JPH0296590A - Novel nucleic acids - Google Patents
Novel nucleic acidsInfo
- Publication number
- JPH0296590A JPH0296590A JP24433488A JP24433488A JPH0296590A JP H0296590 A JPH0296590 A JP H0296590A JP 24433488 A JP24433488 A JP 24433488A JP 24433488 A JP24433488 A JP 24433488A JP H0296590 A JPH0296590 A JP H0296590A
- Authority
- JP
- Japan
- Prior art keywords
- group
- deoxy
- added
- fluoro
- stirred
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000007523 nucleic acids Chemical class 0.000 title abstract description 6
- 102000039446 nucleic acids Human genes 0.000 title abstract description 6
- 108020004707 nucleic acids Proteins 0.000 title abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 46
- 150000001875 compounds Chemical class 0.000 abstract description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 23
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 11
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 abstract description 9
- 239000012359 Methanesulfonyl chloride Substances 0.000 abstract description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 30
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 23
- -1 acetylthio groups Chemical group 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000002777 nucleoside Substances 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 229940113082 thymine Drugs 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 229940035893 uracil Drugs 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 210000003127 knee Anatomy 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 description 10
- 125000003835 nucleoside group Chemical group 0.000 description 10
- 150000003833 nucleoside derivatives Chemical class 0.000 description 8
- 150000003212 purines Chemical class 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 235000000346 sugar Nutrition 0.000 description 8
- 125000001153 fluoro group Chemical group F* 0.000 description 7
- 150000002391 heterocyclic compounds Chemical class 0.000 description 7
- 125000004430 oxygen atom Chemical group O* 0.000 description 7
- 150000003230 pyrimidines Chemical class 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000004293 19F NMR spectroscopy Methods 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 229960001701 chloroform Drugs 0.000 description 6
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 238000011097 chromatography purification Methods 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 150000002430 hydrocarbons Chemical group 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 description 5
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 3
- 229930024421 Adenine Natural products 0.000 description 3
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 3
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000643 adenine Drugs 0.000 description 3
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- KOSYAAIZOGNATQ-UHFFFAOYSA-N o-phenyl chloromethanethioate Chemical compound ClC(=S)OC1=CC=CC=C1 KOSYAAIZOGNATQ-UHFFFAOYSA-N 0.000 description 3
- 125000000962 organic group Chemical group 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical group FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- PKOBNLOZXOHYOP-XVFCMESISA-N 4-amino-1-[(2r,3s,4s,5r)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](F)[C@@H](CO)O1 PKOBNLOZXOHYOP-XVFCMESISA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical group O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229940104302 cytosine Drugs 0.000 description 2
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000010436 fluorite Substances 0.000 description 2
- 125000000524 functional group Chemical class 0.000 description 2
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000002073 methionyl group Chemical group 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 125000004043 oxo group Chemical group O=* 0.000 description 2
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- 229940075420 xanthine Drugs 0.000 description 2
- IUIHKZFITLQBRP-SOVPELCUSA-N (2r,3r,4s,5s)-2-(6-aminopurin-9-yl)-5-[difluoro(hydroxy)methyl]oxolane-3,4-diol Chemical class C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](C(O)(F)F)[C@@H](O)[C@H]1O IUIHKZFITLQBRP-SOVPELCUSA-N 0.000 description 1
- PLFFHJWXOGYWPR-HEDMGYOXSA-N (4r)-4-[(3r,3as,5ar,5br,7as,11as,11br,13ar,13bs)-5a,5b,8,8,11a,13b-hexamethyl-1,2,3,3a,4,5,6,7,7a,9,10,11,11b,12,13,13a-hexadecahydrocyclopenta[a]chrysen-3-yl]pentan-1-ol Chemical compound C([C@]1(C)[C@H]2CC[C@H]34)CCC(C)(C)[C@@H]1CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@@H]1[C@@H](CCCO)C PLFFHJWXOGYWPR-HEDMGYOXSA-N 0.000 description 1
- FVBOTRDLABQYMI-XVFCMESISA-N 1-[(2r,3s,4s,5r)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@@H]1[C@H](F)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 FVBOTRDLABQYMI-XVFCMESISA-N 0.000 description 1
- BKIUEHLYJFLWPK-SHYZEUOFSA-N 1-[(2r,4s,5r)-4-fluoro-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@H](F)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 BKIUEHLYJFLWPK-SHYZEUOFSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 1
- RTKMFQOHBDVEBC-UHFFFAOYSA-N 3-bromo-3-buten-1-ol Chemical compound OCCC(Br)=C RTKMFQOHBDVEBC-UHFFFAOYSA-N 0.000 description 1
- JCLFHZLOKITRCE-UHFFFAOYSA-N 4-pentoxyphenol Chemical compound CCCCCOC1=CC=C(O)C=C1 JCLFHZLOKITRCE-UHFFFAOYSA-N 0.000 description 1
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- OZSJFVRAJAFIHQ-UHFFFAOYSA-N 7-hydroxypurin-6-amine Chemical compound NC1=NC=NC2=C1N(O)C=N2 OZSJFVRAJAFIHQ-UHFFFAOYSA-N 0.000 description 1
- 102000055025 Adenosine deaminases Human genes 0.000 description 1
- UXCAQJAQSWSNPQ-XLPZGREQSA-N Alovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](F)C1 UXCAQJAQSWSNPQ-XLPZGREQSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102100026846 Cytidine deaminase Human genes 0.000 description 1
- 108010031325 Cytidine deaminase Proteins 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- VYUHZFMIVSJGRA-YAMOITTJSA-N N-[9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-6-yl]benzamide Chemical compound F[C@H]1[C@H]([C@@H](O[C@@H]1CO)N1C2=NC=NC(=C2N=C1)NC(C1=CC=CC=C1)=O)O VYUHZFMIVSJGRA-YAMOITTJSA-N 0.000 description 1
- 229940123752 RNA synthesis inhibitor Drugs 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 241000287433 Turdus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 230000003602 anti-herpes Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical class 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
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- LBCTTYYPEKBXFU-UHFFFAOYSA-N carbonyl dichloride N,N-dimethylbenzamide sulfane Chemical compound S.ClC(Cl)=O.CN(C)C(=O)C1=CC=CC=C1 LBCTTYYPEKBXFU-UHFFFAOYSA-N 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940075610 mercuric cyanide Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003865 nucleic acid synthesis inhibitor Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DTLKWZKUAHYQGX-UHFFFAOYSA-N polyanine Natural products CC1CCC2(NC1)OC3CC4C5CCC6CC(CCC6(C)C5CCC4(C)C3C2C)OC7OC(CO)C(O)C(OC8OCC(O)C(O)C8O)C7OC9OCC(O)C(O)C9O DTLKWZKUAHYQGX-UHFFFAOYSA-N 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Substances [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-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
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】 本発明は新規核酸類に関するものである。[Detailed description of the invention] The present invention relates to novel nucleic acids.
ヌクレオシドやヌクレオチド及びその種々の誘導体など
の核酸類縁体物質は、悪性腫瘍細胞などの必須代謝物質
と拮抗して細胞の発育、増殖を抑制する代謝拮抗物質と
して、またはRNA合成阻害剤として、抗n・!瘍剤、
あるいはまた抗エイズ剤を始めとする抗ウィルス剤など
の治療薬として広く用いられている。Nucleic acid analog substances such as nucleosides, nucleotides, and their various derivatives are used as antimetabolites that inhibit the growth and proliferation of malignant tumor cells by antagonizing essential metabolic substances, or as RNA synthesis inhibitors.・! anticancer drugs,
Alternatively, it is widely used as a therapeutic drug such as anti-AIDS drugs and other antiviral drugs.
なかでもヌクレオシドの5゛位に酸素原子以外のへテロ
原子を有する化合物、例えばアミノ基、メルカプト基、
アセチルチオ基、などの置換基を有するヌクレオシドは
、ウィルス由来のチミジンキナーゼによって選択的にリ
ン酸化されることから、抗ヘルペス剤とて注目されてい
る。(K、A、Watanabe他、J、Med、Ch
cm、 、 (1987)30巻、 226−229)
。Among them, compounds having a heteroatom other than an oxygen atom at the 5' position of the nucleoside, such as an amino group, a mercapto group,
Nucleosides having substituents such as acetylthio groups are attracting attention as anti-herpes agents because they are selectively phosphorylated by virus-derived thymidine kinase. (K, A, Watanabe et al., J, Med, Ch.
cm, (1987) vol. 30, 226-229)
.
またメチルチオ基、フェニルチオ基等のアルキルチオ基
、アリールチオ基やメチオニル基、システニル基等のア
ミノ酸残基を5゛位に有するヌクレオチドも知られてお
り、脳代謝改善等の効果を有することも報告されている
(T、tlata他、Tctral+edron Lc
tters、 (1975)1409−1412、日本
薬理学雑誌87巻、6(+986)。Nucleotides containing an alkylthio group such as a methylthio group or a phenylthio group, or an amino acid residue such as an arylthio group, a methionyl group, or a cystenyl group at the 5' position are also known, and have been reported to have effects such as improving brain metabolism. (T, tlata, etc., Tctral+edron Lc
(1975) 1409-1412, Japanese Pharmacological Journal, Vol. 87, 6 (+986).
フッ素を有するヌクレオシド、なかてもフッ素原子を糖
部に有するヌクレオシドは抗腫瘍剤や抗ウィルス剤とし
て近年、特に注目されている。それはフッ素原子か水酸
基と比較して電子的等画性を有し、水酸基に比較して炭
素原子に対する結合力が極めて犬きく、不活性て、しか
も水酸基に近似した原子サイズを有しているからである
。従って水耐ノ、(をフッ素原子に置換する拮抗作用な
どの面て優れた効果を期待しうる。Nucleosides containing fluorine, especially nucleosides containing a fluorine atom in the sugar moiety, have recently attracted particular attention as antitumor and antiviral agents. It has electronic isotropy compared to a fluorine atom or a hydroxyl group, has a much stronger bonding force to a carbon atom than a hydroxyl group, is inert, and has an atomic size similar to that of a hydroxyl group. It is. Therefore, excellent effects can be expected in terms of water resistance and the antagonistic effect of replacing (with fluorine atoms).
5゛位に酸素原子以外のへテロ原子を有するヌクレオシ
ドのうち、糖部にフッ素原子を有するものはほとんどな
く2°−フルオロアラビノフラノシルピリミシンの誘導
体か知られている(K、A、Watanabc 他、J
、Med、Chell、 、(1987):10巻、2
26−229)たけて3“位にフッ素原子を有するもの
は知られていない。Among nucleosides that have a heteroatom other than an oxygen atom at the 5' position, there are almost no nucleosides that have a fluorine atom in the sugar moiety, and derivatives of 2'-fluoroarabinofuranosylpyrimicin are known (K, A, Watanabc et al., J.
, Med, Chell, (1987): Volume 10, 2
26-229) No compound having a fluorine atom at the 3'' position is known.
公知の含フッ素糖としては例えば2°−デオキシ−2’
、2’ −ジフルオロアデノシン誘導体(特開昭59−
175498号公報参照)、3−デオキシ−3−フルオ
ロ−β−D−キシロフラノシド誘導体(J、A、Wri
ght他、CarbonhydraLe Re5ear
ch、。Examples of known fluorine-containing sugars include 2°-deoxy-2'
, 2'-difluoroadenosine derivatives (Japanese Unexamined Patent Application Publication No. 1983-1999)
175498), 3-deoxy-3-fluoro-β-D-xylofuranoside derivatives (J, A, Wri
ght et al., CarbonhydraLe Re5ear
Ch.
18.345(197]、)) 、 3°−デオキシ−
3°−フルオロヌクレオシド(特開昭62−81379
号公報参照)3゛−デオキシ−3゛−フルオロチミジン
(P、 Langen他、Pure & AppHl:
hem、 、27,246:I(1971)、などが知
られている。18.345(197], )), 3°-deoxy-
3°-Fluoronucleoside (JP-A-62-81379
3'-deoxy-3'-fluorothymidine (P, Langen et al., Pure & AppHl:
Hem, 27, 246: I (1971), etc. are known.
公知の含フッ素糖のなかて、2゛−デオキシ−2°、2
゛ −ジフルオロアデノシン誘導体であっては本来水酸
基の存在しなかった位置にもフッ素原子か存在し、3−
フルオロ−β−D−キシロフラノシド誘導体にあっては
、リボースの形をとっていないなど、上記公知の含フッ
素糖はリボースや2−デオキシリボースの水酸基の立体
的位置のみにフッ素原子か置換されていないことかある
。従って、ヌクレオシドの構造単位であるリボースや2
−デオキシリボースか応用範囲か広いことかわかる。Among the known fluorine-containing sugars, 2゛-deoxy-2゜, 2
゛ - In difluoroadenosine derivatives, fluorine atoms are present even in positions where hydroxyl groups were not originally present, and 3-
In the case of fluoro-β-D-xylofuranoside derivatives, the above-mentioned known fluorine-containing sugars are not substituted with fluorine atoms only at the steric position of the hydroxyl group of ribose or 2-deoxyribose, such as not in the form of ribose. There is a thing. Therefore, ribose and 2, which are the structural units of nucleosides,
- I understand that deoxyribose has a wide range of applications.
本発明者は、上記公知の3゛−デオキシ−3゛−フルオ
ロヌクレオシドの医薬としての薬効を向−1−すべく鋭
意検g4を改ねた結果、その5゛位に酸素原子以外のへ
テロ原子を有する新規なヌクレオシ1へ類を見出すに至
った。本発明は下記式[I]て表されるヌクレオシド誘
導体の5゛位に酸素原子以外のへテロ原子を有するヌク
レオシド類に関するものである。The present inventor has conducted extensive research to improve the medicinal efficacy of the above-mentioned known 3'-deoxy-3'-fluoronucleoside. We have discovered a new nucleoside 1 class with atoms. The present invention relates to nucleosides having a heteroatom other than an oxygen atom at the 5'-position of the nucleoside derivative represented by the following formula [I].
下記式[I]て表される3−デオキシ−3−フルオロ−
5−置換−〇−リボフラノシド誘導体。3-deoxy-3-fluoro- represented by the following formula [I]
5-Substituted-〇-ribofuranoside derivatives.
たたし、
X : NR’R2(R’、R2は水素原子、置換基を
含んていてもよいアルキル基またはアリールノ、(、あ
るいは保護基) 、−83基、−3R’(R:lは水素
原子、置換基を含んでいてもよいアルキル基またはアリ
ール基、あるいは保護基)。However, hydrogen atoms, alkyl or aryl groups that may contain substituents, or protective groups).
B:核酸塩基類または核酸塩基類縁体の残基。B: Residues of nucleobases or nucleobase analogs.
Y・水素原子又は水酸基。Y. Hydrogen atom or hydroxyl group.
核酸塩基類とは、置換基を有していてもよいプリン類、
およびピリミジン類をいい、その残基とは、置換基を有
していてもよい9−プリニル基およびl−ピリミジニル
基をいう。置換基としては、アミノ基、オキソ基、メチ
ル基は勿論、他の置換基、例えばハロゲン原子、アルキ
ル基、ハロアルキル基、へロビニル基、アルコキシ基、
ヒドロアルキル基、アルキルアミノ基、ジアルキルアミ
ノ基、アシルアミノ基、メルカプト基、アルキルチオ基
、シクロアルキル基、アリール基、アリールオキソ基、
アルアルキル基、などてあってもよい。なおここにおい
て、ハロゲンとはフッ素、塩素、ヨウ素をいい、特に言
及しないかぎり以下においても同様である。これら1σ
換基の結合位置は、プリン類ては2位、6位、および8
位のすくなくとも1つ、ピリミジン残基ては、2位、4
位、および5位の少なくとも1つである。さらに、環の
窒素原子に酸素原子か結合したアミツキシトも有用であ
る。具体的な置換基を有するプリン類としては、たとえ
ば、グアニン、アデニン、ヒボキサンチン、キサンチン
、2.6−ジアミツプリン、6−ハロプリン、2−ハロ
プリン、2,6−シハロプリン、6−アルキルアミノプ
リン、6−アシルアミノプリン、アデニン−1−オキシ
ト、アデニン−7−オキシドなどかあり、置換基を有す
るピリミジン類としては、たとえば、ウラシル、シトシ
ン、チミン、5−へロウラシル、5−ハロメチルウラシ
ル、5−ハロチミン、5−ハロメチルチミン、5−β−
ノブロビニルチミンなどかある。好ましい核MJt1基
類は、2−および/または6−置換プリンであり、特に
、アデニン、グアニン、ヒボキサンチン、キサンチン、
2,6−ジアミツプリン、6−へロブリン、2−ハロア
デニン、2,6−シハロプリン N6 fl換アデニ
ン、ウラシル、シトシン、チミン、5−ハロウラシルな
どが好ましい。Nucleic acid bases include purines that may have substituents,
and pyrimidines, and the residue thereof refers to a 9-purinyl group and an l-pyrimidinyl group which may have a substituent. Examples of substituents include amino groups, oxo groups, and methyl groups, as well as other substituents such as halogen atoms, alkyl groups, haloalkyl groups, herovinyl groups, alkoxy groups,
Hydroalkyl group, alkylamino group, dialkylamino group, acylamino group, mercapto group, alkylthio group, cycloalkyl group, aryl group, aryloxo group,
Aralkyl groups, etc. may also be present. Note that herein, halogen refers to fluorine, chlorine, and iodine, and the same applies hereinafter unless otherwise specified. These 1σ
The bonding positions of substituents are 2-position, 6-position, and 8-position for purines.
At least one of the pyrimidine residues in the 2nd and 4th positions
and at least one of 5th place. Also useful are amituxites in which an oxygen atom is bonded to the nitrogen atom of the ring. Examples of purines having specific substituents include guanine, adenine, hypoxanthine, xanthine, 2,6-diamitpurine, 6-halopurine, 2-halopurine, 2,6-cyhalopurine, 6-alkylaminopurine, 6- Examples include acylaminopurine, adenine-1-oxyto, adenine-7-oxide, and pyrimidines having substituents include uracil, cytosine, thymine, 5-herouracil, 5-halomethyluracil, and 5-halothymine. , 5-halomethylthymine, 5-β-
There are things like nobrovinylthymine. Preferred nuclear MJt1 groups are 2- and/or 6-substituted purines, especially adenine, guanine, hyboxanthin, xanthine,
Preferred are 2,6-diamitpurine, 6-herobulin, 2-haloadenine, 2,6-cyhalopurine N6 fl-converted adenine, uracil, cytosine, thymine, 5-halouracil, and the like.
本発明における上記核酸塩基類縁体とは、プリン類ある
いはピリミジン類に対応する環を有する複素環化合物あ
るいはその誘導体をいい、その残基(B)とは、プリン
類の9位、ピリミジン類の1位に対応する位置に結合手
を有する残基をいう。このような複素環化合物としては
、核酸塩基の類縁体として公知のものか好ましい。具体
的には、プリン類あるいはピリミジン類の環の窒素原子
の少なくとも1つを炭素原子あるいは窒素原子以外のへ
テロ原子に変換するか、環の炭素原子の少なくとも1つ
を窒素原子あるいは他のへテロ原子に変換するか、また
はそれら変換の両方を行なって得られるような複素環化
合物か好ましい。さらに好ましくは、プリン類の環1つ
の窒素原子(特に、1位、3位あるいは7位の窒素原子
)を炭素原子あるいは酸素原子に変換して得られる複素
Jマ化合物、プリン類の環の1つの炭素原子(特に、2
位、5位あるいは8位の炭素原子)を窒素原子に変換し
て得られる複素環化合物およびこの両変換を行なって得
られる(即ち1つの窒素原子を炭素原子あるいは酸素原
子に変換し、かつ1つの炭素原子を窒素原子に変換して
得られる)複素環化合物か好ましい。また、ピリミジン
類では同様に3位の窒素原子を炭素原子に変換するか、
5位あるいは6位の)欠素原子に変換して得られる複素
環化合物かより好ましい。これらの複素環化合物の誘導
体は、前記と同様の置換基を導入した化合物てあり、置
換基としては特にアミノ基、オキソ基、ハロゲ原子、メ
チル基か好ましい。具体的化合物としては、例えばグア
ニンの類縁体である5−アミノ−3,6−ジヒトロ=7
11−1.2.:l−トリアゾロロ、5.−dlピリミ
ジン−7−オン(下記構造式第1番目参照)がある。The above-mentioned nucleobase analog in the present invention refers to a heterocyclic compound or a derivative thereof having a ring corresponding to purines or pyrimidines, and the residue (B) is the 9-position of purines or the 1-position of pyrimidines. It refers to a residue that has a bond at the position corresponding to the position. Such heterocyclic compounds are preferably those known as analogs of nucleobases. Specifically, at least one nitrogen atom in the ring of purines or pyrimidines is converted to a carbon atom or a heteroatom other than a nitrogen atom, or at least one carbon atom in the ring is converted to a nitrogen atom or another atom. Heterocyclic compounds obtained by conversion to a telo atom or both of these conversions are preferred. More preferably, a heterocompound obtained by converting one nitrogen atom (particularly the nitrogen atom at the 1st, 3rd or 7th position) of a ring of purines to a carbon atom or an oxygen atom, one carbon atom (in particular, two
Heterocyclic compounds obtained by converting one carbon atom, 5th or 8th carbon atom) into a nitrogen atom, and the other by converting one nitrogen atom into a carbon atom or an oxygen atom, and Heterocyclic compounds (obtained by converting one carbon atom to a nitrogen atom) are preferred. In addition, in the case of pyrimidines, the nitrogen atom at the 3rd position is similarly converted to a carbon atom, or
Heterocyclic compounds obtained by converting the atom into a missing atom (at the 5th or 6th position) are more preferred. Derivatives of these heterocyclic compounds are compounds into which substituents similar to those mentioned above have been introduced, and the substituents are particularly preferably an amino group, an oxo group, a halogen atom, or a methyl group. Specific compounds include, for example, 5-amino-3,6-dihydro-7, which is an analog of guanine.
11-1.2. : l-triazololo, 5. -dlpyrimidin-7-one (see structural formula 1 below).
さらに核酸塩基類縁体の残基の具体的例を下記に示すが
、これらに限られるものてはない。なお、化学式下の(
)内に対応する核酸塩基を示す。Furthermore, specific examples of the residues of the nucleobase analogs are shown below, but are not limited thereto. In addition, under the chemical formula (
) indicates the corresponding nucleobase.
(多アニン)
(アデニン)
(アデニン)
(アデニン)
(アデニン)
(シトシン)
また下記式[II ]に示すようなトリアゾール残基を
有するような有機基てもよい。(Polyanine) (Adenine) (Adenine) (Adenine) (Adenine) (Cytosine) It may also be an organic group having a triazole residue as shown in the following formula [II].
U、Vはアミド基、シアノ基、カルボキシ基、あるいは
アルコキシカルボニル基から選ばれる基てあり、U、V
は−Co−NR’R5てあられされるアミド基、−CN
て表されるシアノ基、−C00Hで表されるシアノ基、
および−GOOR6で表されるアルコキシカルボニル基
を表わす。R4およびR5は、それぞれ水素原子あるい
は1価の炭化水素基を表わし、R6は1価の炭化水素基
を表わす。1価の炭化水素基としては、アルキル基、ア
ルケニル基、シクロアルキル基、アリール基、アルアル
キル基などを表わし、特に炭素数8以下のこれらの炭化
水素基、その内でもアルキル基か好ましい。これら炭化
水素基はまたハロゲン原子、アルコキシ基、その他の置
換基を有していてもよい。好ましいアミド基は、R4と
R5の少なくとも一方が水素原子である基、特にいずれ
も水素原子である一CON 11 、である。アルコキ
シカルボニル基のR6としては炭素数4以下のアルキル
基か好ましい。U and V are groups selected from an amide group, a cyano group, a carboxy group, or an alkoxycarbonyl group;
is an amide group formed by -Co-NR'R5, -CN
A cyano group represented by -C00H,
and an alkoxycarbonyl group represented by -GOOR6. R4 and R5 each represent a hydrogen atom or a monovalent hydrocarbon group, and R6 represents a monovalent hydrocarbon group. Examples of the monovalent hydrocarbon group include an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, and an aralkyl group. Among these hydrocarbon groups having 8 or less carbon atoms, alkyl groups are particularly preferred. These hydrocarbon groups may also have halogen atoms, alkoxy groups, and other substituents. A preferred amide group is a group in which at least one of R4 and R5 is a hydrogen atom, particularly -CON 11 in which both are hydrogen atoms. R6 of the alkoxycarbonyl group is preferably an alkyl group having 4 or less carbon atoms.
上記式[11]で示されるような有機基を持つヌクレオ
シド類縁体は、前記のように3−デオキシ−3−フルオ
ロ−β−D−リボフラノシド誘導体に上記式[II ]
で示されるような有機基を導入して合成することがてき
る。上記式[II ]に示した複素環の導入は、糖に、
直接複素環を導入するよりも、まず複素環の前駆体基を
導入し、次に環化により前駆体基を複素環とする方法が
好ましい。この前駆体基の導入やその環化反応の際には
砧の水酸基は前記のように保護基で保護しておく必要か
ある。環化反応か容易に行なえるように、通常環化反応
により生成する複素環はUやVかアルコキシカルボニル
基である複素環である。さらに、UやVかアルコキシカ
ルボニル基である類縁体より、UやVをカルボキシル基
、アミド基、シアノ基へ変換することができる。この官
能基の変換の際、糖の水酸基を保護する必要性は少ない
。A nucleoside analog having an organic group as represented by the above formula [11] can be converted into a 3-deoxy-3-fluoro-β-D-ribofuranoside derivative by the above formula [II].
It can be synthesized by introducing an organic group as shown in . The introduction of the heterocycle shown in the above formula [II] into the sugar,
Rather than directly introducing a heterocycle, it is preferable to first introduce a precursor group of the heterocycle and then convert the precursor group into a heterocycle by cyclization. During the introduction of this precursor group and its cyclization reaction, it is necessary to protect the hydroxyl group of Kinuta with a protecting group as described above. In order to facilitate the cyclization reaction, the heterocycle produced by the cyclization reaction is usually a U, V, or alkoxycarbonyl group. Furthermore, U or V can be converted into a carboxyl group, an amide group, or a cyano group using analogs in which U or V is an alkoxycarbonyl group. During this functional group conversion, there is little need to protect the hydroxyl group of the sugar.
前記Xは酸素以外のへテロ原子を含む置換基であり1例
えばアジド基や下記式[ml、[+71で表される構造
を有している。The above X is a substituent containing a heteroatom other than oxygen, and has, for example, an azide group or a structure represented by the following formula [ml, [+71].
−NR’R2・・・ [III]
−5o3 ・・・ [
rV]ここでRIJ+2.R)は水素原子、置換基を含
んでいてもよいアルアルキル基、アリール基あるいは保
護基てあり、具体的には、炭素数15以下のアルキル基
、アルケニル基、アリール基、アルアルキル基、または
アセチル基、ベンゾイル基、などの保護基てあり、R3
にあってはメチオニル基や、システニル基などのアミノ
酸残基であってもよい。-NR'R2... [III] -5o3... [
rV] where RIJ+2. R) is a hydrogen atom, an aralkyl group that may contain a substituent, an aryl group, or a protective group, specifically an alkyl group, an alkenyl group, an aryl group, an aralkyl group having 15 or less carbon atoms, or There are protective groups such as acetyl group and benzoyl group, and R3
In this case, it may be an amino acid residue such as a methionyl group or a cystenyl group.
前記式[IIて表される化合物の前駆体3゛−デオキシ
−3′−フルオロヌクレオシド誘導体は前記特開昭62
−81397号公報記載の方法て製造されることか好ま
しい。しかし、これに限られるものではなく、公知の方
法を適用して製造することもできる。この化合物は、通
常フラノシルハライドや1−O−アシル化糖を原料とし
、フッ素化工程を含み、かつ公知のヌクレオシド合成法
を適用して製造することかできる。例えばフラノシルハ
ライドを原料とした場合は、メルクリ法、シアン化水銀
法、II i l be rt−Johnsn法、Ro
bins法(J、Am、Chem、Soc、 、 10
6.6:l79(1984))を用いることかてき、シ
リル化塩基−ルイス酸法を用いることが好ましい。The precursor 3'-deoxy-3'-fluoronucleoside derivative of the compound represented by the formula [II] is disclosed in the above-mentioned JP-A-62
Preferably, it is produced by the method described in JP-A-81397. However, it is not limited to this, and it is also possible to manufacture by applying a known method. This compound can usually be produced using furanosyl halide or 1-O-acylated sugar as a raw material, including a fluorination step, and applying a known nucleoside synthesis method. For example, when furanosyl halide is used as a raw material, Merckli method, mercuric cyanide method, II bert-Johnsn method, Ro
bins method (J, Am, Chem, Soc, 10
6.6:179 (1984)), and it is preferable to use the silylated base-Lewis acid method.
プリン核の2位、6位に置換基を持つ化合物、ピリジン
核の4位に置換基を持つ化合物は例えば次のようにして
製造することかできる。Compounds having substituents at the 2nd and 6th positions of the purine nucleus and compounds having a substituent at the 4th position of the pyridine nucleus can be produced, for example, as follows.
コ°−デオキシー3°−フルオロアデノシンにアデノシ
ンデアミナーゼを反応させ6−011体としく3“−デ
オキシ−3゛−フルオロシチジンの場合にはシチジンデ
アミナーゼと反応させ4−011体とする)、ヒドロキ
シ基をアセチル基などで適当に保護したのち、N、N−
ジメチルアニリンなどの塩基存在下、オキシ塩化リンて
クロロ化する。また、上記Robinsの方法によれば
、直接6−クロロ体または2,6−ジクロロ体を製造す
ることもできる。クロロ体からの変換には、硫化水素を
用いればメルカプト体に、メチルアミンを用いれば、ジ
メチルアミン体等を製造することかでき、アジ化ナトリ
ウムを用いれば、アジド体を製造することかできる。ピ
リミジン核の場合もプリン核の場合と同様の工程を経て
鐙換体を製造することかできる。メルカプト体、アミノ
体、アジド体からの変換は、既知の方法を用いることが
できる。Co°-deoxy-3°-fluoroadenosine is reacted with adenosine deaminase to form a 6-011 form, and in the case of 3"-deoxy-3'-fluorocytidine, it is reacted with cytidine deaminase to form a 4-011 form), and the hydroxy group is After appropriately protecting with an acetyl group etc., N,N-
Chlorinates phosphorus oxychloride in the presence of a base such as dimethylaniline. Moreover, according to the Robins method, the 6-chloro compound or the 2,6-dichloro compound can also be directly produced. For conversion from the chloro form, hydrogen sulfide can be used to produce the mercapto form, methylamine can be used to produce the dimethylamine form, and sodium azide can be used to produce the azide form. In the case of a pyrimidine nucleus, a stirrup compound can also be produced through the same steps as in the case of a purine nucleus. Conversion from the mercapto form, amino form, and azide form can be performed using known methods.
ヌクレオシドの5′位に酸素原子以外の置換基の導入は
、文献記載の方法(例えばに、八。Introduction of a substituent other than an oxygen atom to the 5'-position of a nucleoside can be carried out by methods described in the literature (for example, 8.
Watanabe他、J、Med、Chem、 、(1
987)30巻、 226−229)を採用することか
できる。木置換反応にあたっては、2′位水酸基および
ヌクレオシド塩基部の反応性官能基を保護する必要かあ
る場合もある。実際上は1級水酸基と2級水酸基を区別
して選択的に5′位の1級水酸基だけを脱離基に変換す
ることができる。即ち3°−デオキシ−3゜−フルオロ
フラノシルヌクレオシドを塩基存在下トリフルオロメタ
ンスルホニルクロリド、p−トルエンスルホニルクロリ
ド、メタンスルホニルクロリド、イミタゾリルスルホニ
ルクロリドなどによって脱離基に変換したのに、ナ1〜
リウムアジト、カリウムアジドなどによってアジド体に
変換したのち、量元によってアミノ基に変換することか
てきる。またチオ酢酸カリウムを用いアセチルチオ基を
導入し、保護基をはずすことによりメルカプト基に変換
することもできる。ヌクレオシド5′位の置換反応は2
′位の水酸基の脱離をおこなう前ても後でもよく、脱離
後に行なう場合は2′位の保護の必要なく、2′、3°
−ジデオキシ−3゛−フルオロリボフラノシルヌクレ
オシドを原料に用いればよいことになる。Watanabe et al., J, Med, Chem, (1
987) Vol. 30, 226-229). In the wood substitution reaction, it may be necessary to protect the 2'-position hydroxyl group and the reactive functional group of the nucleoside base moiety. In practice, it is possible to distinguish between primary hydroxyl groups and secondary hydroxyl groups and selectively convert only the 5'-position primary hydroxyl group into a leaving group. That is, even though 3°-deoxy-3°-fluorofuranosyl nucleoside was converted into a leaving group with trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, imitazolylsulfonyl chloride, etc. in the presence of a base, ~
After converting to an azide form using lithium azide, potassium azide, etc., it can be converted to an amino group depending on the quantity. Alternatively, it can be converted to a mercapto group by introducing an acetylthio group using potassium thioacetate and removing the protective group. The substitution reaction at the 5' position of the nucleoside is 2
It may be done before or after the removal of the hydroxyl group at the 'position; if it is done after the removal, there is no need to protect the 2' position, and the 2', 3°
-dideoxy-3'-fluororibofuranosyl nucleoside may be used as the raw material.
上記式[I]においてYか水酸基の場合その水酸基の脱
離は還元反応などを用いて行なわれる。脱離には強い還
元剤の使用か必要てあり、この場合5位の保護された水
酸基や他の基の影響が及ぶおそれもある。従って、この
水酸基をよりマイル1−な条件下て脱離しうる基に変換
することが好ましい。このためには、2′位の水酸基を
脱離基に変えつる反応剤と反応させ脱離活性化基とし、
次に還元して脱#基に脱離する。In the above formula [I], when Y is a hydroxyl group, the hydroxyl group is removed using a reduction reaction or the like. Elimination requires the use of a strong reducing agent, and in this case there is a risk that the protected hydroxyl group at the 5-position or other groups may be affected. Therefore, it is preferable to convert this hydroxyl group into a group that can be eliminated under more severe conditions. For this purpose, the hydroxyl group at the 2' position is changed into a leaving group and reacted with a vine reactant to form an leaving-activating group.
Next, it is reduced and eliminated to a de# group.
これによって2′位の水酸基の代りに水素原子か導入さ
れる。水酸基を脱離基に変える反応剤としては、NN−
チオカルボニルシイミタゾール、フェニルクロロチオノ
カーボナート、N、N−ジメチルベンズアミド−ホスゲ
ン−硫化水素(詳しくはり、11.R,Barton他
、J、C,S、Perkin 1(1975) 157
4)などを用いることかてきる。また、水酸基をm−)
リフルオロメチルベンゾイル化した後に光照射により1
選択的に水酸基を除去することもてきる(T、Mats
uura他、J、Am。As a result, a hydrogen atom is introduced in place of the hydroxyl group at the 2' position. As a reactant for converting a hydroxyl group into a leaving group, NN-
Thiocarbonylcimitazole, phenylchlorothionocarbonate, N,N-dimethylbenzamide-phosgene-hydrogen sulfide (for details, 11. R, Barton et al., J.C.S., Perkin 1 (1975) 157
4) etc. can be used. In addition, the hydroxyl group is m-)
After refluoromethylbenzoylation, 1
It is also possible to selectively remove hydroxyl groups (T, Mats
uura et al., J. Am.
Chem、Soc、、(1986) 108.3115
)。水酸基の脱離工程は通常ベンゼン、トルエンなどの
不活性溶媒中て行なわれ、0°Cから溶媒速流温度の範
囲内の反応温度が採用され、特に室温から120°C程
度の温度か好ましい。Chem, Soc, (1986) 108.3115
). The step of eliminating the hydroxyl group is usually carried out in an inert solvent such as benzene or toluene, and the reaction temperature is within the range of 0°C to the solvent flow temperature, preferably from room temperature to about 120°C.
以下、本発明の実施例により具体的に説明するか1本発
明はこれら実施例に限られるものではない。Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.
実施例1 化合物]の合成。Example 1 synthesis of compounds].
2’ −0,N’−ジベンゾイル−3°−デオキシ−3
フロオロアデノシン[特願昭62−177233] 9
5301g(2,0mmo I )を無水ピリジン(6
,4m1)に溶解し、メタンスルホニルクロリド0.]
99m12.6m1lol)を水冷下で滴下した。反応
液は水冷下で15時間攪拌した後に飽和型背水にあけク
ロロホルム(:10m1)で3回抽出した。クロロホル
ム層を合せて、無水硫酸マグネシウムで乾燥した後に減
圧下濃縮した。2'-0,N'-dibenzoyl-3°-deoxy-3
Fluoroadenosine [Patent Application 177233/1982] 9
5301 g (2,0 mmol I) was dissolved in anhydrous pyridine (6
, 4ml) and 0.0ml of methanesulfonyl chloride. ]
99ml (12.6ml) was added dropwise under water cooling. The reaction solution was stirred for 15 hours under water cooling, poured into saturated backwater, and extracted three times with chloroform (10 ml). The chloroform layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
この残渣に無水ジメチルホルムアミド(10ml)を加
えて溶解し、アシ化ナトリウム(500mg)を加え、
90°Cで15時間攪拌した。反応液を飽和重汀水にあ
け、ベンゼンて3回抽出した。このベンゼン層を合せて
、無水硫酸マグネシウムて乾燥した後に減圧下?3縮し
た。この残渣にメタノール(20i1)、1Mナトリウ
ムメトキシド・メタノール溶液(3,6m1)を加え3
0分間加熱還流した。反応液を減圧下濃縮し、残渣に水
を加えた後に2N酢酸で中和し、酢酸エチルで3回洗浄
した。水層を減圧下濃縮し、残渣をシリカゲルカラムク
ロマトグラフィー(クロロホルム−メタノール、20・
1)て精製し表出化合物を得た。収量182mg(36
,7%)。Anhydrous dimethylformamide (10 ml) was added to this residue to dissolve it, sodium acyde (500 mg) was added,
The mixture was stirred at 90°C for 15 hours. The reaction solution was poured into saturated barley water and extracted three times with benzene. Combine this benzene layer, dry with anhydrous magnesium sulfate, and then under reduced pressure. It shrunk by 3. To this residue, methanol (20ml) and 1M sodium methoxide methanol solution (3.6ml) were added.
The mixture was heated to reflux for 0 minutes. The reaction solution was concentrated under reduced pressure, and water was added to the residue, which was then neutralized with 2N acetic acid and washed three times with ethyl acetate. The aqueous layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform-methanol, 20%
1) to obtain the surface compound. Yield 182 mg (36
, 7%).
’ )I−NMR(DMSO−d6) ::1.28−
3.88(m、3H) 、 4.44(d+++、J二
24.9tlz、l1l) 。') I-NMR (DMSO-d6)::1.28-
3.88 (m, 3H), 4.44 (d+++, J224.9tlz, l1l).
5.12(bs、IH)、 5.15(dm、J=54
.211z、III)5.08(m、IH)、 7.4
4(bs、211)、 8.29(s、III)。5.12 (bs, IH), 5.15 (dm, J=54
.. 211z, III) 5.08 (m, IH), 7.4
4 (bs, 211), 8.29 (s, III).
8.55(s、IH)。8.55 (s, IH).
”F−NMR(DMSO−d6.C[I、F基準)19
:1.5ppm(dt、J=24.911z、 54.
2117.)。"F-NMR (DMSO-d6.C [I, F standard) 19
: 1.5ppm (dt, J=24.911z, 54.
2117. ).
IR: 2110crB−’
実施例2
2°−0,N6−シベンゾイルー3′−デオキシ−3゛
一フロオロアデノシン953mg(2,Otmol)を
出発原料とし、実施例1と同様にアジド化を行なった。IR: 2110crB-' Example 2 Azidation was carried out in the same manner as in Example 1 using 953 mg (2, Otmol) of 2°-0,N6-cybenzoyl-3'-deoxy-3'-fluoroadenosine as a starting material.
この残渣な10i1のエタノールに溶解し、10%パラ
ジウム炭素(50mg)を加え水素雰囲気下で2時間攪
拌した。反応液をセライトIl!過した後に減圧下濃縮
し、残渣をシリカゲルカラムクロマトグラフィー(クロ
ロホルム−メタノール10:1)で精製した。この残渣
にメタノール(10ml) l Mナトリウムメトキシ
ド・メタノール溶液(3,6m1)を加え、1時間加熱
還流した。反応液を減圧下濃縮し、残渣に水を加えたの
ちに2N酢酸て中和した後に減圧下濃縮してシリカゲル
カラムクロマトクラフィー(クロロホルム−メタノール
、51)て精製し表出化合物を得た。収rf1120m
g(25,5%)。This residue was dissolved in 10 ml of ethanol, 10% palladium on carbon (50 mg) was added, and the mixture was stirred for 2 hours under a hydrogen atmosphere. Pour the reaction solution onto Celite Il! After filtering, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol 10:1). Methanol (10 ml) and 1 M sodium methoxide in methanol solution (3.6 ml) were added to this residue, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and water was added to the residue, which was neutralized with 2N acetic acid, concentrated under reduced pressure, and purified by silica gel column chromatography (chloroform-methanol, 51) to obtain the target compound. Collection rf1120m
g (25,5%).
’ lilJMR(DMSO−d6):3.28−3.
88(m、3H)、 4.20−5.51(11,:I
H)。' lilJMR (DMSO-d6): 3.28-3.
88 (m, 3H), 4.20-5.51 (11,:I
H).
5.98(d、J=8.511z、1ll)、 7.4
:1(bs、211)。5.98 (d, J=8.511z, 1ll), 7.4
:1 (bs, 211).
8.26(s、l11)、 8.55(S、III)。8.26 (s, l11), 8.55 (S, III).
”F−NMR(DhlSO−d6.CCl3F基*>
ニー192.1ppm(dtj=27.1Hz、56.
0llz)。"F-NMR (DhlSO-d6.CCl3F group*>
knee 192.1ppm (dtj=27.1Hz, 56.
0llz).
実施例3
3°、5′ −ジデオキシ−3′−フルオロ−5“フェ
ニルチオアデノシン[式[I]に於いてXかフェニルチ
オ基、Yが水酸基、Bかアゾ実施例4
3゛−デオキシ−3゛−フロオロアデノシン[特開昭6
11−220186] 300mg(1,12mmol
)を無水ジメチルホルムアミド(51)に溶解し、ジフ
ェニルジスルフィド2.45g(11,2mmol)
、 トリブチルホスフィン2.79m1(11,2m
ll1ol)を加え、室温で15時間攪拌した。反応液
を減圧下濃縮し、シリカゲルカラムクロマトクラフィー
(クロロホルムメタノール、20:1)を行ない、次い
てクロロルムより再結晶し表出化合物を得た。収量20
8mg(52,4%)。Example 3 3°,5'-dideoxy-3'-fluoro-5'phenylthioadenosine [In formula [I], X is a phenylthio group, Y is a hydroxyl group, and B is azoExample 4 3'-deoxy-3゛-Fluoroadenosine [Unexamined Japanese Patent Publication No. 6
11-220186] 300 mg (1,12 mmol
) was dissolved in anhydrous dimethylformamide (51), and 2.45 g (11.2 mmol) of diphenyl disulfide was added.
, tributylphosphine 2.79 m1 (11.2 m
11 ol) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, subjected to silica gel column chromatography (chloroform methanol, 20:1), and then recrystallized from chloroform to obtain the surface compound. Yield 20
8 mg (52,4%).
’ +1−NMR(DMSO−d6):3.47(bd
、J=7.711z、2tl) 。' +1-NMR (DMSO-d6): 3.47 (bd
, J=7.711z, 2tl).
4.30(dm、J=24.9Hz、LH)、 5.1
6(bs、1tl)。4.30 (dm, J=24.9Hz, LH), 5.1
6 (bs, 1tl).
5.17(dm、J=54.711z、1ll)、 6
.07(m、1ll)。5.17 (dm, J=54.711z, 1ll), 6
.. 07 (m, 1ll).
7.60−7.70([11,7t()、 8.28(
s、IH)。7.60-7.70([11,7t(), 8.28(
s, IH).
8.50(s、l1l)。8.50 (s, l1l).
”F−NMR(DMSO−d6.C[I:+F基準)ニ
ー191.6ppm(dt、J=24.9)1z、 5
4.711z)。"F-NMR (DMSO-d6.C [I:+F standard) knee 191.6 ppm (dt, J=24.9) 1z, 5
4.711z).
3−デオキシ−3−フロオロアデノシン223mg(0
,83mmol)を無水ジメチルホルムアミド(1,6
m1)に溶解し、ジメチルジスルフィド(743pl)
、トリブチルホスフィン(2,07m1)を加え室温で
15時間攪拌した。反応液を減圧下濃縮し、残渣を水に
溶解した後にアンバーライトCG −120[I++型
)カラムに通し、水洗後、20%ピリジン水で溶出した
。溶出液を減圧下a Mdし、表出化合物を得た。収量
120mg(48,8%)。3-deoxy-3-fluoroadenosine 223 mg (0
, 83 mmol) in anhydrous dimethylformamide (1,6
dimethyl disulfide (743 pl)
, tributylphosphine (2.07 ml) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water, passed through an Amberlite CG-120 [I++ type] column, washed with water, and eluted with 20% pyridine water. The eluate was subjected to aMd under reduced pressure to obtain the surface compound. Yield 120 mg (48.8%).
’ )l−NMR(DMSO−d6):2.09(s、
:1tl)、 2.91(d、J=6.9Hz、211
)。) l-NMR (DMSO-d6): 2.09 (s,
:1tl), 2.91(d, J=6.9Hz, 211
).
4.10−5.42(m、:IH)、 6.02(m、
LH)。4.10-5.42 (m, :IH), 6.02 (m,
LH).
7.44(bs、2H)、 8.28(s、IH)、
8.53(s、IN)。7.44 (BS, 2H), 8.28 (S, IH),
8.53 (s, IN).
19F−NMR(DMSO−d6.CCl3F基準)ニ
ー192.37ppm(dt、J=25.411z、
54.211z)。19F-NMR (DMSO-d6.CCl3F standard) knee 192.37 ppm (dt, J=25.411z,
54.211z).
実施例5
メチル3−デオキシ−3−フルオロ−2,5−〇−ジベ
ンゾイルーβ−D−リボフラノシド0.75g (2,
0mmol)を酢酸(3,8i1)に溶解し、無水酢酸
(0,15m1)と30%臭化水素−酢酸溶液(121
)を加え、3時間攪拌した。溶媒を留去した後、チミン
ビストリメチルシリルエーテル0.71g (2,6+
nmol)のジクロロエタン溶液、ならびにトリメチル
シリルトリプルオロメタンスルホナート(0,36m1
)を加え1.5時間還流した。反応液に飽和型9V液を
加え、有機層を乾燥、濃縮し、カラムクロマトグラフ精
製し、1−(3−デオキシ−3−フルオロ−2,5−0
−ジベンゾイル−β−D−リボフラノシル)チミン0.
80g(収率85%)を得た。Example 5 Methyl 3-deoxy-3-fluoro-2,5-〇-dibenzoyl-β-D-ribofuranoside 0.75 g (2,
0 mmol) in acetic acid (3,8i1), acetic anhydride (0,15ml) and 30% hydrogen bromide-acetic acid solution (121
) and stirred for 3 hours. After distilling off the solvent, 0.71 g of thymine bistrimethylsilyl ether (2,6+
nmol) in dichloroethane, as well as trimethylsilyl triple olomethane sulfonate (0.36 ml
) and refluxed for 1.5 hours. A saturated 9V solution was added to the reaction solution, the organic layer was dried, concentrated, and purified by column chromatography to obtain 1-(3-deoxy-3-fluoro-2,5-0
-dibenzoyl-β-D-ribofuranosyl)thymine 0.
80 g (yield 85%) was obtained.
上記製造したジベンゾイル体o、ao g(1,7me
al)をメタノール(4,4i1)に溶解し、IM−ナ
トリウムメトキシド−メタノール溶液(3,4m1)を
加え、1時間加熱還流した。溶媒な留去後、2N−酢酸
て中和し、カラムクロマトグラフ精製し、1−(3−デ
オキシ−3−フルオロ−β−D−リボフラノシル)チミ
ン0.43g (収率87%)を得た。Dibenzoyl derivatives o and ao g (1,7me) produced above
al) was dissolved in methanol (4,4i1), IM-sodium methoxide-methanol solution (3,4ml) was added, and the mixture was heated under reflux for 1 hour. After distilling off the solvent, it was neutralized with 2N acetic acid and purified by column chromatography to obtain 0.43 g (yield: 87%) of 1-(3-deoxy-3-fluoro-β-D-ribofuranosyl)thymine. .
上記製造したジオール0.43g (1,6II1mo
l)をN、N−ジメチルホルムアミド(4ml)に溶解
し イミダゾール0.28g (4,1,mmol)お
よび、七−ブチルジメチルシリルクロリド0.40g
(2,711101)のN、N−ジメチルホルムアミド
(2ml)を加え、0°Cで2時間攪拌した。水処理し
た後、カラムクロマトグラフ精製し、1− (3−デオ
キシ−3−フルオロ−5−O−t−ブチルジメチルシリ
ル−β−D−リボフラノシル)チミン0.60g (収
*97%)を得た。0.43g of the diol produced above (1,6II1mo
l) in N,N-dimethylformamide (4 ml), 0.28 g (4,1, mmol) of imidazole and 0.40 g of 7-butyldimethylsilyl chloride.
(2,711101) in N,N-dimethylformamide (2 ml) was added, and the mixture was stirred at 0°C for 2 hours. After water treatment, column chromatography purification yielded 0.60 g of 1-(3-deoxy-3-fluoro-5-O-t-butyldimethylsilyl-β-D-ribofuranosyl)thymine (yield*97%). Ta.
上記製造したモノシリル体0.60g (1,61ol
)をジクロロメタン(91)に溶解し、4−N−ジメチ
ルアミノピリジン0.59g (4,8mmol)およ
びフェニルクロロチオノカーボナート0.56g(:1
.2111!001)のジクロロメタン(5ml)溶液
を0°Cて加え、1.5時間攪拌した。水を加え、ジク
ロロメタンて抽出した後、乾燥、濃縮しカラムクロマト
グラフ精製し、1−(3−デオキシ3−フルオロ−5−
0−t−ブチルジメチルシリル−2−〇−フェノキシチ
オカルボニル)チミン0.55g (収率68%)を得
た。0.60 g (1,61 ol) of the monosilyl compound produced above
) was dissolved in dichloromethane (91), 0.59 g (4.8 mmol) of 4-N-dimethylaminopyridine and 0.56 g of phenylchlorothionocarbonate (:1
.. A solution of 2111!001) in dichloromethane (5 ml) was added at 0°C, and the mixture was stirred for 1.5 hours. After adding water and extracting with dichloromethane, it was dried, concentrated, and purified by column chromatography.
0.55 g (yield: 68%) of 0-t-butyldimethylsilyl-2-〇-phenoxythiocarbonyl)thymine was obtained.
L記製造したフェノキシカルボニル体0.55g(1,
1mmol)をベンゼン(28+++I)に溶解し、ア
ゾイソフチロニトリル(18mg)およびトリブチルス
ズヒFリド0.88IIll(:1.:1ml1ol)
を加え、3時間加熱還流した。溶媒を留去し、カラムク
ロマトグラフ精製し、1−(2,3,ジデオキシ−3−
フルオロ−5−0−t−ツチルジメチルシリルーβ−〇
−リボフラノシル)チミン0.24g (収率63%)
を得た。0.55 g (1,
Dissolve 1 mmol) in benzene (28+++I) and add azoisophthyronitrile (18 mg) and tributyl tin Flide 0.88IIll (:1.:1ml1ol)
was added and heated under reflux for 3 hours. The solvent was distilled off and purified by column chromatography to obtain 1-(2,3,dideoxy-3-
Fluoro-5-0-t-tutyldimethylsilyl-β-〇-ribofuranosyl)thymine 0.24g (yield 63%)
I got it.
」二足製造したデオキシ体0.24g (0,68mm
ol)をテトラヒドロフラン(5ml)に溶解し、IM
テトラブチルアンモニウムフルオリト1.:]77m1
.37[1moりをo ’cで加え、15分攪拌した。” 0.24g (0.68mm) of the deoxy compound produced
ol) in tetrahydrofuran (5 ml) and IM
Tetrabutylammonium fluorite 1. :]77m1
.. 37 [1 mole] was added at o'c and stirred for 15 minutes.
溶媒を留去後、カラムクロマトグラフ精製し、■−(2
,3−ジデオキシ−3−フルオロ−β−D−リボフラノ
シル)チミン75II1gをを得た。After distilling off the solvent, column chromatography purification was carried out to obtain ■-(2
, 3-dideoxy-3-fluoro-β-D-ribofuranosyl)thymine 75II (1 g) was obtained.
上記製造したアルコール75mg(OJlmmol)を
ピリジン(311111)に溶解し、メタンスルホニル
クロリド(50ml)を加え、0℃て1時間反応した。75 mg (OJlmmol) of the alcohol produced above was dissolved in pyridine (311111), methanesulfonyl chloride (50 ml) was added, and the mixture was reacted at 0°C for 1 hour.
重曹水を加え、通常通り後処理した後カラムクロマトグ
ラフ精製し、1−(2,3−ジデオキシ−3−フルオロ
−5−0−メタンスルホニル−β−D−リボフラノシル
)チミン88mg (収率89%)を得た。After adding sodium bicarbonate solution and post-treatment as usual, column chromatography purification yielded 88 mg of 1-(2,3-dideoxy-3-fluoro-5-0-methanesulfonyl-β-D-ribofuranosyl)thymine (yield 89%). ) was obtained.
上記製造したメタンスルホニル体88mg(0,27I
Ilffiol)をN、N−ジメチルホルムアミド(7
1)に溶解し、ナトリウムアジド110mg(1,6m
+5ol)を加え、60°Cで1時間反応した。溶媒を
留去後。88 mg of the methanesulfonyl compound produced above (0,27I
Ilffiol) to N,N-dimethylformamide (7
1) and 110 mg (1.6 m
+5 ol) was added and reacted at 60°C for 1 hour. After distilling off the solvent.
カラムクロマトグラフ精製し、1− (2,:1.5−
)−リゾオキシ−3−フルオロ−5−アジド−β−D
−リボフラノシル)チミン75II1g(収率100%
)を得た。Column chromatography purification and 1-(2,:1.5-
)-lysooxy-3-fluoro-5-azido-β-D
-ribofuranosyl)thymine 75II 1 g (yield 100%)
) was obtained.
上記製造したアジド体75mg(0,28mmol)を
エタノール(71)溶解し、5%パラジウム−炭素(3
0mg)を加え、水素雰囲気下3.5時間攪拌した。セ
ライト濾過し、濃縮し表出化合物58B(収率86%)
を得た。75 mg (0.28 mmol) of the azide prepared above was dissolved in ethanol (71), and 5% palladium-carbon (3
0 mg) was added thereto, and the mixture was stirred for 3.5 hours under a hydrogen atmosphere. Filtered through Celite and concentrated to obtain compound 58B (yield 86%)
I got it.
1)1−NMR(CD、OD) :
1.4−2.7(m、2H)、 1.91(d、J=1
.5tlz、:It()。1) 1-NMR (CD, OD): 1.4-2.7 (m, 2H), 1.91 (d, J=1
.. 5tlz, :It().
:1.2−3.4(m、2H)、 4.15(dm、J
=27.1Hz、l1l)。:1.2-3.4 (m, 2H), 4.15 (dm, J
=27.1Hz, l1l).
5.19(dm、J=49.1Hz、1ll)。5.19 (dm, J=49.1Hz, 1ll).
6.21(dd、J=5.9,8.511z、1ll)
。6.21 (dd, J=5.9, 8.511z, 1ll)
.
実施例6
実施例5の化合物の合成中間体である1−(3−デオキ
シ−3−フルオロ−β−D−リボフラノシル)チミン0
,31g (1,2m5ol)をN、N −ジメチルホ
ルムアミド(3ml)に溶解し、0℃てイミダゾール0
.20g (3,0mmol)および、t−ブチルジメ
チルシリルクロリド0.20g(lJmmol)をN、
N−ジメチルホルムアミド(1,511)に溶解したも
のを加え、6時間攪拌した。水処理し、有機層を濃縮、
カラムクロマトグラフ精製により1−(3−デオキシ−
3−フルオロ−5−0−t−ブチルジメチルシリル−β
−D−リボフラノシル)チミン0.21gを得た。Example 6 1-(3-deoxy-3-fluoro-β-D-ribofuranosyl)thymine 0, a synthetic intermediate for the compound of Example 5
, 31g (1,2m5ol) was dissolved in N,N-dimethylformamide (3ml) and added with imidazole at 0°C.
.. 20g (3.0mmol) and 0.20g (1Jmmol) of t-butyldimethylsilyl chloride with N,
A solution dissolved in N-dimethylformamide (1,511) was added and stirred for 6 hours. Water treatment, concentration of organic layer,
1-(3-deoxy-
3-Fluoro-5-0-t-butyldimethylsilyl-β
-D-ribofuranosyl)thymine 0.21 g was obtained.
上記製造したモノアルコール0.21g (0,55m
mol)をピリジン(2ml)に溶解し、0°Cでベン
ゾイルクロリド0.13i1(1,1ml1ol)を加
えた。0.21g (0.55m) of the monoalcohol produced above
mol) was dissolved in pyridine (2 ml), and 0.13 il (1.1 ml 1 ol) of benzoyl chloride was added at 0°C.
12時間後ピリジンを留去し、カラムクロマトグラフ精
製により、1−(3−デオキシ−5−〇−1−ブチルジ
メチルシリルー2−〇−ベンゾイルーβ−D−リボフラ
ノシル)チミン0.12gを得た。After 12 hours, pyridine was distilled off, and 0.12 g of 1-(3-deoxy-5-〇-1-butyldimethylsilyl-2-〇-benzoyl-β-D-ribofuranosyl)thymine was obtained by column chromatographic purification. .
上記製造したベンゾイル体0.12g (0,25mm
ol)をテトラヒドロフラン(31)に溶解し、0℃で
IM−テトラブチルアンモニウムフルオリト0.5m1
((1,5mmol)を加え、15分攪拌した。テトラ
ヒドロフランを留去し、カラムクロマトグラフ精製によ
り、1−(3−デオキシ−3−フルオロ−2−0−ベン
ゾイル−β−D−リボフラノシル)チミン口、07gを
得た。0.12g of the benzoyl compound produced above (0.25mm
ol) in tetrahydrofuran (31) and 0.5 ml of IM-tetrabutylammonium fluorite at 0°C.
((1.5 mmol) was added and stirred for 15 minutes. Tetrahydrofuran was distilled off, and 1-(3-deoxy-3-fluoro-2-0-benzoyl-β-D-ribofuranosyl)thymine was purified by column chromatography. 07g was obtained.
」−記製造したアルコール0.07g (0,2mff
1ol)をピリジン(4ml)に溶解し、O’Cてメタ
ンスルホニルクロリド0.039m1(0,5ml1o
l)を加え、1時間攪拌した。重曹水を加え、ジクロロ
メタン抽出した後、有機層を濃縮し、カラムクロマトグ
ラフ精製により、1−(3−デオキシ−3−フルオロ−
2−〇−ベンゾイルー5−〇−メタンスルホニル−β−
D−リボフラノシル)チミン0.068gを得た。- 0.07g of alcohol produced (0.2mff
Dissolve 1 mol) in pyridine (4 ml), add 0.039 ml (0.5 ml 1 mol) of methanesulfonyl chloride at O'C.
1) was added and stirred for 1 hour. After adding aqueous sodium bicarbonate and extracting with dichloromethane, the organic layer was concentrated and purified by column chromatography to obtain 1-(3-deoxy-3-fluoro-
2-〇-benzoyl-5-〇-methanesulfonyl-β-
0.068 g of D-ribofuranosyl)thymine was obtained.
上記製造したメシル体0.068g (0,15mmo
l)をN、N−ジメチルホルムアミド(3it)に溶解
し、ナトリウムアジド0.10g (1,5a+l1o
l)を加え、60°Cて4.5時間攪拌した。溶媒を留
去した後、カラムクロマトグラフ精製により、1−(3
,5−ジデオキシ−3−フルオロ−5−アジド−2−0
−ベンゾイル−β−D−リボフラノシル)チミン0.0
58gを得た。0.068 g (0.15 mmo) of the mesyl body produced above
l) in N,N-dimethylformamide (3 it) and 0.10 g of sodium azide (1,5a+l1o
1) was added and stirred at 60°C for 4.5 hours. After distilling off the solvent, 1-(3
,5-dideoxy-3-fluoro-5-azido-2-0
-benzoyl-β-D-ribofuranosyl)thymine 0.0
58g was obtained.
上記製造したアシドエステル0.058g (0,+
5ma+ol)をメタノール(41)に溶解し、IN−
ナトリウムメトキシドO,15m1(0,15m1ll
ol)を加え、30分加熱還流した。メタノール留去後
、水(2it)を加え、2N−酢酸て中和し、さらに溶
媒を留去した。カラムクロマトグラフ精製により、1−
(L5−ジデオキシ−3−フルオロ−5−アジド−β−
D−リボフラノシル)チミン0.04gを得た。0.058g of acid ester produced above (0,+
5ma+ol) was dissolved in methanol (41) and IN-
Sodium methoxide O, 15 ml (0.15 ml
ol) was added, and the mixture was heated under reflux for 30 minutes. After methanol was distilled off, water (2 it) was added, neutralized with 2N acetic acid, and the solvent was further distilled off. By column chromatographic purification, 1-
(L5-dideoxy-3-fluoro-5-azido-β-
0.04 g of D-ribofuranosyl)thymine was obtained.
’ +1−NMR((:D[I3) :61.92(s
)t()、 3.7(dd、J=14.2.811z、
l1l)。'+1-NMR((:D[I3):61.92(s
)t(), 3.7(dd, J=14.2.811z,
l1l).
:1.95(dd、J−14,2,8t!z、111)
。:1.95 (dd, J-14, 2, 8t!z, 111)
.
4.40(di、25Hz、1tl)、 4.6−4.
7(s、l1l)。4.40 (di, 25Hz, 1tl), 4.6-4.
7 (s, l1l).
4.95(dm、J=56Hz、IH) 、6.05(
d、J−7,511z、III) 。4.95 (dm, J=56Hz, IH), 6.05 (
d, J-7,511z, III).
7.35(s、IH)。7.35 (s, IH).
上記製造したアジドアルコール0.04g(0,15m
1ol)をエタノール(3ml)に溶解し、5%パラジ
ウム−炭素20mgを加え、水素雰囲気下て1.5時間
攪拌した。セライト濾過し、表出化合物0.03gを得
た。0.04 g (0.15 m
1 ol) was dissolved in ethanol (3 ml), 20 mg of 5% palladium-carbon was added, and the mixture was stirred for 1.5 hours under a hydrogen atmosphere. It was filtered through Celite to obtain 0.03 g of the surface compound.
’II−NMR(CD30D): δ1.92(s、:IH)、:lJ(m、2t()。'II-NMR (CD30D): δ1.92(s, :IH), :lJ(m, 2t().
4.13(ds、J=26Hz、LH)、4.55(d
m、J=20Hz、1.11)。4.13 (ds, J=26Hz, LH), 4.55 (d
m, J=20Hz, 1.11).
4.95(da、J−54,6t(z、l1l)。4.95 (da, J-54, 6t (z, l1l).
6.85(d、J冨8.4Hz、IH)、7.54(s
、IH)。6.85 (d, J 8.4Hz, IH), 7.54 (s
, IH).
”F−NMR(CD:1OD)ニ
ー175.0(ddd、J−54,6,26,2,2Q
、0f(z)。"F-NMR (CD: 1OD) knee 175.0 (ddd, J-54, 6, 26, 2, 2Q
, 0f(z).
実施例7
成
メチル3−デオキシ−3−フルオロ−2,5−〇−ジベ
ンゾイルーβ−D−リボフラノシド0.50g (1,
3mmol)を酢酸(2,4m1)に溶解し、無水酢酸
(0,10m1)と30%臭化水素−酢酸溶液(12I
111)を加え、3時間攪拌した。溶媒を留去した後、
ウラシルビストリメチルシリルエーテル0.45g (
1,,7+mol)のジクロロエタン溶液、ならびにト
リメチルシリルトリフルオロメタンスルホナート(0,
2:1m1)を加え、1.5時間還流した。Example 7 0.50 g of synthetic methyl 3-deoxy-3-fluoro-2,5-〇-dibenzoyl-β-D-ribofuranoside (1,
3 mmol) in acetic acid (2.4 ml), acetic anhydride (0.10 ml) and 30% hydrogen bromide-acetic acid solution (12I
111) was added and stirred for 3 hours. After distilling off the solvent,
Uracil bistrimethylsilyl ether 0.45g (
1,,7+ mol) in dichloroethane, as well as trimethylsilyltrifluoromethanesulfonate (0,
2:1 ml) was added and refluxed for 1.5 hours.
反応液に飽和重曹液を加え、有Ja、層を乾燥、濃縮し
、カラムクロマトグラフ精製し、1−(3−デオキシ−
3−フルオロ−2,5−0−ジベンゾイル−β−D−リ
ボフラノシル)ウラシルo、4tg (収率69%)を
得た。A saturated sodium bicarbonate solution was added to the reaction solution, the layer was dried, concentrated, and purified by column chromatography to obtain 1-(3-deoxy-
4tg (yield: 69%) of 3-fluoro-2,5-0-dibenzoyl-β-D-ribofuranosyl)uracil was obtained.
上記製造したジベンゾイル体0.41g (0,90m
mo+)をメタノール(2,0m1)に溶解し、IM−
ナトリウムメトキシド−メタノール溶液(3,41)を
加え、1時間加熱量流した。溶媒を留去後、2N−酢酸
で中和し、カラムクロマトグラフ精製し、1−(3〜デ
オキシ−3−フルオロ−β−D−リボフラノシル)ウラ
シル0.22g(収率97%)を得た。0.41g (0.90m) of the dibenzoyl compound produced above
mo+) in methanol (2.0ml) and IM-
Sodium methoxide-methanol solution (3,41) was added and heated for 1 hour. After distilling off the solvent, it was neutralized with 2N acetic acid and purified by column chromatography to obtain 0.22 g (yield 97%) of 1-(3-deoxy-3-fluoro-β-D-ribofuranosyl)uracil. .
上記製造したジオール0.22g (0,88■ol)
をN、N−ジメチルホルムアミド(31)に溶解し、イ
ミダゾール0.15g (2,2■ol)および、t−
ブチルジメチルシリルクロリド0.14g (0,91
!1IIol)のN、N−ジメチルホルムアミド(l
ml)を加え、0°Cで2時間攪拌した。水処理した後
カラムクロマトグラフ精製し、1−(3−デオキシ−3
−フルオロ−5−O−t−ブチルジメチルシリルーβ−
D−リボフラノシル)ウラシルO,14g (収率43
%)を得た。Diol produced above 0.22g (0.88■ol)
was dissolved in N,N-dimethylformamide (31), imidazole 0.15g (2,2■ol) and t-
Butyldimethylsilyl chloride 0.14g (0,91
! 1IIol) of N,N-dimethylformamide (l
ml) and stirred at 0°C for 2 hours. After water treatment, column chromatography purification and 1-(3-deoxy-3
-Fluoro-5-O-t-butyldimethylsilyl β-
D-ribofuranosyl) uracil O, 14 g (yield 43
%) was obtained.
上記製造したモノシリル体0.14g (0,:18m
mol)をジクロロメタン(3ml)に溶解し、4−N
−ジメチルアミノピリジン0.14g (1,1mmo
l)およびフェニルクロロチオノカーボナート0.1:
1g(0,95mmol)のジクロロメタン(2ll1
l)溶液を0°Cで加え、1.5時間攪拌した。水を加
え、ジクロロメタンで抽出した後、乾燥、BKaしカラ
ムクロマトグラフ精製し、1−(3−デオキシ3−フル
オロ−5−0−t−ブチルジメチルシリル−2−〇−フ
ェノキシチオカルボニル)ウラシル0.]、66g収率
84%)を得た。0.14g of the monosilyl body produced above (0,:18m
mol) in dichloromethane (3 ml), 4-N
-dimethylaminopyridine 0.14g (1,1mmo
l) and phenylchlorothionocarbonate 0.1:
1g (0.95mmol) of dichloromethane (2ll1
l) The solution was added at 0°C and stirred for 1.5 hours. After adding water and extracting with dichloromethane, drying, BKa and column chromatography purification, 1-(3-deoxy3-fluoro-5-0-t-butyldimethylsilyl-2-〇-phenoxythiocarbonyl)uracil 0 .. ], 66 g (yield: 84%) were obtained.
上記製造したフェノキシカルボニル体0.16g(Q、
:llmmol)をベンゼン(10ml)に溶解し、ア
ゾイソブチロニトリル(18B)およびトリフチルスズ
ヒトリド0.88i1(:1.:1m1lol)を加え
、3時間加熱還流した。溶媒を留去し、カラムクロマト
グラフ精製し、l −(2,’II−ジデオキシー3−
フルオロ−5−O−t−ブチルジメチルシリル−β−D
−リボフラノシル)ウラシル0.066g (収率61
%)を得た。0.16 g of the phenoxycarbonyl compound produced above (Q,
: 1mmol) was dissolved in benzene (10ml), azoisobutyronitrile (18B) and 0.88i1 (:1.:1ml) of triphthyltin hydride were added, and the mixture was heated under reflux for 3 hours. The solvent was distilled off and purified by column chromatography to obtain l-(2,'II-dideoxy-3-
Fluoro-5-O-t-butyldimethylsilyl-β-D
-ribofuranosyl) uracil 0.066 g (yield 61
%) was obtained.
’II−NMR(CD[I+) :
60.00(s、6tl)、 0.80(s、9H)、
2.0−3.0(m、2tl)。'II-NMR (CD[I+): 60.00 (s, 6tl), 0.80 (s, 9H),
2.0-3.0 (m, 2tl).
3.7−3.9(m、2H)、 4.28(da、J=
2.7Hz、IH)。3.7-3.9 (m, 2H), 4.28 (da, J=
2.7Hz, IH).
5.12(dd、J=54.5.4Hz、III)。5.12 (dd, J=54.5.4Hz, III).
5.68(d、J=7.9)1z、IH)。5.68(d, J=7.9)1z, IH).
7.32(dd、J−3,4,911z、1ll)。7.32 (dd, J-3, 4,911z, 1ll).
8.85(d、J−掌7.9Hz、IH)。8.85 (d, J-palm 7.9Hz, IH).
’9F−NMR(CDC1,、CC1,F基準)ニー1
75.1ppm(ddd、J=21.5.27.54H
z)。'9F-NMR (CDC1, CC1, F standard) Knee 1
75.1ppm (ddd, J=21.5.27.54H
z).
上記製造したデオキシ体0.066 g (0,19+
amol)をテトラヒドロフラン(21)に溶解し、L
M−テトラブチルアンモニウムフルオリド0.391(
(1,39mmol)を0℃で加え、15分攪拌した。Deoxy compound produced above 0.066 g (0,19+
amol) in tetrahydrofuran (21), L
M-tetrabutylammonium fluoride 0.391 (
(1.39 mmol) was added at 0°C and stirred for 15 minutes.
溶媒な留去後、カラムクロマトグラフ精製し、1−(2
,3−ジデオキシ−3−フルオロ−β−D−リボフラノ
シル)ウラシル47ragを得た。After distilling off the solvent, column chromatography purification was performed to obtain 1-(2
, 3-dideoxy-3-fluoro-β-D-ribofuranosyl)uracil 47rag was obtained.
上記製造したアルコール47B(0,21mmol)を
ピリジン(2ml)に溶解し、メタンスルホニルクロリ
ド(40sl)を加え、0℃て1時間反応した。Alcohol 47B (0.21 mmol) produced above was dissolved in pyridine (2 ml), methanesulfonyl chloride (40 sl) was added, and the mixture was reacted at 0°C for 1 hour.
重曹水を加え、通常通り後処理した後カラムクロマトグ
ラフ精製し、1− (2,3−ジデオキシ−3−フルオ
ロ−5−〇−メタンスルホニルーβ−D−リボフラノシ
ル)ウラシル25mg (収率40%)を得た。After adding sodium bicarbonate solution and post-treatment as usual, column chromatography purification gave 25 mg of 1-(2,3-dideoxy-3-fluoro-5-〇-methanesulfonyl-β-D-ribofuranosyl)uracil (yield 40%). ) was obtained.
上記製造したメタンスルホニル体25mg(0,08m
mol)をN、l1l−ジメチルホルムアミド(2ml
)に溶解し、ナトリウムアシド54B(0,8mmol
)を加え、60°Cて1時間反応した。溶媒を留去後、
カラムクロマトグラフ精製し、l−<2.3.5−トリ
デオキシ−3−フルオロ−5−アシド−β−〇−リボフ
ラノシル)ウラシル3311g (収率100%)を得
た。25 mg (0.08 m
mol) of N, l1l-dimethylformamide (2 ml
) and sodium acid 54B (0.8 mmol
) and reacted at 60°C for 1 hour. After distilling off the solvent,
The product was purified by column chromatography to obtain 3311 g (yield: 100%) of l-<2.3.5-trideoxy-3-fluoro-5-acido-β-0-ribofuranosyl)uracil.
’II−NMR(CD[I :
81.9−2.7(m、211)、 3.5−3.8(
m、211)。'II-NMR (CD[I: 81.9-2.7 (m, 211), 3.5-3.8 (
m, 211).
4.32(dm、J=26.411z、 III) 。4.32 (dm, J=26.411z, III).
5.15(td、J=5.4,541+2.IH)。5.15 (td, J=5.4,541+2.IH).
5.82(d、J=8.611z、IH)。5.82 (d, J=8.611z, IH).
6.34(dd、J=5.4,911z、1ll)。6.34 (dd, J=5.4,911z, 1ll).
7.57(d、J=8.6tlz、1.tl)。7.57 (d, J=8.6tlz, 1.tl).
19F−NMR(CD[I=)ニ
ー175.4pplI(dddd、J=22.0,26
.4,35.2゜54.0tlz)
IR([II[I:+): 2250,1695cn
+−’上記製造したアジド体33sg(0,(18mI
lol)をエタノール(3it)溶解し、5%パラジウ
ム−炭素(10mg)を加え、水素雰囲気下3.5時間
攪拌した。セライト濾過し、濃縮し大損化合物30ng
(収率100%)を得た。19F-NMR (CD[I=) knee 175.4 pplI (dddd, J=22.0, 26
.. 4,35.2゜54.0tlz) IR([II[I:+): 2250,1695cn
+-' 33sg of azide prepared above (0, (18mI
lol) was dissolved in ethanol (3 it), 5% palladium-carbon (10 mg) was added, and the mixture was stirred for 3.5 hours under a hydrogen atmosphere. Celite filter and concentrate 30ng of large loss compound
(yield 100%).
” F−NMR(CD:1OD) ニ
ー1715ppm(dt、J=23. 57Hz)実施
例8
る化合物、Bかウリジン残基]の合成
実施例5の化合物の合成中間体である1〜(3−デオキ
シ−3−フルオロ−β−D−リボフラノシル)ウラシル
010g (1,1mmol)をN、N−ジメチルホル
ムアミド(3ml)に溶解し、00Cてイミダゾール0
.27g (19mmol)および、tブチルジメチル
シリルクロリド0.27g(1,8mmol)をN、N
−ジメチルホルムアミド(1,5011)に溶解したも
のを加え、6時間攪拌した。水処理し、有機層を濃縮、
カラムクロマトグラフ精製により1−(3−デオキシ−
3−フルオロ−5−0−t−ブチルジメチルシリル−β
−D−リボフラノシル)ウラシル[1,20gを得た。"F-NMR (CD: 1OD) K 1715 ppm (dt, J = 23.57 Hz) Example 8 Synthesis of the compound B or uridine residue] 1 to (3- Dissolve 010 g (1.1 mmol) of deoxy-3-fluoro-β-D-ribofuranosyl (deoxy-3-fluoro-β-D-ribofuranosyl) uracil in N,N-dimethylformamide (3 ml),
.. 27g (19mmol) and 0.27g (1.8mmol) of t-butyldimethylsilyl chloride were mixed with N,N
-A solution dissolved in dimethylformamide (1,5011) was added and stirred for 6 hours. Water treatment, concentration of organic layer,
1-(3-deoxy-
3-Fluoro-5-0-t-butyldimethylsilyl-β
-D-ribofuranosyl)uracil [1.20 g was obtained.
上記製造したモノアルコール0.20g (0,54+
++nol)をピリジン(3ml)に溶解し、0℃てベ
ンゾイルクロリド0.13m1(1,1m1ol)を加
えた。0.20g of the monoalcohol produced above (0.54+
++nol) was dissolved in pyridine (3 ml), and 0.13 ml (1.1 ml) of benzoyl chloride was added at 0°C.
12時間後ピリジンを留去し、カラムクロマトグラフ精
製により、1−(3−デオキシ−5−〇−t−ブチルジ
メチルシリルー2−〇−ベンゾイルーβ−D−リボフラ
ノシル)ウラシル0.19gを得た。After 12 hours, pyridine was distilled off, and 0.19 g of 1-(3-deoxy-5-〇-t-butyldimethylsilyl-2-〇-benzoyl-β-D-ribofuranosyl)uracil was obtained by column chromatography purification. .
上記製造したベンゾイル体0.19g (0,42mm
ol)をテトラヒドロフラン(51)に溶解し、0°C
でIM−テトラブチルアンモニウムフルオすl〜0.8
4sl(0,5mmol)を加え、15分攪拌した。テ
トラヒドロフランを留去し、カラムクロマトグラフ精製
により、1−(3−デオキシ−3−フルオロ−2−0−
ベンゾイル−β−D−リボフラノシル)ウラシル0.1
:Igを得た。0.19g of the benzoyl compound produced above (0.42mm
ol) in tetrahydrofuran (51) and heated to 0°C.
IM-tetrabutylammonium fluorosol ~ 0.8
4 sl (0.5 mmol) was added and stirred for 15 minutes. Tetrahydrofuran was distilled off, and 1-(3-deoxy-3-fluoro-2-0-
Benzoyl-β-D-ribofuranosyl)uracil 0.1
:Ig was obtained.
上記製造したアルコール0.13g (0,:16+a
mol)をピリジン(4ml)に溶解し、0°Cてメタ
ンスルホニルクロリド0.072m1(0,7n+mo
l)を加え、1時間撹拌した。重曹水な加え、ジクロロ
メタン抽出した後、有機層を濃縮し、カラムクロマトグ
ラフ精製により、1−(3−デオキシ−3−フルオロ−
2−0−ベンゾイル−5−〇−メタンスルホニルーβ−
D−リボフラノシル)ウラシルO,14gを得た。0.13g of the alcohol produced above (0,:16+a
mol) in pyridine (4 ml), and added 0.072 ml (0.7 n+mol) of methanesulfonyl chloride at 0°C.
1) was added and stirred for 1 hour. After addition of aqueous sodium bicarbonate and extraction with dichloromethane, the organic layer was concentrated and purified by column chromatography to obtain 1-(3-deoxy-3-fluoro-
2-0-benzoyl-5-〇-methanesulfonyl β-
14 g of D-ribofuranosyl)uracil O was obtained.
上記製造したメシル体0.14g (012mlol)
をN、N−ジメチルホルムアミド(61)に溶解し、ナ
トリウムアジド0.21 g (3,2mmol)を加
え、60°Cて4.5時間攪拌した。溶媒を留去した後
、カラムクロマトグラフ精製により、■=(3,5−ジ
デオキシ−3−フルオロ−5−アジド−2−0−ベンゾ
イル−β−D−リボフラノシル)ウラシル0.086z
得た。0.14g (012ml) of the mesyl body produced above
was dissolved in N,N-dimethylformamide (61), 0.21 g (3.2 mmol) of sodium azide was added, and the mixture was stirred at 60°C for 4.5 hours. After distilling off the solvent, column chromatography purification yields ■=(3,5-dideoxy-3-fluoro-5-azido-2-0-benzoyl-β-D-ribofuranosyl)uracil 0.086z
Obtained.
上記製造したアジドエステル0.086g (0,23
[+111101)をメタノール(51)に溶解し、I
N−ナトリウムメトキシド0.23m1(0,23mm
al)を加え、30分加熱還流した。メタノール留去後
、水(2ll)を加え、2N−酢酸で中和し、さらに溶
媒を留去した。カラムクロマトグラフ精製により、1−
(3,5−ジデオキシ−3−フルオロ−5−アジド−
β−D−リボフラノシル)ウラシルo、osgを得た。0.086g of the azide ester produced above (0.23
[+111101) was dissolved in methanol (51) and I
N-sodium methoxide 0.23 ml (0.23 mm
al) was added, and the mixture was heated under reflux for 30 minutes. After methanol was distilled off, water (2 1) was added, neutralized with 2N acetic acid, and the solvent was further distilled off. By column chromatographic purification, 1-
(3,5-dideoxy-3-fluoro-5-azido-
β-D-ribofuranosyl) uracil o, osg was obtained.
上記製造したアシトアルコールロ、05g (0,21
mmol)をエタノール(3if)に溶解し、5%パラ
ジウム−炭素20IIIgを加え、水素雰囲気下て1.
5時間攪拌した。セライト濾過し、表出化合物0.04
6 gを得た。Acitoalcohol produced above, 05g (0,21
mmol) was dissolved in ethanol (3if), 20IIIg of 5% palladium-carbon was added, and the mixture was stirred under hydrogen atmosphere for 1.
Stirred for 5 hours. Celite filtered, surface compound 0.04
6 g was obtained.
’H−NMR(CD、OD):
63.7−3.8(m、211)、 4.24(ds
、J=2511z、l1l)。'H-NMR (CD, OD): 63.7-3.8 (m, 211), 4.24 (ds
, J=2511z, l1l).
4.46(dIl、J=20tlz、 III) 。4.46 (dIl, J=20tlz, III).
4.95(da、54.611z、IH)。4.95 (da, 54.611z, IH).
5.75(d、J=8Hz、III)、 5.87(
d、J=7.011z、III)。5.75 (d, J=8Hz, III), 5.87 (
d, J=7.011z, III).
7.72(d、J=8.0tlz、l1l)。7.72 (d, J=8.0tlz, l1l).
19F−NMR(CD、OD、にCl3F基準)ニー1
94.0(dddd、J=1.1. 20.2. 26
.4,54.611z)。19F-NMR (CD, OD, Cl3F standard) knee 1
94.0 (dddd, J=1.1.20.2.26
.. 4,54.611z).
実施例9
3°−デオキシ−3°−フルオロ−2°、5’、N6−
トリベンゾイル0.15g (0,26mQlol)
をエタノール(21)に溶解し、0℃で2N−水酸化ナ
トリウム溶液(2ml)を−度に加え、30分攪拌した
。2N−塩酸で中和した後、溶媒を留去し、カラムクロ
マトグラフ精製によって、3°−デオキシ−3゛−フル
オロ−N6−ベンゾイルアデノシン84II1gを得た
。Example 9 3°-deoxy-3°-fluoro-2°,5',N6-
Tribenzoyl 0.15g (0.26mQlol)
was dissolved in ethanol (21), 2N sodium hydroxide solution (2 ml) was added at 0°C, and the mixture was stirred for 30 minutes. After neutralization with 2N-hydrochloric acid, the solvent was distilled off, and 1 g of 3°-deoxy-3'-fluoro-N6-benzoyladenosine 84II was obtained by column chromatography purification.
上記製造したジオール84mg(0,23■ol)をN
、N−ジメチルホルムアミド(2ml)に溶解し、0℃
てイミダゾール61mg(0,9mLlol)および、
七−ブチルジメチルシリルクロリド41B(0,27m
a+ol)を加え、30分攪拌した。水を加え、ベンゼ
ン抽出し、乾燥濃縮によって、3゛−デオキシ−3′フ
ルオロ−N6−ペンゾイルー5−O−t−ブチルジメチ
ルシリルアデノシンな78111g得た。84 mg (0.23 ■ ol) of the diol produced above was added to N
, dissolved in N-dimethylformamide (2 ml) and heated to 0°C.
61 mg (0.9 mL lol) of imidazole and
7-Butyldimethylsilyl chloride 41B (0.27m
a+ol) was added and stirred for 30 minutes. Water was added, extracted with benzene, and dried and concentrated to obtain 78,111 g of 3'-deoxy-3'fluoro-N6-penzoyl-5-O-t-butyldimethylsilyladenosine.
上記製造したモノオール78mg(0,+6a+ioり
をジクロロメタン(3ml)に溶解し、4−ジメチルア
ミノピリジン51mg (0,5m1ol)およびクロ
ロチオツギ酸フェニルエステル60.u、 I(0,:
15mmol)を加え、0°Cて40分攪拌した。水を
加え、クロロホルム抽出し、カラムクロマトグラフ精製
により、3゛−デオキシ−3′−フルオロ−N6−ペン
ゾイルー5°−0−t−ブチルジメチルシリル−2゜−
フェノキジオカルボニルアデノシン24Bを得た。78 mg (0,+6a+io) of the above-produced monol was dissolved in dichloromethane (3 ml), and 51 mg (0,5 ml) of 4-dimethylaminopyridine and 60.u, I(0,:
15 mmol) was added thereto, and the mixture was stirred at 0°C for 40 minutes. Add water, extract with chloroform, and purify by column chromatography to obtain 3゛-deoxy-3'-fluoro-N6-penzoyl-5°-0-t-butyldimethylsilyl-2゜-
Phenokidiocarbonyladenosine 24B was obtained.
上記製造したチオカーボナート体24mg(0,004
mmol)をベンゼン(2lll1)に溶解し、 N、
N−アゾイソブチロニトリル2mgおよびトリフチルス
ズヒドリド0.04m1(0,11!++aol)を加
え、20分加熱還流した。ベンゼンを留去後、カラムク
ロマトグラフ精製により、3“−デオキシ−3°−フル
オロ−N6−ペンゾイルー5−O−t−ブチルジメチル
シリルアデノシン15IIgを得た。24 mg of the above-produced thiocarbonate (0,004
mmol) in benzene (2lll1), N,
2 mg of N-azoisobutyronitrile and 0.04 ml (0.11!++ aol) of triphthyltin hydride were added, and the mixture was heated under reflux for 20 minutes. After distilling off the benzene, column chromatography purification yielded 15IIg of 3"-deoxy-3°-fluoro-N6-penzoyl-5-O-t-butyldimethylsilyladenosine.
上記製造したデオキシ体15mg(0,0:I:IIl
mol)をテトラヒドロフラン(1,5m1)に溶解し
、IM−テトラブチルアンモニウムフルオリドーテトラ
ヒドロフラン溶液70#L1を加え、室温で10分間攪
拌した。カラムクロマトグラフ精製により、3゛−デオ
キシ−3°−フルオロ−N6−ベンゾイルアデノシン1
4Bをを得た。15 mg of the deoxy compound produced above (0,0:I:IIl
mol) was dissolved in tetrahydrofuran (1.5 ml), 70 #L1 of IM-tetrabutylammonium fluoride tetrahydrofuran solution was added, and the mixture was stirred at room temperature for 10 minutes. By column chromatographic purification, 3'-deoxy-3'-fluoro-N6-benzoyladenosine 1
I got 4B.
上記製造したアルコール14+H(0,04wmol)
をピリジン(11)に溶解し、メタンスルホニルクロリ
ド70g l(0,9mmol)を室温で加え、1.5
時間攪拌した。飽和重曹水を加え、クロロホルム抽出し
、有機層を乾燥Dt1i!シた。カラムクロマトグラフ
精製により、3“−デオキシ−3′−フルオローN6−
ペンゾイルー5°−0−メタンスルホニルアデノシン2
7tagを得た。Alcohol 14+H produced above (0.04 wmol)
was dissolved in pyridine (11), 70 g l (0.9 mmol) of methanesulfonyl chloride was added at room temperature, and 1.5
Stir for hours. Add saturated sodium bicarbonate solution, extract with chloroform, and dry the organic layer. Shita. By column chromatographic purification, 3"-deoxy-3'-fluoroN6-
Penzoyl-5°-0-methanesulfonyladenosine 2
Obtained 7 tags.
上記製造したメタンスルホニル体27mg(0,04m
mol)をN−ジメチルホルムアミド(21)に溶解し
、ナトリウムアジトロ5mg (1■ol)を加え、0
°C″′c1時間攪拌した。反応液をeliI後カラム
クロマトグラフ精製により、3′、5° −ジデオキシ
−3゛−フルオロ−5゛−アジド−N6−ベンゾイルア
デノシン18Bを得た。27 mg (0.04 m
mol) in N-dimethylformamide (21), added 5 mg (1 mol) of sodium agitator, and dissolved
The reaction mixture was stirred for 1 hour at 15°C. The reaction solution was purified by eliI column chromatography to obtain 3',5'-dideoxy-3'-fluoro-5'-azido-N6-benzoyladenosine 18B.
19F−NMR(CDC1,、CCl3F基準)ニー1
76.4 ppm(dddd、 J−22,0,25,
4,:15.6゜53.7Hz)。19F-NMR (CDC1, CCl3F standard) knee 1
76.4 ppm (dddd, J-22,0,25,
4, :15.6°53.7Hz).
In([II[I:+): 3400,3020,21
00,1710.1205cm−’上記製造したアジド
体18mg(0,04o+mol)に溶解し、炭酸カリ
ウム14B(0,111@ol)を加え、室温で45分
、50°Cで30分加熱した。溶媒を留去し、カラムク
ロマトグラフ精製により、3°、5°−ジデオキシ−3
°−フルオロ−5°−アジドアデノシン1011gを得
た。In([II[I:+): 3400,3020,21
00,1710.1205 cm-' The above-produced azide compound was dissolved in 18 mg (0.04 o+mol), potassium carbonate 14B (0.111@ol) was added, and the mixture was heated at room temperature for 45 minutes and at 50°C for 30 minutes. The solvent was distilled off and 3°,5°-dideoxy-3 was purified by column chromatography.
1011 g of °-fluoro-5°-azidoadenosine was obtained.
19F−NMR([Ill[I3.CCl1F基準)ニ
ー175.9 ppm(dddd、J=21.5,2
5.4,35.6゜53.211z)。19F-NMR ([Ill[I3.CCl1F standard) knee 175.9 ppm (dddd, J=21.5,2
5.4, 35.6°53.211z).
上記製造したアジド体をエタノール(21)に溶解し、
5%パラジウム−炭素(3mg)を加え、水素雰囲気下
で3時間攪拌した。セライト濾過濃縮により大損化合物
5mgを得た。The azide produced above was dissolved in ethanol (21),
5% palladium-carbon (3 mg) was added, and the mixture was stirred for 3 hours under a hydrogen atmosphere. 5 mg of a large loss compound was obtained by filtration and concentration through Celite.
19F−NMR(メタノール−d、、C[I、F基準)
ニー173.4 ppm(dddd、 J−21,5,
26,4,37,1゜53.2Hz)。19F-NMR (methanol-d,,C[I,F standard)
knee 173.4 ppm (dddd, J-21,5,
26,4,37,1°53.2Hz).
Claims (1)
オロ−5−置換−D−リボフラノシド誘導体。 ▲数式、化学式、表等があります▼・・・[ I ] ただし、 X:NR^1R^2(R^1、R^2は水素原子、置換
基を含んでいてもよいアルキル基またはアリー ル基、あるいは保護基)、−N_3基、−SR^3(R
^3は水素原子、置換基を含んでいてもよいアルキル基
またはアリール基、あるいは保護基)。 Y:水素原子又は水酸基。 B:核酸塩基類または核酸塩基類縁体の残基。[Claims] 1. A 3-deoxy-3-fluoro-5-substituted-D-ribofuranoside derivative represented by the following formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I] However, X: NR^1R^2 (R^1 and R^2 are hydrogen atoms, alkyl groups or aryl groups that may contain substituents , or protecting group), -N_3 group, -SR^3(R
^3 is a hydrogen atom, an alkyl group or aryl group that may contain a substituent, or a protective group). Y: hydrogen atom or hydroxyl group. B: Residues of nucleobases or nucleobase analogs.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP24433488A JPH0296590A (en) | 1988-09-30 | 1988-09-30 | Novel nucleic acids |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP24433488A JPH0296590A (en) | 1988-09-30 | 1988-09-30 | Novel nucleic acids |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0296590A true JPH0296590A (en) | 1990-04-09 |
Family
ID=17117163
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP24433488A Pending JPH0296590A (en) | 1988-09-30 | 1988-09-30 | Novel nucleic acids |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0296590A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994026762A1 (en) * | 1993-05-12 | 1994-11-24 | Rhone-Poulenc Chemicals Limited | Preparation of fluoro-nucleosides and intermediates for use therein |
WO1994026756A1 (en) * | 1993-05-12 | 1994-11-24 | Rhone-Poulenc Chemicals Limited | Preparation of fluoro-compounds |
WO2002051425A1 (en) * | 2000-12-26 | 2002-07-04 | Mitsubishi Pharma Corporation | Remedies for hepatitis c |
-
1988
- 1988-09-30 JP JP24433488A patent/JPH0296590A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994026762A1 (en) * | 1993-05-12 | 1994-11-24 | Rhone-Poulenc Chemicals Limited | Preparation of fluoro-nucleosides and intermediates for use therein |
WO1994026756A1 (en) * | 1993-05-12 | 1994-11-24 | Rhone-Poulenc Chemicals Limited | Preparation of fluoro-compounds |
WO2002051425A1 (en) * | 2000-12-26 | 2002-07-04 | Mitsubishi Pharma Corporation | Remedies for hepatitis c |
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