低50%所需的细胞毒性浓度(以μM表示)。
表2
实施例71:抗水痘带状疱疹病毒和人巨细胞病毒的抗病毒活性
针对水痘带状疱疹病毒(VZV)菌株Oka和胸苷激酶缺陷型(TK-)VZV菌株07-1和人巨细胞病毒(HCMV)菌株AD-169和Davis评价本发明的化合物。抗病毒测定基于人胚肺(HEL)成纤维细胞中的病毒诱导的细胞病变或空斑形成的抑制。使用100CCID50的HCMV(1CCID50是感染50%的细胞培养物的病毒剂量)或使用20个空斑形成单位(PFU)(VZV)接种微滴定96孔板中的融合细胞培养物。在1-2小时的吸附期后,除去残余的病毒,并在不同浓度的测试化合物存在下温育细胞培养物。一旦它在没有使用测试化合物处理的对照病毒感染的细胞培养物中达到完成,就记录病毒细胞病变(HCMV)或空斑形成(VZV)。抗病毒活性表示为将病毒诱导的致细胞病变或病毒空斑形成减少50%所需的EC50或浓度(以微摩尔表示)。细胞生长抑制测量基于细胞生长的抑制。将HEL细胞以5×103个细胞/孔的比例接种到96孔微量滴定板中并使其增殖24小时。然后,加入含有不同浓度的测试化合物的培养基。在37℃下温育3天后,用库尔特计数器测定细胞数目。细胞生长抑制浓度(以微摩尔表示)计算为CC50或相对于未处理的对照中的细胞数量细胞增殖减少50%所需的化合物浓度。根据细胞数量(对照百分比)作为测试化合物的浓度的函数的图形绘制来估算CC50值。或者,测试化合物的细胞毒性表示为最小细胞毒浓度(MCC)或引起细胞形态的显微镜可检测的改变的化合物浓度。包括更昔洛韦和西多福韦作为HCMV测试的阳性对照,而阿昔洛韦和溴呋啶用作VZV测定中的参照药物。数据显示在表3中。
aEC50=将病毒诱导的细胞病变减少50%所需的有效浓度(以μM表示)。
bMCC=引起细胞形态的微观可检测改变所需的最小浓度(以μM表示)。
cCC50=将细胞生长降低50%所需的细胞毒性浓度(以μM表示)。
dND=未测定的
表3
参考文献
1.Pertusati,F.;Hinsinger,K.;Flynn,A.S.;Powell,N.;Tristram,A.;Balzarini,J.;McGuigan,C.Eur.J.Med.Chem.2014,78,259-268.
2.Pomeisl,K.;Pohl,R.;Holy,A.;Votruba,I.Collect.Czech.Chem.Commun.2005,70,1465-1481.
3.Jindrich,J.;Holy,A.;Dvorakova,H.Collect.Czech.Chem.Commun.1993,58,1645-1667.
4.Baszczynski,O.;Hockova,D.;Janeba,Z.;Holy,A.;Jansa,P.;Dracinsky,M.;Keough,D.T.;Guddat,L.W.Eur.J.Med.Chem.2013,67,81-89。
Claims (16)
1.一种式I的化合物:
其中
-B是任何天然或修饰的核碱基
-R1具有通式II
其中
-R3选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8-环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基和烷氧基烷基组成的组;
-R4选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基、烷氧基烷基、X-COOR5、X-O(C=O)-R5组成的组;
其中X是芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基或C3-C8-环烷基,并且其中所述芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C8-环烷基任选地包含一个或多个独立地选自由卤素、卤代烷基、氰基、C1-C7烷氧基组成的组的官能团、原子或自由基;并且
其中R5选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基和烷氧基烷基组成的组;
-R2是O-Ar,其中Ar是稠合二环芳基部分或单环芳基部分,其中任一个芳基部分是碳环或杂环并且任选地被卤素、C1-C6烷基、C1-C6烷氧基取代;
或者R2具有通式II
其中R1和R2可以相同或不同;
和/或其药学上可接受的加成盐和/或其立体异构体和/或其溶剂化物。
2.根据权利要求1所述的化合物,其中B选自腺嘌呤、胸腺嘧啶、胞嘧啶和鸟嘌呤的组。
3.根据权利要求1或2所述的化合物,其中R2是O-Ph。
4.根据权利要求1至3中任一项所述的化合物,其中R3选自C1-C10烷基。
5.根据声明项1至4中任一项所述的化合物,其中R4是X-COOR5并且其中X是芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基或C3-C8-环烷基,并且其中所述芳基、杂芳基、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C8-环烷基任选地包含一个或多个独立地选自由卤素、卤代烷基、氰基、C1-C7烷氧基组成的组的官能团、原子或自由基;并且其中R5选自由芳基、杂芳基、C1-C10烷基、C3-C8-环烷基、C3-C8环烷基-烷基、芳基(C1-C6)烷基、C2-C10烯基、C2-C10炔基、羟基C1-C10烷基、卤代C1-C10烷基和烷氧基烷基组成的组。
6.根据权利要求1至5中任一项所述的化合物,其中X是C1-C10烷基且R5是C1-C10烷基。
7.根据权利要求1至6中任一项所述的化合物,其中R2是O-Ph并且其中R1是
8.一种选自由:(S)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胸腺嘧啶;(R)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胸腺嘧啶;(S)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}腺嘌呤;(R)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}腺嘌呤;(S)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胞嘧啶;(R)-1-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胞嘧啶;(S)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}鸟嘌呤;(R)-9-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}鸟嘌呤;(S)-O2-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胞嘧啶;(R)-O2-{3-氟-2-[苯基氧基-双(戊基-L-天冬氨酰基)磷酰基]甲氧基]丙基}胞嘧啶;二戊基(((((R)-1-(2-氨基-4-氧代-3,4-二氢-7H-吡咯并[2,3-d]嘧啶-7-基)-3-氟丙烷-2-基)氧基)甲基)(苯氧基)磷酰基)-L-天门冬氨酸酯;四戊基2,2’-((((((R)-1-(2-氨基-4-氧代-3,4-二氢-7H-吡咯并[2,3-d]嘧啶-7-基)-3-氟丙烷-2-基)氧基)甲基)磷酰基)双(氮烷二基))(2S,2’S)-丁二酸氢酯组成的组的化合物。
9.根据权利要求1至8中任一项所述的化合物,用于作为药物的用途。
10.根据权利要求1至8中任一项所述的化合物,用于作为预防或治疗动物、哺乳动物或人类中的病毒感染的药物的用途。
11.根据权利要求10所述的化合物,其中所述病毒感染是由乙型肝炎病毒(HBV)、人类免疫缺陷病毒(HIV)、水痘带状疱疹病毒(VZV)、巨细胞病毒(CMV)、牛痘病毒(VV)、单纯性疱疹病毒(HSV)、BK病毒、埃博斯坦-巴病毒(EBV)、乳头瘤病毒、猴痘病毒、牛痘病毒、丙型肝炎病毒(HCV)、呼吸道合胞体病毒(RSV)、登革病毒、流感病毒、腺病毒、副流感病毒和/或鼻病毒的感染。
12.根据权利要求1至8中任一项所述的化合物,用于作为预防或治疗动物、哺乳动物或人类中的诸如癌症的增殖性疾病的药物的用途。
13.一种包含治疗有效量的根据权利要求1至8中任一项所述的化合物和一种或多种药学上可接受的赋形剂的药物组合物。
14.根据权利要求13所述的药物组合物,还包含一种或多种选自由抗病毒药物和/或抗增殖药物组成的组的生物活性药物。
15.一种预防或治疗动物、哺乳动物或人类中的病毒感染的方法,包括施用治疗有效量的根据权利要求1至8中任一项所述的化合物,任选地结合一种或多种药学上可接受的赋形剂。
16.一种预防或治疗动物、哺乳动物或人类中的增殖性疾病的方法,包括施用治疗有效量的根据权利要求1至8中任一项所述的化合物,任选地结合一种或多种药学上可接受的赋形剂。
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB1616196.0A GB201616196D0 (en) | 2016-09-23 | 2016-09-23 | Prodrugs of fluorinated acyclic nucleoside phosphonates |
GB1616196.0 | 2016-09-23 | ||
GB1620710.2 | 2016-12-06 | ||
GBGB1620710.2A GB201620710D0 (en) | 2016-12-06 | 2016-12-06 | Prodrugs of fluorinated acyclic nucleoside phosphonates |
GB1702321.9 | 2017-02-13 | ||
GBGB1702321.9A GB201702321D0 (en) | 2017-02-13 | 2017-02-13 | Prodrugs of fluorinated acyclic nucleoside phosphonates |
GBGB1709147.1A GB201709147D0 (en) | 2017-06-08 | 2017-06-08 | Prodrugs of fluorinated acyclic nucleoside phosphonates |
GB1709147.1 | 2017-06-08 | ||
PCT/EP2017/073988 WO2018055071A1 (en) | 2016-09-23 | 2017-09-22 | Prodrugs of fluorinated acyclic nucleoside phosphonates |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108137630A true CN108137630A (zh) | 2018-06-08 |
Family
ID=60201499
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201780001997.4A Pending CN108137630A (zh) | 2016-09-23 | 2017-09-22 | 氟化无环核苷膦酸酯的前药 |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP3515923A1 (zh) |
CN (1) | CN108137630A (zh) |
WO (1) | WO2018055071A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112661788A (zh) * | 2020-11-17 | 2021-04-16 | 万华化学集团股份有限公司 | 一种含磷聚天门冬氨酸酯及其制备方法和应用 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1950383A (zh) * | 2003-12-30 | 2007-04-18 | 吉里德科学公司 | 用于治疗病毒性疾病的膦酸酯、单膦酸酰胺化物、双膦酸酰胺化物 |
CN103435672A (zh) * | 2013-04-25 | 2013-12-11 | 刘沛 | 含有取代苄基的新型核苷磷酸酯前药的结构与合成 |
WO2014026582A1 (zh) * | 2012-08-13 | 2014-02-20 | 洛阳聚慧投资股份有限公司 | 替诺福韦双酯类化合物、其制备方法、用途以及包含其的药物组合物 |
CN104119385A (zh) * | 2014-07-24 | 2014-10-29 | 廖国超 | 核苷类似物的磷酸酯前药及其应用 |
WO2015161781A1 (zh) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | 一种核苷类似物及其中间体的制备方法 |
US20160015726A1 (en) * | 2013-03-15 | 2016-01-21 | The Regents Of The University Of California | Acyclic nucleoside phosphonate diesters |
CN105315319A (zh) * | 2014-07-30 | 2016-02-10 | 南京圣和药业股份有限公司 | 丙型肝炎病毒抑制剂及其应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10745427B2 (en) * | 2016-03-09 | 2020-08-18 | Janssen Biopharma, Inc. | Acyclic antivirals |
-
2017
- 2017-09-22 WO PCT/EP2017/073988 patent/WO2018055071A1/en unknown
- 2017-09-22 CN CN201780001997.4A patent/CN108137630A/zh active Pending
- 2017-09-22 EP EP17791943.8A patent/EP3515923A1/en not_active Withdrawn
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1950383A (zh) * | 2003-12-30 | 2007-04-18 | 吉里德科学公司 | 用于治疗病毒性疾病的膦酸酯、单膦酸酰胺化物、双膦酸酰胺化物 |
WO2014026582A1 (zh) * | 2012-08-13 | 2014-02-20 | 洛阳聚慧投资股份有限公司 | 替诺福韦双酯类化合物、其制备方法、用途以及包含其的药物组合物 |
US20160015726A1 (en) * | 2013-03-15 | 2016-01-21 | The Regents Of The University Of California | Acyclic nucleoside phosphonate diesters |
CN103435672A (zh) * | 2013-04-25 | 2013-12-11 | 刘沛 | 含有取代苄基的新型核苷磷酸酯前药的结构与合成 |
WO2015161781A1 (zh) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | 一种核苷类似物及其中间体的制备方法 |
CN104119385A (zh) * | 2014-07-24 | 2014-10-29 | 廖国超 | 核苷类似物的磷酸酯前药及其应用 |
CN105315319A (zh) * | 2014-07-30 | 2016-02-10 | 南京圣和药业股份有限公司 | 丙型肝炎病毒抑制剂及其应用 |
Non-Patent Citations (2)
Title |
---|
FABRIZIO PERTUSATI ET AL.,: ""PMPA and PMEA prodrugs for the treatment of HIV infections and human papillomavirus (HPV) associated neoplasia and cancer"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
PETR JANSA ET AL.,: ""A novel and efficient one-pot synthesis of symmetrical diamide (bis-amidate)prodrugs of acyclic nucleoside phosphonates and evaluation of their biological activities"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112661788A (zh) * | 2020-11-17 | 2021-04-16 | 万华化学集团股份有限公司 | 一种含磷聚天门冬氨酸酯及其制备方法和应用 |
CN112661788B (zh) * | 2020-11-17 | 2023-01-13 | 万华化学集团股份有限公司 | 一种含磷聚天门冬氨酸酯及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
EP3515923A1 (en) | 2019-07-31 |
WO2018055071A1 (en) | 2018-03-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9487544B2 (en) | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs | |
EP0322384B1 (en) | Nucleosides for use in therapy | |
CA2479846C (en) | Phosphonomethoxymethylpurine/pyrimidine derivatives | |
US10118941B2 (en) | Methods for the preparation of diastereomerically pure phosphoramidate prodrugs | |
WO2003062256A1 (en) | 2'-beta-modified-6-substituted adenosine analogs and their use as antiviral agents | |
CN102348712A (zh) | 用于治疗病毒感染的鸟苷核苷类化合物的磷酰胺酯衍生物 | |
CN102924549A (zh) | 作为抗病毒剂的修饰的4'-核苷 | |
CN103403014A (zh) | O-(经取代的苯甲基)氨基磷酸酯化合物及其治疗用途 | |
CA2794671A1 (en) | Stereoselective synthesis of phosphorus containing actives | |
JP2937532B2 (ja) | プリン及びピリミジン複素環式塩基のn−(3−フルオロ−2−ホスホニルメトキシプロピル)誘導体、それらの製造法及び使用 | |
Pertusati et al. | Phosphonoamidate prodrugs of C5-substituted pyrimidine acyclic nucleosides for antiviral therapy | |
JP4545434B2 (ja) | 抗ウイルス活性を有する6−‘2−(ホスホノメトキシ)アルコキシピリミジン誘導体 | |
CN108137630A (zh) | 氟化无环核苷膦酸酯的前药 | |
CN107820499B (zh) | 抗病毒化合物、其制备工艺、以及其用于治疗病毒感染的用途 | |
Raju et al. | Synthesis and biological properties of purine and pyrimidine 5'-deoxy-5'-(dihydroxyphosphinyl)-. beta.-D-ribofuranosyl analogs of AMP, GMP, IMP, and CMP | |
CN110520195B (zh) | 新型核苷膦酸酯前药 | |
Hiebl et al. | Side-Chain Derivatives of Biologically Active Nucleosides. Part 2: Synthesis and anti-HIV Activity of 5′-C-Methyl Derivatives of 3′-Fluoro-3′-Deoxythymidine | |
PL217694B1 (pl) | Analog nukleotydu, sposób otrzymywania analogu nukleotydu, zastosowanie analogu nukleotydu, pro-nukleotyd antywirusowy, kompozycja farmaceutyczna | |
Angell | Design, synthesis and evaluation of some novel antiviral nucleosides | |
WO2007059330A2 (en) | Cubane nucleoside analogs | |
WO2012148295A1 (en) | Antiviral drug derivative | |
MX2008004079A (en) | Modified 4'-nucleosides as antiviral agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180608 |