CN1777432B - 用于hiv感染的抗病毒核苷类似物 - Google Patents
用于hiv感染的抗病毒核苷类似物 Download PDFInfo
- Publication number
- CN1777432B CN1777432B CN2004800105296A CN200480010529A CN1777432B CN 1777432 B CN1777432 B CN 1777432B CN 2004800105296 A CN2004800105296 A CN 2004800105296A CN 200480010529 A CN200480010529 A CN 200480010529A CN 1777432 B CN1777432 B CN 1777432B
- Authority
- CN
- China
- Prior art keywords
- virus
- hiv
- group
- chemical compound
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000002777 nucleoside Substances 0.000 title abstract description 47
- 230000000840 anti-viral effect Effects 0.000 title abstract description 30
- 150000003833 nucleoside derivatives Chemical class 0.000 title description 31
- 208000031886 HIV Infections Diseases 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims description 111
- -1 A-83962 Chemical compound 0.000 claims description 78
- 241000700605 Viruses Species 0.000 claims description 66
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 49
- 239000003814 drug Substances 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 201000010099 disease Diseases 0.000 claims description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 230000009385 viral infection Effects 0.000 claims description 26
- 238000011282 treatment Methods 0.000 claims description 25
- 208000036142 Viral infection Diseases 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- 208000030507 AIDS Diseases 0.000 claims description 11
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 claims description 10
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 claims description 9
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 claims description 9
- 229960004748 abacavir Drugs 0.000 claims description 8
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims description 8
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 229960001830 amprenavir Drugs 0.000 claims description 7
- 229960004525 lopinavir Drugs 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 229960001852 saquinavir Drugs 0.000 claims description 7
- BEUUJDAEPJZWHM-COROXYKFSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(2-methoxyethylamino)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[(2,3,4-trimethoxyphenyl)methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@H](C(=O)NCCOC)C(C)C)CC=1C(=C(OC)C(OC)=CC=1)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 BEUUJDAEPJZWHM-COROXYKFSA-N 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 claims description 6
- 229940124411 anti-hiv antiviral agent Drugs 0.000 claims description 6
- 229960001936 indinavir Drugs 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- 229950004697 lasinavir Drugs 0.000 claims description 4
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- XCVGQMUMMDXKCY-WZJLIZBTSA-N (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-bis[4-(hydroxymethyl)benzyl]-1,3-diazepan-2-one Chemical compound C1=CC(CO)=CC=C1CN1C(=O)N(CC=2C=CC(CO)=CC=2)[C@H](CC=2C=CC=CC=2)[C@H](O)[C@@H](O)[C@H]1CC1=CC=CC=C1 XCVGQMUMMDXKCY-WZJLIZBTSA-N 0.000 claims description 3
- LTDCCBLBAQXNKP-VMHSAVOQSA-N 4-amino-1-[(2r,3s,5s)-3-fluoro-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](F)C[C@@H](CO)O1 LTDCCBLBAQXNKP-VMHSAVOQSA-N 0.000 claims description 3
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 claims description 3
- 108010019625 Atazanavir Sulfate Proteins 0.000 claims description 3
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 claims description 3
- 229960003277 atazanavir Drugs 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- RXBWRFDZXRAEJT-SZNOJMITSA-N palinavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)C=1N=C2C=CC=CC2=CC=1)C(C)C)[C@H](O)CN1[C@@H](C[C@@H](CC1)OCC=1C=CN=CC=1)C(=O)NC(C)(C)C)C1=CC=CC=C1 RXBWRFDZXRAEJT-SZNOJMITSA-N 0.000 claims description 3
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 claims description 3
- UYZMZENNYRSFDS-QNWDWTFCSA-N (2s)-n-[(2s,3s)-4-[(2s)-2-(tert-butylcarbamoyl)pyrrolidin-1-yl]-3-hydroxy-4-oxo-1-phenylbutan-2-yl]-2-(quinoxaline-2-carbonylamino)butanediamide Chemical compound CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=NC=1)CC1=CC=CC=C1 UYZMZENNYRSFDS-QNWDWTFCSA-N 0.000 claims description 2
- UFSMRNQSQSGJII-QYRZKEDASA-N (2s)-n-[(2s,3s)-4-[(4r)-4-(tert-butylcarbamoyl)-5,5-dimethyl-1,3-thiazolidin-3-yl]-3-hydroxy-4-oxo-1-phenylbutan-2-yl]-2-[(2-naphthalen-1-yloxyacetyl)amino]butanediamide Chemical compound C1SC(C)(C)[C@@H](C(=O)NC(C)(C)C)N1C(=O)[C@@H](O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)COC=1C2=CC=CC=C2C=CC=1)CC1=CC=CC=C1 UFSMRNQSQSGJII-QYRZKEDASA-N 0.000 claims description 2
- SSIBMWPFXYSVEK-CUPIEXAXSA-N A 80987 Chemical compound N([C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)[C@@H](O)C[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=NC=CC=1)C(=O)OCC1=CC=CC=N1 SSIBMWPFXYSVEK-CUPIEXAXSA-N 0.000 claims description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 2
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 claims description 2
- PUSXDQXVJDGIBK-NKWVEPMBSA-N [(2s,5r)-5-(6-aminopurin-9-yl)oxolan-2-yl]methyl dihydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](COP(O)(O)=O)O1 PUSXDQXVJDGIBK-NKWVEPMBSA-N 0.000 claims 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 claims description 2
- 229960003205 adefovir dipivoxil Drugs 0.000 claims description 2
- ZVWSWYSIMOZTTG-QVDBQUMVSA-N benzyl n-[(2s)-1-[[(2s,3r,4r)-3-hydroxy-5-[[(1s,2r)-2-hydroxy-2,3-dihydro-1h-inden-1-yl]amino]-4-[(4-methoxyphenyl)methylamino]-5-oxo-1-phenylpentan-2-yl]amino]-3,3-dimethyl-1-oxobutan-2-yl]carbamate Chemical compound C1=CC(OC)=CC=C1CN[C@@H](C(=O)N[C@H]1C2=CC=CC=C2C[C@H]1O)[C@H](O)[C@@H](NC(=O)[C@@H](NC(=O)OCC=1C=CC=CC=1)C(C)(C)C)CC1=CC=CC=C1 ZVWSWYSIMOZTTG-QVDBQUMVSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 2
- 238000011161 development Methods 0.000 claims description 2
- 229950006460 palinavir Drugs 0.000 claims description 2
- CRROWNPCQUJQGS-MCEBTLFFSA-N pyridin-2-ylmethyl n-[(2s)-1-[[(2s,4s,5s)-4-hydroxy-1,6-diphenyl-5-(1,3-thiazol-5-ylmethoxycarbonylamino)hexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)OCC1=CC=CC=N1 CRROWNPCQUJQGS-MCEBTLFFSA-N 0.000 claims description 2
- 229960001355 tenofovir disoproxil Drugs 0.000 claims description 2
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229960000838 tipranavir Drugs 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 2
- GTEZSHJBMRWRIG-UHFFFAOYSA-N 2-amino-3-[4-(naphthalene-2-carbonyloxy)phenyl]propanoic acid Chemical group C1=CC(CC(N)C(O)=O)=CC=C1OC(=O)C1=CC=C(C=CC=C2)C2=C1 GTEZSHJBMRWRIG-UHFFFAOYSA-N 0.000 claims 1
- ZQUDHBMLXPGCHF-DOEKTCAHSA-N [(3s)-oxolan-3-yl] n-[(2s,3r)-4-[cyclopentylmethyl-(4-methoxyphenyl)sulfonylamino]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(CC1CCCC1)C[C@@H](O)[C@@H](NC(=O)O[C@@H]1COCC1)CC1=CC=CC=C1 ZQUDHBMLXPGCHF-DOEKTCAHSA-N 0.000 claims 1
- LTVDTKRMOQDRCH-UHFFFAOYSA-N furan;1h-pyrrole Chemical class C=1C=CNC=1.C=1C=COC=1 LTVDTKRMOQDRCH-UHFFFAOYSA-N 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 69
- 229910019142 PO4 Inorganic materials 0.000 abstract description 21
- 239000010452 phosphate Substances 0.000 abstract description 21
- 125000002252 acyl group Chemical group 0.000 abstract description 13
- 229910052740 iodine Inorganic materials 0.000 abstract description 13
- 229910052794 bromium Inorganic materials 0.000 abstract description 12
- 229910052731 fluorine Inorganic materials 0.000 abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 11
- 229910052801 chlorine Inorganic materials 0.000 abstract description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 8
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 abstract description 8
- 125000001033 ether group Chemical group 0.000 abstract description 6
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 abstract description 5
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 abstract description 4
- 239000001177 diphosphate Substances 0.000 abstract description 3
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 abstract description 3
- 235000011180 diphosphates Nutrition 0.000 abstract description 3
- 125000003835 nucleoside group Chemical group 0.000 abstract description 3
- 239000001226 triphosphate Substances 0.000 abstract description 3
- 235000011178 triphosphate Nutrition 0.000 abstract description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 abstract description 3
- 125000003277 amino group Chemical group 0.000 abstract description 2
- 150000004713 phosphodiesters Chemical group 0.000 abstract description 2
- 239000012453 solvate Substances 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 4
- 235000021317 phosphate Nutrition 0.000 abstract 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 abstract 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 112
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 91
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 42
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 41
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical class O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 37
- 210000004027 cell Anatomy 0.000 description 33
- 239000000460 chlorine Substances 0.000 description 31
- 230000000694 effects Effects 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 29
- 238000003756 stirring Methods 0.000 description 29
- 239000012044 organic layer Substances 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- 210000001541 thymus gland Anatomy 0.000 description 25
- 239000007864 aqueous solution Substances 0.000 description 24
- 238000001704 evaporation Methods 0.000 description 24
- 239000000376 reactant Substances 0.000 description 24
- 238000000034 method Methods 0.000 description 22
- 238000010898 silica gel chromatography Methods 0.000 description 22
- 229910052786 argon Inorganic materials 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- 235000002639 sodium chloride Nutrition 0.000 description 21
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 20
- 238000001035 drying Methods 0.000 description 20
- 102000006601 Thymidine Kinase Human genes 0.000 description 19
- 108020004440 Thymidine kinase Proteins 0.000 description 19
- 239000002585 base Substances 0.000 description 19
- 230000008020 evaporation Effects 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 18
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 17
- 229960002555 zidovudine Drugs 0.000 description 17
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 230000026731 phosphorylation Effects 0.000 description 16
- 238000006366 phosphorylation reaction Methods 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- 241001597008 Nomeidae Species 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 14
- 229960002656 didanosine Drugs 0.000 description 14
- 241000701806 Human papillomavirus Species 0.000 description 13
- 208000015181 infectious disease Diseases 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 241000711549 Hepacivirus C Species 0.000 description 12
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 101710132082 Pyrimidine/purine nucleoside phosphorylase Proteins 0.000 description 12
- 102000013537 Thymidine Phosphorylase Human genes 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 12
- 239000007789 gas Substances 0.000 description 12
- 238000011160 research Methods 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 11
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 11
- 230000036436 anti-hiv Effects 0.000 description 11
- 239000003443 antiviral agent Substances 0.000 description 11
- 238000004364 calculation method Methods 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 230000001988 toxicity Effects 0.000 description 11
- 231100000419 toxicity Toxicity 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 241001536481 Banzi virus Species 0.000 description 10
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 10
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 10
- 108020005196 Mitochondrial DNA Proteins 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 10
- 241000725643 Respiratory syncytial virus Species 0.000 description 10
- 230000004071 biological effect Effects 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 9
- 230000009977 dual effect Effects 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- 229920002554 vinyl polymer Polymers 0.000 description 9
- 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 description 8
- 241000701022 Cytomegalovirus Species 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 210000001744 T-lymphocyte Anatomy 0.000 description 8
- 241000710772 Yellow fever virus Species 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 8
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 8
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 8
- 229940104230 thymidine Drugs 0.000 description 8
- 229940051021 yellow-fever virus Drugs 0.000 description 8
- 241000725619 Dengue virus Species 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 208000006454 hepatitis Diseases 0.000 description 7
- 231100000283 hepatitis Toxicity 0.000 description 7
- 241000701161 unidentified adenovirus Species 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical group OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 230000010261 cell growth Effects 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000003612 virological effect Effects 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 5
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 5
- 241000714259 Human T-lymphotropic virus 2 Species 0.000 description 5
- 241000710842 Japanese encephalitis virus Species 0.000 description 5
- 201000006449 West Nile encephalitis Diseases 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 230000003213 activating effect Effects 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000010985 leather Substances 0.000 description 5
- 230000002969 morbid Effects 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 4
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 4
- 206010014596 Encephalitis Japanese B Diseases 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 201000005807 Japanese encephalitis Diseases 0.000 description 4
- 206010025323 Lymphomas Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 4
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 4
- 108010077895 Sarcosine Proteins 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 230000000975 bioactive effect Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000011284 combination treatment Methods 0.000 description 4
- 229940104302 cytosine Drugs 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 229960005319 delavirdine Drugs 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 4
- 229960003804 efavirenz Drugs 0.000 description 4
- 229940125777 fusion inhibitor Drugs 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 229960000884 nelfinavir Drugs 0.000 description 4
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 229920000052 poly(p-xylylene) Polymers 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 210000000664 rectum Anatomy 0.000 description 4
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 4
- 229960000311 ritonavir Drugs 0.000 description 4
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 4
- 229940043230 sarcosine Drugs 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 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 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 206010059313 Anogenital warts Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000000907 Condylomata Acuminata Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000255925 Diptera Species 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 241000710831 Flavivirus Species 0.000 description 3
- 206010019799 Hepatitis viral Diseases 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 230000000680 avirulence Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- LLYJISDUHFXOHK-GOCONZMPSA-N ferroptocide Chemical compound C[C@@H]1CC[C@@]23C[C@@H](C(=O)[C@]2([C@@]1([C@@H](C[C@H]([C@@H]3C)C4=CCN5C(=O)N(C(=O)N5C4)C6=CC=CC=C6)OC(=O)CCl)C)O)O LLYJISDUHFXOHK-GOCONZMPSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000012447 hatching Effects 0.000 description 3
- 150000002460 imidazoles Chemical class 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 3
- 229930027917 kanamycin Natural products 0.000 description 3
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 3
- 229960000318 kanamycin Drugs 0.000 description 3
- 229930182823 kanamycin A Natural products 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 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 3
- 229960001627 lamivudine Drugs 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 3
- 229940127073 nucleoside analogue Drugs 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 229960002668 sodium chloride Drugs 0.000 description 3
- 229960001203 stavudine Drugs 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 150000003673 urethanes Chemical class 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 201000001862 viral hepatitis Diseases 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- 229960000523 zalcitabine Drugs 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- ARVZUQISYCBJRH-KCJUWKMLSA-N 1-[(2r,5s)-5-(hydroxymethyl)-5-methyl-2h-furan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@](C)(CO)O1 ARVZUQISYCBJRH-KCJUWKMLSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- HSBKFSPNDWWPSL-CAHLUQPWSA-N 4-amino-5-fluoro-1-[(2r,5s)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1C=C[C@@H](CO)O1 HSBKFSPNDWWPSL-CAHLUQPWSA-N 0.000 description 2
- HSBKFSPNDWWPSL-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@@H]1C=C[C@H](CO)O1 HSBKFSPNDWWPSL-VDTYLAMSSA-N 0.000 description 2
- QBEIABZPRBJOFU-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)CC1 QBEIABZPRBJOFU-VDTYLAMSSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 206010065553 Bone marrow failure Diseases 0.000 description 2
- 201000006082 Chickenpox Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 208000007514 Herpes zoster Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 206010046980 Varicella Diseases 0.000 description 2
- 208000000260 Warts Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 125000005340 bisphosphate group Chemical group 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- GYOZYWVXFNDGLU-XLPZGREQSA-N dTMP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)C1 GYOZYWVXFNDGLU-XLPZGREQSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 238000006356 dehydrogenation reaction Methods 0.000 description 2
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 210000004392 genitalia Anatomy 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 230000002008 hemorrhagic effect Effects 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 229950003188 isovaleryl diethylamide Drugs 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 229960000689 nevirapine Drugs 0.000 description 2
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 2
- 229940071536 silver acetate Drugs 0.000 description 2
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 2
- 201000010153 skin papilloma Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960004556 tenofovir Drugs 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 229940035893 uracil Drugs 0.000 description 2
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- DVRKESVZZVYJRB-JXOAFFINSA-N 1-[(2r,3r,4s,5s)-4-azido-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](N=[N+]=[N-])[C@@H](CO)O1 DVRKESVZZVYJRB-JXOAFFINSA-N 0.000 description 1
- QAPSNMNOIOSXSQ-YNEHKIRRSA-N 1-[(2r,4s,5r)-4-[tert-butyl(dimethyl)silyl]oxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C1 QAPSNMNOIOSXSQ-YNEHKIRRSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ODSQODTUNULBHF-JGVFFNPUSA-N 2',3'-dehydro-2',3'-deoxy-thymidine 5'-triphosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO[P@@](O)(=O)O[P@](O)(=O)OP(O)(O)=O)O1 ODSQODTUNULBHF-JGVFFNPUSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- ZMGMDXCADSRNCX-UHFFFAOYSA-N 5,6-dihydroxy-1,3-diazepan-2-one Chemical class OC1CNC(=O)NCC1O ZMGMDXCADSRNCX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000701242 Adenoviridae Species 0.000 description 1
- 241000256111 Aedes <genus> Species 0.000 description 1
- 241000256118 Aedes aegypti Species 0.000 description 1
- 241000256173 Aedes albopictus Species 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 206010001580 Albuminuria Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 201000004813 Bronchopneumonia Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010009192 Circulatory collapse Diseases 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 102000016911 Deoxyribonucleases Human genes 0.000 description 1
- 108010053770 Deoxyribonucleases Proteins 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 101100001675 Emericella variicolor andJ gene Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 208000004576 Flaviviridae Infections Diseases 0.000 description 1
- 206010060891 General symptom Diseases 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 241000256069 Haemagogus <genus> Species 0.000 description 1
- 208000034507 Haematemesis Diseases 0.000 description 1
- 208000037319 Hepatitis infectious Diseases 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 208000001688 Herpes Genitalis Diseases 0.000 description 1
- 206010019973 Herpes virus infection Diseases 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 206010053961 Mitochondrial toxicity Diseases 0.000 description 1
- 206010027906 Monocytosis Diseases 0.000 description 1
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 108091093105 Nuclear DNA Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 101150003085 Pdcl gene Proteins 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
- 206010034620 Peripheral sensory neuropathy Diseases 0.000 description 1
- 241000711902 Pneumovirus Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 206010039587 Scarlet Fever Diseases 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 102100037357 Thymidylate kinase Human genes 0.000 description 1
- 241000710924 Togaviridae Species 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- OTUXCLKRSRDYPV-UHFFFAOYSA-N acetylene hydrochloride Chemical compound Cl.C#C OTUXCLKRSRDYPV-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 108700010877 adenoviridae proteins Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000010420 art technique Methods 0.000 description 1
- 239000005441 aurora Substances 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical group C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- KRJUSWXDFZSJQD-UHFFFAOYSA-N benzoic acid;lead Chemical compound [Pb].OC(=O)C1=CC=CC=C1 KRJUSWXDFZSJQD-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000003914 blood derivative Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000012928 buffer substance Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 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
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001721 carbon Chemical class 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007766 cera flava Substances 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 231100000313 clinical toxicology Toxicity 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 230000002153 concerted effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000009133 cooperative interaction Effects 0.000 description 1
- 229940088900 crixivan Drugs 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 108010000742 dTMP kinase Proteins 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001739 density measurement Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229950006528 elvucitabine Drugs 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- HFUPPCDTZFFGFP-UHFFFAOYSA-N ethynylalumane Chemical compound [AlH2]C#C HFUPPCDTZFFGFP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 201000004946 genital herpes Diseases 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- NUBQKPWHXMGDLP-BDEHJDMKSA-N indinavir sulfate Chemical compound OS(O)(=O)=O.C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 NUBQKPWHXMGDLP-BDEHJDMKSA-N 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229940088976 invirase Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 108010075606 kynostatin 272 Proteins 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 210000001595 mastoid Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- HHUJMWDBSFEZKJ-UHFFFAOYSA-N methyl 1-(hydroxymethyl)-2-oxocyclopentane-1-carboxylate Chemical compound COC(=O)C1(CO)CCCC1=O HHUJMWDBSFEZKJ-UHFFFAOYSA-N 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 231100000296 mitochondrial toxicity Toxicity 0.000 description 1
- 238000000329 molecular dynamics simulation Methods 0.000 description 1
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000012587 nuclear overhauser effect experiment Methods 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 210000002856 peripheral neuron Anatomy 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- SGDMQXAOPGGMAH-UHFFFAOYSA-N phenol;thiophene Chemical compound C=1C=CSC=1.OC1=CC=CC=C1 SGDMQXAOPGGMAH-UHFFFAOYSA-N 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 201000005572 sensory peripheral neuropathy Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 206010040560 shock Diseases 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 208000026843 stiff neck Diseases 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- KOLLFWOTBZCTDF-XFTNXAEASA-N tert-butyl (2s)-1-[(2r,3s)-3-[[(2s)-4-amino-2-(naphthalene-2-carbonylamino)-4-oxobutanoyl]amino]-2-hydroxy-4-phenylbutyl]pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)C=1C=C2C=CC=CC2=CC=1)CC1=CC=CC=C1 KOLLFWOTBZCTDF-XFTNXAEASA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940048102 triphosphoric acid Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000001521 two-tailed test Methods 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 229940087450 zerit Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/14—Pyrrolo-pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- 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)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及根据通式(I、II、III、IV或V)的新化合物,其中B为根据结构(VI)的核苷碱;R为H、F、Cl、Br、I、C1-C4烷基(优选地CH3)、-C≡N、-C≡C-Ra、式(VII);X为H、C1-C4烷基(优选CH3)、F、Cl、Br或I;Z为O或CH2,条件是当化合物是通式II化合物,R3为-C≡C-H以及R2为H、磷酸酯、二磷酸酯、三磷酸酯、磷酸三酯基团的时候,Z为CH2且不为O;R1为H、酰基、C1-C20烷基或醚基团;R2为H、酰基、C1-C20烷基或醚基团、磷酸酯、二磷酸酯、三磷酸酯、磷酸二酯基团或式(VIII)或式(IX)基团,Nu为生物活性抗病毒化合物的的基团以使所述的生物活性抗病毒化合物的氨基或羟基与邻近的部分形成磷酸酯、氨基磷酸酯、碳酸酯或氨基甲酸乙酯基团;R8为H,或C1-C20烷基或醚基团,优选C1-C12烷基;k为0-12,优选0-2;R3选自C1-C4烷基(优选CH3)、-(CH2)n-C≡C-Ra、式(X)或式(XI)基团;R3a和R3b独立地选自H、F、Cl、Br或I;R4和R5独立地选自H、F、Cl、Br、I、OH、C1-C4烷基(优选CH3)、-(CH2)n-C≡C-Ra、式(XII)或式(XIII)基团,条件是R4和R5不都为H;Ra为H、F、Cl、Br、I或-C1-C4烷基,优选H或CH3;Y为H、F、Cl、Br、I或-C1-C4烷基,优选H或CH3;以及n为0、1、2、3、4或5,优选0、1或2;以及其差向异构体、可药用盐、溶剂合物或其多晶形。
Description
相关申请
本申请要求2003年2月19日提交的临时申请号60/448,554的优选权,其整体这里引入作为参考。
发明领域
本发明涉及新的2’,3’-双脱氧和双脱氢核苷类似物以及相关的前药以及其在用于治疗多种病毒(其中,更具体地,逆转录病毒)感染和疾病状态尤其是包括HIV以及相关的疾病AIDS中的用途。
该项工作得到源自国立卫生研究院的公共卫生服务资助AI-38204的支持。美国政府持有本发明的一些权利。
发明背景
人免疫缺陷病毒(HIV/AIDS)已经超过疟疾和肺结核而成为全球的主要感染性死亡病因。WHO AIDS Epidemic Update,2002年12月的数据报道了310万的死亡以及目前有4,200万人患有AIDS。对具有更好疗效的新治疗性剂的需求是很显然的。双脱氧核苷是一类重要的抗病毒化合物(16,26,27)。其中,3’-叠氮基-3’-脱氧胸苷(AZT,Retovir,齐多夫定)是第一个批准用于治疗HIV的药物。其剂量限制性副作用是骨髓抑制(14、36、39),并且这种副作用会被引起骨髓抑制或被肝脏代谢的其他药物的伴随给药进一步恶化。接着2’,3’-双脱氢-3’-脱氧胸苷(D4T,司他夫定,Zerit)由于更好的生物利用度记忆较低的急性毒性也被批准(1)。D4T被长期延迟毒性,外周感觉神经病(4)所限制使用,后者与线粒体损伤有关(3、5、6、13、18、22、30、33、34)。2’,3’-双脱氧肌苷(ddI,地达诺新,Videx)和2’,3’-双脱氧胞嘧啶(ddC,扎西他滨)为双脱氧核苷抗HIV化合物,并且也具有作为其主要副作用的外 周神经病。在寻找具有更少神经病变抗HIV核苷类似物中,许多种类的化合物已经被合成出来并评价其抗病毒活性以及细胞毒性包括其对线粒体DNA的影响。由β-L-2’,3’-双脱氧-3’-硫杂胞嘧啶(3TC,拉米夫定),其5-氟类似物(FTC,Emtricitabine)和β-L-2’,3’-双脱氧-2’,3’-双脱氢-5-氟胞嘧啶(LFd4C,Elvucitabine)代表的非天然L构型的双脱氧核苷,已经由我们(2、11、12、23-25)以及其他的研究者(8、9、15、37)证实具有良好的抗病毒活性以及低的线粒体毒性。但是,即使用对线粒体相对无毒性的化合物也缺乏持久的反应。这种情形是由抗性病毒的快速出现或被引起药物代谢中的差异的宿主变化所引起的(10、19、35)。
与该问题斗争的一个方法是开发具有更低的毒性以及对其他抗病毒药物缺乏交叉抗性的化合物。当与这些化合物联合使用的时候,可降低现有药物需要的剂量以实现同样的抗病毒效果同时具有更小的毒性。此外,这些化合物甚至可以延缓抗性的发作,其可能基于在治疗期间的下降的病毒滴度。在寻找新的抗病毒化合物中,其他研究者着眼于4’-取代的dThd类似物(29)(32),而我们合成了一系列的4’-取代的D4T类似物。筛选揭示4’-乙炔基D4T为测试的化合物中活性最强的(17)。在这里描述的研究中,我们描述了这类化合物的结构活性关系并更详细地表征了4’-乙炔基D4T的HIV作用方式以及其与介导其活性的关键细胞酶的相互作用。
发明目的
本发明的目的之一在于提供用于治疗病毒感染或癌症的化合物。
本发明的另一个目的在于提供可以用来治疗病毒感染或癌症的药物组合物。
本发明的另一目的在于提供可与已知的抗病毒剂用于联合治疗的化合物和药物组合物。
本发明另一种目标在于提供根据本发明的化合物的前药形式,其可联用其他的抗病毒剂进行配制。
本发明的另一目标在于提供用于治疗如这里描述的多种病毒或癌症的治疗方法。
本发明的另一目的在于提供合成根据本发明化合物的方法。
本发明的这些和/或其他的目的从下述本发明的描述中可以很容易地得出。
附图简述
图1描述了多种优选的根据本发明化合物。
图2描述了抗HIV化合物L(-)Fd4C、L(-)SddC、ddC和D4T。
图3描述了优选的根据本发明二核苷化合物。
图4显示了以路线A进行的TDK-4-152的化学合成。
图5显示了以路线B进行的TDK-4-114的化学合成。
图5A显示了TDK4-114的另一种化学合成方法。
图5B显示了根据本发明的酰氧基核苷化合物中间体的另一种制备,该中间体可用于制备图5A的TKD-4-114。
图6显示了KMA-23-153的化学合成。
图7A显示了根据Nomura等J.Med.Chem.,42,2901-2908(1999)的方法从2’-脱氧核苷合成4’乙炔基-2’-脱氧核苷。注意SiR3为叔丁基二甲基甲硅烷基并且SiR’3为叔丁基二苯基甲硅烷基基团。X为卤原子,如氯且B为核苷碱如尿嘧啶、腺嘌呤、鸟嘌呤或胞嘧啶。
图7B显示了根据Ohrui等J.Med.Chem.43,4516-4525(2000)的方法从保护的糖前体合成4’-乙炔基-2’-脱氧核苷。注意B为核苷碱。
图7C显示了从根据本发明相应的2’脱氧核苷类似物合成2’,3’-双脱氢核苷化合物的一般方法。
图8显示了4’取代的D4T类似物的抗HIV活性:4’-乙炔基D4T、D4T、4’-乙炔基甲基D4T和4’-氰基D4T的抗病毒活性按照在实施例中材料和方法部分中的描述的MT-2/HIVIIIB体系进行测定。通过将O.D.595nm的读数与未感染未处理的(UIUT)对照MT-2细胞进行比较测定抑制水平。
图9显示了4’-乙炔基D4T、dThd(10μM)、dThd(1μM)和ddCyd(10μM)在THU(5μM)存在下加入到标准抗病毒分析中的抗HIV效果。通过比较O.D.595nm处的读数以及未感染的未处理的(UIUT)对照MT-2细胞确定抑制水平。
图10显示了在MT-2/HIV IIIB***中得到的数据得到的D4T和4’-乙 炔基D4T与下述成分组合的抗病毒等效线图:A)3TC和B)LFd4C。各坐标轴显示的数字与显示的作为单剂的药物的EC50(视作1)成比例。[单剂EC50:1.4μM D4T,0.5μM 4’-乙炔基D4T,1.0μM 3TC和0.18μM LFd4C]。各数据点代表了产生与任一单药的EC50等效的活性的组合。协同指数(SI)计算为45°线至表示加和的药物相互作用线的分数,总的距离为1.0。
图11显示了D4T类似物用胸苷磷酸化酶处理的结果:dThd、D4T和4’-乙炔基D4T与源于人肝脏提取物的部分纯化的TP制剂一起孵育。按照材料和方法部分的描述,利用反相HPLC在Beckman ODS柱上测定碱与核苷的比率。
发明概述
本发明涉及根据通式I、II、III、IV或V的新化合物:
其中B为根据下述结构的核苷碱:
X为H、C1-C4烷基(优选地、CH3)、F、Cl、Br或I;
Z为O或CH2,条件是当化合物为通式II的化合物,R3为-C≡C-H且R2为H或磷酸酯、二磷酸酯、三磷酸或磷酸三酯基团的时候,Z为CH2且不为O;
R1为H、酰基、C1-C20烷基或醚基团;
R2为H、酰基、C1-C20烷基或醚基团、磷酸酯(phosphate)、二磷酸酯(diphosphate)、三磷酸酯(triphosphate)、磷酸二酯基团或
或 基团;
Nu为生物活性抗病毒化合物的基团以使所述的生物活性抗病毒化合物的氨基或羟基与相邻的成分形成磷酸酯、氨基磷酸酯、碳酸酯或氨基甲酸乙酯基团;
R8为H,或C1-C20烷基或醚基团,优选地C1-C12烷基;
k为0-12,优选地,0-2;
R3选自C1-C4烷基(优选地,CH3)、-(CH2)n-C≡C-Ra、 或
R3a和R3b独立地选自H、F、Cl、Br或I;
Ra为H、F、Cl、Br、I或-C1-C4烷基,优选地H或CH3;
Y为H、F、Cl、Br、I或-C1-C4烷基,优选地H或CH3;并且
n为0、1、2、3、4或5,优选地0、1或2;
以及其差向异构体、可药用盐、溶剂合物,或多晶形。
优选地,B为胸腺嘧啶碱(即,带有5-甲基取代的尿嘧啶碱)或未取代的腺嘌呤碱。R1和R2优选地H。R3为优选地CH3、-C≡CH或-(CH2)n-CH=CH2,其中n为1。
在另一个优选的本发明发面,生物活性抗病毒剂为选自ddC、ddI、ddA、B-LFd4C、B-LFddC、AZT、阿巴卡韦、3TC、D4T和FTC的核苷化合物,其中生物活性剂通过核苷糖合成子的5’位羟基连接至磷酸酯、氨基磷酸酯、碳酸酯或氨基甲酸乙酯成分。
在另一种根据本发明的实施方案中,药物组合物包括有效量的一或多种如上所述的化合物,任选组合可药用载体、赋形剂或添加剂。
病毒感染和/或预防或延缓与病毒感染的有关的疾病的发作的治疗方法是本发明的另一方面。化合物可用来治疗与病毒相关的感染或疾病,所述的病毒包括,例如,人免疫缺陷病毒1和2(HIV-1和HIV-2)包括药物抗性株、人T-细胞白血病病毒1和2(HTLV-1和HTLV-2)、呼吸道合胞病毒(RSV)、人***瘤病毒(HPV)、腺病毒、B型肝炎病毒(HBV)、C型肝炎病毒(HCV)、Epstein-Barr病毒(EBV)、水痘-带状疱疹病毒(VZV)、巨细胞病毒(CMV)、单纯疱疹病毒1和2(HSV-1和HSV-2)、人疱疹病毒8(HHV-8,已知也为卡波西肉瘤相关病毒)和黄病毒,包括黄热病毒、登革病毒、日本脑炎和西尼罗脑炎病毒。优选地,根据本发明的化合物可用于治疗HIV感染。此外,本发明的化合物可用于预防和/或降低病毒感染如HIV感染或继发于病毒感染的疾病如AIDS、EBV-相关淋巴瘤或HHV-8相关的癌症(肉瘤)发生的可能性。
发明详述
这里使用的术语“化合物”,除非另有指明,指这里公开的任何特定的化合物。在上下文的使用中,术语通常指单一的化合物优选地,β差向异构体,但是在一些例子中也可以指立体异构体和/或光学异构体(包括消旋混合物),优选地为特定的对映体,具体地,β-D或β-L,优选地公开的化合物的β-D核苷类似物或对映富集的混合物。在本发明的一些例子中,尤其 是在本发明的双重拮抗剂/二核苷前药方面,根据本发明的化合物经生物活性抗病毒剂的胺或羟基通过磷酸酯(包括多磷酸酯)、氨基磷酸酯、碳酸酯或氨基甲酸乙酯成分化学连接生物活性抗病毒剂。
术语“双重拮抗剂”(在上下文中,“二核苷”)指包括两种活性剂的前药化合物,一种为根据本发明的活性核苷化合物并且另一种为已知的活性剂,优选地已知的抗病毒剂,更优选地具有游离的氨基或羟基的抗HIV剂,所述的游离的氨基或羟基可用于将所述的药剂通过磷酸酯或碳酸酯基团连接至根据本发明的化合物。在本发明的双重拮抗剂方面,具有游离的羟基或氨基的生物活性剂可通过磷酸酯或碳酸酯成分用于连接根据本发明的化合物以产生显示生物活性的前药化合物,优选地抗病毒活性。在这方面,根据本发明的核苷类似物连接至生物活性剂,优选地通过糖合成子5’OH位的伯醇以产生磷酸酯、氨基磷酸酯、碳酸酯或氨基甲酸乙酯(urethane)成分。或者,本发明的核苷化合物的仲醇或游离胺可用于与在本发明的双重拮抗剂方面中的其他的生物活性剂形成连接基。优选地,β-D或β-L核苷类似物可用作生物活性剂并连接至本发明的核苷化合物(其自身可为对映体富集的β-D或β-L核苷化合物、消旋体或非对映体混合物)以形成二核苷前药,取决于选择使用的核苷化合物的活性。在优选的本发明的方面,生物活性抗病毒剂优选地为另一种抗病毒核苷剂如ddC、阿巴卡韦、ddI、ddA、3TC、AZT、D4T、FTC、FddC和Fd4C。优选的二核苷化合物为在附图3中显示的那些。
示例性的可用于本发明的双重拮抗剂方面的生物活性剂,尤其是抗HIV剂,包括,例如(化合物名称以及通过连接根据本发明的核苷化合物的活性成分):
Atazanavir(BMS-232632),利用游离的二级羟基;
双(POM)-PMEA(阿德福韦二吡呋酯),利用游离的胺基;
双(POC)-PMPA(Tenofovir disoproxil),利用游离的胺基;
Etecavir,利用碳环状的糖合成子上的伯羟基;
茚地那韦(Merck的Crixivan,MK-639 L-735,524),利用游离的二级 羟基;
KHI-227(Nikko Kyodo Co.的Kynostatin),利用游离的二级羟基;
2-[3-[3-(S)-[[(四氢呋喃基氧基)羰基]氨基]-4-苯基-2(R)-羟基丁基]]-N-(1,1-二甲基乙基)十氢-3-异喹啉甲酰胺(Merck的异喹啉CON呋喃基氨基甲酸乙酯类似物),利用游离的二级羟基;
氨基甲酸,[3-{[(4-甲氧基苯基)磺酰基](环戊基甲基)氨基]-2-羟基-1-(苯基甲基)丙基]-,四氢呋喃基酯(Vertex的VB-11,328),利用游离的二级羟基;
Nikko Kyodo Co.的KNI-174,利用游离的二级羟基(或游离胺)基团;
Sandoz(Austria)的Val-Val-Sta,利用游离的二级羟基;
Ciba-Geigy的CPG53820,利用游离的二级羟基;
双-Val HOEt-N2氮杂肽电子等排体,利用游离的二级羟基;
Hoechst AG的C2-Sym次膦酸酰胺衍生物,利用游离的胺基;
Abbott的2,5,-二氨基-N,N’-双(N-苄氧基羰基uelyl)-1,6-二苯基-3(S),4(S)-己烷二醇BzOCValPhe[二CHOH(SS]PheValBzOC,利用游离的二级羟基;
Abbott的2,5,-二氨基-N,N’-双(N-苄氧基羰基uelyl)-1,6-二苯基-3(R),4(R)-己烷二醇BzOCValPhe[二CHOH(RR]PheValBzOC,利用游离的二级羟基;
ddA的双(S-乙酰基-2-硫代乙基)磷酸三酯或[双(SATE)ddAMP],利用游离胺;
BILA 2186 BS(Bio-Mega/Boehringer Ingelheim),利用游离的二级羟基;
Vertex/Kissei/Glaxo Wellcome的Agenerase(安泼那韦;VX-478;141W94),利用游离的二级羟基或胺基团;
Abbott的A-98881(氮杂环状的脲衍生物),利用游离的二级羟基或酚羟基;
Abbott的A-83962(Rifonavir衍生物),利用游离的二级羟基;
Abbott的A-80987(Rifonavir衍生物),利用游离的二级羟基;
Roche的(2-萘羰基)Asn[decarbonylPhe-羟基乙基]ProO叔丁基或2NaphCOAsnPhe[CHOHCH2]Pro-OtBu,利用游离的二级羟基;
Sandoz的2-氨基苄基他汀Valyl Cbz衍生物,利用游离的二级羟基或胺;
Sandoz的2-氨基苄基他汀Valyl Cbz衍生物,利用游离羟基;
Sandoz的10H-2(Cbz-ValNH)3PhPr[14]二聚对二甲苯邻甲酸衍生物,利用游离二级羟基;
Sandoz的10H-2(Cbz-ValNH)3PhPr[13]二聚对二甲苯邻甲酸衍生物,利用游离二级羟基;
Sandoz的10H-2(Cbz-ValNH)3PhPr[13]二聚间二甲苯邻甲酸(metacyclophane)衍生物,利用游离二级羟基;
Sandoz的10H-2(Cbz-Tle)3PhPr[14]二聚对二甲苯邻甲酸衍生物,利用游离二级羟基;
1-(20HPr)-4-取代的-哌嗪(环丙基),噻吩基氨基甲酸酯衍生物(Merck),利用游离的二级羟基;
1-(20HPr)-4-取代的-哌嗪(环丁基),噻吩基氨基甲酸酯衍生物(Merck),利用游离的二级羟基;
1-(20HPr)-4-取代的-哌嗪(3-戊基),噻吩基氨基甲酸酯衍生物(Merck),利用游离的二级羟基;
10H-2(Cbz-ValNH)3PhPr[17]二聚对二甲苯邻甲酸衍生物(Sandoz),利用游离二级羟基;
A-81525(Abbott),利用游离的二级羟基;
XM323(DuPont Merck的DMP-323),利用游离伯或仲羟基;
替拉那韦(Pharmacia&Upjohn的U-140690或PHU-140690),利用酚羟基;
噻酚并吡啶CON噻吩基氨基甲酸乙酯衍生物(Lilly的HOCH2CH2 电子等排体)(苄基取代的衍生物或甲基巯基苯基取代的衍生物),利用游离的二级羟基;
SDZ PRI 053(Sandoz),利用游离的二级羟基;
SD146(DuPont Merck),利用游离的二级羟基的醚;
替利那韦(Searle/Monsanto的SC-52151),利用游离的二级羟基或胺;
(R)2喹啉COAsnPhe[CHOHCH2]PipCONHtBu(Roche),利用游离的二级羟基或胺;
沙奎那韦(Roche的Invirase或RO 31-8959),利用游离的二级羟基或胺;
沙奎那韦/Melfinavir衍生物(Lilly),利用游离的二级羟基;
异喹啉CON Thf-Thf氨基甲酸乙酯类似物(Merck),利用游离的二级羟基;
异喹啉CON噻吩基氨基甲酸乙酯类似物(Merck),利用游离的二级羟基;
R-87366(Sankyo的AHPBA类似物),利用游离的胺基;
DMP 460(Dupont Merck/Avid),利用游离的二级羟基或任一苯胺胺基团;
L685,434(Merck),利用游离的二级羟基;
L685,434-6-羟基衍生物(Merck),利用游离的二级羟基;
L685,434-OEtNMe2(Merck),利用游离的二级羟基;
L685,434-OPrMorph衍生物(Merck),利用游离的二级羟基;
L689,502(Merck),利用游离的二级羟基;
拉西那韦(CIBA/Novartis的CGP 61755),利用游离的二级羟基;
Aluviran(Abbott的洛匹那韦,ABT-378,RS-346 A157378),利用游离的二级羟基;
Nelfinavir-八氢-噻酚并吡啶类似物(Lilly),利用游离的二级羟基;
P9941(DuPot Merck),利用任一游离的二级羟基;
帕利那韦(BIO-MEGA/Boehringer Ingelheim 的BILA 2011 BS),利用游离的二级羟基;
青霉素,2异喹啉-OHPrNH2类似物(Glaxo Wellcome),利用游离的二级羟基等。
用于本发明的双重拮抗剂方面的上述活性化合物以及其他的相关的生物活性剂可在NIH网址上见到://www.niaid.nih.gov/daids/dtpdb/,相关的部分这里引入作为参考。尽管不是必要的或重要的,优选地在本发明的双重拮抗剂方面,形成双重拮抗剂的两种活性剂具有不同的作用机理,如逆转录酶抑制、蛋白酶抑制、锌指抑制、TAT抑制、整合酶抑制或其他的抑制性活性。注意的是事实上上述活性剂的每一种,不受限制地可与一或多种没有被化学连接的本发明化合物一起给药。
这里使用的术语“有效的”,除非另有指明,在上下文中,为了描述化合物的量,用于产生或实现预定的结果,无论该结果涉及病毒疾病状态或与病毒疾病相关的病症或治疗,或者,用于以产生另一种化合物、药剂或组合物。该术语包括所有在本申请中没有描述的其他的有效量或有效的浓度术语。
术语“患者”说明书中通篇使用的用来描述用根据本发明的组合物进行治疗包括预防性治疗的动物,通常哺乳动物并优选地为人。对于对特定动物如人患者特异的这些感染、疾病或疾病状态的治疗而言,术语患者指特定的动物。
术语“病毒”用来描述所有类型的病毒,其生长或复制可利用一或多种根据本发明方法抑制或疾病状态。可根据本发明抑制的病毒包括,例如,人免疫缺陷病毒1和2(HIV-1和HIV-2)、人T-细胞白血病病毒1和2(HTLV-1和HTLV-2)、呼吸道合胞病毒(RSV)、人***瘤病毒(HPV)、腺病毒、B型肝炎病毒(HBV)、C型肝炎病毒(HCV)、Epstein-Barr病毒(EBV)、水痘-带状疱疹病毒(VZV)、巨细胞病毒(CMV)、单纯疱疹病毒1和2(HSV-1和HSV-2)、人疱疹病毒8(HHV-8,已知也为卡波西肉瘤相关病毒)和黄病毒,包括黄热病毒,登革病毒、日本脑炎和西尼罗脑炎病毒等。
术语“人免疫缺陷病毒”用来描述人免疫缺陷病毒(HIV)及其感染,该术语应该用于包括人免疫缺陷病毒1(HIV-1)和人免疫缺陷病毒2(HIV-2)二者。
术语“人T-细胞白血病病毒”用来描述人T-细胞白血病病毒及其感染,该术语应该包括人T-细胞白血病病毒1(HTLV-1)合人T-细胞白血病病毒2(HTLV-2)二者。
术语“B型肝炎病毒(HBV)”用于描述在人中产生B型病毒肝炎的病毒(血清肝炎病毒)。与A型肝炎病毒(感染性肝炎病毒)具有短的潜伏期不同,该病毒疾病具有长的潜伏期(约50~160天)。病毒通常通过输注了感染的血液或血液衍生物或仅仅通过使用了污染的针头、小刀或其他的器械。临床和病理上,该疾病类似于A型病毒肝炎;但是,没有交叉保护性免疫。感染后,病毒抗原(HBAg)可见于血清。
说明书中通篇使用的术语“单纯疱疹病毒”(HSV)用来描述HSV1和HSV2,其为疱疹感染包括生殖器疱疹感染的致病病毒。
说明书中通篇使用的术语“C型肝炎病毒(HCV)”用来描述非-A、非-B肝炎致病病毒的肝炎病毒。急性期的该疾病,通常较肝炎B温和,但是更大比例的这种感染将变成慢性。
说明书中通篇使用的术语“Epstein-Barr病毒(EBV)”用来描述见于Burkitts淋巴瘤细胞培养物中的滑柱病毒(herpetovirus)。EBV是传染性单核细胞增多症以及多种其他有关的病症/疾病状态包括EBV-相关的淋巴瘤中致病因素。
术语“Varicella-Zoster病毒(VZV)”用于描述疱疹病毒科,已知也为水痘或带状疱疹。水痘源自病毒的初步感染;带状疱疹源自相同感染或感染再活化的继发侵入,感染再活化在许多情形下可潜伏很多年。VZV的初步和继发感染可利用根据本发明的组合物进行治疗。
说明书中通篇使用的术语“呼吸道合胞病毒(RSV)”用来描述引起小的呼吸性感染的肺病毒属的含RNA-病毒,在成人中引起鼻炎和咳嗽,但是在年轻的儿童中能引起支气管炎以及支气管肺炎。病毒根据其在组织培养物有形成合胞体的趋势而命名。
说明书中通篇使用的术语“腺病毒”用来描述含有具有双链DNA的病毒的腺病毒科的病毒,其传染哺乳动物和鸟类。病毒颗粒为70~90nm直径并 且是裸露的(没有包膜)。病毒在感染细胞的核中发育;由于实验动物对明显的感染不敏感,分离需要组织培养。该科包括两个属,哺乳动物腺病毒和Acvi腺病毒。
说明书中通篇使用的术语“人疱疹病毒8(HHV-8)”用来描述滑柱病毒,据信是AIDS患者中Kaposis肉瘤的致病因素。
说明书中通篇使用的术语“人***瘤病毒(HPV)”用来描述引起生殖器疣的病毒。已知也为传染性的疣病毒,HPV为普遍、常见的、经常复发的病毒感染,具有大量的血清型。HPV感染可导致生殖器疣的形成,后者反过来,导致生殖器和/或***症。HPV1、2、6、11、16和18型导致的生殖器疣通常通过性途径转播并且通常与宫颈和/或生殖器癌症相关。HPV可成熟以产生乳突肿瘤或疣,其为限定的相对于周围表面突出的良性上皮肿瘤。其通常良性上皮肿瘤,由肿瘤细胞覆盖的纤维血管间质的绒毛状或乔木状赘疣组成。
术语“黄病毒”说明书中通篇使用的用来描述属于披膜病毒科黄病毒属的病毒。根据病毒分类学,约50病毒包括C型肝炎病毒(HCV)、黄热病毒、登革病毒、日本脑炎病毒、西尼罗脑炎病毒以及相关的黄病毒属于该属。属于黄病毒属的病毒简单地称为黄病毒。这些病毒以前归类为B组虫媒病毒。黄病毒是传染性疾病的致病因素并主要在东、东南以及南亚和非洲流行,尽管它们也可见于世界的其他地方。
术语“黄热病毒”用于描述为黄热致病因素的黄病毒。黄热为热带的蚊子携带的病毒肝炎,由于黄热病毒(YFV),具有通过Aedes aegypti传播的城市形式,并在乡村,由Haemagogus物种复合物的多种蚊子传播的源自树栖哺乳动物的热带植丛或森林形式。黄热临床特征为发热、迟脉、蛋白尿、黄疸、面部淤血以及出血,尤其是呕血(黑色呕吐物)。死亡率约占病例的5-10%。
说明书中通篇使用的术语“登革病毒”描述为登革发热/登革出血性发热致病因素的黄病毒。登革为热带和亚热带地区流行发生的一种疾病并由登革病毒引起,引起出血性发热综合征的虫媒病毒之一。根据严重程度分为4级:I级:发热和全身症状,级II:I级以及自发性出血(皮肤、龈或胃肠道),III级:II级以及精神激动和循环衰竭以及级IV:深度休克。该疾病由Aedes 属的蚊子(通常A.aegyptiI,但是更通常地,A.albopictus)传播。也称为Aden,bouquet、breakbone、dandy、date、登革(出血性)或polka、solar发热、失枕发热、scarlatina rheumatica或exanthesis arthorosia。出血性登革为更具致病性的流行的登革形式,近年已经在太平洋地区爆发流行了多次。
说明书中通篇使用术语“可药用盐”用来描述一或多种组合物成分的盐形式(并且具体地根据本发明优选的方面,磷酸盐),以增加化合物在盐水中的溶解度适于肠胃外给药或在患者的胃肠道中的胃液中溶解度以促进化合物的溶解和生物利用度。可药用盐包括那些衍生自可药用无机或有机碱和酸的盐。合适的盐包括那些衍生自碱金属如钾和钠,碱土金属如钙、镁和铵盐以及制药领域公知的其他的酸的盐。钠和钾盐是特别优选的,因为是根据本发明成分包含羧酸以及游离磷酸的中和盐。术语“盐”应该指与本发明化合物用途一致的任何盐。在其中化合物用于药用目的,包括***包括癌症的时候,术语“盐”应该指与化合物用作药剂一致的可药用盐。
说明书中通篇使用的术语″可药用衍生物″用来描述任何可药用前药形式(如酯或醚或其他的前药基团),其一旦给药于患者,直接地或间接地提供本发明地化合物或本发明化合物的代谢物。
在上下文中的术语“烷基”指C1-C20,优选地C1-C10线性的、支链或环状的完全饱和的烃基团。术语“醚”指C1-C20醚基团,由氧和烷基在本发明化合物糖成分上形成,或者,也可在烷基链中包含至少一个氧原子。
说明书中通篇使用的术语“酰基”用来描述核苷类似物(即在糖合成子中的游离羟基位)5′位的基团,其包含C1-C20线性的、支链的或环状的烷基链。5′位的酰基,与5′羟基结合产生酯,其在给药后,可裂解以产生本发明的游离核苷形式。根据本发明的酰基用下述结构表示:
其中R4为C1-C20线性的、支链的或环状的烷基、烷氧基烷基、芳基氧基烷基,如苯氧基甲基、芳基、烷氧基,其中,优选的酰基为那些其中R4为C1 至C10烷基的基团。根据本发明的酰基还包括,例如,那些衍生自下列这些 酸的酰基:苯甲酸以及相关的酸、3-氯苯甲酸、琥珀酸、羊蜡酸和正己酸、十二烷酸、十四[烷]酸、棕榈酸硬脂酸以及油酸以及其他的酸包括甲磺酸。本领域的普通技术人员将意识到酰基在本发明中有用,或者用于合成目标药用化合物或作为根据本发明核苷的前药形式。
说明书中通篇使用的术语“磷酸酯”或“磷酸二酯”用来描述在二氧杂环己基(dioxanyl)成分或糖合成子的5′位的单-磷酸酯基团,其被二酯化以使磷酸酯成为中性,即,具有中性电荷。用于本发明的磷酸酯包括下述结构代表的那些:
其中R5、R6和R”选自C1至C20线性的、支链的或环状的烷基、烷氧基烷基、芳基氧基烷基,如苯氧基甲基、芳基和烷氧基等,并且R7为C1至C20线性的、支链的或环状的烷基或酰基、烷氧基烷基、芳基氧基烷基,如苯氧基甲基、芳基和烷氧基等,优选的用于根据本发明的前药形式的单磷酸酯酯为那些其中R5为C1至C20为线性的或支链的链烷基,更优选地C1~C3烷基。
术语“保护基”或“封闭基团(blocking group)”在上下文中,指化学基团或成分,用于预防其他的化学成分如胺、羟基或巯基参与指定反应路线的反应并且其在温和的条件下容易去除,所述的温和条件不对保护基连接的分子或化合物产生不利的影响。在本发明中,可以使用多种保护基以产生根据本发明的化合物,优选的基团包括苯甲酸酯基以保护或封闭伯或仲羟基以及甲硅烷基基团(具体地,叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基或相关的甲硅烷基保护基)以封闭伯(或仲)羟基。本领域的普通技术人员将意识到可用于产生本发明化合物和中间体的多种保护基。
说明书中通篇使用的术语″抑制性有效的浓度″或″抑制性有效量″用来描述基本上或显著地抑制易感病毒的生长或复制的根据本发明化合物的浓 度或量,所述的病毒尤其是包括人免疫缺陷病毒1和2(HIV-1和HIV-2)、人T-细胞白血病病毒1和2(HTLV-1和HTLV-2)、呼吸道合胞病毒(RSV)、人***瘤病毒(HPV)、腺病毒、B型肝炎病毒(HBV)、C型肝炎病毒(HCV)、Epstein-Barr病毒(EBV)、水痘-带状疱疹病毒(VZV)、巨细胞病毒(CMV)、单纯疱疹病毒1和2(HSV-1和HSV-2)、人疱疹病毒8(HHV-8,已知也为卡波西肉瘤相关病毒)和黄病毒、包括黄热病毒、登革病毒、日本脑炎和西尼罗脑炎病毒等。
说明书中通篇使用的术语“预防有效量”用来描述本发明化合物的浓度或用量,对在预防、降低下列病毒感染的可能性或延缓患者中由下列病毒引起的感染的发作的预防有效:人免疫缺陷病毒1和2(HIV-1和HIV-2)、人T-细胞白血病病毒1和2(HTLV-1和HTLV-2)、呼吸道合胞病毒(RSV)、人***瘤病毒(HPV),、腺病毒、B型肝炎病毒(HBV)、C型肝炎病毒(HCV)、Epstein-Barr病毒(EBV)、水痘-带状疱疹病毒(VZV)、巨细胞病毒(CMV)、单纯疱疹病毒1和2(HSV-1和HSV-2)、人疱疹病毒8(HHV-8,已知也为卡波西肉瘤相关病毒)和黄病毒,包括黄热病毒、登革病毒、日本脑炎和西尼罗脑炎病毒等。
术语“同时给药”或“联合治疗”用于描述一种疗法,其中至少两种活性化合物以有效量同时于治疗病毒感染。尽管术语同时给药优选地包括将两种活性化合物同时给药患者,但是并不是必要地所述的化合物同时给药予患者,尽管单个化合物的有效量同时存在于患者体内。根据本发明化合物可与一或多种抗病毒剂一起给药,所述的药剂包括抗HIV剂如核苷逆转录酶抑制剂(NRTI)、非-核苷逆转录酶抑制剂、蛋白酶抑制剂、融合抑制剂,其中,示例性的化合物可包括,例如,3TC(拉米夫定)、AZT(齐多夫定)、(-)-FTC、ddI(地达诺新)、ddC(扎西他滨)、阿巴卡韦(ABC)、替诺福韦(PMPA)、D-D4FC(逆t)、D4T(司他夫定)、Racivir、L-FddC、L-FD4C、NVP(奈韦拉平)、DLV(地拉韦啶)、EFV(依法韦仑)、SQVM(甲磺酸噻喹努佛)、RTV(利托那韦)、IDV(茚地那韦)、SQV(沙奎那韦)、NFV(Nelfinavir)、APV(安泼那韦)、LPV(洛匹那韦)、融合抑制剂如T20,其中,fuseon及其混合物,包括目前在临床试验或在开发中的抗HIV化合物。共同给药也包括二核苷类似物(即,其中至少两种生物活性核苷通过化学连接基团进行化学连接的化合物,所述的 的连接基团如,例如,不限于,磷酸酯基团或羧酸酯基团等)或其他双重拮抗剂的给药,其中二核苷化合物中至少一种活性核苷化合物为不是这里描述的化合物。
根据本发明的化合物可用于具有生物/药理活性的药物组合物,以用于治疗例如病毒感染以及许多其他的疾病和/或疾病状态,所述的疾病或疾病状态继发于病毒感染出现或发生。这些组合物包括有效量的上述公开的化合物中任何一或多种,任选结合可药用添加剂、载体或赋形剂。根据本发明化合物也可用作用于合成显示生物活性的化合物中间体以及判定本发明的化合物以及其他的生物活性化合物的生物活性的标准。
本发明的组合物可一或多种可药用载体按照常规的方式进行配方。可用于这些药物组合物的可药用载体包括,但不限于,离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白,缓冲物质如磷酸盐、氨基乙酸、山梨酸、山梨酸钾、饱和的植物脂肪酸的部分甘油酯混合物、水、盐或电解质如硫酸谷醇溶蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体硅酸、三硅酸镁、聚乙烯基吡咯烷酮、基于纤维素的物质、聚乙二醇、羧基甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙基烯嵌段聚合物、聚乙二醇以及羊毛脂。
本发明的组合物可经口服、肠胃外、吸入喷雾、局部、直肠、鼻、面颊、***或通过植入的长效制剂给药。这里使用的术语″肠胃外″包括皮下、静脉内、肌肉内、关节内、滑液内、胸内、鞘内、肝脏内、损害部位内以及颅内注射或输液技术。优选地,组合物经口服、腹膜内或静脉内给药。
本发明的组合物的无菌注射形式可为水性或油性悬浮液。这些悬浮液可根据本领域公知的技术进行配制,利用合适的分散或湿润剂以及助悬剂。无菌注射剂也可为在无毒的肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如为在1,3-丁二醇中的溶液。可使用的可接受的溶媒和溶剂为水、Ringer′s溶液以及等张的氯化钠溶液。此外,无菌的、不挥发性油通常用作溶剂或悬浮介质。为了这种目的,可以使用任何温和的不挥发性油包括合成的单-或二-甘油酯。脂肪酸,如油酸以及其甘油酯衍生物可用于制备注射剂,如天然的药用可接受的油,如橄榄油或蓖麻油,尤其是其聚氧乙烯化的衍生物。这些油溶液或悬浮液也可包含长-链醇稀释剂或分散剂, 如Ph.Helv或类似的醇。
本发明的药物组合物可以任何口服可接受的剂型经口服给药,包括但不限于,胶囊、片剂、水性悬浮液或溶液。在口服片剂的情形下,通常使用的载体包括乳糖和玉米淀粉。润滑剂,如硬脂酸镁,也可典型地加入。对于胶囊形式的口服给药,有用的稀释剂包括乳糖以及干燥的玉米淀粉。当需要水性悬浮液用于口服的时候,活性成分与乳化以及混悬剂混合。如果需要,一些甜味剂、调味剂或着色剂剂也可加入。或者,本发明的药物组合物可以栓剂的形式经直肠给药。这些剂型可通过将所述的药剂与合适的非刺激性的赋形剂进行混合物,所述的赋性剂在室温为固体但是在直肠唯独为液体并因此在直肠中熔化从而释放药物。所述的物质包括可可脂、蜂蜡和聚乙二醇。
本发明的药物组合物还可经局部给药,尤其是治疗的目标包括局部应用容易接触的区域或器官的时候,包括眼睛、皮肤或较末端的肠道。合适的局部制剂容易配制以用于这些区域或器官的每一种。
用于较末端的肠道的局部应用可用直肠制剂(见上)实现或以合适的灌肠剂实现。局部-透皮贴剂也可使用。
对于局部应用,药物组合物可配制在合适的软膏种,活性成分悬浮或溶解在一或多种载体中。用于本发明化合物局部给药的载体包括,但不限于,矿物油、液体凡士林、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡以及水。或者,药物组合物可配制在合适的洗液或乳膏中,活性成分悬浮或溶解在一或多种可药用载体中。合适的载体包括但不限于矿物油、脱水山梨醇单硬脂酸酯,聚聚山梨酯60、鲸蜡基l酯蜡、cetearyl醇、2-辛基十二(烷)醇、苄基醇以及水。
对于眼用,药物组合物可配制成在等张、调节pH的无菌盐水中微粉化的悬浮液,或,优选地,为在等张、调节pH的无菌盐水溶液,有或无防腐剂如benzyl alkonium chloride。或者,对于眼科使用,药物组合物在软膏如凡士林中配制。
本发明的药物组合物也可经鼻气雾剂或吸入给药。所述的组合物可根据制剂领域公知的技术进行配制并可配制成盐水溶液,使用苄基醇或其他合适的防腐剂、吸收促进剂以提高生物利用度、碳氟化合物和/或其他常规的 助溶或分散剂。
可与载体物质混合物以产生单一剂型的本发明新颖核苷的用量随治疗的宿主、具体的给药方式而变。优选地,组合物应该配制成以使剂量介于约0.01和150之间,优选地约0.5~约25mg/kg患者/天/新颖核苷可对接受这些组合物的患者给药。
应该理解为针对任何特定的患者的具体的剂量和治疗方案将取决于多种因素,包括使用具体化合物的活性、年龄、体重、一般状况、性别、饮食、给药时间、***速率、药物联用以及治疗医师的判断以及具体治疗疾病或病症的严重程度。
活性化合物的给药可在连续(静脉滴注)至每天口服给药数次(例如,Q.I.D.)并可包括口服、局部、肠胃外、肌肉内、静脉内、皮下、透皮(其可包括渗透增强剂)、含服以及栓剂给药以及其他的给药途径。肠溶包衣的片剂也可用于提高化合物口服给药途径的生物利用度。最有效的剂型取决于选择的具体药剂的药代动力学以及患者疾病的严重程度。口服剂型是特别优选的,由于服药方便以及预期的有利的患者顺从性。
为了制备根据本发明的药物组合物,根据常规的制药混合技术,将治疗上有效量一或多种根据本发明的化合物优选地与可药用载体密切混合以产生剂型。载体可采取多种形式,取决于期望给药如口服或肠胃外的制剂形式。在制备口服剂型的药物组合物的时候,可以使用任何常规的药用介质。因此,对于液体口服制剂如混悬剂、酏剂和溶液、合适的载体以及添加剂包括水、二醇、油类、醇、调味剂、防腐剂、着色剂等可以使用。对于固体口服制剂如散剂、片剂、胶囊,并且对于固体制剂如栓剂,合适的载体合添加剂包括淀粉、糖载体,如葡聚糖、甘露醇、乳糖以及相关的载体、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等可以使用。如果需要,片剂或胶囊剂可以利用标准的技术进行肠溶包衣或缓释。这些急性的使用可以显著地改善患者体内的化合物的生物利用度。
对于肠胃外制剂,载体通常包括无菌水或氯化钠水溶液,尽管其他的成分,包括有助于分散的那些,也可包括在其中。当然,其中无菌水可以使用并保持无菌状态,组合物和载体也必须是无菌的。也可制备注射悬浮液,在这种情形下适当的液态载体、助悬剂等也可使用。
脂质体悬浮剂(包括靶向病毒抗原的脂质体)也可利用常规的方法进行制备以产生可药用载体。这对输送游离核苷、酰基/烷基核苷或根据本发明的核苷化合物的磷酸酯酯前药形式是适当的。
具体地,根据本发明的优选的实施方案,所述的化合物和组合物可用于治疗、预防或延迟哺乳动物病毒感染的发作,并且具体地HIV、HBV、HSV1和/或II、EBV、HHV-8和黄病毒感染等。在该优选的实施方案中,所述的化合物可用于治疗HIV、HSVI和/或II、HBV、EBV或HHV-8感染,尤其是人的HIV感染。优选地,对于治疗、预防或延迟病毒感染的发作,所述的组合物以约250毫克高达约500mg或更多剂量口服剂型进行给药,用于治疗性治疗的剂量范围内至少每天给药一次,优选地,高达每天4次。本发明的化合物优选地经口服给药,但是可经肠胃外、局部以栓剂或其他的形式给药。
根据本发明的化合物,由于其对宿主细胞的低毒性,可有利地预防性使用以预防病毒感染或以预防与病毒感染相关的临床症状的发生,例如继发于HIV的AIDS、继发于EBV淋巴瘤或继发于HHV-8的Kaposi’s肉瘤。因此,本发明还包括病毒感染预防性治疗的方法(预防、降低发作的可能性或延缓发作),并且具体地HIV和EBV以及具体地,继发于这些病毒的病症。在本发明的这方面,本发明的组合物可用于预防降低可能性或延缓病毒感染的发作,具体地,HIV、HSV、EBV或另一种病毒感染或病毒有关的疾病或病症如AIDS或EBV-有关的淋巴瘤或Kaposi’s肉瘤(HHV-8)。该预防性方法包括对需要所述治疗的患者或处于发展HIV、EBV、HHV-8或其他病毒感染的患者给药有效减轻、预防或延缓病毒感染的发作的一定量的本发明化合物。在根据本发明的预防性治疗中,优选的利用的抗病毒化合物为低毒性并优选地对患者无毒性。在本发明这方面特别优选的使用的化合物应该对抗病毒最大地有效并对患者的毒性应该最小。在本发明的化合物用于预防性病毒感染的治疗的情形下,这些化合物可以在用于治疗性治疗的同样的剂量范围给药(如上所述,作为预防性剂以预防病毒感染或或者的增殖,延长病毒感染的发作或降低患者显示病毒感染自身临床症状的可能性。
此外,根据本发明化合物可单独给予或组合其他试剂给予,包括其他的本发明化合物。一些本发明化合物可有效用于提高一些根据本发明的药剂 的生物活性,通过降低代谢、分解代谢或其他化合物的失活等,为了这种效果可共同给药。
如上所示,根据本发明的化合物可单独给药或连用其他的抗病毒剂用于治疗上面没有描述的其他病毒感染,尤其是包括本发明的其他的化合物或其他地方公开的可用于治疗HIV或黄病毒的化合物,包括那些目前用于治疗HIV的药物如核苷逆转录酶抑制剂(NRTI)、非核苷逆转录酶抑制剂、蛋白酶抑制剂、融合抑制剂,其中,其示例性的化合物可包括,例如,3TC(拉米夫定)、AZT(齐多夫定)、(-)-FTC、ddI(地达诺新)、ddC(扎西他滨)、阿巴卡韦(ABC)、替诺福韦(PMPA)、D-D4FC(逆t)、D4T(司他夫定)、Racivir、L-FddC、L-D4FC、NVP(奈韦拉平)、DLV(地拉韦啶)、EFV(依法韦仑)、SQVM(甲磺酸噻喹努佛)、RTV(利托那韦)、IDV(茚地那韦)、SQV(沙奎那韦)、NFV(Nelfinavir)、APV(安泼那韦)、LPV(洛匹那韦)、融合抑制剂如T20等,fuseon及其混合物,包括目前正在进行临床试验或正在开发的抗HIV化合物,以及尤其在下述专利文献中公开的化合物,U.S.6,240,690;6,316,505;6,316,492;6,232,120;6,180,604;6,114,327;5,891,874;5,821,242;5,532,215;5,491,135;5,179,084;以及4,880,784,其中,相关的部分这里引入作为参考。
在上述参考的专利中公开的化合物可与本发明的化合物联合用药以利用其加和活性或抗HIV和/或抗病毒的治疗特性,并且在一些情形下,利用与本发明化合物的协同作用。优选的与本发明化合物联用的第二种或其他的化合物是那些不抑制HIV或另一种病毒的化合物。一些根据本发明的化合物可有效提高一些根据本发明药剂的生物活性,通过降低代谢、分解代谢或其他化合物的失活等,为了这种效果可共同给药。
本发明将在下述实施例中进行描述,仅仅是举例说明。本领域的普通技术人员应该理解这些实施例不以任何方式进行限定并且在不偏离本发明的精神和范围的前提下,可以有细节的变化。
化学
本发明的新化合物通常按照图4-7C中显示的一般性的合成描述进行制备。其他的化合物可类似地容易地合成得到。通常,初始制备核苷类似物(即, 含碱和糖合成子的化合物),并按照路线A和B中一般性地描述将相应的4’基团导入,或者按照实验部分其他的记载。本领域的普通技术人员容易合成根据本发明的化合物,通过类似地按照在实验部分中提供的合成方法,并不需要额外的实验。
如图4中所显示,5’-碘,3’-O-保护的2’-脱氧核苷转化成4’5’-乙烯基保护的核苷2,后者然后经过一系列的步骤通过4’5’-环氧乙烷保护的核苷4转化成4’-乙烯基化合物TDK-4-152。如图5中所示,TKD-4-114从5’-碘-3’-O-保护的核苷化合物7进行合成,通过形成4’,5’-乙烯基化合物8,在保护的核苷的4’-位引入乙炔基以形成核苷10a并最终通过化合物13的3’位甲磺酰化的羟基的消去形成2’,3’不饱和的双键。根据本发明的其他化合物类似地利用上述化学路线进行合成。
图5A显示了从图5的中间体9合成TDK-4-114的另外一条路线。在本发明的该方面,中间体9与苯甲酸铅Pb(OCOPh)或四乙酸铅Pb(OAc)4在清除碱如三乙基胺、二异丙基乙基胺,或吡啶存在下在合适的溶剂中反应以产生4’5’-二酰基(苯甲酰基或乙酰基)保护的核苷2(图5A),取决于使用的d铅(Pb)酰化剂。引入4’乙炔基通过中间体保护的核苷2,利用铝乙炔剂EtAl(Cl)-C≡SiMe3(参见图5A)的作用在溶剂中以产生4’乙炔核苷化合物3(图5A)。TKD-4-114的合成方法较为直接,消去甲磺酰化的羟基形成4’-乙炔基-2’,3’不饱和的核苷化合物7。注意图5A(和5B)的中间体3可另外从图5A和5B的4’,5’乙烯基保护的核苷化合物1(与图5的化合物9相同)合成得到,通过两步反应以形成图5B二-O-苯甲酰基化合物3(或二-O-乙酰基)的,利用第一步碘和苯甲酸银(乙酸银)在溶剂中形成中间体2(图5B),其可进一步与苯甲酸银(乙酸银)在溶剂中在升高的温度下反应以形成中间体3(或类似地二-O-乙酰基化合物)。
在图6中的化学合成路线举例说明了不饱和的碳环状的类似物KMA-23-153(图6)的合成形成环戊酮酯1(图6),其经过多种中间体以形成中间体8(图6),可与核苷碱缩合形成中间体9,其中4’酯可转化成4’-乙炔基化合物10,然后去除5’保护基以产生KMA-23-153。
图7A显示了按照Nomura,等,J. Med.Chem.,42,2901-2908(1999)的一般方法进行4’-乙炔基-2’-脱氧核苷化合物的合成,通过在核苷的4’位引入 卤代的乙烯基,发生脱去卤化氢形成4’-乙炔基核苷化合物8(图7A)。图7B显示了从易得的糖前体9合成4’-乙炔基-2’-脱氧核苷的步骤(图7B),将4’-卤化的乙烯基导入糖合成子10的4’-甲酰基形成11(图7B),然后脱卤化氢,引入核苷碱并经过系列步骤转化2’羟基形成化合物18。图7C路线3显示了在4’-乙炔基类似物中引入2’,3’-双键,利用甲磺酰化3’OH基团然后将甲磺酰化的中间体与强碱反应以产生在糖的2’,3’位形成双键。
按照一或多种上述合成方法并利用本领域中公知的常规合成方法,本领域的普通技术人员很容易地得到根据本发明的化合物。
具体实施例
按照图5和图6中的路线A和B的化学合成
TKD-4-152(图4)的合成
TKD-4-152(4′-烯丙基胸苷)利用在图5路线A中显示的系列反应进行合成,起始物质化合物1根据已经发表的文献进行合成:J.P.H.Verheyden和J.G.Moffatt,J.Org.Chem.,39,3573-3579(1974)。
1-[3-O-(叔丁基二甲基甲硅烷基)-2,5-双脱氧-β-D-甘油基-呋喃戊糖-4-烯基]胸腺嘧啶(3)
在0℃氩气气氛下,向1(11.9 g,30.19mmol)的CH3CN(150mL)溶液中加入DBN(11.2mL,90.57mmol),并将整个反应在室温搅拌过夜。用AcOH中和后,将反应混合物蒸发至干并将残留物在CHCl3/饱和的NaHCO3水溶液之间分配(200mL×2/50mL)。有机层的硅胶柱层析(己烷/AcOEt=5/1-1/2)得到为泡沫的2(6.98g,87%)。将化合物2(6.90g,25.92mmol)用饱和的NH3 的MeOH溶液(350mL)在0℃处理过夜。将反应混合物蒸发至干并真空干燥过夜。在0℃氩气气氛下向残留物的DMF溶液(60mL)中加入咪唑(5.29g,77.75mmol)和叔丁基二甲基甲硅烷基氯(7.81g,51.83mmol),并将混合物在室温搅拌过夜。将反应混合物在AcOEt/H2O之间分配(300mL/100mL×5)。有机层的硅胶柱层析(己烷/AcOEt=10/1-3/1)得到为泡沫的3(7.87g,90%):UV(MeOH)λmax 264nm(ε11100),λmin 234nm(ε4900);1H NMR(CDCl3) δ0.13(6H,s,SiMe),0.91(9H,s,SiBu-t),1.94(3H,d,J6,Me=1.2 Hz,Me),2.13-2.20(1H,m,H-2′a),2.40(1H,ddd,Jgem=13.6Hz,J2’b,3’=3.4Hz and J1’,2’b =6.2 Hz,H-2′b),4.24(1H,d,Jgem=2.0Hz,H-5′a),4.54(1H,d,Jgem=2.0Hz,H-5′b),4.75(1H,dd,J2’a,3’=6.0 and J2’,b,3’=3.4Hz,H-3′),6.49(1H,t,J1’,2’a=J1’,2’b=6.2 Hz,H-1′),6.98(1H,d,J6,Me=1.2Hz,H-6),8.47(1H,br,NH);FAB-MS m/z 339(M++H)。C16H26N2O4Si分析计算值:C,56.78;H,7.74;N,8.28。实测值:C,57.04;H,7.99;N,8.14。
3’-O-(叔丁基二甲基甲硅烷基)胸苷4’,5’-环氧化物(4)
在-30℃氩气气氛下,向3(20mg,0.059mmol)的CH2Cl2(3mL)溶液中加入二甲基dioxirane(0.072M的丙酮溶液,1.2mL,0.089mmol),并将反应混合物在-30℃搅拌30分钟。蒸发溶剂得到为固体的4:1H NMR(CDCl3)δ 0.09,0.10(6H,各为s,SiMe),0.90(9H,s,SiBu-t),1.95(3H,d,J6,Me=1.3 Hz,Me),2.25(1H,ddd,Jgem=14.0Hz,J2’a,3’=4.9Hz and J1’,2’a=7.1Hz,H-2′a),2.52(1H,ddd,Jgem=14.0Hz,J2’b,3’=1.6Hz and J1’,2’b=6.2Hz,H-2′b),3.07(1H,d,Jgem=3.3Hz,H-5′a),3.36(1H,d,Jgem=3.3Hz,H-5′b),4.26(1H,dd,J2’a,3’=4.9and J2’,b,3’=1.6Hz),6.12(1H,dd,J1’,2’a=7.1Hz and J1’,2’b=6.2 Hz,H-1′),7.27(1H,d,J6,Me=1.3Hz,H-6),9.06(1H,br,NH);FAB-MS m/z 355(M++H)。
3’-O-(叔丁基二甲基甲硅烷基)-4’-α-烯丙基胸苷(5)
在30C氩气气氛下,向3(80mg,0.24mmol)的CH2Cl2(5mL)溶液中加入二甲基dioxirane(0.098M的丙酮溶液,3.6mL,0.36mmol),并将混合物在-30℃搅拌30分钟。蒸发溶剂并将残留物真空干燥1小时得到4。在-30℃氩气气氛下,向4的CH2Cl2(5mL)溶液中加入烯丙基三甲基甲硅烷(0.11mL,0.71mmol)和SnCl4(1M的CH2Cl2溶液,0.71mL,0.71mmol),并将混合物在-30℃搅拌4小时。用饱和的NaHCO3水溶液终止后,将反应混合物滤过celite垫。将滤液在CHCl3/饱和的NaHCO3水溶液之间分配(60mL×3/20mL)。将有机层蒸发至干并将残留物用饱和的NH3的MeOH溶液(30mL)在室温处理12小时。有机层蒸发然后经制备性TLC(己烷/EtOAc=2/3)纯化得到泡沫的5(75mg,80%):UV(MeOH)λmax 267nm(ε12700),λmin 235nm (ε5900);1H NMR(CDCl3)δ 0.08,0.08(6H,各为s,SiMe),0.89(9H,s,SiBu-t),1.87(3H,d,J6,Me=1.1Hz,Me),2.16(1H,dd,Jgem=14.5Hz和J6’a,7’=8.1Hz,CH 2CH=CH2),2.27-2.39(2H,m,H-2′),2.44(1H,dd,Jgem=14.5 Hz和J6’b,7’=6.3 Hz,CH 2CH=CH2),2.94(1H,br,OH),3.52(1H,dd,Jgem=11.8Hz和J5’,OH=6.1Hz,H-5′a),3.73(1H,dd,Jgem=11.8Hz和J5’,OH=2.7Hz,H-5′b),4.62(1H,dd,J2’a,3’=5.8Hz和J2’,b,3’=7.0Hz,H-3′),5.07-5.13(2H,m,CH2CH=CH 2),5.83-5.93(1H,m,CH2CH=CH2),6.11(1H,dd,J1’,2’a=5.8 Hz和J1’,2’b=6.9Hz,H-1′),7.45(1H,d,J6,Me=1.1Hz,H-6),9.40(1H,br,NH);nOe实验,H-1’/CH 2 CH=CH2(0.8%),CH2-5’/H-3’(5.3%),CH2-5’/H-6(0.6%),HO-5’/H-3’(0.7%)和HO-5’/H-6(1.2%);FAB-MS m/z 397(M++H)。分析计算值C19H32N2O5Si·1/3H2O:C,56.69;H,8.18;N,6.96。实测值:C,56.46;H,8.18;N,6.87.
TKD-4-152(4′-烯丙基胸苷)图4
将5(59mg,0.149mmol)和氟化四丁基铵(58mg,0.223mmol)在THF(3mL)中的混合物在室温搅拌12小时。反应混合物蒸发后硅胶柱层析(CHCl3/MeOH=20/1)得到为泡沫的TKD-4-152(37.7mg,90%):UV(MeOH)λmax 267nm(ε9300),λmin 235nm(ε2000);1H NMR 1.86(3H,d,J6,Me=1.2Hz,Me),2.27-2.35(3H,m,H-2′和CH 2CH=CH2),2.42-2.48(1H,m,CH 2CH=CH2),3.56(1H,d,Jgem=11.8 Hz,H-5′a),3.64(1H,d,Jgem=11.8Hz,H-5′b),4.48(1H,t,J2′a3′=J2′b 3′=5.8Hz,H-3′),5.04-5.13(2H,m,CH2CH=CH 2),5.88-5.98(1H,m,CH2CH=CH2),6.23(1H,t,J1′ 2′a=J1′,2′b=6.5Hz,H-1′),7.89(1H,d,J6,Me=1.2Hz,H-6);FAB-MS m/z 283(M++H),321(M++K)。C13H18N2O5 ·1/2H2O分析计算值:C,54.16;H,6.57;N,9.62。实测值:C,53.87;H,6.49;N,9.28.
TKD-4-114(2′,3′-双脱氢-3′-脱氧-4′-乙炔基胸苷,4′-乙炔基-d4T)利用在路线B中显示的系列反应进行合成,起始物化合物6根据发表的文献进行合成:B.V.Joshi和C.B.Reese,Tetrahedron Lett.,32,2371-2374(1992)。
1-(3-O-乙酰基-2,5-双脱氧-5-碘-β-D-苏-呋喃戊糖基)-胸腺嘧啶(7)
将6(5.3g,15.05mmol)和Ac2O(4.3mL,45.15mmol)在吡啶(30mL)中的混合物在室温搅拌13小时。将反应混合物在CHCl3/饱和的NaHCO3水溶液之间分配(250mL×3/50mL)。有机层的硅胶柱层析(己烷/EtOAc=1/1-1/2)得到为泡末的7(5.53g,93%):1H NMR(CDCl3)δ1.96(3H,s,Me),2.11(3H,s,Ac),2.11-2.16(1H,m,H-2’a),2.82(1H,ddd,Jgem=15.8Hz,J1’,2’b=8.0Hz和J2’b,3’=5.7Hz,H-2’b),3.32-3.39(2H,m,H-5’),4.28(1H,dt,J3’,4’=3.3Hz andJ4’,5’=7.1Hz,H-4’),5.48(1H,dd,J2’b,3’=5.7Hz and J3’,4’=3.3Hz H-3’),6.30(1H,dd,J1’,2’a=2.8Hz和J1’,2’b=8.0Hz,H-1’),7.38(1H,d,J6,Me=0.7Hz,H-6),8.59(1H,br,NH);FAB-MS m/z 395(M++H)。
1-(3-O-乙酰基-2,5-双脱氧-β-L-甘油基-呋喃戊糖-4-烯基)-胸腺嘧啶(8)
在0℃,向7(5.5g,13.95mmol)的CH3CN(40mL)溶液中加入DBN(6.9mL,55.81mmol),并将反应混合物在室温搅拌17小时。用AcOH中和后,将反应混合物蒸发至干。将残留物在CHCl3/饱和的NaHCO3水溶液之间分配(200mL×3/50mL)。有机层的硅胶柱层析(己烷/EtOAc=2/1-1/1)得到为泡沫的8(3.34g,90%):1H NMR(CDCl3)δ:1.96(3H,d,J6,Me=1.3Hz,Me),2.06(3H,s,Ac),2.21(1H,dt,Jgem=15.2Hz,J1’,2’a=J2’a,3’=2.7Hz,H-2’a),2.83(1H,dt,Jgem=15.2Hz,J1’,2’b=J2’b,3’=7.1Hz,H-2’b),4.51(1H,dd,Jgem=2.4Hz,J3’,5’a=0.8Hz,H-5’a),4.73(1H,dd,Jgem=2.4Hz和J3’,5’b=0.7Hz,H-5’b),5.70-5.73(1H,m,H-3’),6.44(1H,dd,J1’,2’a=2.7Hz和J1’,2’b=7.1Hz,H-1’),7.25(1H,d,J6,Me=1.3Hz,H-6),8.54(1H,br,NH);FAB-MS m/z 267(M++H)。
1-[3-O-(叔丁基二甲基甲硅烷基)-2,5-双脱氧-β-L-甘油基-呋喃戊糖-4-烯基]胸腺嘧啶(9)
将化合物8(5.2g,19.53mmol)在饱和的NH3的MeOH溶液(150mL)中在室温保持9小时。蒸发后,将残留物溶解在DMF(60mL)中。在0℃向其中加入咪唑(5.32g,78.12mmol)和叔丁基二甲基甲硅烷基氯(8.83g,58.59mmol)。将反应混合物在室温搅拌11小时,并且然后在EtOAc/H2O之间分配(250mL/50mL×4)。有机层的硅胶柱层析(己烷/EtOAc=10/1)得到为泡沫 的9(6.43g,97%):UV(MeOH)λmax 266nm(ε11600),λmin 236nm(ε5700);1H NMR(CDCl3)δ0.11和0.14(6H,各为s,SiMe),0.88(9H,s,SiBu-t),1.92(3H,d,J6,CH3=1.2Hz,Me),2.03(1H,dt,Jgem=10.8Hz,J1’,2’a=3.2Hz和J2’a,3’=3.2Hz,H-2’a),2.61-2.68(1H,m,H-2’b),4.25(1H,d,Jgem=2.2Hz,H-5’a),4.57(1H,d,Jgem=2.2Hz,H-5’b),4.68(1H,dd,J2’a,3’=3.2Hz,J2’b,3’=6.8HzH-3’),6.46(1H,dd,J1’,2’a=3.2Hz and J1’,2’b=7.2Hz,H-1’),7.44(1H,d,J6,CH3=1.2Hz,H-6),9.12(1H,br,NH);FAB-MS m/z 339(M++H)。C16H26N2O4Si分析计算值:C,56.78;H,7.74;N,8.28。实测值:C,56.61;H,7.87;N,8.17.
1-[2-脱氧-3-O-(叔丁基二甲基甲硅烷基)-4-乙炔基-β-D-苏-呋喃戊糖基]胸腺嘧啶(10a)和1-[2-脱氧-3-O-(叔丁基二甲基-甲硅烷基)-4-乙炔基-β-L-赤-呋喃戊糖基]胸腺嘧啶(10b)
在-30℃,向9(60mg,0.177mmol)的CH2Cl2(5mL)溶液中加入二甲基dioxirane(0.09M的丙酮溶液,3.0mL,0.266mmol)。搅拌0.5小时后,将混合物蒸发并真空干燥1小时。将残留物溶解在CH2Cl2(5mL)中。在-30℃氩气气氛下,向该溶液中加入三乙炔基铝(0.3M的CH2Cl2溶液,1.8mL,0.532mmol),并将反应混合物在室温搅拌17小时。用饱和的NH4Cl水溶液终止后,将反应混合物滤过celite垫。将滤液在CHCl3/饱和的NH4Cl水溶液之间分配(60mL×3/20mL)。有机层的HPLC分离(己烷/EtOAc=2/3)得到10a(tR=10.8分钟,39.3mg,58%,泡沫)和10b(tR=16.2分钟,18.8mg,28%,固体)。10a的物理数据:UV(MeOH):λmax 266nm(ε12100),λmin 235nm(ε6000);1H NMR(CDCl3)δ0.11和0.16(6H,各为s,SiMe),0.90(9H,s,SiBu-t),1.91(3H,d,J6,Me=1.3Hz,Me),1.91-1.96(1H,m,H-2’a),2.33(1H,br,OH),2.62(1H,s,乙炔基),2.95(1H,ddd,Jgem=14.6Hz,J1’,2’b=7.9Hz和J2’b,3’=5.5Hz,H-2’b),3.93(1H,d,Jgem=11.6Hz,H-5’a),3.99(1H,d,Jgem=11.6Hz,H-5’b),4.49(1H,dd,J2’a,3’=2.0Hz和J2’b,3’=5.5Hz,H-3’),6.39(1H,dd,J1’,2’a=3.7Hz和J1’,2’b=7.9Hz,H-1’),7.65(1H,d,J6,CH3=1.3Hz,H-6),8.72(1H,br,NH);FAB-MS m/z 381(M++H)。分析计算值C18H28N2O5Si·H2O:C,54.24;H,7.59;N,7.03。实测值:C,54.46;H,7.20;N,6.72.
10b的物理数据:mp 96-98℃;UV(MeOH):λmax 267nm(ε9300),λ min 235nm(ε1700)。1H NMR(CDCl3)δ0.08和0.13(6H,各为s,SiMe),0.89(9H,s,SiBu-t),1.93(3H,d,J6,CH3=0.9Hz,Me),2.12-2.17(1H,m,H-2’a),2.63(1H,br,OH),2.71-2.77(1H,m,H-2’b),2.75(1H,s,乙炔基),3.67(1H,d,Jgem=11.5Hz,H-5’a),3.74(1H,d,Jgem=11.5Hz,H-5’b),4.47(1H,t,J2’a,3’=J2’b,3’=5.3Hz,H-3’),6.30(1H,dd,J1’,2’a=4.8Hz和J1’,2’b=6.9Hz,H-1’),7.80(1H,d,J6,CH3=0.9Hz,H-6),9.00(1H,brs,NH);FAB-MS m/z 381(M++H)。分析计算值C18H28N2O5Si:C,56.82;H,7.42;N,7.36。实测值:C,56.57;H,7.58;N,7.19.
1-[5-O-乙酰基-2-脱氧-3-O-(叔丁基二甲基甲硅烷基)-4-乙炔基-β-D-苏-呋喃戊糖基]胸腺嘧啶(11)
在0℃,向10a(161mg,0.423mmol)的吡啶(4mL)溶液中加入Ac2O(120mL,1.269mmol),并将混合物在室温搅拌11小时,将反应混合物在CHCl3/饱和的NaHCO3水溶液之间分配(60mL×3/20mL)。有机层的硅胶柱层析(己烷/EtOAc=3/1)得到为泡沫的11(169.7mg,95%):UV(MeOH):λmax 266nm(ε9200),λmin 234nm(ε2000);1H NMR(CDCl3)δ0.10和0.14(6H,各为s,SiMe),0.90(9H,s,SiBu-t),1.90-1.94(4H,m,H-2’a和Me),2.14(3H,s,Ac),2.58(1H,s,乙炔基),3.01(1H,ddd,Jgem=14.8Hz,J1’,2’b=8.3Hz和J2’b,3’=5.0Hz,H-2’b),4.37(1H,d,Jgem=11.1Hz,H-5’a),4.45(1H,d,J2’b,3’=5.0Hz,H-3’),4.53(1H,d,Jgem=11.1Hz,H-5’b),6.40(1H,dd,J1’,2’a=2.8Hz和J1’,2’b=8.3Hz,H-1’),7.53(1H,d,J6,Me=1.3Hz,H-6),8.04(1H,br,NH);FAB-MS m/z 461(M++K)。分析计算值C20H30N2O6Si:C,56.85;H,7.16;N,6.63。实测值:C,56.84;H,7.35;N,6.26.
1-(5-O-乙酰基-2-脱氧-4-乙炔基-β-D-苏-呋喃戊糖基)-胸腺嘧啶(12)
在氩气气氛下,向11(169.7mg,0.402mmol)的THF(4mL)溶液中加入氟化四丁基铵(1M的THF溶液,602 L,0.602mmol)。在室温搅拌1小时后,蒸发溶剂,将残留物硅胶柱层析(CHCl3/MeOH=100/1)得到为泡沫的12(114.7mg,93%):UV(MeOH)λmax 265nm(ε8400),λmin233nm(ε1700); 1H NMR(CDCl3,加入D2O后)δ1.93(3H,d,J6,Me=1.3Hz,Me),2.14-2.18(1H, m,H-2’a),2.18(3H,s,Ac),2.59(1H,s,乙炔基),2.94-3.02(1H,m,H-2’b),4.22(1H,d,Jgem=11.4Hz,H-5’a),4.31(1H,d,J2’b,3’=5.5Hz,H-3’),4.68(1H,d,Jgem=11.4Hz,H-5’b),6.24(1H,dd,ssJ1’,2’a=2.9Hz和J1’,2’b=9.0Hz,H-1’),7.60(1H,d,J6,Me=1.3Hz,H-6);13C NMR(CDCl3)δ12.52,20.84,38.76,63.30,74.73,76.23,79.85,82.08,85.33,111.41,137.93,150.53,163.63,171.98;FAB-HR-MS m/z C14H17N2O6计算值309.1087(M++H),实测值309.1074.
1-(5-O-乙酰基-2-脱氧-3-O-甲烷磺酰基-4-乙炔基-β-D-苏-呋喃戊糖基)胸腺嘧啶(13)
在0℃,向12(76mg,0.247mmol)的吡啶(4mL)溶液中加入甲烷磺酰氯(57μL,0.74mmol),并将混合物在室温搅拌16小时。将反应混合物在CHCl3/饱和的NaHCO3水溶液(60mL×3/20mL)之间分配。有机层的硅胶柱层析(CHCl3/MeOH=100/0-100/1)得到泡沫的13(95.0mg,100%):1H NMR(CDCl3)δ1.96(3H,d,J6,Me=1.2Hz,Me),2.16(3H,s,Ac),2.38(1H,ddd,Jgem=16.0Hz,J1’,2’a=3.5Hz和J2’a,3’=0.7Hz,H-2’a),2.70(1H,s,乙炔基),3.11(1H,s,Ms),3.19(1H,ddd,Jgem=16.0Hz,J1’,2’b=8.4Hz和J2’b,3’=5.5Hz,H-2’b),4.48(1H,d,Jgem=11.3Hz,H-5’a),4.53(1H,d,Jgem=11.3Hz,H-5’b),5.27-5.28(1H,m,H-3’),6.52(1H,dd,J1’,2’a=3.5Hz和J1’,2’b=8.4Hz,H-1’),7.33(1H,d,J6,Me=1.2Hz,H-6),8.86(1H,brs,NH);FAB-MS m/z 387(M++H)。
TKD-4-114(2′,3′-双脱氢-3′-脱氧-4′-乙炔基胸苷)
将13(105mg,0.272mmol)和DBN(101μL,0.815mmol)在CH3CN(10mL)中的混合物回流11小时。用AcOH终止后,将反应混合物在CHCl3/饱和的NaHCO3水溶液(60mL×3/20mL)之间分配。经有机层经硅胶柱层析(己烷/EtOAc=1/1)纯化后得到的产物溶解在饱和的NH3的MeOH(30mL)溶液中,并在室温保持12小时。蒸发溶剂,然后经制备性TLC(己烷/EtOAc=1/1)纯化得到固体的TKD-4-114(49.6mg,74%):mp 207-209℃;UV(MeOH)λ max 264nm(ε10800),λmin 235nm(ε4800);1H NMR(CDCl3)δ1.83(3H,s,Me),2.63(1H,s,乙炔基),3.47(1H,br,OH),3.88(1H,d,Jgem=12.5Hz,H-5’a),3.96(1H,d,Jgem=12.5Hz,H-5’b),5.91(1H,dd,J1’,2’=1.1Hz和J2’,3’=5.9Hz, H-2’),6.30(1H,dd,J1’,3’=2.0Hz和J2’,3’=5.9Hz,H-3’),7.16-7.17(1H,m,H-1’),7.44(1H,d,J6,Me=1.1Hz,H-6),9.06(1H,br,NH);FAB-MS m/z 249(M++H)。C12H12N2O41/6H2O分析计算值:C,57.37;H,4.95;N,11.15。实测值:C,57.36;H,4.69;N,10.98.
TDK-4-114(图5A)的另一种化学合成
TKD-4-114(2′,3′-双脱氢-3′-脱氧-4′-乙炔基胸苷,4′-乙炔基-d4T)利用在反应路线(参见图5A)中显示的系列反应进行合成,起始物质化合物1的制备前面已经报告。
二苯甲酰基化合物2(两种非对映体的混合物)的制备
在0℃氩气气氛下,向1(3.98mg,11.76mmol)的甲苯(70mL)溶液中加入i-Pr2NEt(5.1mL,29.4mmol)和Pb(OCOPh)4(20.33g,29.4mmol),并将混合物搅拌4小时。将反应混合物用饱和的NaHCO3水溶液终止,并滤过celite。将滤液在CHCl3/饱和的NaHCO3水溶液之间分配。有机层经硅胶柱层析(己烷/AcOEt=2/1)纯化得到泡沫的2(4.84g,71%):1H NMR(CDCl3)δ0.02,0.07,0.15和0.20(6H,各为s,SiMe),0.75和0.93(9H,各为s,SiBu-t),1.69和1.91(3H,各为d,J6,Me=1.2Hz,Me-5),1.91-2.00,2.33-2.40,2.76-2.83和2.94-3.01(2H,各为m,H-2’),4.73和4.95(1H,t和d,J2’,3’=6.8和4.4Hz,H-3’),4.91,5.08,5.11和5.19(2H,各为d,Jgem=12.0Hz,CH2-5’),4.24(1H,d,Jgem=2.0Hz),6.34和6.64(1H,d和dd,J1’,2’=6.4和J1’,2’=2.8,8.2Hz,H-1’),7.32-7.37,7.45-7.51,7.58-7.67,7.92-7.94,8.02-8.04和8.04-8.13(11H,各为m,H-6和Ph),8.92(1H,br,NH);FAB-MS(m/z)581(M++H)。C30H36N2O8Si分析计算值:C,62.05;H,6.25;N,4.82。实测值:C,61.85;H,6.37;N,4.70。
1-[5-O-苯甲酰基-3-O-(叔丁基二甲基甲硅烷基)-2-脱氧-4-(三甲基甲硅烷基)乙炔基-β-D-苏-呋喃戊糖基]胸腺嘧啶(3)
在0℃氩气气氛下,向HC≡CSiMe3(3.2mL,22.44mmol)的甲苯(40mL)溶液中加入BuLi(2.44M的己烷溶液)(9.2mL,22.44mmol),并将混合物搅拌30分钟。在0℃,向该溶液中加入EtAlCl2(0.94M的己烷溶液)(23.4mL,22.44mmol)。将混合物搅拌30分钟后,在0℃加入2(3.26g,5.61mmol) 的CH2Cl2溶液(50mL),并将混合物搅拌过夜。将反应混合物在CHCl3/饱和的NaHCO3水溶液之间分配。将有机层经硅胶柱层析(己烷/EtOAc=3/1)纯化得到为泡沫的3(1.14g,37%):1H NMR(CDCl3)δ0.09和0.13(6H,各为s,SiMe),0.12(9H,s,C≡CSiMe3),0.89(9H,s,SiBu-t),1.90(3H,d,JMe,6=0.8Hz,Me-5),1.95(1H,ddd,J1’,2’a=2.8,J2’a,3’=1.2和J2’a,2’b=14.6Hz,H-2’a),3.02(1H,ddd,J1’,2’b=8.2,J2’b,3’=5.2和J2’a,2’b=14.6Hz,H-2’b),4.50(1H,dd,J2’a,3’=1.2和J2’b,3’=5.2Hz,H-3’),4.64(1H,d,J5’a,5’b=10.8Hz,H-5’a),4.68(1H,d,J5’a,5’b=10.8Hz,H-5’b),6.40(1H,d,J1’,2’a=2.8和J1’,2’b=8.2Hz,H-1’),7.44-7.48,7.57-7.61和8.07-8.10(6H,各为m,H-6和Ph),8.24(1H,br);FAB-MS(m/z)557(M++H)
1-[5-O-苯甲酰基-2-脱氧-4-乙炔基-β-D-苏-呋喃戊糖基]胸腺嘧啶(4)
在0℃,向3(208.2mg,0.37mmol)的THF(5mL)溶液中加入Bu4NF3H2O(290.2mg,1.11mmol),并将混合物搅拌1小时。将反应混合物蒸发至干。将残留物硅胶柱层析(2%MeOH的CH2Cl2溶液)得到为泡沫的3(115.3mg,84%):1H NMR(CDCl3+D2O)δ1.94(3H,d,JMe,6=1.2Hz,Me-5),2.15(1H,dd,J1’,2’a=3.2和J2’a,2’b=15.0Hz,H-2’a),2.60(1H,s,C≡CH),3.01(1H,ddd,J1’,2’b=9.0,J2’b,3’=5.2和J2’a,2’b=15.0Hz,H-2’b),4.34(1H,d,J2’b,3’=5.2Hz,H-3’),4.40(1H,d,J5’a,5’b=11.2Hz),4.96(1H,d,J5’a,5’b=11.2Hz),6.34(1H,d,J1’,2’a=3.2和J1’,2’b=9.0Hz,H-1’),7.46-7.51,7.61-7.65和8.09-8.11(5H,各为m,Ph),7.70(1H,d,JMe,6=1.2Hz),8.47(1H,br);FAB-MS(m/z)371(M++H)。
1-[5-O-苯甲酰基-2-脱氧-4-乙炔基-3-O-甲烷磺酰基-β-D-苏-呋喃戊糖基]胸腺嘧啶(5)
在0℃氩气气氛下,向4(110.9mg,0.30mmol)的吡啶(3.5mL)溶液中加入MsCl(0.12mL,1.5mmol),并将混合物搅拌6小时。将反应混合物在CHCl3/饱和的NaHCO3水溶液之间分配。有机层的硅胶柱层析(1.5%MeOH的CH2Cl2溶液)得到为泡沫的5(105.2mg,78%):1H NMR(CDCl3)δ1.92(3H,d,JMe,6=1.2Hz,Me-5),2.43(1H,dd,J1’,2’a=3.6和J2’a,2’b=16.0Hz,H-2’a),2.72(1H,s,C≡CH),3.07(3H,s,SO2Me),3.23(1H,ddd,J1’,2’b=8.2,J2’b,3’=5.2和 J2’a,2’b=16.0Hz,H-2’b),4.72(1H,d,J5’a,5’b=11.2Hz),4.76(1H,d,J5’a,5’b=11.2Hz),5.37(1H,d,J2’b,3’=5.2Hz,H-3’),6.56(1H,d,J1’,2’a=3.6和J1’,2’b=98.2Hz,H-1’),7.36(1H,d,JMe,6=1.2Hz),7.47-7.51,7.60-7.64和8.07-8.10(5H,各为m,Ph),8.32(1H,br);FAB-MS(m/z)449(M++H)。
5’-O-苯甲酰基-2’,3’-双脱氢-3’-脱氧-4’-乙炔基胸苷(6)
在0℃氩气气氛下,向5(101.9mg,0.23mmol)的CH3CN(4mL)溶液中加入DBN(67μL,0.54mmol),并将混合物在80℃搅拌9小时。将反应混合物加入AcOH中和,并在CHCl3/饱和的NaHCO3水溶液之间分配。硅胶柱层析(1.5%MeOH的CH2Cl2溶液)有机层的得到固体的6(60mg,74%):1HNMR(CDCl3)δ1.42(3H,d,JMe,6=1.2Hz,Me-5),2.70(1H,s,C≡sCH),),4.59(1H,d,J5’a,5’b=12.0Hz,H-5’a),4.76(1H,d,J5’a,5’b=12.0Hz,H-5’b),5.99(1H,dd,J1’,2’=1.2,J2’,3’=5.9,H-2’),6.38(1H,dd,J1’,3’=2.0和J2’,3’=5.9Hz,H-3’),6.98(1H,d,JMe,6=1.2Hz),7.12(1H,m,H-1’),7.45-7.49,7.60-7.63和8.00-8.03(5H,各为m,Ph),8.37(1H,br);FAB-MS(m/z)353(M++H)。
2’,3’-双脱氢-3’-脱氧-4’-乙炔基胸苷(7)(TKD-4-114,4’-乙炔基-d4T)
在0℃氩气气氛下,向6(56mg,0.16mmol)的MeOH(3mL)悬浮液中加入1M NaOMe(0.32mL,0.32mmol),并将混合物在室温搅拌0小时。将反应混合物加入AcOH中和并在硅胶柱上层析(2%MeOH的CH2Cl2溶液)得到固体的7(35.8mg,90%)。
7(TKD-4-114)的物理数据同上。
KMA-23-153:TKD-4-114的碳环类似物(参见图6)的化学合成
利用在图6中显示的反应路线的顺序,KMA-23-153制备成外消旋混合物(等量的D-和L-对映体混合物)。起始物质2的制备方法已经发表:参见,Kato等,Chem.Pharm.Bull.,47,1256-1264(1999)。
1-羟基甲基-2-氧代环戊烷羧酸甲基酯(3,图6)
在0℃正压干燥的氩气下,向2(10g,55.48mmol)和HMPA(29mL, 166.44mmol)的THF(450ml)悬浮液中加入Bu3SnCl(16.5mL,61.0mmol)。在0℃搅拌30分钟后,将(CH2O)n(8.32g,277.4mmol)加入至混合物中并将整个反应混合物在室温搅拌48小时。将反应混合物在AcOEt和盐水之间分配。将有机层干燥(Na2SO4),蒸发,并在硅胶柱上层析(己烷/EtOAc=1/1)。得到油状的3(7.13g,77%)。
1HNMR(CDCl3)δ:1.97-2.18(2H,m,CH2),2.21-2.25(1H,m,CH2),2.29-2.53(3H,m,OH和CH2),2.62-2.66(1H,m,CH2),3.74(3H,s,Me),3.81(1H,dd,J=11.2和8.0Hz,CH2OH),3.89(1H,dd,J=11.2和4.4Hz,CH2OH)。
1-(叔丁基二苯基甲硅烷基氧基甲基)-2-氧代-环戊烷羧酸甲基酯(图6的4)
将3(10.35g,60.1mmol)、咪唑(8.18g,120.2mmol)和TBDPSCl(15.6ml,60.1mmol)在DMF(40ml)中的混合物在室温在正压干燥的氩气下搅拌16小时。将混合物在EtOAc和饱和的NaHCO3水溶液之间分配。将有机层干燥(Na2SO4)并蒸发。将得到的糖浆残留物用MeOH(约40ml)处理得到沉淀的4。将该步骤再重复3次得到白色固体的4(18.97g,77%)。
1HNMR(CDCl3)δ:1.02(9H,s,SiBu-t),2.03-2.11(2H,m,CH2),2.26-2.35(1H,m,CH2),2.41-2.53(3H,m,CH2),3.65(3H,s,Me),3.87(1H,d,J=9.6Hz,CH2OSi),4.09(1H,d,J=9.6Hz,CH2OSi),7.37-7.46(6H,m,Ph),7.61-7.65(4H,m,Ph)。
1-(叔丁基二苯基甲硅烷基氧基甲基)-2-氧代环戊-3-烯羧酸甲基酯(5,图6)
在0℃正压干燥的氩气下,向搅拌的4(3.58g,8.72mmol)和Et3N(6.1ml,43.6mmol)的混合物中加入Me3SiOSO2CF3(2.56mL,13.0mmol)。将混合物在同样的温度下搅拌30分钟,并且然后在CH2Cl2和饱和的NaHCO3水溶液之间分配。将有机层干燥(Na2SO4)并蒸发。将残留物溶解在DMSO(12mL)中。向该溶液中加入Pd(OAc)2(98mg,0.44mmol),并将混合物在正压O2 下搅拌36小时。将混合物在EtOAc和盐水之间分配。将有机层干燥(Na2SO4),蒸发,并在硅胶柱上层析(己烷/EtOAc=5/1)得到为白色固体的5 (3.13g,88%)。
1HNMR(CDCl3)δ:0.97(9H,s,SiBu-t),2.99-3.05(1H,m,CH2),3.21-3.26(1H,m,CH2),3.66(3H,s,Me),3.98(1H,d,J=10.0Hz,CH2OSi),4.18((1H,d,J=10.0Hz,CH2OSi),6.24-6.26(1H,m,CH=CH),7.37-7.45(6H,m,Ph),7.58-7.62(4H,m,Ph),7.86-7.88(1H,m,CH=CH)。
l-(叔丁基二苯基甲硅烷基氧基甲基)-(反式-2-乙酰氧基)环戊-3-烯羧酸甲基酯(6,图6)
将NaBH4(628mg,16.6mmol)和MeOH(50ml)的混合物冷却并在-70℃搅拌。向其中用15分钟滴加5(3.39g,8.3mmol)和CeCl3·7H2O(3.1g,8.3mmol)在THF/MeOH=1/1(50ml)中的混合物。将得到的悬浮液在-70℃搅拌l小时。加入AcOH(约1mL)终止反应。将反应混合物蒸发。将残留物悬浮在MeCN(15ml)中。向该悬浮液中加入DMAP(1.02g,8.3mmol)、i-Pr2NEt(1.45mL,8.3mmol)和Ac2O(1.57mL,16.6mmol)。将混合物在0°在干燥的氩气正压下搅拌30分钟,并在CH2Cl2和饱和的NaHCO3水溶液之间分配。将有机层干燥(Na2SO4)、蒸发并在硅胶柱上层析(己烷/EtOAc=4/1)。得到油状的6(3.74g,100%)。
1HNMR(CDC13)δ:1.02(9H,s,SiBu-t),1.87(3H,s,Ac),2.50-2.55(1H,m,CH2),2.91-2.97(1H,m,CH2),3.71(3H,s,Me),3.87(1H,d,J=9.6Hz,CH2OSi),4.08(1H,d,J=9.6Hz,CH2OSi),5.76-5.78(1H,m,CH=CH),5.99-6.00(1H,m,CH=CH),6.07-6.08(1H,m,AcOCH),7.29-7.45(4H,m,Ph),7.61-7.65(4H,m,Ph)。
1-(叔丁基二苯基甲硅烷基氧基甲基)-(反式-4-羟基)环戊-2-烯羧酸甲基酯(7,图6)
将6(1.87g,4.13mmol)、PdCl2(MeCN)2(106mg,0.41mmol)和对醌224mg,2.07mmol)在THF(17mL)中的混合物在氩气正压下回流3小时。将混合物在CH2Cl2以及饱和的Na2S2O3水溶液之间分配。将有机层干燥(Na2SO4)、蒸发。将残留物溶解在MeOH(5ml)中并在搅拌下用K2CO3(685mg,4.96mmol)处理1小时。将混合物在CHCl3和盐水之间分配。将有机层干燥 (Na2SO4)、蒸发并在硅胶柱上层析(己烷/EtOAc=6/1)。得到油状的7(1.14g,67%)。
1HNMR(CDCl3)δ:1.02(9H,s,SiBu-t),1.87(1H,dd,J=14.4和2.4Hz,CH2),2.73(1H,dd,J=14.4和7.2Hz,CH2),3.65(3H,s,Me),3.79(1H,d,J=9.6Hz,CH2OSi),3.85(1H,d,J=9.6Hz,CH2OSi),4.82-4.87(1H,m,CHOH),5.84-5.87(1H,m,CH=CH),6.02-6.04(1H,m,CH=CH),7.38-7.44(6H,m,Ph),7.63-7.65(4H,m,Ph)。
1-(叔丁基二苯基甲硅烷基氧基甲基)-(顺式-4-羟基)环戊-2-烯羧酸甲基酯(8,图6)
在氩气正压下,将7(1.08g,2.63mmol)、Ph3P(897mg,3.42mmol)和AcOH(301μL,5.26mmol)在THF(10mL)中的混合物冷却到0℃。向其中滴加偶氮二羧酸二乙基酯(2.3M的甲苯溶液,1.49mL,3.42mol)。搅拌30分钟后,将混合物在CH2Cl2以及饱和的NaHCO3水溶液之间分配。将有机层干燥(Na2SO4)并蒸发。将残留物用K2CO3(727mg,5.26mmol)的MeOH溶液(5mL)处理1小时。将混合物在CHCl3和盐水之间分配。将有机层干燥(Na2SO4),蒸发,并在硅胶柱上层析(己烷/EtOAc=4/1)。得到油状的8(892mg,83%)。
1HNMR(CDCl3)δ:1.02(9H,s,SiBu-t),2.20-2.31(3H,m,CH2和OH),3.70(1H,d,J=9.6Hz,CH2OSi),3.71(3H,s,Me),3.87(1H,d,J=9.6Hz,CH2OSi),4.76-4.81(1H,m,CHOH),5.88(1H,d,J=5.6Hz,CH=CH),6.03(1H,dd,J=5.6和2.4Hz,CH=CH),7.36-7.46(6H,m,Ph),7.61-7.65(4H,m,Ph)。
1-[顺式-4-(叔丁基二苯基甲硅烷基氧基甲基)-反式-4-甲氧基羰基环戊-2-烯-1-基]胸腺嘧啶(9,图6)
在0°正压干燥的氩气下,向PPh3(2.28g,8.68mmol)的THF(25mL)溶液中滴加偶氮二羧酸二乙基酯(2.3M的甲苯溶液,3.63mL,8.35mol)。搅拌30分钟后,滴加包含8(1.37g,3.34mmol)和N3-苯甲酰基胸腺嘧啶(1.15g,5.01mmol)的THF(76mL)悬浮液。将混合物在在室温搅拌70小时,蒸发并且然后用2M NaOMe的MeOH(6.7mL)溶液处理2小时。用AcOH(1.15mL) 中和反应混合物并且然后在CH2Cl2和饱和的NaHCO3水溶液之间分配。将有机层干燥(Na2SO4),蒸发,并在硅胶柱上层析(己烷/EtOAc=1/1)。得到白色泡沫的9(1.21g,70%)。
1HNMR(CDCl3)δ:1.05(9H,s,SiBu-t),1.74(3H,d,J=1.2Hz,胸腺嘧啶-5-Me),1.75(1H,dd,J=14.0和6.8Hz,CH2),3.01(1H,dd,J=14.0和8.4Hz,CH2),3.70(3H,s,Me),3.87(1H,d,J=10.0Hz,CH2OSi),3.90(1H,d,J=10.0Hz,CH2OSi),5.79(1H,dd,J=5.2和2.0Hz,CH=CH),5.83-5.88(1H,m,CHN),6.10(1H,dd,J=5.2和2.4Hz,CH=CH),6.88(1H,q,J=1.2Hz,胸腺嘧啶-H-6),4.36-7.47(6H,m,Ph),7.61-7.64(4H,m,Ph),8.89(1H,br,胸腺嘧啶-NH)。
1-[顺式-4-(叔丁基二苯基甲硅烷基氧基甲基)-反式-4-乙炔基环戊-2-烯-1-基]胸腺嘧啶(10,图6)
在-70℃正压干燥的氩气下,向9(550mg,1.06mmol)的CH2Cl2(10mL)溶液中滴加i-Bu2AlH(1.01M的甲苯溶液,1.16mL,1.17mmol)。搅拌20分钟后,加入另外的异Bu2AlH(2.32mL,2.34mmol)并再搅拌20分钟。用AcOH(200mL)终止后蒸发。短硅胶柱层析(己烷/EtOAc=1/5)得到反式-4-羟基甲基衍生物(294mg)。将反式-4-羟基甲基衍生物溶解在CH2Cl2(10mL)中,并用Dess-Martin periodinane(477mg,1.12mmol)氧化。搅拌1.5小时后,将混合物在CH2Cl2和饱和的NaHCO3水溶液之间分配。将有机层干燥(Na2SO4)并蒸发得到粗制的反式-4-醛(274mg)。将醛溶解在包含K2CO3(310mg,2.24mmol)的MeOH中,并在0°正压干燥的氩气下搅拌10分钟。向其中加入二甲基(1-重氮基-2-氧代丙基)膦酸酯*(270mg,1.4mmol)。将混合物搅拌1小时,并且然后在EtOAc和饱和的NaHCO3水溶液之间分配。将有机层干燥(Na2SO4),蒸发,并在硅胶柱上层析(己烷/EtOAc=1/1)。得到白色泡沫的10(138mg,27%)。
1HNMR(CDCl3)δ:1.07(9H,s,SiBu-t),1.71(3H,d,J=1.2Hz,胸腺嘧啶-5-Me),2.02(1H,dd,J=13.2和7.6Hz,CH2),2.20(1H,s,C≡CH),2.70(1H,dd,J=13.2和8.0Hz,CH2),3.69(1H,d,J=9.6Hz,CH2OSi),3.83(1H,d,J=9.6Hz,CH2OSi),5.76(1H,dd,J=5.2和2.0Hz,CH=CH),5.91-5.95(1H,m,CHN), 6.02(1H,dd,J=5.2和2.4Hz,CH=CH),6.98(1H,q,J=1.2Hz,胸腺嘧啶-H-6),7.37-7.48(6H,m,Ph),7.63-7.66(4H,m,Ph),8.20(1H,br,胸腺嘧啶-NH)。
FAB-MS(m/z):485(M++H)。
*该试剂的制备参见:P.Callant,L.D’Haenes和M.Vandewalle,Synth.Commun.,14,155-161(1984)。
*该试剂用于将RCHO转化为RC≡CH:I.Gillaizeau,I.M.Lagoja,S.P.Nolan,V.Aucagne,J.Rozenski,P.Herdewijn和L.A.Agrofoglio,Eur.J.Org.Chem.,666-671(2003)。
1-(顺式-4-羟基甲基-反式-4-乙炔基环戊-2-烯-1-基)胸腺嘧啶(11,图6):KMA-23-153
将10(101mg,0.21mmol)和Bu4NF(1M的THF溶液,230μL,0.23mmol)在THF(3mL)中的混合物在室温搅拌2小时。向该混合物中加入4-二甲基氨基吡啶(51mg,0.42mmol)、i-Pr2NEt(73μL,0.42mmol)和Ac2O(80μL,0.84mmol)。将反应混合物搅拌30分钟,并在CH2Cl2和饱和的NaHCO3水溶液之间分配。将有机层干燥(Na2SO4),蒸发,并在硅胶柱上层析(AcOEt)。得到为白色固体的乙酸酯(52mg)。将该乙酸酯用NH3/MeOH(35ml)在低于0℃下处理12小时。蒸发溶剂过程中,出现沉淀。将沉淀用热苯(50ml)洗涤得到分析纯的11(31mg,60%)。
1HNMR(CDCl3)δ:1.96-1.94(5H,m,CH2,OH和胸腺嘧啶-5-Me),2.30(1H,s,C≡CH),2.81(1H,dd,J=13.6和8.8Hz,CH2),3.65(1H,dd,J=10.0和7.6Hz,CH 2OH),3.78(1H,dd,J=10.0和4.8Hz,CH 2OH),5.78-5.80(1H,m,CH=CH),5.85-5.89(1H,m,CHN),6.04-6.06(1H,m,CH=CH),7.10(1H,q,J=1.2Hz,胸腺嘧啶-H-6),8.09(1H,br,胸腺嘧啶-NH)。C13H14N2O3·1/5H2O分析计算值:C,62.49;H,5.81;N,11.21。实测值:C,62.57;H,5.65;N,11.22。
生物活性
方法和材料:
化学品:4’-D4T类似物(图1)在Dr.Hiromichi实验室Tanaka,School of Pharmaceutical Sciences,Showa University,Japan中合成。dThd、D4T和AZT从Sigma-Aldrich Corp.St.Louis,MO购买得到。ddI从ICN Biochemicals Inc.,Aurora,OH购得。3TC从Triangle Pharmaceuticals,Durham,NC得到。LFd4C从Vion Inc.,New Haven,CT得到。使用的所有其他试剂为试剂级或更高。
细胞系以及病毒:用于毒性研究和病毒繁殖的H9细胞系,以及用于抗病毒活性研究的MT-2细胞系都从AIDS Research and Reference ReagentProgram of the National Institutes of Health得到,并由Dr.Robert Gallo和Dr.Douglas Richman分别惠赠。HIV-1株IIIB来自Dr.John Mellors。
抗病毒活性的测定:基本上按照前述的方法(31),将化合物在用HIV-1株IIIB感染的MT-2细胞中测试。简言之,将连续稀释的药物以一式三份地放入到96孔组织培养板中,然后将在补充10%透析的胎牛血清和10μg/ml卡那霉素的RPMI 1640培养基中生长的MT-2细胞,以104细胞/100μl±0.1m.o.i.的HIV-1IIIB。5天后,将MTT染料加入到孔中并在595nm处测定染料的颜色用来定量细胞活力(20)。按照描述进行百分保护的计算以及isobologram组合研究(12)。
核苷类似物的细胞毒性:这些dThd类似物已经在数种细胞系:H9、CEM、MT-2和HepG2中进行评价。基本的步骤类似。将细胞以低浓度接种,然后加入连续稀释的受试化合物。我们使用的CEM、MT-2和H9细胞系,将其在RPMI 1640中生长,补充10%透析的胎牛血清和10μg/ml卡那霉素。在5%CO2湿度培养箱中在37℃培养48~96小时后,终止分析。将药物处理的样品与未处理的对照样品进行比较。悬浮细胞系利用细胞计数进行实现,或者用血细胞计数器或利用Coulter Counter。HepG2细胞,一种人肝癌细胞系,在DMEM培养基中生长,补充10%透析的胎牛血清和10μg/ml卡那霉素。在倾析生长培养基后,对HepG2单层细胞系的作用,用溶解在50%乙醇中的1.0%亚甲基蓝染料染色定量。然后将细胞层溶解在5%肌氨酰溶液中,将形成的颜色在Molecular Devices model Vmax板读数分光光度计(Menlo Park,CA)上在595nm处测定。未处理的对照的颜色与药物处理的样品进行比较。
线粒体DNA:核苷类似物对mtDNA含量的作用按照前述方法进行评估(2)。简言之,将保持在补充了10%透析胎牛血清的RPMI 1640中的CEM细胞以2×105/ml铺板在24孔组织培养板中。用以作为单独试剂或联用的不同的浓度的药物处理细胞生长4天。然后富集细胞,用蛋白酶K和无DNase的RNase处理。将提取物应用到尼龙膜上并用mtDNA探针杂交。去除膜后,通过用Alu探针再杂交膜,将负载归一化。将斑点用带有ImageQuaNT分析软件的Molecular Dynamics个人光密度计SI定量。
胸苷激酶对类似物的单磷酸化:测试所有的类似物被源自CEM细胞的胸苷激酶(TK-1)磷酸化的能力。该酶利用该实验室中发展的亲和柱技术进行纯化(7)。将胸苷类似物(250uM)在混合物中进行孵育,所述的混合物包含150mM Tris HCl pH 7.5,2.4mM ATP,2.4mM MgCl2,0.6mgs磷酸肌氨酸、5.8单位的肌氨酸磷酸激酶、0.19mgs白蛋白和0.07单位的TK-1,总体积200ul。在孵育结束的时候,加入3部分冷的HPLC级甲醇终止反应。在冰上孵育至少10分钟后,将甲醇不溶物利用离心沉淀并将甲醇可溶的上清放置在干净的微量离心管中。将这些样品在Speedvac Centrifuge至干。将样品溶解在水中并在Shimatzu HPLC model SCL 10Avp上分离,利用水至300mM磷酸钾的梯度溶液和Whatman 10/25微粒SAX柱上。Km和相对的Vmax研究按照类似的方式进行,利用同样的混合物以及不同量的底物和酶。
酸稳定性研究:核苷样品与1N HCl混和并在37℃孵育2.5小时。然后,然后通过HPLC利用Bechman ODS柱使用水至80%甲醇的梯度溶液考察样品。
胸苷磷酸化酶分析:核苷类似物(100μM)在75mM磷酸钾缓冲液pH 7.3在37℃孵育,利用部分纯化的人肝脏提取物制剂(28)作为胸苷磷酸化酶(TP)源。孵育后,将反应通过加入三氯乙酸至终浓度15%终止反应。然后将样品在冰上孵育。离心去除酸不溶成分后,通过用一半体积的三辛胺/氟利昂(45∶55)萃取两次使上清液中性。将水性上清液利用HPLC检测,利用 Beckman ODS柱方法,如在酸稳定性研究中所记载的。
胸苷激酶分析:胸苷激酶分析与以前记载的方法相同(21)。简言之,分析使用[14C]-dThd(100μM,6.7mCi/mmol)的混合物溶液,所述的混合物包含2.4mM ATP-Mg,156mM Tris-HCl pH 7.5,0.23mg磷酸肌氨酸、7μg肌氨酸磷酸激酶、67μgBSA和1.9mM DTT,体积75μl。将反应孵育不同的时间,然后通过将50μl等分喷到DE-81阴离子交换圆片(Whatman Inc.,Clifton,NJ)上终止,立即在95%乙醇中浸泡。经在乙醇中另外洗涤2次后,将圆片干燥丙放置在含5ml SafeScint Scintillation Cocktail(AmericanBioanalytical,Natick,MA)的闪烁小瓶中。在Beckman LS5000TD ScintillationCounter(Beckman Instruments Inc.,Palo Alto,CA)中定量放射活性的量,该量表征形成的dTMP量。
生物活性结果:
4’-取代的D4T类似物的抗病毒效果:
在MT-2/IIIB抗HIV-1体系中进行实验,加入在D4T的4’位被甲基、乙烯基、乙炔基、乙炔基甲基、乙炔基氯、烯丙基或氰基取代的化合物(图1)。结果表明与母体化合物D4T相比,4’-乙炔基类似物具有更有效的抗HIV作用以及更小的毒性作用。其中,4’-氰基D4T和4’-乙炔基甲基D4T活性弱于D4T的抗HIV活性(图8);4’-甲基、4’-乙烯基、4’-乙炔基氯和4’-烯丙基取代的D4T类似物的EC50没有达到浓度100μM。这些化合物以及D4T的抗HIV的EC50总结在下表1中。
表1:4’-取代的D4T类似物对HIV的效果
a)在MT-2细胞中实现50%免于HIV感染需要的有效的浓度
b)50%抑制MT-2细胞生长需要的浓度
c)测试的最高浓度。
d)以前报道的EC50(17)。
为了确定4’-乙炔基D4T是否与dThd类似物一样抗HIV作用,考察了加入dThd或dCyd对4’-乙炔基D4T抗病毒活性的影响。为了预防在细胞中dCyd脱氨基成dUrd的可能性,也加入无毒水平的胞嘧啶脱氨基抑制剂四氢尿嘧啶。观察到dThd以浓度依赖的方式降低了4’-乙炔基D4T的抗病毒效果。但是,dCyd对4’-乙炔基D4T的抗HIV活性没有显著的作用(图9)。
为了评价与其他的抗病毒核苷类似物的相互作用,得到了4’乙炔基D4T联用3TC、LFd4C、ddI和AZT的抗病毒等效线图。4’乙炔基D4T显示出与3TC和LFd4C对HIV具有协同的相互作用(图10),并且测量相对于表征加和药物作用线的距离测定协同指数(SI)。但是,其与ddI和AZT的抗病毒作用只是加和性的(数据未显示)。
细胞毒性:4’-取代的D4T类似物对细胞生长和mtDNA含量的作用在 CEM中进行了测定(表2a,见下面描述)。这些类似物中没有一种,除了4’-乙炔基氯D4T,可以阻滞4天的细胞生长,ID50小于100μM。在HepG2细胞中的72小时毒性研究结果也显示D4T、4’-乙烯基D4T和4’-乙炔基D4T的ID50大于100μM。4’-乙炔基D4T可降低细胞内线粒体DNA,ID50 为100μM,其比D4T的浓度高10倍。考虑4’-乙炔基D4T与3TC和LFd4C抗HIV的协同作用,也评价了这些化合物对细胞生长的相互作用。在H9细胞中,在48小时的分析期间没有观察到毒性相互作用的显著升高(表2b,见下)。
表2a:CEM细胞中的核苷类似物毒性
材料和方法中记载的步骤:a)与未处理的对照相比通过细胞计数测定毒性。b)利用Southern印迹分析以及密度测定读数测定线粒体DNA含量并与未处理的CEM对照细胞进行比较。数据为引起50%对照细胞抑制的μM浓度以及标准差。括号中的数字表示在标示的浓度下未处理的CEM对照细胞的百分比的平均值以及标准偏差。
表2b:以相对于未处理的对照的百分比表示的4’-乙炔基D4T在H-9细胞中单用以及与其他的抗HIV化合物的联用的毒性*
*H-9细胞按照在材料和方法中记载的方法在单种化合物或组合化合物存在下生长48小时。对于各条件,利用Coulter Counter对3或多个孔一式二份计数。数字表示平均值以及标准偏差。
4’-取代的D4T类似物与TK-1的相互作用:
评价了由纯化的人TK-1对化合物磷酸化的可能性(表3a,见下面)。AZT转化成单磷酸形式的速度同dThd一样快,然而4’-甲基D4T以及4’-乙烯基D4T的速率类似于D4T的速率(约为dThd的2%)。4’-乙炔基D4T的转化率优于D4T,置信水平为0.06。利用two tailed测试,置信水平为0.91的时候,4’-乙炔基D4T和4’-乙炔基氯D4T的磷酸化率没有明显的差异。4’-乙炔基D4T的Km估计为52μM,低于D4T的133μM,但是高于dThd。为了确证这些dThd类似物中无一种可作为TK-1的潜在抑制剂,甚至它们也不是底物,将dThd、AZT、D4T和D4T的4’-取代的类似物加入到胸苷激酶分析中,浓度为[14C]-dThd浓度的10倍,然后将转化为[14C]-dTMP的量与未加入的反应进行比较(见下表3b)。被TK-1良好磷酸化的化合物如AZT能 影响磷酸化的dThd的量。加入磷酸化不佳的D4T或其类似物,甚至在10倍过量的情形下,对由TK-1导致的[14C]-dThd磷酸化的作用,仍然小于AZT。
表3a:人胞质胸苷激酶的磷酸化
250μM dThd或类似物和2.4mM ATP与0.07单位的TK-1在37℃孵育285分钟。以前发表的数值(21)。
表3b:加入胸苷类似物对胸苷激酶分析的影响*
*分析基本上按照材料和方法中描述的步骤进行,除了将分析中的[14 C]-dThd浓度降低至25μM并且加入的核苷的浓度为250μM。
4’-乙炔基D4T与胸苷磷酸化酶的相互作用以及酸稳定性:
源于人肝的部分纯化的胸苷磷酸化酶(TP)制剂用于这些研究。dThd快速分解而D4T慢至少10倍。在研究的整个孵育期,分解的4’乙炔基D4T低于检测水平(图11)。D4T和4’-乙炔基D4T在pH1和在37℃的稳定性考察了2.5小时。任一种化合物没有检测到可检测到的裂解。
讨论:
D4T为有效的抗HIVD-双脱氧-胸苷类似物。长期治疗的时候其有限的临床毒性,为外周神经病变,与其降低外周神经元的线粒体DNA含量有关(4、5、33、34)。D4T的生化作用不同于3TC、ddI或ddC。D4T的类似物,其具有更强的抗HIV活性以及对核或线粒体DNA合成具有较小的作用,可比D4T具有更好的治疗效果并可取代D4T用于抗HIV的组合治疗。因此,具有更好药理特性的的D4T类似物的合成已经成为抗HIV药物发现中的方 向。在由我们以及其他人合成的4’-取代的D4T类似物中,4’-乙炔基D4T为抗培养的HIV活性最强的一种。Maag等描述了4’-叠氮基D4T,其在无毒性水平对HIV没有活性(29)以及O-Yang等描述了3种4’-取代的D4T类似物,其无毒性并且也没有抗HIV活性(32)。
D4T相当快地被肝脏中的肝细胞(38)发生分解代谢成β-氨基异丁酸和胸腺嘧啶。负责该断裂的酶为TP,在磷酸酯存在下裂解dThd成胸腺嘧啶和2-脱氧-D-核糖-1-磷酸。通过将4’-乙炔基D4T和D4T与部分纯化的人肝脏TP制剂孵育,显示4’-乙炔基D4T比D4T对TP更具抗性。这表明从药代动力学的角度4’-乙炔基比D4T更具有优势。此外,在模仿胃的酸性条件下,4’-乙炔基D4T与D4T一样稳定(数据未显示)。这暗示4’-乙炔基D4T可与D4T一样成为口服的活性剂。在将来的某个时候进行详细的药代动力学研究。由于4’-乙炔基D4T活性强于D4T,可以想到4’-乙炔基D4T会具有更低的病毒药物抗性问题。当4’-乙炔基D4T以与D4T以相同的剂量对患者给药的时候,病毒滴度将变得更小,从而,降低抗性株出现的可能性。也可能以高于D4T的剂量给药4’-乙炔基D4T,由于4’-乙炔基D4T对细胞生长具有更小的抑制性并引起更低的线粒体DNA降低,与D4T相比。但是,安全使用4’-乙炔基D4T的量的测定需要进一步的考察。
与组合疗法相比,单一疗法将导致病毒的抗性株出现更为容易。因此必须将抗病毒化合物与其他批准的具有不同的药物抗性生化机制抗病毒药物一起使用。如果化合物在其抗病毒活性方面而不是其对宿主细胞的细胞毒性作用方面为协同作用,或至少为加和作用,可以实现改进的治疗。的确,对HIV的组合疗法已经在AIDS的管理方面取得巨大的进步,并且D4T通常用作组合方案中的一种药物。为了评价组合疗法中4’-乙炔基D4T的潜在应用,我们考察了该化合物与4种抗病毒核苷类似物的相互作用。在抗HIV活性方面,而不是细胞毒性方面(表2b),4’-乙炔基D4T与3TC和LFd4C具有协同作用(图9)并且与AZT和ddI具有加和作用(数据未显示)。这暗示4’-乙炔基D4T可能为用于组合疗法的有用的化合物,并可用于对抗对目前使用的核苷有抗性的病毒,通过协同反应增加其有效性。4’-乙炔基D4T对其他的核苷类似物的有抗性的病毒的活性目前正在考察。
使4’-乙炔基D4T比其他的4’-取代的D4T类似物在抗HIV研究中活性更强的潜在机制还不清楚。脱氧核苷类似物一般转化成5’三磷酸代谢物, 后者为病毒DNA聚合酶的底物。已知的抗HIV双脱氧核苷的三磷酸代谢物优选与病毒逆转录酶相互作用并当它们掺入到DNA链中的时候充当链终止子。单磷酸酯代谢物的形成是成为三磷酸代谢物过程中的第一步。4’-取代的D4T化合物,与D4T一样,为dThd类似物,因此我们使用纯化的TK-1以检测其是否磷酸化这些类似物至其各自的单磷酸酯形式。结果表明4’-乙炔基D4T磷酸化的速度是D4T的两倍,尽管比dThd或AZT的磷酸化速度要慢。很有趣地注意到4’-甲基D4T和4’-乙烯基D4T类似物以与D4T同样的速率磷酸化,但是无一种具有显著的抗HIV活性。因此,可以认为这些4’-取代的D4T类似物中的一些化合物的的抗HIV活性的丧失不是因为它们不能被TK-1磷酸化。TK-1对4’-乙炔基D4T的磷酸化是一个必要的步骤,但是不足以具有抗病毒活性。由于其抗病毒活性可被dThd而不是dCyd中和,4’-乙炔基D4T,与D4T一样,如dThd类似物一样发挥作用,4’-乙炔基D4T的抗病毒作用机制仍然与D4T有很大的不同。我们未发表的结果表明D4T比4’-乙炔基D4T可以更有效地磷酸化得到三磷酸代谢物,利用CEM细胞提取物补充部分纯化的TK-1以及重组的人dTMP激酶。这又提出了4’-乙炔基D4TMP而不是4’-乙炔基D4TTP为活性代谢物的问题,并且需要进一步的研究。
总之,在细胞培养中,与D4T相比,4’-乙炔基D4T更有更强的抗HIV活性以及更低的毒性。由于其不是胸苷磷酸化酶底物,预期比D4T有更佳的药代动力学优势。因此,4’-乙炔基D4T显示了作为新的抗HIV药物的优良的潜能。
本领域的普通技术人员应该理解,前述的描述和实施例只是实施本发明的说明,并不以任何方式限制本发明。在不偏离由下述权利要求限定的本发明的精神和范围的前提下,可以对这里提供的细节进行改变。
参考文献:
1.August,E.M.,M.E.Marongiu,T.S.Lin,and W.H.Prusoff.1988.Initialstudies on the cellular pharmacology of 3′-deoxythymidin-2′-ene(d4T):apotent and selective inhibitor of human immunodeficiency virus.BiochemPharmacol 37:4419-22.
2.Bridges,E.G.,G.E.Dutschman,E.A.Gullen,and Y.C.Cheng.1996.Favorable interaction of beta-L(-)nucleoside analogues with clinicallyapproved anti-HIV nucleoside analogues for the treatment of humanimmunodeficiency virus.Biochem Pharmacol 51:731-6.
3.Brinkman,K.,H.J.ter Hofstede,D.M.Burger,J.A.Smeitink,and P.P.Koopmans.1998.Adverse effects of reverse transcriptase inhibitors:mitochondrial toxicity as common pathway.Aids 12:1735-44.
4.Browne,M.J.,K.H.Mayer,S.B.Chafee,M.N.Dudley,M.R.Posner,S.M.Steinberg,K.K.Graham,S.M.Geletko,S.H.Zinner,S.L.Denman,and et al.1993.2′,3′-didehydro-3′-deoxythymidine (d4T)in patients withAIDS or AIDS-related complex:a phase I trial.J Infect Dis 167:21-9.
5.Chen,C.H.,and Y.C.Cheng.1989.Delayed cytotoxicity and selectiveloss of mitochondrial DNA in cells treated with the anti-humanimmunodeficiency virus compound 2′,3′-dideoxycytidine.J Biol Chem264:11934-7.
6.Chen,C.H.,M.Vazquez-Padua,and Y.C.Cheng.1991.Effect ofanti-human immunodeficiency virus nucleoside analogs on mitochondrialDNA and its implication for delayed toxicity.Mol Pharmacol 39:625-8.
7.Cheng,Y.C.1978.Thymidine Kinase from Blast Cells of MyelocyticLeukemia,p.365-371,Methods in Enzymology,vol.LI.Academic Press,New York.
8.Coates,J.A.,N.Cammack,H.J.Jenkinson,A.J.Jowett,M.I.Jowett,B.A.Pearson,C.R.Penn,P.L.Rouse,K.C.Viner,and J.M.Cameron.1992.(-)-2′-deoxy-3′-thiacytidine is a potent,highly selective inhibitor of humanimmunodeficiency virus type 1 and type 2 replication in vitro.AntimicrobAgents Chemother 36:733-9.
9.Coates,J.A.,N.Cammack,H.J.Jenkinson,I.M.Mutton,B.A.Pearson,R.Storer,J.M.Cameron,and C.R.Penn.1992.The separatedenantiomers of 2′-deoxy-3′-thiacytidine(BCH 189)both inhibit humanimmunodeficiency virus replication in vitro.Antimicrob AgentsChemother 36:202-5.
10.De Clercq,E.1994.HIV resistance to reverse transcriptase inhibitors.Biochem Pharmacol 47:155-69.
11.Doong,S.L.,C.H.Tsai,R.F.Schinazi,D.C.Liotta,and Y.C.Cheng.1991.Inhibition of the replication of hepatitis B virus in vitro by2′,3′-dideoxy-3′-thiacytidine and related analogues.Proc Natl Acad Sci USA 88:8495-9.
12.Dutschman,G.E.,E.G.Bridges,S.H.Liu,E.Gullen,X.Guo,M.Kukhanova,and Y.C.Cheng.1998.Metabolism of2′,3′-dideoxy-2′,3′-didehydro-beta-L(-)-5-fluorocytidine and its activity incombination with clinically approved anti-human immunodeficiency virusbeta-D(+)nucleoside analogs in vitro.Antimicrob Agents Chemother42:1799-804.
13.Feng,J.Y.,A.A.Johnson,K.A.Johnson,and K.S.Anderson.2001.Insights into the molecular mechanism of mitochondrial toxicity by AIDSdrugs.J Biol Chem 276:23832-7.
14.Gelmon,K.,J.S.Montaner,M.Fanning,J.R.Smith,J.Falutz,C.Tsoukas,J.Gill,G.Wells,M.O′Shaughnessy,M.Wainberg,and et al.1989.Nature,time course and dose dependence of zidovudine-related side effects:results from the Multicenter Canadian Azidothymidine Trial.Aids3:555-61.
15.Gosselin,G.,R.F.Schinazi,J.P.Sommadossi,C.Mathe,M.C.Bergogne,A.M.Aubertin,A.Kirn,and J.L.Imbach.1994.Anti-humanimmunodeficiency virus activities of the beta-L enantiomer of2′,3′-dideoxycytidine and its 5-fiuoro derivative in vitro.AntimicrobAgents Chemother 38:1292-7.
16.Hamamoto,Y.,H.Nakashima,T.Matsui,A.Matsuda,T.Ueda,and N.Yamamoto. 1987.Inhibitory effect of2′,3′-didehydro-2′,3′-dideoxynucleosides on infectivity,cytopathic effects,and replication of human immunodeficiency virus.Antimicrob AgentsChemother 31:907-10.
17.Haraguchi,K.,S.Takeda,H.Tanaka,T.Nitanda,M.Baba,G.E.Dutschman,and Y.C.Cheng.2003.Synthesis of a Highly Active NewAnti-HIV Agent 2′,3′-Didehydro-3′deoxy-4′-ethynylthymidine.BioorgMed Chem Setter 13:3775-3777.
18.Johnson,A.A.,A.S.Ray,J.Hanes,Z.Suo,J.M.Colacino,K.S.Anderson,and K.A.Johnson.2001.Toxicity of antiviral nucleosideanalogs and the human mitochondrial DNA polymerase.J Biol Chem 276:40847-57.
19.Larder,B.A.1995.Viral resistance and the selection of antiretroviralcombinations.J Acquir Immune Defic Syndr Hum Retrovirol 10 Suppl1:S28-33.
20.Larder,B.A.,B.Chesebro,and D.D.Richman.1990.Susceptibilities ofzidovudine-susceptible and -resistant human immunodeficiency virusisolates to antiviral agents determined by using a quantitative plaquereduction assay.Antimicrob Agents Chemother 34:436-41.
21.Lee,L.S.,and Y.C.Cheng.1976.Human deoxythymidine kinase.I.Purification and general properties of the cytoplasmic and mitochondrialisozymes derived from blast cells of acute myelocytic leukemia.J BiolChem 251:2600-2604.
22.Lewis,W.,and M.C.Dalakas.1995.Mitochondrial toxicity of antiviraldrugs.Nat Med 1:417-22.
23.Lin,T.S.,M.Z.Luo,M.C.Liu,S.B.Pai,G.E.Dutschman,and Y.C.Cheng.1994.Antiviral activity of 2′,3′-dideoxy-beta-L-5-fluorocytidine(beta-L-FddC)and 2′,3′-dideoxy-beta-L-cytidine(beta-L-ddC)againsthepatitis B virus and human immunodeficiency virus type 1 in vitro.Biochem Pharmacol 47:171-4.
24.Lin,T.S.,M.Z.Luo,M.C.Liu,S.B.Pai,G.E.Dutschman,and Y.C.Cheng.1994.Synthesis and biological evaluation of2′,3′-dideoxy-L-pyrimidine nucleosides as potential antiviral agentsagainst human immunodeficiency virus(HIV)and hepatitis B virus(HBV).J Med Chem 37:798-803.
25.Lin,T.S.,M.Z.Luo,M.C.Liu,Y.L.Zhu,E.Gullen,G.E.Dutschman,and Y.C.Cheng.1996.Design and synthesis of2′,3′-dideoxy-2′,3′-didehydro-beta-L-cytidine(beta-L-d4C)and2′,3′-dideoxy 2′,3′-didehydro-beta-L-5-fluorocytidine(beta-L-Fd4C),twoexceptionally potent inhibitors of human hepatitis B virus(HBV)andpotent inhibitors of human immunodeficiency virus(HIV)in vitro.J MedChem 39:1757-9.
26.Lin,T.S.,R.F.Schinazi,M.S.Chen,E.Kinney-Thomas,and W.H.Prusoff.1987.Antiviral activity of 2′,3′-dideoxycytidin-2′-ene(2′,3′-dideoxy-2′,3′-didehydrocytidine)against human immunodeficiencyvirus in vitro.Biochem Pharmacol 36:311-6.
27.Lin,T.S.,R.F.Schinazi,and W.H.Prusoff.1987.Potent and selective invitro activity of 3′-deoxythymidin-2′-ene(3′-deoxy-2′,3′-didehydrothymidine)against human immunodeficiencyvirus.Biochem Pharmacol 36:2713-8.
28.Lu,Z.H.,R.Zhang,and R.B.Diasio.1993.Comparison ofdihydropyrimidine dehydrogenase from human,rat,pig and cow liver.Biochemical and immunological properties.Biochem Pharmacol46:945-52.
29.Maag,H.,R.M.Rydzewski,M.J.McRoberts,D.Crawford-Ruth,J.P.Verheyden,and E.J.Prisbe.1992.Synthesis and anti-HIV activity of4′-azido-and 4′-methoxynucleosides.J Med Chem 35:1440-51.
30.Medina,D.J.,C.H.Tsai,G.D.Hsiung,and Y.C.Cheng.1994.Comparison of Mitochondrial Morphology,Mitochondrial DNA Content, and Cell Viability in Cultured Cells Treated with Three Anti-HumanImmunodeficiency Virus Dideoxynucleosides.Antimicrob AgentsChemother 38:1824-1828.
31.Mellors,J.W.,G.E.Dutschman,G.J.Im,E.Tramontano,S.R.Winkler,and Y.C.Cheng.1992.In vitro selection and molecular characterization ofhuman immunodeficiency virus-1 resistant to non-nucleoside inhibitors ofreverse transcriptase.Mol Pharmacol 41:446-51.
32.O-Yang,C.,H.Y.Wu,B.Fraser-Smith,and K.A.M.Walker.1992.Synthesis of 4′-Cyanothymidine and Analogs as Potent Inhibitors of HIV.Tetrahedron Letters 33:37-40.
33.Parker,W.B.,and Y.C.Cheng.1995.“Disruption of Energy Metabolismand Mitochondrial Function”,p.483-490,Neurotoxicology:Approachesand Methods.Academic Press Inc.,New York.
34.Parker,W.B.,and Y.C.Cheng.1994.Mitochondrial Toxicity of AntiviralNucleoside Analogs.The Journal of HIH Reasearch 6:57-61.
35.Richman,D.D.1993.Resistance of clinical isolates of humanimmunodeficiency virus to antiretroviral agents.Antimicrob AgentsChemother 37:1207-13.
36.Richman,D.D.,M.A.Fischl,M.H.Grieco,M.S.Gottlieb,P.A.Volberding,O.L.Laskin,J.M.Leedom,J.E.Groopman,D.Mildvan,M.S.Hirsch,and et al.1987.The toxicity of azidothymidine(AZT)in thetreatment of patients with AIDS and AIDS-related complex.Adouble-blind,placebo-controlled trial.N Engl J Med 317:192-7.
37.Schinazi,R.F.,C.K.Chu,A.Peck,A.McMillan,R.Mathis,D.Cannon,L.S.Jeong,J.W.Beach,W.B.Choi,S.Yeola,and et al.1992.Activities ofthe four optical isomers of 2′,3′-dideoxy-3′-thiacytidine(BCH-189)againsthuman immunodeficiency virus type 1 in human lymphocytes.AntimicrobAgents Chemother 36:672-6.
38.Sommadossi,J.P.,Z.Zhou,M.J.Hitchcock,H.M.McClure,M.el Kouni,and E.Cretton.1992.Catabolism of2′,3′-Didehydro-2′,3-DideoxyThymidine(D4T)in Isolated Hepatocytesand in Rhesus Monkeys.Proc.Annu.Meeting American Cancer Research33:A3253.Univ.of Alabama.
39.Yarchoan,R.,J.M.Pluda,R.V.Thomas,H.Mitsuya,P.Brouwers,K.M.Wyvill,N.Hartman,D.G.Johns,and S.Broder.1990.Long-termtoxicity/activity profile of 2′,3′-dideoxyinosine in AIDS or AIDS-relatedcomplex.Lancet 336:526-9.
Claims (13)
3.药物组合物,包括有效量的根据权利要求1的化合物,以及可药用载体、添加剂或赋形剂。
4.药物组合物,包括有效量的根据权利要求2的化合物以及可药用载体、添加剂或赋形剂。
5.权利要求3-4中任一项的药物组合物,还包括至少一种另外的抗HIV剂。
6.根据权利要求5的组合物,其中所述的抗HIV剂选自ddC、阿巴卡韦、ddI、ddA、3TC、AZT、D4T、FTC、FddC、Fd4C、Atazanavir、阿德福韦二吡呋酯、Tenofovir disoproxil、Etecavir、茚地那韦、KHI-227、2-[3-[3-(S)-[[(四氢呋喃基氧基)羰基]氨基]-4-苯基-2(R)-羟基丁基]]-N-(1,1-二甲基乙基)十氢-3-异喹啉甲酰胺、VB-11,328、KNI-174、Val-Val-Sta、CPG53820、双-Val HOEt-N2氮杂-肽等排物、2,5-二氨基-N,N’-双(N-苄氧基羰基uelyl)-1,6-二苯基-3(S),4(S)-己烷二醇BzOCValPhe[二CHOH(SS]PheValBzOC、
2,5,-二氨基-N,N’-双(N-苄氧基羰基uelyl)-1,6-二苯基-3(R),4(R)-己烷二醇BzOCValPhe[二CHOH(RR]PheValBzOC、
[双(SATE)ddAMP]、BILA 2186BS、Agenerase、A-98881、A-83962、A-80987、(2-萘基羰基)Asn[decarbonylPhe-羟基乙基]ProO叔丁基、
A-81525、XM323、替拉那韦,
SDZ PRI 053、SD146、替利那韦、(R)2喹啉COAsnPhe[CHOHCH2]PipCONHtBu、沙奎那韦、R-87366、DMP 460、L685,434、L685,434-6-羟基、L685,434-OEtNMe2、L685,434-OPr吗啉、L689,502、拉西那韦、
Aluviran、P9941、帕利那韦、
及其混合物。
7.根据权利要求6的组合物,其中所述的抗HIV剂选自ddC、阿巴卡韦、ddI、ddA、3TC、AZT、D4T、FTC、FddC和Fd4C。
8.根据权利要求3-7中任一项的组合物在制备治疗由人免疫缺陷病毒引起的病毒感染的药物中的用途。
9.根据权利要求8的用途,其中所述的病毒为HIV 1。
10.根据权利要求8的用途,其中所述的病毒为HIV 2。
11.权利要求3-7中任一项的组合物在制备用于降低处于有发展所述病症患者中继发于人免疫缺陷病毒感染的病症的可能性或延缓继发于人免疫缺陷病毒感染的病症发作的药物中的用途。
12.根据权利要求11的用途,其中所述的病症为AIDS。
13.权利要求1-2中任一项的化合物在制备用于在患者中治疗HIV感染的药物中的用途。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US44855403P | 2003-02-19 | 2003-02-19 | |
US60/448,554 | 2003-02-19 | ||
PCT/US2004/004713 WO2005011709A1 (en) | 2003-02-19 | 2004-02-18 | Anti-viral nucleoside analogs and methods for treating viral infections, especially hiv infections |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2011100686277A Division CN102174038A (zh) | 2003-02-19 | 2004-02-18 | 用于治疗病毒感染的抗病毒核苷 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1777432A CN1777432A (zh) | 2006-05-24 |
CN1777432B true CN1777432B (zh) | 2011-06-08 |
Family
ID=34115263
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2011100686277A Pending CN102174038A (zh) | 2003-02-19 | 2004-02-18 | 用于治疗病毒感染的抗病毒核苷 |
CN2004800105296A Expired - Lifetime CN1777432B (zh) | 2003-02-19 | 2004-02-18 | 用于hiv感染的抗病毒核苷类似物 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2011100686277A Pending CN102174038A (zh) | 2003-02-19 | 2004-02-18 | 用于治疗病毒感染的抗病毒核苷 |
Country Status (14)
Country | Link |
---|---|
US (3) | US7589078B2 (zh) |
EP (2) | EP1653976A4 (zh) |
JP (1) | JP4980059B2 (zh) |
KR (2) | KR101228503B1 (zh) |
CN (2) | CN102174038A (zh) |
AU (1) | AU2004260630B2 (zh) |
BR (1) | BRPI0407374A (zh) |
CA (1) | CA2514466C (zh) |
EA (1) | EA012844B1 (zh) |
HK (1) | HK1087341A1 (zh) |
MX (1) | MXPA05008736A (zh) |
PL (2) | PL219609B1 (zh) |
WO (1) | WO2005011709A1 (zh) |
ZA (1) | ZA200506630B (zh) |
Families Citing this family (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1313472C (zh) | 2002-04-26 | 2007-05-02 | 吉里德科学公司 | Hiv蛋白酶抑制剂化合物的膦酸酯类似物的细胞蓄积及这类化合物 |
BRPI0407374A (pt) | 2003-02-19 | 2006-01-10 | Univ Yale | Análogos de nucleosìdeo antiviral e métodos para tratar infecções virais, especialmente infecções de hiv |
AU2004233897A1 (en) | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Kinase inhibitor phosphonate conjugates |
WO2005002626A2 (en) | 2003-04-25 | 2005-01-13 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
US7452901B2 (en) * | 2003-04-25 | 2008-11-18 | Gilead Sciences, Inc. | Anti-cancer phosphonate analogs |
EA014685B1 (ru) | 2003-04-25 | 2010-12-30 | Джилид Сайэнс, Инк. | Фосфонатсодержащие антивирусные соединения (варианты) и фармацевтическая композиция на их основе |
US7407965B2 (en) * | 2003-04-25 | 2008-08-05 | Gilead Sciences, Inc. | Phosphonate analogs for treating metabolic diseases |
CN101410120A (zh) * | 2003-04-25 | 2009-04-15 | 吉里德科学公司 | 抗炎的膦酸酯化合物 |
US7427636B2 (en) * | 2003-04-25 | 2008-09-23 | Gilead Sciences, Inc. | Inosine monophosphate dehydrogenase inhibitory phosphonate compounds |
US7432261B2 (en) * | 2003-04-25 | 2008-10-07 | Gilead Sciences, Inc. | Anti-inflammatory phosphonate compounds |
US7470724B2 (en) * | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
WO2004096285A2 (en) | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Anti-infective phosphonate conjugates |
US20050261237A1 (en) * | 2003-04-25 | 2005-11-24 | Boojamra Constantine G | Nucleoside phosphonate analogs |
GB0317009D0 (en) * | 2003-07-21 | 2003-08-27 | Univ Cardiff | Chemical compounds |
US7273715B2 (en) | 2003-10-24 | 2007-09-25 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds with GS-9005 ester hydrolase A |
WO2005044279A1 (en) * | 2003-10-24 | 2005-05-19 | Gilead Sciences, Inc. | Purine nucleoside phosphonate conjugates |
US7432273B2 (en) * | 2003-10-24 | 2008-10-07 | Gilead Sciences, Inc. | Phosphonate analogs of antimetabolites |
BRPI0417988A (pt) * | 2003-12-22 | 2007-04-27 | Gilead Sciences Inc | análogos de fosfonato antivirais |
US20050153990A1 (en) * | 2003-12-22 | 2005-07-14 | Watkins William J. | Phosphonate substituted kinase inhibitors |
BRPI0418031A (pt) * | 2003-12-22 | 2007-04-17 | Gilead Sciences Inc | inibidores de quinase fosfonato-substituìdos |
CA2502109C (en) | 2004-03-24 | 2010-02-23 | Yamasa Corporation | 4'-c-substituted-2-haloadenosine derivative |
ATE505196T1 (de) | 2004-07-27 | 2011-04-15 | Gilead Sciences Inc | Nukleosid phosphonat konjugate als anti hiv mittel |
WO2006044968A2 (en) * | 2004-10-19 | 2006-04-27 | Achillion Pharmaceuticals, Inc. | Combination therapy for treating viral infections |
EA200800932A1 (ru) * | 2005-09-26 | 2008-10-30 | Фармассет, Инк. | Модифицированные 4`-нуклеозиды в качестве противовирусных агентов |
WO2007065032A2 (en) * | 2005-12-02 | 2007-06-07 | The Regents Of The University Of California | Compounds and methods for inhibiting viral entry |
WO2007067364A2 (en) * | 2005-12-02 | 2007-06-14 | Yale University | Methods of treating cancer and other conditions or disease states using l-cytosine nucleoside analogs |
US20080078560A1 (en) * | 2006-10-02 | 2008-04-03 | Kevin Hall | Motor seal |
CN101796040A (zh) * | 2007-07-06 | 2010-08-04 | 吉里德科学公司 | 治疗剂的药代动力学特性调节剂 |
JP5511389B2 (ja) * | 2007-12-27 | 2014-06-04 | オンコリスバイオファーマ株式会社 | 4’−エチニルd4Tの製造方法 |
WO2009119785A1 (ja) * | 2008-03-28 | 2009-10-01 | 浜理薬品工業株式会社 | エチニルチミジン化合物の精製方法 |
US8445669B2 (en) * | 2008-04-10 | 2013-05-21 | Hamari Chemicals, Ltd. | Production process of ethynylthymidine compounds from 5-methyluridine as a starting material |
US20100093667A1 (en) | 2008-07-08 | 2010-04-15 | Gilead Sciences, Inc. | Salts of hiv inhibitor compounds |
PA8852101A1 (es) * | 2008-12-08 | 2010-07-27 | Medivir Ab | Nucleótidos uracil ciclopropílicos |
JP2012514657A (ja) * | 2009-01-09 | 2012-06-28 | ユニバーシテイ・カレツジ・オブ・カーデイフ・コンサルタンツ・リミテツド | ウィルス感染を治療するためのグアノシンヌクレオシド化合物のホスホルアミダート誘導体 |
BRPI1005828A2 (pt) * | 2009-02-27 | 2017-07-18 | Siga Tech Inc | composição farmacêutica; método para o tratamento ou a profilaxia de uma infecção viral ou doença associada com a mesma; composto; método para a preparação de uma mistura de terc-butil(4e)-4-(hidroximetileno)-5-oxoazepano-1-carboxilato e terc-butil (3e)-3-(hidroximetileno)-4-oxoazepano-1-carboxilato; método para a preparação de uma mistura de terc-butil 3-ciano-2-tioxo-1,2,5,6,8,9-hexaidro-1h-pirido [2,3-d] azepina-7-carboxilato e terc-butil 3-ciano-2-tioxo-1,2,5,7,8,9-hexaidro-6h-pirido [3,2-c] azepina-6-carboxilato; método para a preparação de ácido 3-amino-7-terc-butiloxicarbonil-6,7,8,9-tetraidro-5h-1-tia-7,10-diaza-ciclohepta [f] indeno-2-carboxílico (5-fenil-[1,3,4]tiazol-2-il)-amida; método para a preparação de ácido 3-amino-6,7,8,9-tetraidro-5h-1-tia-7,10-diaza-ciclohepta [f] indeno-2-carboxílico (5-fenil-[1,3,4] tiadiazol-2-il)-amida; método para a preparação de ácido 3-amino-6-tercbutiloxicarbonil-6,7,8,9-tetraidro-5h-1-tia-6,10-diaza-ciclohepta [f] indeno-2-carboxílico (5-fenil-[1,3,4] tiadiazol-2-il)-amida e método para a preparação de ácido 3-amino-6,7,8,9-tetraidro-5h-1-tia-6,10-diaza-ciclohepta [f] indeno-2-carboxílico (5-fenil-[1,3,4] tiadiazol-2-il)-amida |
GB0907551D0 (en) | 2009-05-01 | 2009-06-10 | Univ Dundee | Treatment or prophylaxis of proliferative conditions |
CN102741237B (zh) | 2010-02-15 | 2015-04-29 | 日产化学工业株式会社 | β-二氢呋喃衍生化合物的制造方法 |
US8975394B2 (en) | 2010-02-15 | 2015-03-10 | Nissan Chemical Industries, Ltd. | Process for preparation of β-glycoside compounds |
WO2011126082A1 (ja) | 2010-04-07 | 2011-10-13 | 日産化学工業株式会社 | アシロキシピラノン化合物の製造方法、アルキン化合物の製造方法及びジヒドロフラン化合物の製造方法 |
WO2012048271A1 (en) * | 2010-10-08 | 2012-04-12 | The Board Of Trustees Of The University Of Illinois | Phosphoramidate derivatization of inorganic polyphosphates and methods |
WO2012166645A1 (en) * | 2011-06-01 | 2012-12-06 | Syndax Pharmaceuticals, Inc. | Prodrugs of azacitidine 5' -diphosphate |
WO2013066991A1 (en) * | 2011-10-31 | 2013-05-10 | Inhibitex, Inc. | Crystalline solvates of nucleoside phosphoroamidates, their stereoselective preparation, novel intermediates thereof, and their use in the treatment of viral disease |
LT2794627T (lt) | 2011-12-22 | 2019-01-10 | Alios Biopharma, Inc. | Pakeistieji nukleozidai, nukleotidai ir jų analogai |
US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
CN104379571A (zh) * | 2012-05-23 | 2015-02-25 | 百时美施贵宝公司 | 用于制备festinavir的硫亚胺和亚砜方法 |
EP2986602A1 (en) | 2013-04-16 | 2016-02-24 | Bristol-Myers Squibb Company | Method for producing festinavir using 5-methyluridine as starting material |
GB201306947D0 (en) * | 2013-04-17 | 2013-05-29 | Univ Leuven Kath | Novel antiviral compounds |
EP3008060A1 (en) | 2013-06-13 | 2016-04-20 | Bristol-Myers Squibb Company | Tert-butyl-sulphoxide method for producing festinavir |
EP3083654A1 (en) * | 2013-12-18 | 2016-10-26 | Idenix Pharmaceuticals LLC | 4'-or nucleosides for the treatment of hcv |
BR112017006264A2 (pt) * | 2014-09-26 | 2017-12-12 | Riboscience Llc | derivados de nucleosídeo substituído com 4?-vinila como inibidores de replicação de rna do vírus sincitial respiratório |
CN107108681B (zh) * | 2014-10-28 | 2021-04-06 | 詹森生物制药有限公司 | 制备取代的核苷类似物的方法 |
CN108348778A (zh) | 2015-11-20 | 2018-07-31 | Viiv保健英国第四有限公司 | Hiv成熟抑制剂制剂 |
JOP20170038B1 (ar) | 2016-02-12 | 2021-08-17 | Merck Sharp & Dohme | مركبات للاستخدام لعلاج عدوى بفيروس hiv والوقاية منه |
DK3512863T3 (da) | 2016-09-07 | 2022-03-07 | Atea Pharmaceuticals Inc | 2¿-substituerede-N6-substituerede purinnukleotider til behandling af RNA-virus |
SI3661937T1 (sl) | 2017-08-01 | 2021-11-30 | Gilead Sciences, Inc. | Kristalinične oblike etil((S)-((((2R,5R)-5-(6-amino-9H-purin-9-IL)-4- fluoro-2,5-dihidrofuran-2-IL)oksi)metil)(fenoksi)fosforil)-L-alaninata (GS-9131) za zdravljenje virusnih okužb |
JP7299897B2 (ja) * | 2017-09-21 | 2023-06-28 | リボサイエンス リミティド ライアビリティ カンパニー | Hcvのrna複製阻害剤としての4’-フルオロ-2’-メチル置換ヌクレオシド誘導体 |
PE20210367A1 (es) | 2018-02-02 | 2021-02-26 | Maverix Oncology Inc | Conjugados de farmacos de molecula pequena de monofosfato de gemcitabina |
KR101893988B1 (ko) * | 2018-05-16 | 2018-08-31 | (주)에빅스젠 | 로다닌 유도체를 함유하는 aids 예방 또는 치료용 약학 조성물 |
TW202019942A (zh) * | 2018-07-27 | 2020-06-01 | 日商富士軟片股份有限公司 | 環戊烯嘌呤衍生物或其鹽 |
WO2020154656A1 (en) | 2019-01-25 | 2020-07-30 | Brown University | Compositions and methods for treating, preventing or reversing age-associated inflammation and disorders |
CN109761842B (zh) * | 2019-02-01 | 2021-11-30 | 浙江工业大学 | α-F-β-NHAc-羰基化合物的合成方法 |
WO2021188959A1 (en) | 2020-03-20 | 2021-09-23 | Gilead Sciences, Inc. | Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same |
KR20230130898A (ko) | 2022-03-04 | 2023-09-12 | 동아대학교 산학협력단 | N4-이소부티릴옥시시티딘 모방체 합성과 이의 항바이러스 용도를 포함하는 바이러스 감염 치료용 조성물 |
WO2024015916A2 (en) * | 2022-07-13 | 2024-01-18 | Thomas Jefferson University | 4'-alkyne-2'-deoxycytidine-based compounds and anti-cancer uses thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5192749A (en) * | 1990-05-21 | 1993-03-09 | Syntex (U.S.A.) Inc. | 4'-substituted nucleosides |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4978655A (en) | 1986-12-17 | 1990-12-18 | Yale University | Use of 3'-deoxythymidin-2'-ene (3'deoxy-2',3'-didehydrothymidine) in treating patients infected with retroviruses |
US4880784A (en) | 1987-12-21 | 1989-11-14 | Brigham Young University | Antiviral methods utilizing ribofuranosylthiazolo[4,5-d]pyrimdine derivatives |
US5179084A (en) | 1989-04-10 | 1993-01-12 | Nippon Kayaku Kabushiki Kaisha | Antiviral phosphoric acid esters of oxetanocins |
US5739396A (en) | 1991-12-09 | 1998-04-14 | Stanford University | Asymmetric ligands useful for transition metal catalyzed bond forming reactions |
JPH05230058A (ja) * | 1992-02-24 | 1993-09-07 | Yamasa Shoyu Co Ltd | 4’−炭素置換ピリミジンヌクレオシド及びその製造法 |
ZA931934B (en) | 1992-03-18 | 1993-03-18 | Us Bioscience | Compostitions of N-(phosphonoacetyl)-L-aspartic acid and methods of their use as broad spectrum antivirals |
JPH0680688A (ja) * | 1992-09-03 | 1994-03-22 | Asahi Breweries Ltd | 4’−メチルヌクレオシド誘導体 |
US5376633A (en) | 1992-09-30 | 1994-12-27 | Lezdey; John | Method for deactivating viruses in blood component containers |
RU2130029C1 (ru) | 1994-12-13 | 1999-05-10 | Тайхо Фармасьютикал Ко., Лтд. | 3'-замещенные производные нуклеозида, способ их получения (варианты), лекарственное средство, способ лечения и профилактики |
US5888767A (en) | 1996-11-27 | 1999-03-30 | The Johns Hopkins University School Of Medicine | Method of using a conditionally replicating viral vector to express a gene |
EP0842942B1 (en) * | 1996-05-16 | 2003-03-12 | Taiho Pharmaceutical Company, Limited | D-pentofuranose derivatives and process for the preparation thereof |
US5891874A (en) | 1996-06-05 | 1999-04-06 | Eli Lilly And Company | Anti-viral compound |
US5821242A (en) | 1996-06-06 | 1998-10-13 | Eli Lilly And Company | Anti-viral compounds |
US6180604B1 (en) | 1996-08-21 | 2001-01-30 | Micrologix Biotech Inc. | Compositions and methods for treating infections using analogues of indolicidin |
AU6358898A (en) | 1996-09-09 | 1998-04-17 | Alexander V Kabanov | Fluorinated copolymeric pharmaceutical adjuncts |
JP3792005B2 (ja) * | 1997-04-24 | 2006-06-28 | 彰 松田 | 2−デオキシ−3−エチニル−β−D−リボフラノシル誘導体 |
EP1001767A4 (en) | 1997-06-04 | 2001-07-04 | Lilly Co Eli | ANTIVIRAL CONNECTIONS |
JP4211901B2 (ja) * | 1998-06-08 | 2009-01-21 | ヤマサ醤油株式会社 | 4’−メチルヌクレオシド化合物 |
AU751457B2 (en) | 1998-09-25 | 2002-08-15 | Viropharma Incorporated | Methods for treating or preventing viral infections and associated diseases |
ATE250622T1 (de) | 1999-05-12 | 2003-10-15 | Yamasa Corp | 4'-c-ethynyl-pyrimidine nukleoside |
US6240690B1 (en) | 2000-02-02 | 2001-06-05 | Roof & Metal Systems, Inc. | Vented metal roof |
RU2182013C1 (ru) | 2001-03-05 | 2002-05-10 | Казанцева Наталья Вениаминовна | Способ лечения нейродегенеративных заболеваний мозга |
GB0114286D0 (en) * | 2001-06-12 | 2001-08-01 | Hoffmann La Roche | Nucleoside Derivatives |
EP1435974A4 (en) * | 2001-09-28 | 2006-09-06 | Idenix Cayman Ltd | METHOD AND COMPOSITIONS FOR TREATING HEPATITIS C VIRUS WITH 4'-MODIFIED NUCLEOSIDES |
JP2005536440A (ja) | 2001-09-28 | 2005-12-02 | イデニクス(ケイマン)リミテツド | 4’位が修飾されたヌクレオシドを使用するフラビウイルスおよびペスチウイルスの治療のための方法および組成物 |
EP1572705A2 (en) * | 2002-01-17 | 2005-09-14 | Ribapharm, Inc. | Sugar modified nucleosides as viral replication inhibitors |
BRPI0407374A (pt) * | 2003-02-19 | 2006-01-10 | Univ Yale | Análogos de nucleosìdeo antiviral e métodos para tratar infecções virais, especialmente infecções de hiv |
-
2004
- 2004-02-18 BR BR0407374-6A patent/BRPI0407374A/pt not_active Application Discontinuation
- 2004-02-18 WO PCT/US2004/004713 patent/WO2005011709A1/en active Application Filing
- 2004-02-18 EP EP04775776A patent/EP1653976A4/en not_active Withdrawn
- 2004-02-18 JP JP2006532288A patent/JP4980059B2/ja not_active Expired - Lifetime
- 2004-02-18 AU AU2004260630A patent/AU2004260630B2/en not_active Expired
- 2004-02-18 PL PL378354A patent/PL219609B1/pl unknown
- 2004-02-18 EA EA200501325A patent/EA012844B1/ru unknown
- 2004-02-18 MX MXPA05008736A patent/MXPA05008736A/es active IP Right Grant
- 2004-02-18 KR KR1020057015440A patent/KR101228503B1/ko active IP Right Grant
- 2004-02-18 CN CN2011100686277A patent/CN102174038A/zh active Pending
- 2004-02-18 CA CA2514466A patent/CA2514466C/en not_active Expired - Lifetime
- 2004-02-18 CN CN2004800105296A patent/CN1777432B/zh not_active Expired - Lifetime
- 2004-02-18 KR KR1020117014432A patent/KR20110079783A/ko not_active Application Discontinuation
- 2004-02-18 US US10/781,305 patent/US7589078B2/en active Active
- 2004-02-18 EP EP10155533.2A patent/EP2298783B1/en not_active Expired - Lifetime
- 2004-02-28 PL PL398295A patent/PL398295A1/pl unknown
-
2005
- 2005-08-18 ZA ZA200506630A patent/ZA200506630B/en unknown
-
2006
- 2006-07-11 HK HK06107732.2A patent/HK1087341A1/xx not_active IP Right Cessation
-
2009
- 2009-08-17 US US12/583,229 patent/US8193165B2/en not_active Expired - Lifetime
-
2012
- 2012-05-07 US US13/465,315 patent/US9126971B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5192749A (en) * | 1990-05-21 | 1993-03-09 | Syntex (U.S.A.) Inc. | 4'-substituted nucleosides |
Non-Patent Citations (2)
Title |
---|
JP平5-230058A 1993.09.07 |
JP平6-80688A 1994.03.22 |
Also Published As
Publication number | Publication date |
---|---|
US20100048500A1 (en) | 2010-02-25 |
EP2298783A1 (en) | 2011-03-23 |
US7589078B2 (en) | 2009-09-15 |
JP2006528972A (ja) | 2006-12-28 |
BRPI0407374A (pt) | 2006-01-10 |
EA200501325A1 (ru) | 2006-02-24 |
CN102174038A (zh) | 2011-09-07 |
EA012844B1 (ru) | 2009-12-30 |
WO2005011709A1 (en) | 2005-02-10 |
EP2298783B1 (en) | 2017-12-06 |
EP1653976A1 (en) | 2006-05-10 |
KR20110079783A (ko) | 2011-07-07 |
CA2514466A1 (en) | 2005-02-10 |
AU2004260630A1 (en) | 2005-02-10 |
AU2004260630B2 (en) | 2009-12-10 |
ZA200506630B (en) | 2006-06-28 |
CN1777432A (zh) | 2006-05-24 |
PL398295A1 (pl) | 2012-05-21 |
US20040167096A1 (en) | 2004-08-26 |
JP4980059B2 (ja) | 2012-07-18 |
US20120252751A1 (en) | 2012-10-04 |
MXPA05008736A (es) | 2005-10-05 |
PL219609B1 (pl) | 2015-06-30 |
KR20060026402A (ko) | 2006-03-23 |
EP1653976A4 (en) | 2009-07-29 |
HK1087341A1 (en) | 2006-10-13 |
US9126971B2 (en) | 2015-09-08 |
PL378354A1 (pl) | 2006-03-20 |
CA2514466C (en) | 2015-05-26 |
KR101228503B1 (ko) | 2013-01-31 |
US8193165B2 (en) | 2012-06-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1777432B (zh) | 用于hiv感染的抗病毒核苷类似物 | |
CN100560073C (zh) | 用于治疗病毒感染的n4-酰基胞嘧啶核苷 | |
JP6757294B2 (ja) | フィロウイルス科ウイルス感染症を処置するための方法 | |
KR100974917B1 (ko) | 간염 바이러스 감염 치료를 위한 3'- 또는2'-하이드록시메틸 치환된 뉴클레오시드 유도체 | |
CN101862345B (zh) | 用于治疗病毒感染和异常细胞增殖的修饰核苷类化合物 | |
CN101321775B (zh) | 用于治疗疟疾的odcase抑制剂 | |
CN109890831A (zh) | 被取代的核苷、核苷酸以及它们的类似物 | |
EP1346724A1 (en) | Remedies for hepatitis c | |
CN102924549A (zh) | 作为抗病毒剂的修饰的4'-核苷 | |
CN103687866A (zh) | 用于治疗病毒性感染的嘌呤单磷酸酯前药 | |
JPH08501071A (ja) | 1,5−アンヒドロヘキシトールヌクレオシド類似体および該類似体の医薬としての使用 | |
Abu-Zaied et al. | Sofosbuvir thio-analogues: synthesis and antiviral evaluation of the first novel pyridine-and pyrimidine-based thioglycoside phosphoramidates | |
JPH04226999A (ja) | 抗ウイルス剤 | |
TWI789479B (zh) | 胺基磷酸酯(膦醯胺酯)縮醛以及磷酸酯(膦酸酯)縮醛化合物 | |
CN101511185A (zh) | 唑类核苷和作为rna和dna病毒聚合酶抑制剂的用途 | |
Hyde et al. | Antiviral amphipathic oligo-and polyribonucleotides: Analogue development and biological studies | |
NZ541594A (en) | Anti-viral 4'-substituted nucleoside analogs and methods for treating viral infections, especially HIV infections |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1087341 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1087341 Country of ref document: HK |
|
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20110608 |