NO171167B - Analogifremgangsmaate ved fremstilling av cytidin-derivater - Google Patents
Analogifremgangsmaate ved fremstilling av cytidin-derivater Download PDFInfo
- Publication number
- NO171167B NO171167B NO885106A NO885106A NO171167B NO 171167 B NO171167 B NO 171167B NO 885106 A NO885106 A NO 885106A NO 885106 A NO885106 A NO 885106A NO 171167 B NO171167 B NO 171167B
- Authority
- NO
- Norway
- Prior art keywords
- deoxy
- fluorocytidine
- fluoro
- general formula
- radical
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 5
- UHDGCWIWMRVCDJ-XVFCMESISA-N cytidine Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-XVFCMESISA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 48
- -1 R 4 is H Chemical group 0.000 claims description 26
- YSNABXSEHNLERR-ZIYNGMLESA-N 5'-Deoxy-5-fluorocytidine Chemical class O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)N=C(N)C(F)=C1 YSNABXSEHNLERR-ZIYNGMLESA-N 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- JKWULWVOMMYNEZ-XYHAGOFUSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]butanamide Chemical compound C1=C(F)C(NC(=O)CCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 JKWULWVOMMYNEZ-XYHAGOFUSA-N 0.000 claims description 5
- 239000012453 solvate Substances 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- TVYPSLDUBVTDIS-FUOMVGGVSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]-3,4,5-trimethoxybenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NC=2C(=CN(C(=O)N=2)[C@H]2[C@@H]([C@H](O)[C@@H](C)O2)O)F)=C1 TVYPSLDUBVTDIS-FUOMVGGVSA-N 0.000 claims 1
- RHPKHUVKXRTPPD-GDECHXLSSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]-3-methylbutanamide Chemical compound C1=C(F)C(NC(=O)CC(C)C)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 RHPKHUVKXRTPPD-GDECHXLSSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 230000000259 anti-tumor effect Effects 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 201000008808 Fibrosarcoma Diseases 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 208000006268 Sarcoma 180 Diseases 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- NDVQNPZZOOEOPJ-GFOCRRMGSA-N 4-amino-1-[(2r,3r,4r,5r)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-5-methyloxolan-2-yl]-5-fluoropyrimidin-2-one Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)O[C@H]1N1C(=O)N=C(N)C(F)=C1 NDVQNPZZOOEOPJ-GFOCRRMGSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 231100001231 less toxic Toxicity 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- HATCSTARTNBVPI-VPCXQMTMSA-N s-ethyl n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]carbamothioate Chemical compound C1=C(F)C(NC(=O)SCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 HATCSTARTNBVPI-VPCXQMTMSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 231100001274 therapeutic index Toxicity 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JAPYIBBSTJFDAK-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC(C(C)C)=C(S(Cl)(=O)=O)C(C(C)C)=C1 JAPYIBBSTJFDAK-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KHPIVIXIHDRKGY-APMYSVDZSA-N CCCC(=O)C1(C(=CN(C(=O)N1)[C@H]2[C@@H]([C@@H]([C@H](O2)C)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)F)N Chemical compound CCCC(=O)C1(C(=CN(C(=O)N1)[C@H]2[C@@H]([C@@H]([C@H](O2)C)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)F)N KHPIVIXIHDRKGY-APMYSVDZSA-N 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000006552 Lewis Lung Carcinoma Diseases 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- SEVXQFIQWMWYHB-LCPZFUNLSA-N [(2r,3r,4r,5r)-5-(4-amino-5-fluoro-2-oxopyrimidin-1-yl)-4-benzoyloxy-2-methyloxolan-3-yl] benzoate Chemical compound O([C@H]1[C@@H](O[C@@H]([C@H]1OC(=O)C=1C=CC=CC=1)C)N1C(N=C(N)C(F)=C1)=O)C(=O)C1=CC=CC=C1 SEVXQFIQWMWYHB-LCPZFUNLSA-N 0.000 description 2
- IRKZORYJTVUDGR-LHNIVKCTSA-N [(2r,3s,4r,5r)-5-(4-amino-5-fluoro-2-oxopyrimidin-1-yl)-4-hydroxy-2-methyloxolan-3-yl] benzoate Chemical compound O([C@H]1[C@@H](O)[C@@H](O[C@@H]1C)N1C(N=C(N)C(F)=C1)=O)C(=O)C1=CC=CC=C1 IRKZORYJTVUDGR-LHNIVKCTSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
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- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
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- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
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- XRSDKTOPWHLBFL-VPCXQMTMSA-N (2s,3r,4s,5r)-2-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxolane-2-carbaldehyde Chemical compound O=C1N=C(N)C=CN1[C@@]1(C=O)[C@H](O)[C@H](O)[C@@H](CO)O1 XRSDKTOPWHLBFL-VPCXQMTMSA-N 0.000 description 1
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- LXZSBXXDWRABCS-BTVNHDEBSA-N 6-amino-3-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-heptanoyl-1H-pyrimidin-2-one Chemical compound C1=CC(C(=O)CCCCCC)(N)NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 LXZSBXXDWRABCS-BTVNHDEBSA-N 0.000 description 1
- QIMILDBMISQIPJ-GGTFDOENSA-N 6-amino-6-(2-chlorobenzoyl)-3-[(2R,3R,4S,5R)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-1H-pyrimidin-2-one Chemical compound ClC1=C(C(=O)C2(NC(N([C@H]3[C@H](O)[C@H](O)[C@@H](C)O3)C=C2F)=O)N)C=CC=C1 QIMILDBMISQIPJ-GGTFDOENSA-N 0.000 description 1
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- CDMMRFUWLOGTJK-UHEGPQQHSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]-4-nitrobenzamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)N=C(NC(=O)C=2C=CC(=CC=2)[N+]([O-])=O)C(F)=C1 CDMMRFUWLOGTJK-UHEGPQQHSA-N 0.000 description 1
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- JACNBFSKIJZBGJ-FRJWGUMJSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]-5-methylthiophene-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)N=C(NC(=O)C=2SC(C)=CC=2)C(F)=C1 JACNBFSKIJZBGJ-FRJWGUMJSA-N 0.000 description 1
- YXEYSFNNZBSFNU-MSTPSEHLSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]-5-nitrofuran-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)N=C(NC(=O)C=2OC(=CC=2)[N+]([O-])=O)C(F)=C1 YXEYSFNNZBSFNU-MSTPSEHLSA-N 0.000 description 1
- DZSQWRWPYSENHZ-FJGDRVTGSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]formamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)N=C(NC=O)C(F)=C1 DZSQWRWPYSENHZ-FJGDRVTGSA-N 0.000 description 1
- SSADFGJQEZHNLJ-ZRFIDHNTSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]furan-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)N=C(NC(=O)C=2OC=CC=2)C(F)=C1 SSADFGJQEZHNLJ-ZRFIDHNTSA-N 0.000 description 1
- DTFZNTQODBDJLW-QMBPOEKNSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]hexadecanamide Chemical compound C1=C(F)C(NC(=O)CCCCCCCCCCCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 DTFZNTQODBDJLW-QMBPOEKNSA-N 0.000 description 1
- IRHHXZDOVVASFR-LHNIVKCTSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]hexanamide Chemical compound C1=C(F)C(NC(=O)CCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 IRHHXZDOVVASFR-LHNIVKCTSA-N 0.000 description 1
- KNSASLUGVARYPH-YOSASSMQSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]naphthalene-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)N=C(NC(=O)C=2C=C3C=CC=CC3=CC=2)C(F)=C1 KNSASLUGVARYPH-YOSASSMQSA-N 0.000 description 1
- WKQCODJZOXZXFI-BNGXUDDSSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]nonanamide Chemical compound C1=C(F)C(NC(=O)CCCCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 WKQCODJZOXZXFI-BNGXUDDSSA-N 0.000 description 1
- RGPIOUHFMVHLSO-UCRVAIAZSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]octadecanamide Chemical compound C1=C(F)C(NC(=O)CCCCCCCCCCCCCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 RGPIOUHFMVHLSO-UCRVAIAZSA-N 0.000 description 1
- UVWGFHQHHZEJLI-GDECHXLSSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]pentanamide Chemical compound C1=C(F)C(NC(=O)CCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 UVWGFHQHHZEJLI-GDECHXLSSA-N 0.000 description 1
- ZOGCJXDLLWKJKR-MGUDNFKCSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]propanamide Chemical compound C1=C(F)C(NC(=O)CC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 ZOGCJXDLLWKJKR-MGUDNFKCSA-N 0.000 description 1
- NRAIUCAQWOSCHV-ZRFIDHNTSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]thiophene-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)N=C(NC(=O)C=2SC=CC=2)C(F)=C1 NRAIUCAQWOSCHV-ZRFIDHNTSA-N 0.000 description 1
- AEYWPRODWLOEFK-UHFFFAOYSA-N n-methylmethanamine;pyridine Chemical compound CNC.C1=CC=NC=C1 AEYWPRODWLOEFK-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GRSBAMVBFWRBBH-UHFFFAOYSA-N o-ethyl chloromethanethioate Chemical compound CCOC(Cl)=S GRSBAMVBFWRBBH-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- WIAYGVFTFGYKHU-XKVFNRALSA-N octyl n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]carbamate Chemical compound C1=C(F)C(NC(=O)OCCCCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 WIAYGVFTFGYKHU-XKVFNRALSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000005040 tridecenyl group Chemical group C(=CCCCCCCCCCCC)* 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 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
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører analogifremgangsmåte ved fremstilling av terapeutisk aktive 5'-desoksy-5-fluorcytidin-derivater.
Nærmere bestemt angår den foreliggende oppfinnelse fremstilling av nye 5<1->desoksy-5-fluorcytidin-derivater med den generelle formel (I),
hvor R1 er R<4>CO-, R<5>OCO eller R<6>SCO,
2 3
R og R er H eller benzoyl,
R 4er H, alkenyl; cykloalkyl; alkyl; evt. med en eller flere lavere alkyl-, lavere alkanoyl-, lavere alkoksy-, halogen-, nitro-, lavere alkoksykarbonyl-, lavere alkyl-tio- eller alkylendioksygrupper substituert fenyl; naf-tyl; evt. med lavere alkoksy substituert fenyllavere alkyl eller alkenyl; benzyl; pyridyl; en evt. med en lavere alkyl eller nitro substituert tienyl-, furyl-eller pyrrolgruppe eller en benzopyrrolalkylgruppe,
R 5 er alkyl eller benzyl, og
R er alkyl,
samt hydrater eller solvater av forbindelsene med den generelle formell (I), hvilke er brukbare som effektive bestand-deler i antitumor-midler.
Uttrykket "alkyl" henviser i denne beskrivelse til rette eller forgrenede kjeder som har 1. til 19 karbonatomer f.eks. metyl, etyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl isopentyl, neopentyl, heksyl, usiheksyl, heptyl, oktyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, heksadecyl, heptadecyl og nonadecyl. Uttrykket "cykloalkyl" betyr her f.eks. cyklopropyl, cyklobu-tyl, cyklopentyl, cykloheksyl og adamantyl.
Uttrykket "cykloalkyl" betyr her f.eks. cyklopropyl, cyklo-butyl, cyklopentyl, cykloheksyl og adamantyl.
Uttrykket "alkenyl" betyr en usubstituert eller gubstituert alkenylradikal som har 3 til 19 karbonatomer, såsom allyl, butenyl, 3-metyl-2-butenyl, l-metyl-2-propenyl, heksenyl, decenyl, undecenyl, tridecenyl, pentadecenyl, heptadecenyl, heptadecadienyll, heptadecatrienyl, nonadecenyl, nonadecadie-nyl, nonadecatetraenyl og 2-fenylvinyl.
Spesielt foretrukne 5'-deoksy-5-fluorcytidin-derivater som kan fremstilles ved den foreliggende oppfinnelse er: N 4-butyryl-5 ' -deoksy-5-f luorcytidm,
5'-deoksy-5-fluor-N 4-isovalerylcytidm,
5'-deoksy-5-fluor-N 4-(3,4,5-trimetoks<y>benzo<y>l)c<y>tidm,
Ytterligere eksempler på forbindelser med formel (I) er: N 4-acetyl-5 ' -deoksy-5-f luorcytidm, 5'-deoksy-5-fluor-N 4-propionylcytidin, 5'-deoksy-5-fluor-N 4-isobutyrylcytidm, 5' -deoksy-5-f luor-N 4- (2-metylbuturyl) cytidm, 5 ' -deoksy-N 4- (2-etylbutyryl) -5-fluorcytidm, 5'-deoksy-N 4-(3,3-dimet<y>lbut<y>r<y>l)-5-fluorc<y>tidm, 5 1 -deoksy-5-fluor-N 4-pivaloylcytidm, 5 ' -deoksy-5-fluor-N 4-valerylcytidin,
5'-deoksy-5-fluor-N 4-(2-metylvaleryl)cytidin, 5'-deoksy-5-fluor-N 4-(3-metylvaleryl)cytidin, 5'-deoksy-5-fluor-N 4-(4-metylvaleryl)cytidin, 5'-deoksy-5-fluor-N 4-heksanoylcytidin, 51-deoksy-5-fluor-N 4-heptanoylcytidin, 51-deoksy-5-fluor-N 4-oktanoylcytidin, 5'-deoksy-5-fluor-N 4-nonanoylcytidin, 5'-deoksy-5-fluor-N 4-heksadecanoylcytidin, N 4-benzoyl-5'-deoksy-5-fluorcytidin,
51-deoksy-5-fluor-N 4-(4-metylbenzoyl)cytidin, 5'-deoksy-5-fluor-N 4-(3-metylbenzoyl)cytidin, 5'-deoksy-5-fluor-N 4-(2-metylbenzol)-cytidin, 51-deoksy-N 4-(4-etylbenzoyl)-5-fluorcytidin, 5'-deoksy-N 4-(3,4-dimetylbenzoyl)-5-fluorcytidin, 51-deoksy-N 4-(3,5-dimetylbenzoyl)-5-fluorcytidin, 5'-deoksy-5-fluor-N 4-(4-metoksybenzoyl)cytidin, 5'-deoksy-N 4-(3,4-dimetoksybenzoyl)-5-fluorcytidin, 5'-deoksy-N 4-(3,5-dimetoksybenzoyl)-5-fluorcytidin, 5'-deoksy-fluor-N 4-(3,4, 5-trimetoksybenzoyl)cytidm, 5'-deoksy-5-fluor-N 4-(3,4,5-trietoks<y>benzo<y>l)c<y>tidm, 5'-deoksy-N 4-(4-etoksybenzoyl)-5-fluorcytidin, 5'-deoksy-5-fluor-N 4-(4-propoksybenzoyl)cytidin, 5'-deoksy-N 4-(3 , 5-dietoksybenzoyl)-5-fluorcytidm, N -(4-klorbenzoyl)-5'-deoksy-5-fluorcytidin, 5'-deoksy-N 4-(3,4-diklorbenzo<y>l)-5-fluorc<y>tidm, 5'-deoksy-N 4-(3,5-diklorbenzo<y>l)-5-fluorc<y>tidm, 5'-deoksy-5-fluor-N 4-(4-nitrobenzoyl)cytidin, 5'-deoksy-5-fluor-N 4-(4-metoks<y>karbon<y>lbenzo<y>l)c<y>tidm, N -(4-ecetylbenzoyl)-5<1->deoksy-5-fluorcytidin, 5'-deoksy-5-fluor-N 4-(fenylacetyl)cytidin, 5'-deoksy-5-fluor-N 4-(4-metoksyfenylacetyl)cytidin, 5 ' -deoksy-5-f luor-N 4-nikotinoylcytidm, 5<1->deoksy-5-fluor-N 4-isonikotino<y>lc<y>tidm, 51-deoksy-5-fluor-N 4-pikolinoylcytidin, 5'-deoksy-5-fluor-N 4-(2-furoyl)cytidin, 5'-deoksy-5-fluor-N 4-(5-nitro-2-furoyl)cytidin,
5'-deoksy-5-fluor-N 4-(2-thenoyl)cytidin,
5'-deoksy-5-fluor-N 4-(5-metyl-2-tenoyl)cytidin, 5'-depoksy-5-fluor-N 4-(l-metyl-2-pyrrolkarbonyl)cytidin, 5'-deoksy-5-fluor-N 4-(3-indolylacetyl)cytidin, N 4-(3-butenoyl)-5'-deoksy-5-fluorcytidin,
3'-0-benzoyl-5'-deoksy-5-fluorcytidin,
N 4-3'-0-dibenzoyl-5'-deoksy-5-fluorcytidin,
5'-deoksy-N 4-(etyltio)karbonyl-5-fluorcytidin, 5'-deoksy-5-fluor-N 4-oktadekanoylcytidin,
N 4-cyklopropankarbonyl-5'-deoksy-5-fluorcytidin, N 4-cykloheksankarbonyl-5'-deoksy-5-fluorcytidin, N 4-(1-adamantankarbonyl)-51-deoksy-5-fluorcytidin, 5 1 -deoksy-5-fluor-N 4-(2-metoksybenzoyl)cytidin,
5 ' -deoksy-N 4-(2,4-dimetoksybenzoyl)-5-fluorcytidin, 5 ' -deoksy-5-fluor-N 4-piperonyloylcytidin, 5'-deoksy-5-fluor-N 4-(4-fluorbenzoyl)cytidin, N 4-(2-klorbenzoyl)-5'-deoksy-5-fluorcytidin, N 4-(3-klorbenzoyl)-51-deoksy-5-fluorcytidin, 5 ' -deoksy-5-fluor-N 4-(3-nitrobenzoyl)cytidin, 5 ' -deoksy-5-fluor-N 4-[4-(metyltio)benzoyl]cytidin, 5'-deoksy-5-fluor-N 4-(2-naftoyl)cytidin,
5'-deoksy-5-fluor-N 4-(3-furoyl)cytidin,
5'-deoksy-5-fluor-N 4-(3-fenylpropionyl)cytidin, N 4-cinnamoyl-51-deoksy-5-fluorcytidin,
2',3'-di-0-benzoyl-5'-deoksy-5-fluorcytidin,
N 4,21-0,31-O-tribenzoyl-5'-deoksy-5-fluorcytidin, 5 '-deoksy-5-fluor-N 4-(oktyloksykarbonyl)cytidin, N 4-(benzyloksykarbonyl)-5'-deoksy-5-fluorcytidin og 5' -deoksy-5-fluor-N 4-formylcytidin.
De nye 5'-deoksy-5-fluorcytidin-derivater som er betegnet med den generelle formel (I) samt hydrater eller solvater av forbindelser med den generelle formel (I) fremstilles i samsvar med den foreliggende oppfinnelse ifølge en metode som omfatter en reaksjon mellom en forbindelse med den generelle formel (II) hvor R 7 betegner et hydrogenatom eller en amino-beskyttende radikal, R 8 og R 9 er uavhengig et hydrogenatom eller en hydroksybeskyttende radikal, eller R 8 og R 9 kan sammen danne en cyklisk hydroksybeskyttende radikal, med en forbindelse betegnet med den generelle formel
(III) ,
hvor X betegner en avgående radikal og R 4 er som
angitt ovenfor,
eller en forbindelse betegnet med den generelle formel
(IV) ,
hvor Y representerer et halogenatom og R betegner en radikal med formelen
5 6
hvor R og R er som angitt, ovenfor,
etterfulgt, hvis nødvendig, av fjerning av en beskyttende radikal.
Betegnelsen "amino-beskyttende radikal" betyr f.eks.
benzyloksykarbonyl, fenoksykarbonyl, 2 . 2.2.-trikloret-oksykarbonyl, etoksykarbonyl, tert-butoksykarbonyl og trifluor-acetyl. Betegnelsen "hydroksybeskyttende radikal" betyr f.eks. benzyl, metoksybenzyl, trimetylhylsi-lyl, trietylsilyl, isopropyldimetylsilyl, tert-butyldi-etylsilyl, tert-butyldifenylsilyl, teksyldimetylsilyl, allyl, metoksymetyl, (2-metoksyetoksy)metyl og tetrah-ydropyranyl.
Betegnelsen "cyklisk hydroksy-beskyttende radikal" betyr f.eks. cyklisk acetal, cyklisk ketal, cyklisk karbonat, cyklisk ortoester og syklisk 1,3-(1,1,3,3-tetraisopropyl) disiloksandiyl. Betegnelsen "avgående radikal" betyr f.eks. halogenatom, acyloksy, alkyloksykarbonyloksy, succinimidooksy, ftalimidooksy, 4-nitrofenyl, azido, 2, 4,6-triisopropylbenzensulfonyl og dietyloksyfosforyl-oksy. Betegnelsen "halogenatom" betyr klor, brom eller j od.
Blant forbindelsene som betegnes med den generelle formel (II) er 5'-deoksy-5-fluorcytidin en kjent forbindelse [J. Med. Chem. , 2_2, 1330 (1979)], og andre forbindelser som betegnes med den generelle formel (II) kan fremstilles av 5'-deoksy-5-fluorcytidin ved hjelp av kjente metoder eller av 5'-deoksy-5-fluoruridin ved en metode beskrevet i litteraturen [Chem.Pharm. Bull., 33., 2575 (1985)].
Forbindelsene med formel (III) som brukes i ovenstående reaksjon er sure halider, sure anhydrider, blandede anhydrider [fremstilt ved reaksjon melleom R 4C02H og 2,4,6-triisopropylbensensulfonylklorid eller dietylklorfosfat (hvor R 4 er den samme som definert ovenfor)], aktiverte estere (så som N-hydroksysuccinimid-estre, N-hydroksy-ftalimid-estre, 4-nitrofenylestre og lign.), acylazider eller blandede karbonanhydrider.
Reaksjonen mellom en forbindelse med den generelle formel (II) og en forbindelse med den generelle formel (III) eller (IV) kan utføres i et løsningsmiddel som pyridin, dioksan, tetrahydrofuran, acetonitril, kloroform, diklormetan, metanol, etanol eller vann. En blanding av to eller flere løsningsmidler kan også brukes. Reaksjonen kan utføres i nærvær av en syreakseptor, såsom trietylamin, pyridin, pikolin, dimetylaminpyridin, lutidin, N,N-dimetylanilin eller et alkalimetal-hydroksid, -karbonat eller -fosfat. Reaksjonstemperaturen i ovenstående reaksjon kan varieres innen et relativt stort område. Vanligvis utføres reaksjonen ved en temperatur mellom ca 0°C og 120°C, fortrinnsvis mellom 0°C og 50°C. Ved utførelsen av reaksjonen bruker man 1, 2 eller 3 mol eller overskudd av forbindelsen med formel (III) eller (IV) per mol forbindelse med formel (II).
Den beskyttende radikal kan om nødvendig fjernes etter reaksjonen ved hjelp av kjente metoder.
Forbindelsene som fås ved denne oppfinnelses fremgangsmåte, kan isolereres og rengjøres ved konvensjonelle tek-nikker så som inndampning, filtrering, ekstraksjon, ut-feining, kromatografi, omkrystallisering eller en kombi-nasjon av disse.
Forbindelsene med formel (I) kan eksistere både i oppløs-te og uoppløste former, samt i hydratiserte former. Hyd-ratiseringen kan utføres i løpet av fremstillingsproses-sen eller kan oppstå gradvis som resultat av hygroskop-iske egenskaper hos et opprinnelig anhydrert produkt. For å kontrollere fremstillingen av et hydrat, kan et full-stendig eller delvis anhydrert produkt utsettes for en fuktig atmosfære (f.eks. ved +10°C til 40°C). Solvater med farmasøytisk akseptable løsningsmidler så som etanol kan oppnås f.eks. i løpet av en krystallisering.
5'-deoksy-5-fluorcytidin-derivater betegnet med den generelle formel (I) samt hydrater eller solvater av forbindelser med den generelle formel (I) fremstilt ved den foreliggende oppfinnelse er virkningsfulle mot sarcoma 180, Meth A-fibrosarcoma og Lewis lunge-carcinoma i mus over et stort doseringområde både oralt og parenteralt og er nyttige som antitumor-midler. I alminnelighet forårsaker 5-fluoruracil og dens derivater tarmforgiftninger og immunosuppressive forgiftninger, hvilket er deres viktig-ste og doseringsbegrensende giftighet. 5'-deoksy-5-fluorcytidin-derivatene i denne oppfinnelse er meget forbedret når det gjelder sikkerhet. Når de gis oralt, forårsaker
de mindre forgiftning i tarmen og immunsystemet enn 5-fluoruracil (J.A.C.S. 79, 1957, 4559) og dens typiske forløpere tegafur:uracil=l:4 (UFT) og 5'-deoksy-5-fluoruridin (US 4071680). Deror kan forbindelsene som kan fremstilles i foreliggende oppfinnelse, brukes effektivt i behandlingen av forskjellige svulster i mennesker.
Den foreliggende oppfinnelse angår videre farmasøytiske preparater som innholder en eller flere forbindelser fra oppfinnelsen.
Forbindelsene i den foreliggende oppfinnelse kan gis oralt eller ikke-oralt til mennesker ved hjelp av forskjellige konvensjonelle metoder. Videre kan forbindelsene gis alene eller sammensatt med et kompatibelt farma-søytisk bærermaterial. Dette bærermaterial kan være et organisk eller uorganisk inert bærermaterial som passer til å gis enteralt, perkutant eller parenteralt, så som vann, geletin, gummi arabikum, laktose, stivelse, magne-siumstearat, talkum, vegetabilskeoljer, polyalkylenglyko-ler eller vaselin. Farmasøytiske .preparater kan lages i fast form (f.eks. tabletter, drageer, enterisk belagte tabletter, granulater, enterisk belagte granulater, sup-positorier, kapsler eller' enteriske kapsler), i halvfast form (f.eks. som salver) eller i flytende form (f.eks. oppløsninger, suspensjoner eller emulsjoner). De farma-søytiske preparater kan steriliseres og/eller kan inne-holde andre hjelpestoffer så som konserverings-, stabili-serings-, størknings- eller emulgeringsmidler, smaksfor-bedrende midler, salter for å variere det osmotiske tryk-ket eller stoffer som virker som buffer. De farmasøytiske preparater kan fremstilles på kjent måte.
Forbindelsene i foreliggende oppfinnelse kan brukes alene eller sammen med to eller flere forskjellige forbindelser, og mengden av forbindelsene er ca 0.1 til 99,5%, fortrinnsvis 0,5 til 9 5% av det medisinske preparatets vekt.
Det medisinske preparat kan som en blanding av en eller flere av forbindelsene med formel (I) og konvensjonelle forbindelser som er farmasøytisk aktive.
Doseringen per dag til en pasient av de nye 5'-deoksy-5-fluorcytidin-derivatene i denne oppfinnelsen kan varieres i henhold til pasientens vekt og tilstand som skal botes, men vanligvis er doseringen fra 0,5 til 7 00 mg per kg kroppsvekt, fortrinnsvis ca. 3 til 500 mg.
Antitumorvirkningene av forbindelsene i foreliggende oppfinnelse vises som følger:
Antitumor- undersøkelse mot Sarcoma 180
Sarcoma 180-celler (2 x 106 celler) ble implantert subkutant i mus (20 - 22 g) på dag 0. Forbindelsene fremstilt i foreliggende oppfinnelse ble gitt daglig oralt fra dag 1 til 7. Dyrene ble avlivet på dag 14 og svulster ble skåret ut og veid. Svulstens prosentuale veksthemning i tabell 1 nedenfor ble kalkulert utfra formelen:
T = vekten av svulstene fra den behandlede gruppen C = vekten av svulstene fra kontrollgruppen.
Antitumor- undersøkelse på Meth A fibrosarcoma
Meth A fibrosarcoma-celler (2 x 105) ble implantert subkutant i mus (21 - 22 g). Undersøkelsen på Meth A fibrosarcoma og beregningen av prosentual hemning i svulstveksten ble gjort på samme måte som for sarcoma 180. Resultatene er vist i tabell 2.
Den sammenlignende undersøkelsen på antitumor-aktivitet hos en typisk forbindelse (eksempel 3) med 5'-deoksy-5-fluoruridin ble gjort på samme måte som antitumor-under-søkelsen på Meth A fibrosarcoma. Resultatet fra dette eksperimentet og den iakttagelse av faeces på dag 8 vises i Tabell 3. Resultatene indikerer at forbindelsen fra eksempel 3 er mer virkningsfull som antitumor-middel og mindre giftig enn 5'-deoksy-5-fluoruridin. I det samme eksperiment forårsaket forbindelsen i eksempel 3 ikke diaré, hvilket er en dose-begrensende faktor for 5'-deoksy-5-fluoruridin.
Sammenlignende antitumor- undersøkelse på Lewis lunae-carcinoma
Antitumor-virksomhet hos en typisk forbindelse (eksempel 1) i foreliggende oppfinnelse ble sammenligenet med den hos 5'-deoksy-5- fluoruridin og et kombinasjonsmedika-ment, UFT (tegafur:uracil = 1:4). Mus ble innpodet subkutant med Lewis lunge-carcinoma (106 celler) på dag 0. Forbindelsene ble gitt daglig peroralt 14 ganger fra dag 1. Den virksomme dose (ED5Q) hvor svulstveksten ble hemmet med 50% og toksiske doser ble bestemt. Terapeutisk indeks
(toksisk dose/ED 50) som man fikk fra eksperimentene er vist i tabell 4. Som tabell 4 viser, har forbindelsen fra foreliggende oppfinnelse høyere terapeutisk indeks enn typiske medikamenter av 5-fluoruracil, 5'-deoksy-5-fluoruridin og UFT. Den var mindre toksisk for tarmkanalen (diaré) og immunansvarlige organer (thymus og benmarg). Dette indikerer at forbindelsen fra foreliggende oppfinnelse har større sikkerhetspotensial.
Sammenlignende antitumor- undersøkelse mot sarcoma 180, Meth A fibrosarcoma og UV 2237 fibrosarcoma
Antitumor-virkningen av en representativ forbindelse (eksempel 1) i den foreliggende oppfinnelse i tre svulstmodeller hos mus ble sammenlignet med antitumorvirkningen av 5'-deoksy-5-fluoruridin og 5'-deoksy-5-fluorcytidin. Mus ble innpodet subkutant med henholdsvis sarcoma 180, Meth A fibrosarcoma og UV 2237 fibrosarcoma på dag 0. Musene ble gitt daglig oralt av forbindelsene 7 ganger fra dag 1. Virkningen ble uttrykt som terapeutisk indeks (EDmax/ED5o) målt på dag 14 etter svulst-innpodningen, hvor EDm=v er den dosen som viser maksimum hemning isvulst veksten. Resultatene man fikk fra eksperimentene, vises i tabell 5.
Akutt toksisitet
Den akutte toksisitet (LD5Q) hos den representative forbindelse i denne oppfinnelse (eksempel 1, 5, 9, 24, 34, 46 og 47) ble undersøkt ved å gi den oralt til mus. De tilhørende LD5Q-verdiene som man fikk fra eksperimentene var høyere enn 2.000 mg/kg.
Følgende eksempler illustrerer de foretrukne metoder for å fremstille forbindelsene i foreliggende oppfinnelse.
Referanse- eksempel
a) 5'-deoksy-5-fluorcytidin (245 mg), tert-butyldimetylsilyl-klorid (254 mg) og imidazol (284 mg) ble oppløst i dimetyl-foramid (1,5 ml). Blandingen ble rørt i 18 timer ved værel-ses temperatur under nitrogenatmosfære. Reaksjonsblandingen ble deretter helt i vann og ekstrahert med etylacetat. Eks-traktet ble vasket med vann, tørket over anhydrert natriumsulfat og konsentrert under redusert trykk, og man fikk 2',3'-bis-O-(tert-butyldimetylsilyl)-5'-deoksy-5-fluorcytidin (413 mg) , MS 473 (M<+>) . b) En oppløsning av 5'-deoksy-5-fluorcytidin (490 mg), p-toluensulfonsyre-monohydrat (418 mg) og 2,2-metoksypropan
(984 ul) i aceton (10 ml) ble rørti 1,5 timer ved værelsestemperatur. Løsningen ble tilsatt natriumhydrogenkarbonat (900 mg), og blandingen ble rørt i 4 timer ved værelsestemperatur. Felningen ble filtrert av og vasket med aceton. Det samlede filtrat ble konsentrert under redusert trykk. Bunn-fallet ble renset ved hjelp av silikagel kolonnekromatografi (diklormetan - metanol) og gav 5'-deoksy-5-fluor-2',3'-0-isopropylidencytidin (57 0 mg), MS 286 (MH<+>); pikratets smeltepunkt 169-171°C.
Eksempel 1
1(a) 2',3'-bis-O-(tert-butyldimetylsilyl)-5 *-deoksy-5-fluorcytidin (9,46 g) som man hadde fått i referanse-eksempel a), n-butyranhudrid (3,48 g) og 4-dimetylaminopyridin (2,93 g) ble oppløst i metylenklorid (150 ml). Oppløsningen ble omrørt over natten , deretter vasket med vann, tørket over anhydrert natriumsulfat og konsentrert under redusert trykk og gav N 4-butyryl-2',3'-bis-O-(tert-bytyldimetylsilyl)-5'-deoksy-5-fluorcytidin (9,75 g), MS 544 (NH<+>). ;l(b) Produktet fra eksempel l(a) (9,75 g) ble oppløst i tetrahydrofuran (80 ml) som inneholdt 80 mmol tetrabutylammoniumfluorid. Reaksjonsblandingen ble rørt i 1,5 timer ved værelsestemperatur. Etter at løsningsmiddelet var fjernet under redusert trykk, ble resten renset ved hjelp av silikagel-kolonnekromatografi (etylacettat- metanol) etterfulgt av rekrystallisering fra metanol hvilket gav N 4-butyryl-5'-deoksy-5-fluorcytidin (4,5 g). smeltepunkt 156-157°C, MS 316 ;(MH<+>). ;Følgende forbindelser ble fremstilt med samme fremgangsmåte som i eksempel 1: ;Eksempel 4 ;4 (a) 2',3'-bis-O-(tert-butyldimetylsilyl)-5'-deoksy-5-fluorcytidin (14,19 g) som man fikk i referanse-eksempel a) ble oppløst i tørt pyridin (150 ml). Oppløsningen ble tilsatt dråpevis til n-butyrylklorid (3,84 g) under omrøring. Reak-sj onsblandingen ble rørt over natten. Pyridinet ble fjernet under redusert trykk, og resten skilt mellom vann og etylacetat. Etylacetatlaget ble vasket med vann, tørket over anhydrert natriumsulfatogkonsentrert under redusert trykk. Resten ble renset ved hjelp av silikagel-kolonnekromatografi (n-heksan - etylacetat) og gav N 4-butyryl-2',3'-bis-O-(tert-bytyldimetylsilyl)-5'-deoksy-5-fluorcytidin (15,32 g). ;4(b) Produktet fra eksempel 4(a) ble behandlet på samme måte som i eksempel 1 (b) og gav krystaller av N 4-butyryl-5'-deoksy-5-fluorcytidin. ;Følgende forbindelser ble fremstilt på samme måte som i eksempel 4: ;Eksempel 4 3 ;5'-deoksy-5-fluorcytidin (735 mg) og butyranhydrid 91,o4 g) ble oppløst i 7 5% vandig dioksan (20 ml). Blandingen ble rørt i 18 timer ved værelsestemperatur. Etter at løsningsmiddelet var fjernet, ble resten renset ved hjelp av silikagel-kolonnekromatografi og gav farveløse krystaller av N 4-butyryl-5'-deoksy-5-fluorcytidin (420 mg), smeltepunkt 156-157°C; MS 316 ;(MH<+>). ;Eksempel 44 ;(1) 5'-deoksy-5-fluorcytidin (4,9 g) og dimetylsilylklorid (5,58 g) ble oppløst i tørt pyridin (50 ml9. Blandingen ble rørt i to timer. Reaksjonsblandingen ble tilsatt etylklor-tioformat (2,09 ml). Etter at blandingen var blitt rørt i 2,5 timer, ble pyridinet avdampet under redusert trykk. Resten ble skilt mellom vann og etylacetat. Den organiske fasen ble vasket med vann, tørket over anhydrert natriunsulfat og konsentrert under redusert trykk. Sitronsyre (5 g) og metanol (80 ml) tilsattes resten. Blandingen ble rørt i 1 time. Etter at løsningsmiddelet var fjernet under redusert trykk, ble resten renset ved hjelp av silikagel-kolonnekromatografi (metanoldiklormetan) etterfulgt av rekrystallisering i diklormetan . Dette gav 2,66 g 5'-deoksy-N 4-[(etyltio)kar-bonyl] -5-f luorcytidin, smeltepunkt 138-139°C (dek.); MS 334 ;(MH<+>). ;(2) (a) Til en omrørt oppløsning av 5'-deoksy-5-fluor-2<1>,3'-0-isopropylidencytidin (1 g) som man fikk i referanse-eksempel ;b) i pyridin (8 ml) ble det tilsatt etylklorotioformat (365 ul) ved 0°C, og blandingen ble omrørt ved værelsestemperatur ;over natten. Reaksjonsblandingen ble konsentrert under redusert trykk, og resten ble skilt mellom etylacetat og vann. Den organiske fasen ble vasket med natriumhydrogenkarbonat-løsning og vann og tørket over anhydrert natriumsulfat. Etter at løsningsmiddelet var fjernet, ble resten renset ved hjelp av silik4agel-kolonne-kromatografi (CHC13), hvilket gav 5'-deoksy-N -[(etyltio)karbonyl]-5-fluor-21,3'-0-isopropyliden-cytidin (510 mg), MS 374 (MH<+>). ;(b) En løsning av. produktet i eksempel 44(2)(a) (150 mg) i 50% vandig etanol ble tilsatt Dowex 50 (H<+>) (150 mg), og blandingen ble oppvarmet ved 50 - 60°C under omrøring i 4 timer. Dowex 50 ble filtrert av, og filtratet ble konsentrert til tørrhet under redusert trykk. Resten ble renget ved hjelp av silikagelkolonne-kromatografi (CHC13), etterfulgt av ;rekrystallisenng hvilket gav 5 '-deoksy-N 4-[ (etyltio) kar-bonyl] -5-fluorcytidin, smeltepunkt 138 - 139°C (dek.), MS 334 ;(MH<+>). ;Følgende forbindelser ble fremstilt i henhold til fremgangs-måten i eksempel 44 (1) : ;Eksempel 48 ;En løsning av piperonylsyre (0,42 g) i tørt acetonitril (5 ml) som inneholdt trietylamin (0,36 ml) ble behandlet med dietylklorfosfat (0,37 ml) i 1 time. Reaksjonsblandingen ble tilsatt 2',3'-bis-O-(tert-bytyldimetylsilyl)-5'-deoksy-5-fluorcytidin (1,0 g) som var fremstilt etter metoden i eksempel a), trimetylamin (0,36 ml) og 4-dimetylaminpyridin (0,05 ;g). Etter at blandingen var omrørt i 12 timer ved værelsestemperatur, ble acetonitrilen inndunstet under redusert ;trykk. Resten ble skilt mellom vann og eter. Det organiske sjiktet ble vasket med vann, tørket over anhydrert natriumsulfat og konsentrert under redusert trykk. Pulveret som man fikk, ble oppløst i tetrahydrofuran (6,3 ml) som innholdt tetrabutylammoniumfluorid (1,65 g), og reaksjonsblandingen , ble rørt i en time. Etter at løsningsmiddelet var fjernet under redusert trykk, ble resten renset ved hjelp av silikagelkolonne-kromatografi (isopropanol - diklormetan), etterfulgt av rekrystallisering i etylacetat hvilket gav 0,5 g 5'- ;deoksy—5-fluor-N 4-piperonyloylcytidin, smeltepunkt 124 - 125°C (dek.), MS 394 (MH<+>). ;Følgende forbindelser ble fremstilt på samme måte som i eksempel 48: ;Eksempel 50 ;3-Furonsyre (0,355 g) og 2,4,6-triisopropylbenzensulfonyl-klorid (0,96 g) ble oppløst i tørt pyridin (5 ml). Blandingen ble rørt i 1 time. Blandingen ble tilsatt 2<1>,3'-bis-O-(tert-butyldimetylsilyl) -5 ' -deoksy-5-f luorcytidin (1,0 g) som var fremstilt etter referanseeksempel a), og 4-dimetylaminopyridin (0,80 g). Etter at blandingen var rørt i 12 timer ved værelsestemperatur, ble pyridinet inndunstet under redusert trykk. Resten ble så behandlet som i eksempel 48 hvilket gav 5'-deoksy-5-fluor-N 4-(3-furoyl)cytidin, smeltepunkt 173-174°C (etanol), MS 340 (MH<+>). ;Følgende forbindelser ble fremstilt på samme måte som i eksempel 50: ;Eksempel 57 ;(a) Til en omrørt løsning av 5'-deoksy-5-fluorurudin (24,6 g) i tørt pyridin (150 ml) ble det tilsatt dråpevis 24,5 ml benzoylklorid i en periode av 10 minutter ved 0°C, og blandingen ble omrørt i 5 timer ved værelsestemperatur. Etter at pyridinet var fjernet under redusert trykk, ble resten skilt mellom vann og etylacetat. Det organiske sjiktet ble vasket med mettet natriumhydrogenkarbonat-løsning og vann, tørket over anhydrert natriumsulfat og konsentrert under redusert trykk. Resten ble rekrystallisert fra etylacetat-n-heksan hvilket gav 38,9 g 2',3'-di-O-benzoyl-5'-deoksy-5-fluoruridin, MS 455 (MH<+>). (b) Til en blanding av N-methylimidazol (0,8 ml) og fosforyl-klorid (0,28 ml) i acetonitril (20 ml) ble det ved 0°C tilsatt 2',3'-di-O-benzoyl-5'-deoksy-5-fluorcytidin (500 mg) fra ovenstående eksempel. Etter omrøring av reaksjonsblandingen i 1,5 timer ved værelsestemperatur ble det tilsatt 28% ammoni-umhydroksyd (2,5 ml) ved 0°C, og blandingen ble omrørt i 1 time ved værelsestemperatur. Acetonitril og ammoniak ble fjernet under redusert trykk. Resten ble gjort surt med 1N-HC1 og så ekstrahert med etylacetat. Det organiske sjektet ble vasket med vann, tørket over anhydrert natriumsulfat og konsentrert under redusert trykk. Resten ble rekrystallisert fra etylacetat og gav 155 mg 2<*>,3'-di-O-benzoyl-5'-deoksy-5-fluorcytidin, smeltepunkt 192-194°C, MS 476 (M+Na+) .
Eksempel 5 8
(a) Til iskald eddiksyreanhydrid (0,57 ml) ble det tilsatt dråpevis 99% maursyre (286 ml). Blandingen ble omrørt i 15 minutter ved 0°C og i 50 minutter ved 50°C og deretter av-kjølt til 0°C. Løsningen ble tilsatt 2',3'-bis-O-(tert-butyl-dimetylsilyl) -5'-deoksy-5-fluorcytidin (473 mg) fra referanseeksempel a) i tørt pyridin (5 ml) ved 0°C. Reaksjonsblandingen ble omrørt i 10 minutter ved 0°C og i 26 timer ved værelsestemperatur. Etter fjerning av løsningsmiddelet under redusert trykk, ble resten skilt mellom vann og etylacetat. Det organiske sjiktet ble vasket med mettet natriumhydrogenkarbonat-løsning og vann og tørket over anhydrert natriumsulfat. Etylacetaten ble dunstet vekk under reduserttrykk , og resten ble renset ved hjelp av silikagelkolonne-kromatografi (n-heksan - etylacetat) etterfulgt av rekrystallisering i n-heksan - etylacetat hvilket gav 2',3'-bis-O-(tert-butyldimet-ylsilyl)-5'-deoksy-5-fluor-N 4-formylcytidin, smeltepunkt 188°C (dek.), MS 502 (MH+) . (b) Produktet fra eksempel 58(a) ble behandlet på samme måte som i eksempel 1 (b) og gav et amorft pulver 5'-deoksy-5-fluor-N<4->formylcytidin, MS 274 (MH<+>).
Eksempel 59
5'-deoksy-5-fluorcytidin (245) ble oppløst i tørt pyridin (5 ml). Løsningen ble tilsatt benzoylklorid (130 ul) under
omrøring ved 0°C. Reaksjonsblandingen ble omrørt 1 time ved 0°C. Etter at løsningsmiddelet var fjernet under redusert trykk, ble resten renset ved hjelp av silikagelkolonne-kromatografi (diklormetan - metanol), etterfulgt av rekrystallisering fra etylacetat hvilket gav farveløse krystaller av 3'-0-benzoyl-5'deoksy-5-fluorcytidin (51 mg), smeltepunkt 127-129°C, MS 350 (MH<+>).
Eksempel 60
3 5 mg av produktet fra eksempel 59 ble oppløst i tørt pyridin (0,5 ml). Løsningen ble tilsatt trimetylsilylklorid (13,8 ul). Etter omrøring i 2 timer ved værelsestemperatur, ble benzoylklorid (12,6 ul) tilsatt. Reaksjonsblandingen ble omrørt 1 time. Etter fjerning av løsningsmiddelet under redusert trykkk, ble resten oppløst i tørr metanol (0,5 ml). Løsningen ble tilsatt kaliumkarbonat (15 mg), og reaksjonsblandingen ble omrørt i 30 minutter ved 0°C. Etter at løs-ningsmiddeletvar fjernet under redusert trykk, ble resten skilt mellom vann og etylacetat. Det organiske sjiktet ble tørket over anhydrert magnisiumsulfat og konsentrert under redusert trykk. Resten ble renset ved hjelp av silikagelkolonne-kromatografi (diklormetan - metanol), hvilket gav 15 mg av et amorft pulver, N 4,3'-O-benzoyl-51deoksy-5-fluorcytidin , MS 454 (MH<+>).
Eksempel 61
5'-deoksy-5-fluorcytidin (245 mg), benzylklorid (400 ul) og 4-dimetylaminopyridin (122 mg) ble oppløst i tørr pyridin (5 ml). Etter omrøring i 3 timer ved romtemperatur ble pyridin fjernet under redusert trykk. Resten ble skilt mellom etylacetat og vann. Etylacetatsjiktet ble ble tørket over magne-siumsulfat og konsentrert under redusert trykk. Resten ble rekrystallisert fra metanol for å gi N 4, 2'-0,3'-0-triben-zoyl-5'-deoksy-5-fluorcytidin (280 mg), smp.
158 160°C; MS 558 (M+H).
Claims (4)
1. Analogifremgangsmåte ved fremstilling av terapeutisk aktive 5'-deoksy-5-fluorcytidin-derivater med den generelle formel (I),
hvor R<1> er R<4>CO-, R<5>OCO eller R<6>SCO, 2 3
R og R er H eller benzoyl,
R 4er H, alkenyl; cykloalkyl; alkyl; evt. med en eller flere lavere alkyl-, lavere alkanoyl-, lavere alkoksy-, halogen-, nitro-, lavere alkoksykarbonyl-, lavere alkyl-tio- eller alkylendioksygrupper substituert fenyl; naf-tyl; evt. med lavere alkoksy substituert fenyllavere alkyl eller alkenyl; benzyl; pyridyl; en evt. med lavere alkyl eller nitro substituert tienyl-, furyl-eller pyrrolgruppe eller en benzopyrrolalkylgruppe,
R<5> er alkyl eller benzyl, og
R<6> er alkyl,
samt hydrater eller solvater av forbindelsene med den generelle formell (I),
karakterisert ved å omsette en forbindelse med den generelle formel (II)
hvor R 7betegner et hydrogenatom eller en amino-beskyt-8 9
tende radikal, R og R er uavhengig et hydrogenatom eller en hydroksybeskyttende radikal, eller R 8 og R 9 kan sammen danne en cyklisk hydroksybeskyttende radikal, med en forbindelse betegnet med den generelle formel (III), 4 hvor X betegner en avgående radikal og R er som angitt ovenfor,
eller en forbindelse betegnet med den generelle formel (IV) , 10 hvor Y representerer et halogenatom og R betegner en radikal med formelen
hvor R<5> og R<6> er som angitt ovenfor,
etterfulgt, hvis nødvendig, av fjerning av en beskyttende radikal.
2. Fremgangsmåte som angitt i krav 1 ved fremstilling av N 4-butyryl-5'-deoksy-5-fluorcytidin, karakterisert ved at det anvendes tilsva-rende substituerte utgangsmaterialer.
3. Fremgangsmåte som angitt i krav 1 ved fremstilling av 5'-deoksy-5-fluor-N 4-isovalerylcytidin, karakterisert ved at det anvendes tilsva-rende substituerte utgangsmaterialer.
4. Fremgangsmåte som angitt i krav 1 ved fremstilling av 5'-deoksy-5-fluor-N 4-(3,4,5-trimetoksybenzoyl)cytidin, karakterisert ved at det anvendes tilsva-rende substituerte utgangsmaterialer.
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|---|---|---|---|
| EP87116926 | 1987-11-17 |
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| NO171167C NO171167C (no) | 1993-02-03 |
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| NO2001013C NO2001013I2 (no) | 1987-11-17 | 2001-07-17 | Kapecitabin |
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| US3404144A (en) * | 1965-12-23 | 1968-10-01 | Research Corp | 1-beta-d-arabinofuranosyl-5-fluorocytosine compounds |
| GB1379410A (en) * | 1971-06-08 | 1975-01-02 | Upjohn Co | 1-beta-d-arabino-furanosyl-n4-alpha-aminoacylcytosines |
| JPS52153977A (en) * | 1976-06-11 | 1977-12-21 | Daikin Ind Ltd | Synthesis of 5-fluorouracil and its derivatives |
| US4071680A (en) * | 1976-12-20 | 1978-01-31 | Hoffmann-La Roche Inc. | 5'-Deoxy-5-fluoropyrimidine nucleosides |
| CH633810A5 (en) * | 1978-01-01 | 1982-12-31 | Hoffmann La Roche | Novel nucleosides and process for their preparation |
| FR2528311B1 (fr) * | 1982-06-14 | 1985-06-14 | Synthelabo | Compositions pharmaceutiques a base de xylosides et lyxosides de bases puriques et pyrimidiques |
| JPS61112093A (ja) * | 1984-11-05 | 1986-05-30 | Wakunaga Seiyaku Kk | ヌクレオチド誘導体 |
-
1988
- 1988-11-02 CA CA000581964A patent/CA1327358C/en not_active Expired - Lifetime
- 1988-11-07 EP EP88118515A patent/EP0316704B1/de not_active Expired - Lifetime
- 1988-11-07 ES ES88118515T patent/ES2074429T3/es not_active Expired - Lifetime
- 1988-11-07 AT AT88118515T patent/ATE124951T1/de active
- 1988-11-07 DE DE2001199027 patent/DE10199027I2/de active Active
- 1988-11-07 DE DE3854148T patent/DE3854148D1/de not_active Expired - Lifetime
- 1988-11-08 US US07/268,437 patent/US4966891A/en not_active Expired - Lifetime
- 1988-11-10 NZ NZ226923A patent/NZ226923A/xx unknown
- 1988-11-10 YU YU209188A patent/YU47122B/sh unknown
- 1988-11-10 ZA ZA888428A patent/ZA888428B/xx unknown
- 1988-11-11 IL IL88363A patent/IL88363A0/xx not_active IP Right Cessation
- 1988-11-14 HU HU885799A patent/HU199866B/hu unknown
- 1988-11-14 JP JP63285940A patent/JPH0678350B2/ja not_active Expired - Lifetime
- 1988-11-14 MC MC882015A patent/MC1992A1/fr unknown
- 1988-11-15 CS CS747588A patent/CS274486B2/cs not_active IP Right Cessation
- 1988-11-15 KR KR1019880014983A patent/KR970000241B1/ko not_active Expired - Lifetime
- 1988-11-16 PT PT89009A patent/PT89009B/pt not_active IP Right Cessation
- 1988-11-16 NO NO885106A patent/NO171167C/no not_active IP Right Cessation
- 1988-11-16 IS IS3412A patent/IS1895B/is unknown
- 1988-11-16 SU SU884356869A patent/SU1736342A3/ru active
- 1988-11-16 DK DK640388A patent/DK170893B1/da not_active IP Right Cessation
- 1988-11-16 DZ DZ880179A patent/DZ1270A1/fr active
- 1988-11-16 PH PH37820A patent/PH25641A/en unknown
- 1988-11-16 CN CN88107886A patent/CN1022688C/zh not_active Expired - Lifetime
- 1988-11-16 IE IE883430A patent/IE883430L/xx not_active IP Right Cessation
- 1988-11-16 UA UA4356869A patent/UA19333A/uk unknown
- 1988-11-16 AR AR88312471A patent/AR247217A1/es active
- 1988-11-16 AU AU25168/88A patent/AU619220B2/en not_active Expired
- 1988-11-17 FI FI885329A patent/FI89804C/fi not_active IP Right Cessation
- 1988-11-17 MX MX013836A patent/MX173347B/es unknown
-
1993
- 1993-06-08 LV LV930507A patent/LV5624A3/xx unknown
- 1993-07-20 LT LTRP802A patent/LT2185B/xx not_active IP Right Cessation
-
1995
- 1995-10-10 GR GR950402791T patent/GR3017686T3/el unknown
-
1998
- 1998-03-17 HK HK98102225A patent/HK1003114A1/xx not_active IP Right Cessation
-
2001
- 2001-05-02 LU LU90769C patent/LU90769I2/fr unknown
- 2001-05-17 NL NL300045C patent/NL300045I2/nl unknown
- 2001-07-17 NO NO2001013C patent/NO2001013I2/no unknown
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