ES2276515T3 - 2'-fluoronucleosidos. - Google Patents
2'-fluoronucleosidos. Download PDFInfo
- Publication number
- ES2276515T3 ES2276515T3 ES99908437T ES99908437T ES2276515T3 ES 2276515 T3 ES2276515 T3 ES 2276515T3 ES 99908437 T ES99908437 T ES 99908437T ES 99908437 T ES99908437 T ES 99908437T ES 2276515 T3 ES2276515 T3 ES 2276515T3
- Authority
- ES
- Spain
- Prior art keywords
- fluoro
- mmol
- acyl
- alkyl
- base
- 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
- -1 or if appropriate Chemical group 0.000 claims abstract description 59
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims abstract description 58
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 21
- 239000010452 phosphate Substances 0.000 claims abstract description 20
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 18
- 125000002252 acyl group Chemical group 0.000 claims abstract description 17
- 150000002632 lipids Chemical class 0.000 claims abstract description 17
- 229940002612 prodrug Drugs 0.000 claims abstract description 16
- 239000000651 prodrug Substances 0.000 claims abstract description 16
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 13
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000001177 diphosphate Substances 0.000 claims abstract description 10
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims abstract description 10
- 235000011180 diphosphates Nutrition 0.000 claims abstract description 10
- 239000001226 triphosphate Substances 0.000 claims abstract description 10
- 235000011178 triphosphate Nutrition 0.000 claims abstract description 9
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims abstract description 9
- 208000005176 Hepatitis C Diseases 0.000 claims abstract description 8
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 150000004712 monophosphates Chemical class 0.000 claims abstract description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 238000001727 in vivo Methods 0.000 claims abstract description 5
- 150000001413 amino acids Chemical class 0.000 claims abstract description 4
- 238000003776 cleavage reaction Methods 0.000 claims abstract description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 4
- 230000007017 scission Effects 0.000 claims abstract description 4
- 239000003937 drug carrier Substances 0.000 claims abstract 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 15
- 229940104302 cytosine Drugs 0.000 claims description 14
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 claims description 14
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 13
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229960000643 adenine Drugs 0.000 claims description 10
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 8
- 229930024421 Adenine Natural products 0.000 claims description 8
- 208000015181 infectious disease Diseases 0.000 claims description 8
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 229940035893 uracil Drugs 0.000 claims description 7
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 6
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 6
- IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical compound N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 claims description 6
- 229940113082 thymine Drugs 0.000 claims description 6
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 229960004413 flucytosine Drugs 0.000 claims description 5
- 229960002949 fluorouracil Drugs 0.000 claims description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 claims description 3
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 claims description 3
- 229940024606 amino acid Drugs 0.000 claims description 3
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 claims description 2
- MGAXHFMCFLLMNG-UHFFFAOYSA-N 1h-pyrimidine-6-thione Chemical compound SC1=CC=NC=N1 MGAXHFMCFLLMNG-UHFFFAOYSA-N 0.000 claims description 2
- SVXNJCYYMRMXNM-UHFFFAOYSA-N 5-amino-2h-1,2,4-triazin-3-one Chemical compound NC=1C=NNC(=O)N=1 SVXNJCYYMRMXNM-UHFFFAOYSA-N 0.000 claims description 2
- NPYPQKXJJZZSAX-UHFFFAOYSA-N 5-benzylpyrimidine Chemical class C=1N=CN=CC=1CC1=CC=CC=C1 NPYPQKXJJZZSAX-UHFFFAOYSA-N 0.000 claims description 2
- HXXVIKZQIFTJOQ-UHFFFAOYSA-N 5-ethenylpyrimidine Chemical compound C=CC1=CN=CN=C1 HXXVIKZQIFTJOQ-UHFFFAOYSA-N 0.000 claims description 2
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims description 2
- NOYDQGFVFOQSAJ-UHFFFAOYSA-N 5-nitropyrimidine Chemical compound [O-][N+](=O)C1=CN=CN=C1 NOYDQGFVFOQSAJ-UHFFFAOYSA-N 0.000 claims description 2
- PVRBGBGMDLPYKG-UHFFFAOYSA-N 6-benzyl-7h-purine Chemical compound N=1C=NC=2N=CNC=2C=1CC1=CC=CC=C1 PVRBGBGMDLPYKG-UHFFFAOYSA-N 0.000 claims description 2
- DBCMWACNZJYUHS-UHFFFAOYSA-N 6-ethenyl-7h-purine Chemical compound C=CC1=NC=NC2=C1NC=N2 DBCMWACNZJYUHS-UHFFFAOYSA-N 0.000 claims description 2
- 229930010555 Inosine Natural products 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229960003786 inosine Drugs 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- FVLAYJRLBLHIPV-UHFFFAOYSA-N pyrimidin-5-amine Chemical compound NC1=CN=CN=C1 FVLAYJRLBLHIPV-UHFFFAOYSA-N 0.000 claims description 2
- HBCQSNAFLVXVAY-UHFFFAOYSA-N pyrimidine-2-thiol Chemical compound SC1=NC=CC=N1 HBCQSNAFLVXVAY-UHFFFAOYSA-N 0.000 claims description 2
- XVIAPHVAGFEFFN-UHFFFAOYSA-N pyrimidine-5-carbonitrile Chemical compound N#CC1=CN=CN=C1 XVIAPHVAGFEFFN-UHFFFAOYSA-N 0.000 claims description 2
- VBYYJZIWKPTMIE-UHFFFAOYSA-N 2-chloropurin-2-amine Chemical compound NC1(Cl)N=CC2=NC=NC2=N1 VBYYJZIWKPTMIE-UHFFFAOYSA-N 0.000 claims 1
- 150000005697 5-halopyrimidines Chemical class 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 208000010710 hepatitis C virus infection Diseases 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 184
- 239000002777 nucleoside Substances 0.000 description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 73
- 238000005481 NMR spectroscopy Methods 0.000 description 56
- 238000003786 synthesis reaction Methods 0.000 description 51
- 239000000203 mixture Substances 0.000 description 50
- 230000015572 biosynthetic process Effects 0.000 description 49
- 125000003835 nucleoside group Chemical group 0.000 description 47
- 239000000243 solution Substances 0.000 description 47
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- 239000007787 solid Substances 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 229910052757 nitrogen Inorganic materials 0.000 description 34
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- 230000000694 effects Effects 0.000 description 31
- 238000000034 method Methods 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- 238000004458 analytical method Methods 0.000 description 25
- 229910052799 carbon Inorganic materials 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
- 150000003833 nucleoside derivatives Chemical class 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 230000000840 anti-viral effect Effects 0.000 description 21
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 18
- 229910052731 fluorine Inorganic materials 0.000 description 17
- 241000725303 Human immunodeficiency virus Species 0.000 description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 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 15
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 239000011737 fluorine Substances 0.000 description 14
- 235000021317 phosphate Nutrition 0.000 description 14
- 229960002555 zidovudine Drugs 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 12
- 235000000346 sugar Nutrition 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000010409 thin film Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 150000002596 lactones Chemical class 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical group 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 125000003729 nucleotide group Chemical group 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000036436 anti-hiv Effects 0.000 description 7
- 239000003443 antiviral agent Substances 0.000 description 7
- 244000309464 bull Species 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 235000020357 syrup Nutrition 0.000 description 7
- 239000006188 syrup Substances 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 6
- 241000282412 Homo Species 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 150000001720 carbohydrates Chemical group 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 208000006454 hepatitis Diseases 0.000 description 6
- 231100000283 hepatitis Toxicity 0.000 description 6
- 239000002773 nucleotide Substances 0.000 description 6
- 239000012047 saturated solution Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 239000002841 Lewis acid Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000001093 anti-cancer Effects 0.000 description 5
- 239000004599 antimicrobial Substances 0.000 description 5
- 235000014633 carbohydrates Nutrition 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 150000007517 lewis acids Chemical class 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 4
- 241000700721 Hepatitis B virus Species 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 238000012925 biological evaluation Methods 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- JTEGQNOMFQHVDC-UHFFFAOYSA-N 4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1C1OC(CO)SC1 JTEGQNOMFQHVDC-UHFFFAOYSA-N 0.000 description 3
- UNRIYCIDCQDGQE-UHFFFAOYSA-N 6-chloro-2-fluoro-7h-purine Chemical compound FC1=NC(Cl)=C2NC=NC2=N1 UNRIYCIDCQDGQE-UHFFFAOYSA-N 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910000831 Steel Inorganic materials 0.000 description 3
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- 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
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| US8056998P | 1998-04-03 | 1998-04-03 | |
| US80569P | 1998-04-03 |
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1999
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- 1999-02-25 AT AT99908437T patent/ATE344271T1/de active
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- 1999-02-25 EA EA200700564A patent/EA200700564A1/ru unknown
- 1999-02-25 MX MXPA00008348A patent/MXPA00008348A/es active IP Right Grant
- 1999-02-25 EP EP10180488A patent/EP2392580A1/en not_active Withdrawn
- 1999-02-25 KR KR1020097000710A patent/KR100954390B1/ko not_active Expired - Lifetime
- 1999-02-25 EP EP10180480A patent/EP2390257A1/en not_active Withdrawn
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- 1999-02-25 DK DK99908437T patent/DK1058686T3/da active
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- 1999-02-25 WO PCT/US1999/004051 patent/WO1999043691A1/en not_active Ceased
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