GB2072164A - 2%-Deoxy-3%,5%-di-O- alkylcarbonyl-5-fluorouridine derivatives, a process for the preparation of the derivatives and anti-tumor agents containing the derivatives - Google Patents
2%-Deoxy-3%,5%-di-O- alkylcarbonyl-5-fluorouridine derivatives, a process for the preparation of the derivatives and anti-tumor agents containing the derivatives Download PDFInfo
- Publication number
- GB2072164A GB2072164A GB8104375A GB8104375A GB2072164A GB 2072164 A GB2072164 A GB 2072164A GB 8104375 A GB8104375 A GB 8104375A GB 8104375 A GB8104375 A GB 8104375A GB 2072164 A GB2072164 A GB 2072164A
- Authority
- GB
- United Kingdom
- Prior art keywords
- deoxy
- fluorouridine
- benzoyl
- hexanoyl
- pentanoyl
- 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.)
- Granted
Links
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000005843 halogen group Chemical group 0.000 claims abstract description 8
- 125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 87
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 40
- -1 methoxy, ethoxy Chemical group 0.000 claims description 38
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- YKYIFUROKBDHCY-ONEGZZNKSA-N (e)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical group CCO\C=C\C(=O)C(F)(F)F YKYIFUROKBDHCY-ONEGZZNKSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- 150000004665 fatty acids Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
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- 239000004480 active ingredient Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
- 229960004793 sucrose Drugs 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 49
- 239000000126 substance Substances 0.000 description 68
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
- 239000000243 solution Substances 0.000 description 49
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 29
- 229940086542 triethylamine Drugs 0.000 description 27
- 238000004458 analytical method Methods 0.000 description 26
- 239000012295 chemical reaction liquid Substances 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 229910052739 hydrogen Inorganic materials 0.000 description 23
- 125000003118 aryl group Chemical group 0.000 description 21
- 229910052799 carbon Inorganic materials 0.000 description 21
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 20
- 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 19
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 239000012156 elution solvent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000002775 capsule Substances 0.000 description 13
- 230000000259 anti-tumor effect Effects 0.000 description 12
- 231100000419 toxicity Toxicity 0.000 description 11
- 230000001988 toxicity Effects 0.000 description 11
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 10
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 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
- 238000004821 distillation Methods 0.000 description 9
- 235000019256 formaldehyde Nutrition 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- ATKVIWDGWAVUCC-GVDBMIGSSA-N [(2r,3s,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3-hexanoyloxyoxolan-2-yl]methyl hexanoate Chemical compound C1[C@H](OC(=O)CCCCC)[C@@H](COC(=O)CCCCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ATKVIWDGWAVUCC-GVDBMIGSSA-N 0.000 description 7
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 7
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- JQNBCSPQVSUBSR-UHFFFAOYSA-N 2,3-dimethoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1OC JQNBCSPQVSUBSR-UHFFFAOYSA-N 0.000 description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 5
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 5
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- WKOCBSKQJVQFNA-RRFJBIMHSA-N [(2r,3s,5r)-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)-3-pentanoyloxyoxolan-2-yl]methyl pentanoate Chemical compound C1[C@H](OC(=O)CCCC)[C@@H](COC(=O)CCCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 WKOCBSKQJVQFNA-RRFJBIMHSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
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- 239000011541 reaction mixture Substances 0.000 description 4
- SYVNVEGIRVXRQH-UHFFFAOYSA-N 3-fluorobenzoyl chloride Chemical compound FC1=CC=CC(C(Cl)=O)=C1 SYVNVEGIRVXRQH-UHFFFAOYSA-N 0.000 description 3
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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- 230000006181 N-acylation Effects 0.000 description 3
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical class O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
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- 238000011282 treatment Methods 0.000 description 3
- ZRSGZIMDIHBXIN-UHFFFAOYSA-N 1,3-benzodioxole-5-carbonyl chloride Chemical compound ClC(=O)C1=CC=C2OCOC2=C1 ZRSGZIMDIHBXIN-UHFFFAOYSA-N 0.000 description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 2
- ZJIOBDJEKDUUCI-UHFFFAOYSA-N 3,5-dimethylbenzoyl chloride Chemical compound CC1=CC(C)=CC(C(Cl)=O)=C1 ZJIOBDJEKDUUCI-UHFFFAOYSA-N 0.000 description 2
- YHOYYHYBFSYOSQ-UHFFFAOYSA-N 3-methylbenzoyl chloride Chemical compound CC1=CC=CC(C(Cl)=O)=C1 YHOYYHYBFSYOSQ-UHFFFAOYSA-N 0.000 description 2
- KMGCTFHTBKBITO-UHFFFAOYSA-N 4-butoxybenzoyl chloride Chemical compound CCCCOC1=CC=C(C(Cl)=O)C=C1 KMGCTFHTBKBITO-UHFFFAOYSA-N 0.000 description 2
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- IKOZLHKUJQHYFR-YNEHKIRRSA-N [(2r,3s,5r)-3-butanoyloxy-5-(5-fluoro-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl butanoate Chemical compound C1[C@H](OC(=O)CCC)[C@@H](COC(=O)CCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 IKOZLHKUJQHYFR-YNEHKIRRSA-N 0.000 description 1
- VDWAXRJKSAYAFD-IPMKNSEASA-N [(2r,3s,5r)-5-(3-benzoyl-5-fluoro-2,4-dioxopyrimidin-1-yl)-3-butanoyloxyoxolan-2-yl]methyl butanoate Chemical compound C1[C@H](OC(=O)CCC)[C@@H](COC(=O)CCC)O[C@H]1N1C(=O)N(C(=O)C=2C=CC=CC=2)C(=O)C(F)=C1 VDWAXRJKSAYAFD-IPMKNSEASA-N 0.000 description 1
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- YVQAIUALSDIHRC-RBZQAINGSA-N [(2r,3s,5r)-5-[3-(2,3-dimethoxybenzoyl)-5-fluoro-2,4-dioxopyrimidin-1-yl]-3-hexanoyloxyoxolan-2-yl]methyl hexanoate Chemical compound C1[C@H](OC(=O)CCCCC)[C@@H](COC(=O)CCCCC)O[C@H]1N1C(=O)N(C(=O)C=2C(=C(OC)C=CC=2)OC)C(=O)C(F)=C1 YVQAIUALSDIHRC-RBZQAINGSA-N 0.000 description 1
- QJNHAVUCNBGBFP-RCCFBDPRSA-N [(2r,3s,5r)-5-[3-(2,3-dimethoxybenzoyl)-5-fluoro-2,4-dioxopyrimidin-1-yl]-3-propanoyloxyoxolan-2-yl]methyl propanoate Chemical compound C1[C@H](OC(=O)CC)[C@@H](COC(=O)CC)O[C@H]1N1C(=O)N(C(=O)C=2C(=C(OC)C=CC=2)OC)C(=O)C(F)=C1 QJNHAVUCNBGBFP-RCCFBDPRSA-N 0.000 description 1
- QNHFCYVNOQKPNZ-YTFSRNRJSA-N [(2r,3s,5r)-5-[3-(3,5-dimethylbenzoyl)-5-fluoro-2,4-dioxopyrimidin-1-yl]-3-pentanoyloxyoxolan-2-yl]methyl pentanoate Chemical compound C1[C@H](OC(=O)CCCC)[C@@H](COC(=O)CCCC)O[C@H]1N1C(=O)N(C(=O)C=2C=C(C)C=C(C)C=2)C(=O)C(F)=C1 QNHFCYVNOQKPNZ-YTFSRNRJSA-N 0.000 description 1
- PNAGOVBOEWGRFK-RBZQAINGSA-N [(2r,3s,5r)-5-[5-fluoro-2,4-dioxo-3-(4-propoxybenzoyl)pyrimidin-1-yl]-3-pentanoyloxyoxolan-2-yl]methyl pentanoate Chemical compound C1[C@H](OC(=O)CCCC)[C@@H](COC(=O)CCCC)O[C@H]1N1C(=O)N(C(=O)C=2C=CC(OCCC)=CC=2)C(=O)C(F)=C1 PNAGOVBOEWGRFK-RBZQAINGSA-N 0.000 description 1
- XYFYHTNVOIKJSN-BHDDXSALSA-N [(2r,3s,5r)-5-[5-fluoro-3-(2-methoxybenzoyl)-2,4-dioxopyrimidin-1-yl]-3-pentanoyloxyoxolan-2-yl]methyl pentanoate Chemical compound C1[C@H](OC(=O)CCCC)[C@@H](COC(=O)CCCC)O[C@H]1N1C(=O)N(C(=O)C=2C(=CC=CC=2)OC)C(=O)C(F)=C1 XYFYHTNVOIKJSN-BHDDXSALSA-N 0.000 description 1
- AFDGWXDDZLMGCA-RCCFBDPRSA-N [(2r,3s,5r)-5-[5-fluoro-3-(2-methylbenzoyl)-2,4-dioxopyrimidin-1-yl]-3-propanoyloxyoxolan-2-yl]methyl propanoate Chemical compound C1[C@H](OC(=O)CC)[C@@H](COC(=O)CC)O[C@H]1N1C(=O)N(C(=O)C=2C(=CC=CC=2)C)C(=O)C(F)=C1 AFDGWXDDZLMGCA-RCCFBDPRSA-N 0.000 description 1
- JZVFKLNGMOMDQI-GVDBMIGSSA-N [(2r,3s,5r)-5-[5-fluoro-3-(3-fluorobenzoyl)-2,4-dioxopyrimidin-1-yl]-3-propanoyloxyoxolan-2-yl]methyl propanoate Chemical compound C1[C@H](OC(=O)CC)[C@@H](COC(=O)CC)O[C@H]1N1C(=O)N(C(=O)C=2C=C(F)C=CC=2)C(=O)C(F)=C1 JZVFKLNGMOMDQI-GVDBMIGSSA-N 0.000 description 1
- AUIDJARRLHKKKP-RBZQAINGSA-N [(2r,3s,5r)-5-[5-fluoro-3-(3-methoxybenzoyl)-2,4-dioxopyrimidin-1-yl]-3-hexanoyloxyoxolan-2-yl]methyl hexanoate Chemical compound C1[C@H](OC(=O)CCCCC)[C@@H](COC(=O)CCCCC)O[C@H]1N1C(=O)N(C(=O)C=2C=C(OC)C=CC=2)C(=O)C(F)=C1 AUIDJARRLHKKKP-RBZQAINGSA-N 0.000 description 1
- QSJRTVJHHWSIMZ-RBZQAINGSA-N [(2r,3s,5r)-5-[5-fluoro-3-(4-methoxybenzoyl)-2,4-dioxopyrimidin-1-yl]-3-hexanoyloxyoxolan-2-yl]methyl hexanoate Chemical compound C1[C@H](OC(=O)CCCCC)[C@@H](COC(=O)CCCCC)O[C@H]1N1C(=O)N(C(=O)C=2C=CC(OC)=CC=2)C(=O)C(F)=C1 QSJRTVJHHWSIMZ-RBZQAINGSA-N 0.000 description 1
- SVKYWQQUTZNCJF-BHDDXSALSA-N [(2r,3s,5r)-5-[5-fluoro-3-(4-methoxybenzoyl)-2,4-dioxopyrimidin-1-yl]-3-pentanoyloxyoxolan-2-yl]methyl pentanoate Chemical compound C1[C@H](OC(=O)CCCC)[C@@H](COC(=O)CCCC)O[C@H]1N1C(=O)N(C(=O)C=2C=CC(OC)=CC=2)C(=O)C(F)=C1 SVKYWQQUTZNCJF-BHDDXSALSA-N 0.000 description 1
- LWZDZLYOZRRCQP-KQIHHXPCSA-N [(2r,3s,5r)-5-[5-fluoro-3-(4-methylbenzoyl)-2,4-dioxopyrimidin-1-yl]-3-tetradecanoyloxyoxolan-2-yl]methyl tetradecanoate Chemical compound C1[C@H](OC(=O)CCCCCCCCCCCCC)[C@@H](COC(=O)CCCCCCCCCCCCC)O[C@H]1N1C(=O)N(C(=O)C=2C=CC(C)=CC=2)C(=O)C(F)=C1 LWZDZLYOZRRCQP-KQIHHXPCSA-N 0.000 description 1
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- VMPHSYLJUKZBJJ-UHFFFAOYSA-N lauric acid triglyceride Natural products CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
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- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
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Abstract
2%-Deoxy-3%,5%-di-O- alkylcarbonyl-5-fluorouridine derivatives of the general formula: <IMAGE> wherein R is an alkyl group, an alkoxy group or a halogen atom, m is zero or an integer of 1 to 3, and n is an integer of 1 to 14, with the proviso that when m is 2 or 3, the groups R may be the same or different and that when m is 2 and the adjacent two R groups, the two alkyl moieties of the alkoxy group may be combined to form together with the two adjacent oxa bridging members an alkylenedioxy group. The compounds of Formula I are useful as anti-tumor agents.
Description
2,-Deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine derivatives, a process for the preparation of the
derivatives and anti-tumor agents containing the derivatives
The present invention relates to certain 2-deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives, a process for their preparation and anti-tumor agents containing them.
The compounds of the invention are 2'-deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives of the general formula:
wherein R is an alkyl group, an alkoxy group or a halogen atom, m is zero or an integer of 1 to 3, and n is an integer of 1 to 14, with the proviso that when m is 2 or 3, the groups R may be the same or different and that when m is 2 and the adjacent two groups R are alkoxy groups, the two alkyl moieties of the alkoxy groups may be combined to form together with the two adjacent oxa bridging members an alkylenedioxy group.
In the field of chemotherapy, major public attention is now directed to the development of effective anti-tumor agents. Heretofore, various kinds of 5-fluorouridine derivatives have been developed as anti-tumor agents. However, all of these derivatives are quite unsatisfactory as they are either poor in their inherent anti-tumor activity or possess strong toxicity. 2'-Deoxy-5-fluorouridine (referred to hereinafter simply as FUDR) is already used an an anti-tumor agent but this compound has an exceptionally high toxicity and only a narrower safety margin.In addition, this compound is subject to a considerable limitations in actual therapeutic applications since this compound can be administered only by intrarterial injection and cannot be administered orally (Physicians Desk Reference, p. 1387 (1978). 2'-Deoxy-3',5'-0-acetyl-5-fluorouridine (referred to hereinafter simpiy as acetyl--FUDW) is also known as one of the FUDR derivatives. However, this compound is almost equivalent in anti-tumor activity to FUDR and rather poor in effectiveness (Biochem. Pharmacology, 14, 1605 et seq., (1965);
Cancer Research, 23 420 et seq. (1963).
3',5'-Dialkyl esters of FUDR have also been reported as derivatives of FUDR but they are still unsatisfactory in respect of their anti-tumor activity and toxicity Biochem. Pharmacology, 14, 1605-1619 (1965), ibid 15, 627-644(1966). Recently derivatives of FUDR and acetyl-FUlDR have been reported which are compounds in which the hydrogen atom bonded to the 3-nitrogen atom on the uracil ring is substituted by a specific aroyl group (UK Patent Appln. No. 2,025,401 published on
January 23, 1980 and European Patent Application No. 9,882 published on April 1 6, 1980). However, further enhancement in anti-tumor activity is also desired in these compounds.Thus, there is a great demand for developing new FUDR derivatives which possess strong anti-tumor activity with weak toxicity and are suitable for oral administration without the necessity of troublesome intrarterial or intravenous injection.
We have found surprisingly that the new compounds of the general formula (I) are superior in antitumor activity to the known similar compounds at an equivalent toxicity level.
In the general formula (I), the benzoyl group introduced into 3-position of the uracil ring may be ring-substituted by up to 3 groups R which may be the same or different and each represent an alkyl group, an alkoxy group or a halogen atom. When R is an alkyl group, straight or branched chain C~20 alkyl groups are preferred such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, npentyl, isopentyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, n-hexadecyl and n-octadecyl.Examples of R as an alkoxy group are, for example, straight or branched chain C1~20 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyioxy, noctyloxy, n-decyloxy, n-dodecyloxy, n-hexdecycloxy and n-octadecyloxy groups.
When two vicinal lower alkoxy groups exist as ring-substituents in the benzoyl groups (R= a lower alkoxy group and m=2), the alkyl moieties of the two lower alkoxy groups may be combined to form an alkylene group. In this case, the two vicinal lower alkoxy groups form an alkylenedioxy group. Preferred examples of the alkylenedioxy group include methylenedioxy, ethylenedioxy and propylenedioxy groups.
Examples of R as a halogen atom include fluorine, chlorine, bromine and iodine atoms, with fluorine atoms being preferred.
Preferred compounds of the general formula (I) include: 3-benzoyl-2'-deoxy-3',5-di-0-pentanoyl-5-fluorouridine,
3-benzoyl-2'-deoxy-3',5-di-0-hexanoyl-5-fluorouridine, 3-(2,3 or 4-methyl)-benzoyl-2'-deoxy-3',5-di-0-butanoyl-5-fluorouridine, 3-(2,3 or 4-methyl)-benzoyl-2'-deoxy-3',5-di-0-pentanoyl-5-fluorouridine, 3-(2,3 or 4-methyl)-benzoyl-2'-deoxy-3' ,5'-di-0-hexanoyl-5-fl uoridine,
3-(2,3 or 4-methoxy)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl-5-fl uoridine, 3-(2,3 or 4-methoxy)-benzoyl-2'-deoxy-3',5 -di-0-hexanoyl-S4luorouridine, 3-(3,5-dimethyl)-benzoyl-2'-deoxy-3' ,5'-di-0-pentanoyl or -hexanoyl-5-fl uorouridine, 3-(2,3-dimethoxy)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or-hexanoyl-5-fluorouridine, 3-(2,3 or 4-ethyl)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or -hexanoyl-5-fluorouridine,
3-(2,3 or 4-ethoxy)-benzoyl-2'-deoxy-3' ,5'-di-0-pentanoyl or -hexanoyl-5-fluorouridine,
3-(2,3 or 4-propoxy)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or -hexanoyl-5-fluorouridine,
3-(2,3 or 4-fluoro)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or - hexanoyl-5-fiuorouridine, and 3-(2,4-dichloro)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or -hexa noyl-5-fl u orouridi ne.
The new compounds of the general formula (I) of the present invention are prepared by reacting a 2'-deoxy-3',5-di-0-alkylcarbonyl-5-fluorouridine of the general formula:
wherein n is an integer of 1 to 14, with a benzoyl halide of the general formula:
wherein R is an alkyl group, an alkoxy group or a halogen atom, m is zero or an integer of 1 to 3, and Hal is a halogen atom, with the proviso that when m is 2 or 3, the groups R may be the same or different and that when m is 2 and the adjacent two groups R are alkoxy groups, the two alkyl moieties of the alkoxy groups may be combined to form together with the two adjacent oxa bridging members an alkylenedioxy group. The reaction is generally carried out in the presence of a reaction medium and an acid-binding agent.
In general, the 2'-deoxy-3',5-di-0-alkylcarbonyl-5-fluorouridines of the general formula (II) are known or can readily be prepared by acylating one molar proportion of FUDR with two molar proportions of the corresponding fatty acid, preferably in the form of a reactive functional derivative.
Benzoyl halides of the general formula (Ill) are generally known and readily commercially available, or can be prepared in a manner known per se. The use of the corresponding chloride or bromide is preferred.
The benzoyl halide of the general formula (III) is preferably used in an amount of 1 to 3 molar proportion for the 2'-deoxy-3',5-di-0-alkylcarbonyl-5-fluorouridine of the general formula (II).
The reaction between the benzoyl halide of the general formula (III) and the 2'-deoxy-3',5'-di-0alkylcarbonyl-5-fluorouridine of the general formula (II), i.e. the N-acylation reaction of the fluorouridine with the benzoyl halide, is generally carried out in the presence of an organic solvent which is inert to the N-acylation and affords a proper reaction temperature. Illustrative of the preferred organic solvents are aprotic solvents such as diethyl ether, dioxane, chloroform, ethyl acetate, acetonitrile, pyridine, dimethylformamide and dimethylsulfoxide.
The reaction is normaily carried out in the presence of an acid-binding agent. The reaction of the present invention is usually promoted by neutralizing the hydrogen halide liberated on the N-acylation of the fluorouridine with the benzoyl halide. Thus, organic bases are generally used as the acid-binding agent. Preferred examples of the organic base include aliphatic tertiary amines such as triethylamine and the like lower trialkylamines and aromatic and heterocyclic tertiary amines such as N,Ndialkylanilines and pyridine which may be substituted by a lower alkyl group or groups. These organic bases are usually miscible with the organic solvent used as the reaction medium, but are precipitated when combined with the hydrogen halide.
Accordingiy, these organic bases can readily be separated from the reaction mixture after completion of the reaction.
The organic base is usually used in an amount of 1 to 5 moles per mole of the benzoyl halide. The organic bases per se may be used as the reaction medium in an excess amount for example, an amount of 5 to 20 molar proportions with respect to the benzoyl halide may be used in place of a part or all of the reaction solvent.
The reaction is carried out within a wide range of reaction temperatures, for example, under ice cooling or at a temperature up to the boiling point of the reduction reaction solvent used. As a rule, the reaction time is within a period from 30 minutes to 12 hours. It is possible to shorten the reaction time by warming the reaction mixture at the final stage of the reaction.
After completion of the reaction, the end product can be obtained by subjecting the reaction mixture directly to concentration under reduced pressure or by first filtering the reaction mixture and then concentrating the filtrate under the reduced pressure, and finally recrystallizing the resultant residue or subjecting the residue to chromatography on silica gel. If necessary, the last-mentioned purification treatment by the aid of chromatographic operation or recrystallization may be repeated.
When the end product is isolated as a viscous oily substance, it can be obtained in solid or crystalline form by dissoiving the oily substance in a small amount of dimethylsulfoxide and pouring the solution into water under vigorous agitation.
The products of the present invention possess high anti-tumor activity with weak toxicity as compared with the known similar FUDR derivatives. The anti-tumor activity and toxicity of the new compounds of this invention were evaluated according to the following tests.
(A) Pharmacological tests for measuring anti-tumur activity:
About 10,000,000 tumor cells of Sarcoma S--l 80 (successively incubated for several generations in peritoneal cavity of a male mouse of ICR strain), were transplanted subcutaneously into the inguinal region of 5 week-aged male mice of ICR strain. After the lapse of 24 hours, administration of the compounds of this invention started. The administration of the compounds of this invention was forcibly made orally once a day for 7 days. The body weight of each testing animal was measured every day just before the administration. The compounds of this invention were administered in the form dissolved or suspended in polyethylene glycol 400 to each testing animal while polyethylene glycol 400 alone to a control group of the animals.In each case, the same volume of 0.1 ml/1 0 g (body weight) was administered to each animal. Although the exact doses of the compounds of this invention varied according to the sort of the particular compounds used, the doses were approximately within a range from 0.5 to mg/kg to 120 mg/kg. The doses were graded into 3-12 ranks for each testing compound.
At each rank, the compound of this invention was administered to a group consisting of 6 mice. For the control group 1 8 mice were used.
On the 8th day from the transplantation of the tumor ceils, each mouse was put to death by bleeding under ether anesthesia. After the tumor tissue was excised, its weight was immediately measured and recorded. An average value of tumor weights in the teated group (referred to as T) for each test compound and for each dose and an average value of tumor weights in the control group (referred to as C) were calculated, respectively, to estimate a dose corresponding to T/C value of 0.70 or 0.50 for each test compound.
Concerning evaluation of the anti-tumor activity, a T/C value within the range of 0.70-0.51 is regarded to be slightly effective, while a value of less than 0.50 is regarded to be effective [Ohyo-Yakuri, 7, 1277-1292 (1973)]. Accordingly, the anti-tumor activity becomes stronger as the value indicating 0.70 or 0.50 in terms of T/C becomes smaller.
(B) Test for measuring toxicity:
Judging from the effects achieved by the compounds of this invention, toxicity values were measured according to the following method, taking accumulative toxicity into consideration.
Groups of 5 weeks old male mice of ICR strain were used for this test, each group consisting of 10 animals. Test compounds were forcibly administered orally once a day for 7 days. The body weight of each animal was measured every day just before the administration. The compounds of this invention were administered in the form dissolved or suspended in polyethylene glycol 400 to each testing animal in the same volume of 0.1 mI/1 0 g (body weight). Although the exact doses of the compounds of this invention varied according to the sort of the particular compounds used, the doses were approximately within a range from 2 mg/kg to 300 mg/kg. The doses were graded into 3-12 ranks for each testing compound. At each rank, the compound of this invention was administered to each group.On the 14th day from the completion of administration, the survival and death of the tested animals were judged and
LD10 values were calculated according to the Litchfield-Wilcoxon method.
The same tests as in the above (A) and (B) were performed, using the following known similar compounds:
A: 2'-Deoxy-3',5'-di-0-n-propionyl-5-fluorouridine B: 2'-Deoxy-3',5'-di-0-n-butanoyl-5-fluorouridine C: 2'-Deoxy-3',5'-di-0-n-heptanoyl-5-fl uorouridine
D: 2'-Deoxy-3',5'-di-0-n-octanoyl-5-fluorouridine E: 2'-Deoxy-3',5'-di-0-n-palmitoyl-5-fl uorouridine
F: 2'-Deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine G: 2'-Deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine H: 3-(3-methylbenzoyl)-2'-deoxy-5-fluorouridine I: 3-(3-methylbenzoyl)-2'-deoxy-3',5'-di-0-acetyi-5-fluorouridine J: 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3' ,5'-di-0-acetyl-5-fl uorouridine K: :3-(3,4-methylenedioxybenzoyl)-2'-deoxy-5-fluorouridine
L: 3-(3,4-methylenedioxybenzoyl)-2'-deoxy-3',5'-di-0-acetyl-5-fl uorouridine
M: 5-Fluorouracil.
(C) Results of the Tests:
Results of the above Tests (A) and (B) and therapeutic indices calculated therefrom are shown in
Tables 1,2,3 and 4. The therapeutic indices were calculated according to the following equation:
Therapeutic index = LD10value -:T/C value TABLE 1
Compound administered Value Value In General Formula indicating indicating L D 10 Therapeutic (R)m n T/C 0,70 (mg/Kg) T/C 0,50 (mg/Kg) (mg/Kg) index 2,3-Dimethoxy 1 25 44 90 20.6 2,3-Dimethoxy 14 41 89 130 14.6 H (unsubst::) 2 23 43 - 3-Methyl 2 8 23 96 4,17 2-Methyl 5 4 11 - 2,3-Dimethoxy 5 6 13 33 1,83 3-Fluoro 5 1 8 24 3.00 2,3-Dimethoxy 6 6 20 36 1.80 3-Fluoro 6 7 21 41 1.95 A 22 72 108 1.50 B 19 45 70 1.55 C 6 15 24 1.60 D 5 12 19 1.58 E 18 55 71 1.29 TABLE 2
Compound administered In General Formula Value indicating LD 10 Therapeutic (R)m n T/C 0,50 (mg/Kg) (mg/Kg) index H (unsubstituted) 3 1 0 8 6 8 6 0 2-Methyl " 2 0 9 5 4 7 5 3-Methyl " 3 6 8 1 2 2 5 3,5-Dimethyl " 6 0 2 2 3 6 7 3-fluoro " 1 3 3 0 2 3 1 2-Chloro " 1 3 3 3 2 5 4 2,4-Dichloro " 1 4 3 1 2 2 1 H (unsubstituted) 4 1 0 9 4 9 4 0 2-Methyl " 5 9 1 3 2 2 0 3-Methyl " 5 7 1 6 2 8 1 4-Methyl " 5 3 1 2 2 2 6 2,4-Dimethyl " 6 3 1 6 2 5 4 3-Fluoro " 5 8 1 7 2 9 3 4-Fluoro- " 6 1 1 8 2 9 5 3-Chloro " 8 6 2 3 2 6 7 4-Bromo " 1 0 2 6 2 6 0 3,5-Dichloro " 1 3 3 7 2 8 5 F 2 8 2 8 1 0 0 G 9 0 1 9 2 1 1 H 6 2 9 1 1 5 0 I 4 1 8 9 2 1 7 TABLE 3
Compound administered in General Formula Value indicating Value indicating LD 10 Therapeutic (R)m n T/C 0.70 (mg/Kg) T/C 0.50 (mg/kg) (mg/Kg) index 2-methoxy 3 3 6 1 0 3 6 3 6 0 3-methoxy " 2 8 8 3 1 9 2 2 9 4-methoxy " 2 5 7 8 1 7 2 2 4 2-ethoxy " 2 4 8 0 3 5 5 0 0 4-ethoxy " 1 2 5 3 2 7 5 0 9 4-n-propoxy " 1 8 7 4 2 4 3 2 4 4-n-butoxy " 1 0 4 0 1 9 4 7 5 2,3-dimethoxy " 2 0 8 1 2 3 2 8 4 3,5-dimethoxy " 3 0 9 7 3 6 3 7 1 2-methoxy " 2 0 7 6 1 7 2 2 4 3-methoxy " 2 1 9 5 2 6 2 7 4 4-methoxy " 0 9 4 2 1 2 2 8 6 2-ethoxy " 0 8 4 1 2 2 5 3 7 4-ethoxy " - 2,8 1 6 5 7 1 4-n-propoxy " 1 1 4 3 2 0 4 6 5 4-n-butoxy " 2 4 8 0 2 0 2 5 0 2,3-dimethoxy " 2 3 8 0 2 3 2 8 8 F 1 4 2 8 2 8 1 0 0 G 3 1 9 0 1 9 2 1 1 J 1 1 3 4 7 0 2 2 4 TABLE 4
Compound administered Value indicating Value indicating L D 10 Therapeutic In General Formula, (R)m n T/C 0,70 (mg/Kg) T/C 0,50 (mg/Kg) (mg/Kg) index 3,4-Methylenedioxy 3 1,8 7,4 12 1,62 3,4-Methylenedioxy 4 2,7 7,6 15 1,94 K 25 70 61 0,87 L 9 37 43 1,16 M 31 67 63 0,94 As is evident from the results shown in Tables 1, 2, 3 and 4, the compounds of the present
invention exhibit strong anti-tumor activity at a relatively low level of toxicity, in comparison with the
known similar compounds. Thus, the present invention apparently contributes to remarkable
improvement in anti-tumor activity and in reduction of toxicity.
In clinical chemotherapy, the compounds of this invention are preferably administered in a daily dose of 1-1000 mg. As a mode of administration, oral administration is preferably applied to the
compounds of this invention but parenteral administration such as intravenous injection or intrarectal
medication by means of a suppository is also applicable.
As pharmaceutical preparations suitable for oral administration, tablets, capsules (hard capsules
and soft capsules), liquids and pills, each unit containing 0.5-500 mg of the compound of this
invention as active ingredient, come into question. These preparations may contain, in addition to the
active ingredient, other conventional auxiliary components such as milk sugar, corn starch, potato
starch, various cane sugar esters of fatty acids, microcrystalline cellulose and polyethylene glycol 4000
as excipients; acacia, gelatine, hydroxypropylcellulose and potato starch as binders; magnesium
stearate and talc as lubricants; carboxymethylcellulose calcium, potato starch and corn starch as
disintegrating agents.Usual solubilizing agents and suspending agents may also be contained in the
preparations, with polyethylene glycol 200-600 being particularly preferred. Examples for a base of
suppositories include glycerol, cacao butter, glycerogelatine, polyethylene glycol, laurin and other
materials usually employed for this purpose.
Besides the above mentioned additives, materials normally used as carriers for pharmaceutical
preparations may also be contained in the anti-tumor agents of the present invention.
The present invention will now be illustrated in more detail by way of examples.
EXAMPLE 1
2.0 Grams of 2'-deoxy-3',5'-di-0-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane
and the solution is ice cooled. 2 Milliliters of triethylamine and 1.7 g of 2-benzoyl chloride are added to
the solution and the mixture is subjected to reaction at room temperature for 15 minutes and then at
700C for 30 minutes. The reaction liquid is cooled and triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the oily residue is purified by column
chromatography on silica gel (elution solvent: chloroform). The purified oily substance is dissolved in
about 1 5 ml of dimethyl sulfoxide and the solution is added dropwise to about 400 ml of ice water
under vigorous agitation whereupon a precipitate is formed.The resultant precipitate is collected by
filtration, washed with water and dried at room temperature under reduced pressure whereby 1.5 g (yield: 56.4%) of powdery 3-(2-methylbenzoyl)-2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are
obtained.
UV-absorption spectrum: AEtOH 255.5 nm
NMR spectra: S(ppm, CDCl3) Uridine moiety: 7.80 (d, H6), 6.19 (broad-t, H1'), near 2.5 (m, H2'), 5.10-5.30 (m, H3'),
4.16-4.42 (m, H4', H5'), 2.10-2.54 (m, 2 x COCH2), 0.98-1.26 (m, 2 x
CH3)
Benzoyl moiety: 7.63 (d, H6), 7.12-7.56 (m, H3, H4, H5), 2.62 (s, CH3)
Elementary analysis (as C23H2sFN2 s) Calc. (%): C 57.98, H 5.29, N 5.88
Found (%): C 57.82, H 5.49, N 5.99
EXAMPLE 2
2.0 Grams of 2'-deoxy-3',5'-di-0-propionyl-5-fiuorouridine are dissolved in 25 ml of dry dioxane
and the solution is ice cooled. 2 Milliliters of triethylamine and 1.8 g of 3-fluorobenzoyl chloride are
added to the solution and the mixture is subjected to reaction at room temperature for 15 minutes and
then at 600C for 30 minutes.The reaction liquid is worked up in the same manner as described in
Example 1 whereby 2.05 g (yield: 71.5%) of powdery 3-(3-fluorobenzoyl)-2'-deoxy-3',5'-di-O-
propionyl-5-fluorouridine are obtained.
UV-absorption spectra: #maxEtOH 251.5 mm
NMR spectra: S(ppm, CDCl3) Uridine moiety: 7.81 (d, H6), 6.18 (broad-t, H1'), near 2.5 (m, H2'), 5.19-5.36 (m, Hi), 4.24-4.48 (m, H41, Hj), 2.20-2.60 (m, 2 x COCH2), 1.05-1 .3'2 (m, 2 x
CH3)
Benzoyl moiety: 7.28-7.76 (m, aromatic H)
Elementary analysis (as C22H22F2N208): Calc (%): C 55.00, H 4.62, N 5.83
Found (%): C 55.28, H 4.77, N 6.02
EXAMPLE 3
2.0 Grams of 2'-deoxy-3',5'-di-0-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 2.2 g of 2,3-dimethoxybenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 30 minutes and then at 500C for 30 minutes. The reaction liquid is cooled and then triethylamine hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (elution solvent: chloroform). The purified oily substance is allowed to stand overnight at room temperature whereby a part of the substance is crystallized.A small amount of ethanol is added to crystallize the substance wholly and the crystals are collected by filtration whereby 2.3 g (yield: 79.0%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are obtained. M.P. 84.5-860C.
UV-absorption spectra: AEtOH 264.5, 327 nm
NMR spectra: S(ppm, CDCl3)
Uridine moiety: 7.72 (d, He), 6.27 (broad-t, Hi,), near 2.5 (m, H2,), 5.16-5.32 (m, H3,), 4.18-4.48 (m, H4,, H5'), 2.14-2.48 (m, 2 x COCH2), 1.05-1.32 (m, 2 x CH3)
Benzoyl moiety: 7.46-7.64 (m, H6), 7.10-7.26 (m, H4, H5), 3.86 (s, OCH3), 3.84 (s,
OCH3)
Elementary analysis (as C24H27FN2O10): Calc. (%): C 55.17, H 5.21,N 5.36 Found (%):C 55.27, H 5.37, N 5.50
EXAMPLE 4
3.0 Grams of 2'-deoxy-3',5'-di-0-myristoyl-5-fluorouridine are dissolved in 20 ml of dry dioxane
and the solution is ice cooled. 2.1 Milliliters of triethylamine and 1.4 g of 4-methylbenzoyl chloride are
added to the solution and the mixture is subjected to reaction at room temperature for 3 hours. The
triethylamine hydrochloride formed is filtered off and the filtrate is concentrated under reduced
pressure. The residue is purified by column chromatography on silica gel (elution solvent: chloroform).
The resultant purified oily substance is dissolved in ethanol and concentrated under reduced pressure
whereupon a crystalline residue is obtained which, after recrystallization from methanol, gives 1.25 g
(yield: 35.4%) of 3-(4-methylbenzoyl)-2'-deoxy-3',5'-di-O-myristoyl-5-fluorouridine are obtained. M.P.
76-770C.
UV-absorption spectru,: #maxEtOH 2.63 nm
NMR spectra: #(ppm, CDCI3)
Uridine moiety: 7.74 (d, H6), 6.26 (broad-t, H1'), near 2.5 (m, H2,), 5.14-5.32 (m, H3), 4.20-4.44 (m, H4,, H5'). 2.20-2.54 (m, 2 x COCH2), 1.04-1.84 (m,
22 x CH2) 0.76-1.00 (m, 2 x CH3)
Benzoyl moiety: 7.78 (d, H2, H6), 7.30 (d, H3, H5), 2.42 (s, CH3)
Elementary analysis (as C45H69FN2O8):
Calc. (%):C 68.85, H 8.86, N 3.57
Found (%):C 68.76, H 8.55, N 3.79
EXAMPLE 5
3.0 Grams of 2'-deoxy-3',5'-di-0-palmitoyl-5-fluorouridine are dissolved in 25 ml of dry dioxane
and the solution is ice cooled. 2 Milliliters of triethylamine and 1.9 g of 2,3-dimethoxy-benzoyl chloride
are added to the solution and the mixture is subjected to reaction at room temperature for 10 minutes
and then at 70OC for 90 minutes. The reaction liquid is cooled and the precipitated triethylamine
hydrochloride is filtered off. The filtrate is concentrated under reduced pressure and the residue is
dissolved under heating in ethanol and the solution is allowed to stand whereby crystals are obtained
which, after recrystallization from ethanol, affords 2.95 g (yield: 80.2%) of 3-(2,3ai methoxybenzoyl)-2'- deoxy-3',5'-di-0-palmitoyl-5-fluorouridine are obtained.M.P. 77-780C.
UV-absorption spectra: iEtOH 264.5,327 nm
NMR spectra:#(ppm, CDCl3)
Uridine moiety: 7.76 (d, H6), 7.31 (broad-t, H1'), near 2.4 (m, H2,), 5.18-5.34 (m, H3), 4.22-4.48 (m, H4', H5,), 2.10-2.55 (m, 2 x COCH2), 1.08-1.80 (m, 26
x CH2), 0.76-1.06 (m, 2 x CH3)
Benzoyl moiety: 7.59 (dd, H6), 7.12-7.28 (m, H4, H5), 3.90 (broad-s, 2 x OCH3)
Elementary analysis (as C50H79FN2O10):
Calc. (%): C 67.69, H 8.98, N 3.16
Found (%):C 68.09, H 9.11, N 2.99
EXAMPLE 6
3.0 Grams of 2'-deoxy-3',5'-di-O-butanoyl-5-fluorouridine are dissolved in 20 ml of dry dioxane
and the solution is ice cooled. 3 Milliliters of triethylamine and 2.0 g of benzoyl chloride are added to the
solution and the mixture is subjected to reaction at room temperature for 2 hours. The triethylamine
hydrochloride formed is filtered off and the filtrate is concentrated under reduced pressure. The oily
residue is purified by column chromatography on silica gel (elution solvent: chloroform) whereby 2.3 g (yield: 60.7%) of 3-benzoyl-2'-deoxy-3',5'-di-O-butanoyl-5-fluorouridine are obtained as an oily substance.
UV-absorption spectrum: #maxEtOH 253.5 nm
NMR spectra: #(ppm, CDCI3)
Uridine moiety: 7.76 (d, H6), 6.27 (broad-t, H1'), near 2.5 (m, H2'), 5.15-5.32 (m, H3,), 4.20-4.46 (m, H4,, H5'), 2.20-2.52 (m, 2 x COCH2), 1.44-1.92 (m, 2
x CH2), 1.86-1.10 (m, 2 x CH3)
Benzoyl moiety: 7.36-8.02 (m, aromatic H)
Elementary analysis (as C24H27FN2O5): Calc. (%): C 58.77, H 5.55, N 5.71
Found (%): C 58.75, H 5.82, N 5.78
EXAMPLES 7-23 In the same manner as described in Example 6, a 2'-deoxy-3',5'-di-0-alkylcarbonyl-5fluorouridine is reacted with an aroyl chloride.Table 5 shows the resuiting 2'-deoxy-3',5'-di-0alkylcarbonyl-5-fluorouridine derivatives and characteristic physical properties thereof.
TABLE 5
in General Elementary analysis UV Formula (I) Empirical formula #EtOH NMR (CDCl3) #(ppm) Ex. (R)m Yield Calc. (%) C, H, N max No. n (%) Found (%) C, H,N (nm) Uridine moiety Benzoyl moiety 3-methyl C25H29FN2O8 7,75 (d,H6) 8.28 (broad-t,H1') 7.60-7.80 (m, H2, H6) 7 71.6 59.52 5.79 5.55 257 near 2.4 (m, H2') 5.12-5.32 (m, H3') 7.30-7.52 (m, H4, H5) 2 59.59 6.09 5.59 4.29-4.44 (m, H4' H5') 2.12-2.56(m, 2xCOCH2) 2.40 (s, CH3) 1.44-1.92 (m, 2xCH2) 0.84-1.12 (m, 2xCH3) 4-methyl C25H29Fn2O8 7.74 (d, H6) 6.26 (broad-t, H1') 7.79 (d, H2, H5) 8 71.6 59.52 5.79 5.55 263.5 near 2.4 (m, H2') 5.15-5.32 (m, H2') 7.29 (d, H3, H5) 2 59.55 6.82 5.58 4.22-4.45 (m, H4', H5') 2.16-2.52 (m, 2xCOCH3) 2.42 (s, CH3) 1.44-1.92(m, 2xCH2) 0.84-1.08 (m, 2xCH3) 3,4-di- C26H31FN2O10 7.75 (d, H6) 6.26 (broad-t, H1') 7.55 (broad-s, H2) 9 methoxy 56.2 56.72 5.68 5.09 280.5 near 2.5 (m, H2') 5.14-5.32 (m, H3') 7.39 (d, H6) 56.54 5.60 5.14 4.20-4.46 (m, H4', H5') 2,20-2.55 (m, 2xCOCH2) 6.88 (d, H5) 2 315.5 1.50-1.90 (m, 2xCH3) 0.84-1.10 (m, 2xCH3) 3.91 (s, 2xOCH3) 4-fluoro C24H26F2N2O8 7.78 (d, H6) 6.27 (broad-t, H1') 7.96 (dd, H2, H6) 10 71 56.69 5.15 5.51 255 near 2.5 (m, H2') 5.17-5.34 (m, H3') 7.18 (t, H3, H5) 2 56.74 5.29 5.56 4.22-4.48 (m, H4', H5') 2.08-2.60 (m, 2xCOC H2) 1.46-1.96 (m, 2xCH2) 0.84-1.20 (m, 2xCH3) 2-methyl C31H41FN2O8 7.78 (d, h6) 6.27 (broad-t, H1') 7.16-7.68 (m, aromatic H) 11 68.0 63.25 7.02 4.76 255.5 near 2.4 (m, H2') 5.14-5.32 (m, H3') 2.68 (s, CH3) 5 63.31 7.09 4.79 4.18-4.44 (m, H4', H5) 2.16-2.52 (m, 2xCOCH7) 1.08-1.84 (m, 8xCH2) 0.72-1.04 (m, 2xCH3) 2,3-di- C32H43FN2O10 7.80 (d, H6) 6,34 (broad-t, H1') 7.56-7.70 (m, H6) 12 methoxy 89.0 60.56 6.83 4.41 265 near 2.5 (m, H2') 5.20-5.36 (m, H3') 7.18-7.32 (m, H4, H5) 60.60 7.06 4.36 327 4.20-4.59 (m, H4', H5') 2.16-2.56 (m, 2xCOCH2) 3.90 (s, OCH3) 5 1.16-1.88 (m, 8xCH2) 0.76-1.08 (m, 2xCH3) 3.88 (s, OCH3) TABLE 5 (Continued)
in General Elementary analysis UV Formula (I) Empirical formula #'EtOH NMR (CDCl3) #(ppm) Ex. R(m) Yield Calc. (%) C, H, N max No. n (%) Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety 3-fluoro C20H36F2N2O5 7.85 (d, H6) 6.28 (broad-t, H1') 7.28-7.90 (m, aromatic H) 13 83.6 80.80 6.46 4.73 252 near 2.5 (m, H2') 5.16-5.35 (m, H2') 5 80.77 6.48 4.70 4.20-4.48 (m, H4',H5') 2,20-2,56(m, 2xCOCH2) 1.10-1.84 (m, 8xCH2) 0.76-1.05 (m, 8xCH2) 0.76-1.05 (m, 2xCH3) 2-methyl C33H48FN2O6 7.80 (d, H6) 6.27 (broad-t, H1') 7.64 (d, H6) 14 81.6 64.27 7.35 4.54 255.5 near 2,5 (m, H2') 5.16-5.35 (m, H3') 7.20-7.60 (m, H2, H4, H3) 6 64.23 7.31 4.59 4.22-4.46 (m, H4', H5') 2.18-2.52 (m, 2xCOCH3) 2.68 (s, CH3) 1.16-1.90 (m, 10xCh2) 0.76-1.04 (m, 2xCH3) 2,3-di- C34H47FN2O10 7.76 (d, H6) 6.29 (broad-t, H1') 7.58 (dd, H5) 15 methoxy 67.9 61.62 7.15 4.23 265 near 2.5 (m, H2') 5.16-5.33 (m, H5') 7.14-7.30 (m, H4, H5) 61.69 7.02 4.09 327 4.22-4.59 (m, H4', H5') 2.16-2.54 (m, 2xCOCH2) 3.87 (s, OCH2) 6 1.14-1.98 (m, 10-CH2) 0.72-1.04 (m, 2-CH3) 3.85 (s, OCH3) 3-fluoro C32H42F2N2O8 7.86 (d, H6) 6.30 (broad-t, H1') 7.24-7.92 (m, aromatic H) 16 84.0 61.92 6.82 4.51 251.5 near 2.5 (m, H2') 5.29-5.36(m, H3') 6 61.73 6.72 4.40 4.26-4.50 (m, H4', H5') 2.22-2.58 (m, 2xCOCH2) 1.14-2.00 (m, 10xCH2) 0.74-1.06 (m, 2xCH3) hydrogen C40H50FN2O5 7.80 (d, H5) 8.28 (broad-t, H1') 7.40-8.10 (m, aromatic H) 17 66.9 67.20, 8.32 3.92 253 near 2.5 (m, H2') 5.16-5.35 (m, H2') 10 67.16 8.30 4.00 4.20 4.54 (m, H4', H5') 2.20-2.60 (m, 2xCOCH2) 1.20-2.00 (m, 18xCH2) 0.76-1.06 (m, 2xCH3) 3-methyl C41H61FN2O8 7.79 (d, H6) 6.29 (broad-t, H1') 7.30-8.00 (m, aromatic H) 18 54.9 67.56 8.44 3.84 257.5 near 2.5 (m, H2') 5.16-5.36 (m, H2') 2.38 (s, CH3) 10 67.59 8.41 3.81 4.20-4.45 (m, H4', H5') 2.15-2.60 (m, 2xCOCH2) 1.10-2.00 (m, 18xCH2) 0.70-1.10 (m, 2xCF3) TABLE 5 (Continued)
In General Elementary analysis UV Formula (I) Empirical formula #EtOH NMR (CDCl3) #(ppm) Ex. R(m) Yield Calc. (%) C, H, N max No. n (%) Found (%) C, H, N (nm) Uridine moiety Benzoyl moietyl 2,4-di- C42H63FN2O10 7.63 (d, H6) 6.26 (broad-t, H1') 8,10 (d, H6) 19 methoxy 34 65.09 8.19 3.61 278 near 2.5 (m, H2') 5.10-5.30 (m, H3') 6.67 (dd, H5) 65.25 8.65 3.79 304 4.16-4.44 (m, H4', H5') 2.20-2.50 (m, 2xCOCH2) 6.36 (d, H3) 10 1.04-1.80 (m, 18xCH2) 0.78-1.04 (m, 2xCH3) 3.83 (s, OCH3) 3.74 (s, OCH3) hydrogen C44H67FN2O8 7.60 (i, H6) 6,07 (broad-t, H1') 7.10-7.85 (m, aromatic H) 20 43.2 68.54 8.76 3.63 253 near 2.4 (m, H2') 5.00-5.16 (m, H3') 12 68.36 8.75 3.87 4.05-4.35 (m, H4',H5) 2.05-2.50 (m, 2xCOCH2) 1.00-1.80 (m, 22xCH2) 0.70-1.00 (m, 2-CH3) 2-fluoro C44H66F2N2O8 7.62 (d, H6) 6.06 (broad-t, H1') 6.80-7.92 (m, aromatic H) 21 42.3 66.98 8.43 3.55 250 near 2.4 (m, H2') 5.00-5.20 (m, H3') 12 66.89 8.32 3.81 4.04-4.44 (m, H4', H5') 2.04-2.48 (m, 2xCOCH2) 0.96-1.80 (m, 22xCH2) 0.72-0.98 (m, 2xCH3) 2-methyl C49H77FN2O8 7.71 (d, H6) 6.16 (broad-t, H1') 7.54 (d, H6) 22 39.2 69.97 9.23 3.33 245.5 near 2.4 (m, H2') 5.06-5.24 (m, H3') 7.07-7.46 (m, H3, H4, H5) 14 69.89 8.84 3.29 4.10-4.40 (m, H4'H5') 2.15-2.45 (m, 2xCOCH2) 2.62 (s, CH3) 1.00-2.00 (m, 26xCH2) 0.75-1.00 (m, 2xCH3) 3-fluoro C48H74F2N2O8 7.74 (d, H6) 6.21 (broad-t, H1') 7.20-7.76 (m, aromatic H) 23 79.8 68.22 8.83 3.31 252 near 2.4 (m, H2) 5.10-5.28 (m, H3') 14 68.17 8.53 3.35 4.20-4.44 (m, H4', H5') 2.16-2.44 (m, 2xCOCH2) 1.12-1.80 (m, 26xCH2) 0.76-1.02 (m, 2xCH3) EXAMPLE 24
To a solution of 7.0 g of 2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine in 50 ml of dry dioxane were added 3.7 ml of triethylamine and 2.7 g of benzoyl chloride. The mixture was subjected to reacr tion at room temperature for 2 hours and then at 60 C for 30 minutes. The reaction liquid was cooled and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a 0.1-N aqueous soution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate.The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography on silica gel (elution
solvent: chloroform). The resultant oily substance was dissolved in about 80 ml of ethanol and the
solution was treated with active carbon. The ethanol was distilled off under reduced pressure and the
residue was again purified by column chromatography on silica gel (elution solvent: chloroform). The
resultant purified oily substance was dried at room temperature under reduced pressure whereby 7.9 g
(90%) of 3-benzoyl-2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine were obtained as an oily substance.
UV (#maxEtOH, nm): 253
NMR #(ppm, CDCl3):
Uridine moiety: 7.79 (d, H6), 6.26 (broad t, H1,), near 2.4 (m, H2,), 5.16-5.32 (m, H3), 4.20-4.56 (m, H4,), H5'). 2.08-2.64 (m, 2 x COCH2), 1.16-1.84 (m, 4
xCH2), 0.80-1.08 (m, 2 x CH3)
Benzoyl moiety: 7.36-8.02 (m, aromatic H)
Elementary analysis (as C26H3aFN208): Calc. (%): C 60.22 H 6.03 N 5.40
Found (%):C 60.33 H 6.08 N 5.55
EXAMPLE 25-29 In the same manner as described in Example 24, the following 2'-dioxy-3',5'-di-O-alkylcarbonyl- 5-fluorouridine derivatives were prepared. The structures, yields and physical characteristics of the end products obtained were shown in Table 6.
TABLE 6
In General Yield Elementary analysis UV Formula I (%) Empirical formula EtOH NMR (CDCl3) #(ppm) Ex. R(m) Calc. (%) C, H, N #max No. n Nature Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety 25 H 82 C28H35FN2O8 253 7.79 (d, H6) 6.26 (broad-t, H1') 7.40-8.04 (m, aromatic H) (4) (Oily 61.53 6.45 5.12 near 2.4 (m, H2') 5.16-5.32 (m'H3') sub) 61.71 6.54 5.29 4.20-4.57 (m, H4', H5') 2.07-2.65 (m, 2xCOCH2) 1.19-1.88 (m, 6xCH2) 0.78-1.08 (m, 2xCH3) 26 2-methyl 79 C27H33FN2O8 255 7.76 (d, H6) 6.26 (broad-t, H1') 7.16-7.68 (m, aromatic H) (3) (Oily 60.89 6.25 5.26 near 2.4 (m, H2') 5.15-5.32 (m, H3') 2.68 (S, CH3) sub) 60.72 6.34 5.34 4.20-4.56 (m, H4'; H5') 2.04-2.66 (m, 2xCOCH2) 1.16-1.84 (m, 4xCH2) 0.80-1.08 (m, 2xCH3) 27 3-fluoro 76 C26H30F2N2O8 252 7.79 (d, F6) 6.25 (broad-t, H1') 7.24-7.88 (m, aromatic H) (3) (Oily 58.20 5.64 5.22 near 2.4 (m, H2') 5.10-5.32 (m, H3') sub) 58.01 5.74 5.31 4.20-4.56 (m, H4', H5') 2.05-2.66 (m, 2xCOCH2) 1.15-1.82 (m, 4xCH2) 0.79-1.05 (m, 2xCH3) 28 3-methyl 83 C29H37FN2O8 258 7.76 (d, H6) 6.25 (broad-t, H1') 7.61-7.80 (m, H2, H6) (4) (Oily 62.13 6.65 5.00 near 2.4 (m, H2') 5.12-5.30 (m, H1') 7.24-7.54 (m, H4, H5) sub) 62.08 6.78 4.94 4.20-4.56 (m, H1' H5') 2.04-2.66 (m, 2xCOCH2) 2.40 (S, CH3) 1.12-1.82 (m, 6xCH2) 0.77-1.02 (m, 2xCH3) 29 4-dimethyl 87 C29H37FN2O8 264 7.77 (d, H6) 6.22 (broad-t, H1) 7.70 (d, H2, H6) (4) (Oily 62.13 6.65 5.00 near 2.4 (m, H2') 5.10-5.28 (m, H3') 7.24 (d, H3, H5) sub) 62.39 6.68 5.00 4.16-4.52 (m, H4', H5') 2.00-2.64 (m, 2xCOCH2) 7.24 (d, H3, H5) 1.16-1.80 (m, 6xCH2) 0.76-1.00 (m, 2xCH3) 2.40 (s, CH3) EXAMPLE 30
To a solution of 7.0 g of 2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine in 50 ml of dry dioxane were added 4.0 ml of triethylamine and 3.4 g of 3-methylbenzoyl chloride. The mixture was subjected to reaction at room temperature for 5 hours and the reaction liquid was concentrated under reduced pressure.The residue was dissolved in ethyl acetate and the solution was washed with a 0.1-N aqueous solution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified two times by column chromatography on silica gel (elution solvent: chloroform).
The resultant purified oily substance was dried at room temperature under reduced pressure whereby 6.0 g (66%) of 3-(3-methylbenzoyl-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance.
UV(EmTxH, nm): 258 NMR b(ppm, CDCI3):
Uridine moiety: 7.76 (d, H6), 6.26 (broad t, Hí)l near 2.4 (m, H2'), 5.16-5.32 (m, H3,), 4.20-4.56 (m, H4,, h5'), 2.05-2.67 (m, 2 x COCH2), 1.16-1.84 (m, 4 xCH2), 0.80-1.06 (m, 2xCH3)
Benzoyl moiety: 7.28-7.56 (m, H4, H5), 7.64-7.88 (m, H2, H4), 2.38 (s, CH3)
Elementary analysis (as C2,H33FN208): Calc. (%): C 60.89 H 6.25 N 5.26
Found (%):C 60.87 H 6.46 N 5.30
EXAMPLE 31
Using benzoyl chloride in the same manner as described in Example 30, 7.4 g (84%) of 3-benzoyl 2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 24.
EXAMPLE 32
To a solution of 7.5 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 50 ml of dry dioxane were added 10.7 ml of triethylamine and 3.6 g of benzoyl chloride. The mixture was subjected to reaction at room temperature for 4 hours. The reaction liquid was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with a 0.1-N aqueous solution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the
residue was purified twice by column chromatography on silica gel (elution solvent: chloroform).The
resultant purified oily substance was dried at room temperature under reduced pressure whereby 8.1 g (87%) of 3-benzoyl-2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine were obtained as an oily substance.
The physical characteristics of this substance were identical with those of the oily substance obtained in
Example 25.
EXAMPLE 33
To a solution of 7.0 g of 2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine in 50 ml of dry dioxane were added 3.7 ml of triethyl amine and 3.4 g of 3,5-dimethylbenzoyl chloride. The mixture was subjected to reaction at room temperature for one hour and then at 600C for 30 minutes. The reaction liquid was cooled and then treated in the same manner as described in Example 24 whereby 6.6 g (71%) of 3-(3,5-dimethylbenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance.
UV (#maxEtOH, nm):263
NMR (ppm, CDCI3):
Uridine moiety: 7.79 (d, H8), 6.28 (broad t, H1'), near 2.4 (m', H2,), 5.16-5.32 (m, H3,), 4.20-4.46 (m, H4,, H5'), 2.14-2.52 (m, 2 x COCH2), 1.16-1.84 (m,
4 x CH2), 0.82-1.04 (m, 2 x CH3)
Benzoyl moiety: 7.54 (s, H2, H6), 7.30 (s, H4), 2.34 (s, 2x CH3)
Elementary analysis (as C28H35FN208): Calc. (%): C 61.53 H 6.45 N 5.12
Found (%): C 61.69 H 6.63 N 5.31
EXAMPLE 34
Using 3-methylbenzoyl chloride in the same manner as described in Example 33, 6.6 g (73%) of 3 (3-methylbenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an only substance.
The physical characteristics of this substance were identical with those of the oily sunstance obtained in
Example 30.
EXAMPLE 35
To a solution of 7.5 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 50 ml of dry dioxane were added 3.7 ml of triethylamine and 3.2 g of 3-fluorobenzoyl chloride. The mixture was subjected to reaction at room temperature for 4 hours and then at 600C for 30 minutes. The reaction liquid was cooled and then treated in the manner as described in Example 30 whereby 7.0 g (73%) of 3-(3 fluorobenzoyl)-2'-deoxy-3',5'-di-O-n-hexanoyl-S4luorouridine were obtained as an oily substance.
UV (#maxEtOH, nm): 252
NMR #(ppm, CDCl3):
Uridine moiety: 7.77 (d, H6'), 6.24 (broad t, H1'), near 2.4 (m, H2'), 5.14-5.30 (m, H3'),
4.20-4.56 (m, H4',H5'), 2.04-2.68 (m, 2 x CH2), 1.12-1.82 (m,
6 x CH2), 0.78-1.04 (m, 2 x CH3)
Benzoyl moiety: 7.24 7.84 (m, aromatic H)
Elementary analysis (as C28H34F2N208): Calc. (%): C 59.57 H 6.07 N 4.96
Found (%): C 59.69 H 6.31 N 5.02
EXAMPLES 36-43 In the same manner as described in Example 35 or in the same manner as described in that
Example except that the reaction time was varied,2'-deoxy-3',5'-di-O-n-alkylcarbonyl-5-fluorouridine derivatives as shown in Table 7 were prepared. The structures, yields and physical characteristics of the prepared derivatives are shown in Table 7.
TABLE 7
In General Yield Elementary analysis UV Reaction
Formula (%) Empirical formula EtOH NMR (CDCl3) #(ppm) Ex. (R)m Calc. (%) C, H, N #max Room 60 C No. n (nature) Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety (hr) (hr) 36 2-methyl 76 C29H37FN2O8 256 7.75 (d, H6) 6.23 (broad-t, H1') 7.12-7.64 (Oily 62.13 6.65 5.00 near 2.4 (m, H1') 5.12-5.28 (m, H3') (m, aromatic H') 4 0.5 (4) subs) 61.98 6.54 5.02 4.18-4.54 (m, H4, H5') 2.00-2.65 (m, 2xCOCH2) 2.68 'S, CH3) 1.16-1.82 (m, 6xCH2) 0.76-1.02 (m, 2xCH3) 37 2,4-di- 58 C30H30FN2O8 265 7.74 (d, H6) 6.23 (broad-t, H1') 7.46 (d, H6) 1 3 methyl 62,70 6.84 4.87 near 2.4 (m, H2') 5.14-5.29 (m, H3') 7.14 (S, H3) (4) (,,) 62.38 6.92 4.81 4.19-4.54 (m, H4, H5') 2.00-2.64 (m, 2xCOCH3) 7.04 (d, H5) 1.16-1.82 (m, 6xCH2) 0.78-1.04 (m, 2xCH3) 2.66 (S, CH3) 38 2-chloro 70 C26H30ClFN2O8 255 7.78 (d, H6) 6.23 (broad-t, H1') 7.90 (d, H5) 1 2 56.47 5.47 5.07 near 2.4 (m, H2') 5.14-5.32 (m, H3') 7.28-7.59 (3) (,,) 56.65 5.55 4.81 4.20-4.56 (m, H4' H5') 2.04-2.68 (m, 2xCOCH2) (m, H3, H4, H5) 1.12-1.81 (m, 4xCH2) 0.80-1.03 (m, 2xCH3) 39 2,4-dichloro 71 C25H29Cl2FN2O8 263 7.76 (d, H6) 6.23 (broad-t, H1') 7.66 (d, H6) 1 2 53.16 4.98 4.77 near 2.4 (m, H2') 5.15-5.30 (m, H3') 7.22-7.54 (3) (,,) 53.24 5.15 4.53 4.22-4.56 (m, H4'; H5') 2.03-2.69 (m, 2xCOCH2) (m, H3 H5) 1.16-18.2 (m, 4xCH2) 0.82-1.10 (m, 2xCH3) 40 4-fluoro 59 CH28H34F2N2O8 256 7.77 (d, H6) 6.24 (broad-t, H4') 7.84-8.06 1 2 59.57 6.07 4.96 near 2.4 (m, H2') 5.14-5.30 (m, H3') (m, H2H6) (4) (,,) 59.42 5.90 5.03 4.20-4.56 (m, H4' H5') 2.06-2.66 (m, 2xCOCH2) 7.16 (t, H3, H5) 1.14-1.84 (m, 6xCH2) 0.78-1.06 (m, 2xCH3) 41 3-chloro 68 C28H34ClFN2O8 255 7.80 (d, H6) 6.26 (broad-t, H1') 7.24-7.94 1 1 57.88 5.90 4.82 near 2.4 (m, H2') 5.16-5.32 (m, H3') (m, aromatic H) (4) (,,) 57.73 5.78 4.61 4.20-4.60 (m, H4' H5') 2.06-2.70 (m, 2xCOCH2) 1.16-1.66 (m, 6xCH2) 0.80-1.06 (m, 2xCH3) TABLE 7 (Continued)
in General Yield Elementary analysis UV Reaction Formula (%) Empirical formula EtOH NMR (CDCI3) #(ppm) Ex. (R)m Calc. (%) C, H, N #max Room 60 C No. n (nature) Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety (hr) (hr) 42 4-Bromo 62 C28H34BrFN2O8 267 7.78 (d, H6) 6.23 (broad-t, H1') 7.52-7.84 1 1 53.77 5.46 4.48 near 2.4 (m, H2') 5.12-5.30 (m, H3') (m, aromatic H) 53.71 5.42 4.30 4.20-4.56 (m, H4', H5') 2.04-2.68 (m, 2xCOCH2) 1.14-1.84 (m, 6xCH2) 0.76-,1.04 (m, 2xCH3) 43 3,3,5-dichloro 73 C28H33Cl2FN2O8 258 7.80 (d, H6) 6.24 (broad-t, H4') 7.72-7.86 1 2 54.64 5.40 4.55 near 2.4 (m, H2') 5.16-5.32 (m, H1) (m, H2, H6) (4) (,,) 54.61 5.32 4.46 4.16-4.60 (m, H4', H5') 2.08-2.70 (m, 2xCOCH2) 7.60-7.72 1.16-1.84 (m, 6xCH2) 0.80-1.06 (m, 2xCH3) (m, H4) EXAMPLE 44
To a solution of 7.0 g of 2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine in 50 ml of dry acetonitrile were added under ice cooling 7.8 ml of triethylamine and 2.6 g of benzoyl chloride. The mixture was subjected to reaction at room temperature for 3 hours and then at 50--600C for 10 minutes. The reaction liquid was cooled and then concentrated under reduced pressure and the residue was purified twice by column chromatography on silica gel (elution solvent: chloroform).The resultant purified oily substance was dried at room temperature under reduced pressure whereby 7.0 g (79 Ó) of 3-benzoyl-2'-deoxy-3',5'-di-0-n-pentanoyi-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in
Example 24.
EXAMPLE 45
To a solution of 7.5 g of 2'-deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine in 50 ml of dioxane were added 5.2 ml of triethylamine and 2.6 g of benzoyl chloride. The mixture was subjected to reaction at room temperature for 2 hours and then at 50--600C for 30 minutes. The reaction liquid was cooled and filtered to remove insoluble matters. The filtrate was treated in the same manner as described in
Example 44 whereby 7.1 g (76%) of 3-benzoyl-2'-deoxy-3',5'-di-O-n-hexanoyl-S4luornuridine were obtained as an oily substance. The physical characteristics of this substance were identical with those obtained in Example 25.
EXAMPLE 46
Using 2-methylbenzoyl chloride in the same manner as described in Example 44, 6.8 g (75%) of 3 (2-methylbenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fI uorouridine were obtained as an oily substance.
The physical characteristics of this substance were identical with those of the oily substance obtained in
Example 26.
EXAMPLE 47
To a solution of 1.0 g of 2'-deoxy-3',5'-di-O-n-pentanoyl-S4luorouridine in 10 ml of dry dioxane were added under ice cooling 0.52 ml of triethylamine and 0.54 g of benzoyl bromide. The mixture was subjected to reaction at room temperature for 1 5 minutes and then at 700C for 30 minutes. The reaction liquid was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with an aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of edible salt and treated in the same manner as described in Example 30 whereby 0.75 g (60%) of 3-benzoyl-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with the oily substance obtained in Example 24.
EXAMPLE 48
To a solution of 7.5 g of 2'-deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine in 40 ml of ethyl acetate were added 4.6 ml of triethylamine and 2.7 g of 3-fluorobenzoyl chloride. The mixture was subjected to reaction at room temperature for 3 hours and then at 5060oC for one hour. The reaction liquid was cooled and washed with a 0.1-N aqueous solution of the caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was treated in the same manner as described in Example 30 whereby 6.0 g (63%) of 3-(3-fluorobenzoyl)-2'-deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine were obtained as an oily substance.The physical characteristics of this substance were identical with those of the oily substance obtained in Example 35.
EXAMPLE 49
To a solution of 7.0 g of 2'-deoxy-3t,5'-di-0-n-pentanoyl-5-fluorouridine in 50 ml of dry dioxane were added 6.3 ml of triethylamine and 5.7 g of 3,5-dimethylbenzoyl chloride. The mixture was subjected to reaction at room temperature for 4 hours The reaction liquid was treated in the same manner as described in Example 30 whereby 5.9 g (63%) of 3-(3-,5-dimethylbenzoyl)-2'-deoxy-3',5'di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 33.
EXAMPLE 50
To a solution of 4.1 g of 2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine in 20 ml of dry dioxane were added 2.1 ml of triethylamine and 2.6 g of 2,3-dimethoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for one hour and then at 6000 for one hour. The reaction liquid was cooled and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a 0.1-N aquecuasolution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography on silica gel (elution solvent: chloroform).The resultant oily substance was dissolved in about 30 ml of ethanol and the solution was treated with active carbon. The ethanol was distilled off under reduced pressure and the residue was again purified by column chromatography on silica gel (elution solvent: chloroform) whereby 4.7 g (81.0%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5- fluorouridine were obtained as an oily substance.
UV (#maxEtOH, nm): 265, 327
NMR #(ppm, CDCl3):
Uridine moiety: 7.72 (d, H6), 6.26 (broad t, H1,), near 2.4 (m, H2,), 5.16-5.32 (m, H3,), 4.20-4.46 (m, H4,, H5,), 2.02-2.68 (m, 2 x COCH2), 1.20-1.84 (m
4xCH2), 0.82-1.06(m, 2xCH3)
Benzoyl moiety: 7.50-7.62 (m, H60), 7.10-7.22 (m, H4, H5), 3.88 (s, CH3O), 3.86 (s,
CH30)
Elementary analysis (as C28N35FN2O10): Calc. (%): C 58.13 H 6.10 N 4.84
Found (%): C 57.85 H 6.20 N 4.67
EXAMPLES 51-53
In the same manner as described in Example 50, 2'-deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives were prepared. The structures, yields and physical characteristics of the prepared derivatives are shown in Table 8.
TABLE 8
In General Yield Elementary analysis UV Formula (%) Empirical formula EtOH NMR (CDCI3) # (ppm) Ex. (R)m Calc. (%) C, H, N #max No. (n) Nature Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety 51 2-ethoxy 8.50 C28H35FN2O9 259 7.69 (d, H6) 6.28 (broad-t, H1') 8.09 (dd, H6) 59.78 6.27 4.98 near 2.4 (m. H2') 5.14-5.30 (m, H3') 7.55 (td, H4) (3) Oily 59.92 6.44 5.04 324 4.18-4.54 (m, H4', H5') 2.00-2.64 (m, 2xCOCH2) 7.04 (t, H5) sub 1.12-1.82 (m, 4xCH2) 0.80-1.06 (m, 2xCH3) 6.92 (d, H3) 4.02 (q, CH2O) 1.26 (t, CH3) 52 2,3- 7.12 C30H39FN2O10 213 7.74 (d, H6) 8.26 (broad-t, H1') 7.48-7.60 (m, H6) dimethoxy Oily 59.40 6.48 4.62 near 2.4 (m, H2') 5,16-5,30 (m, H3') 7.08-7.22 (m, H4, H5) sub 58.89 6.56 4.35 265 4.20-4.46 (m, H4', H5') 2.10-2.54 (m, 2xCOCH2) 3.86 (2xCH3O) (4) 1.20-1.78 (m, 6xCH2) 0.78-1.02 (m, 2xCH3) 326 53 4-methoxy 7.90 C27H33FN2O9 220 7.73 (d, H6) 6.23 (broad-t, H1') 7.84 (d, H2, H6) Oily 59.12 6.08 5.11 near 2.4 (m, H2') 5.12-5.28 (m, H3') 6.93 (d, H3H5) (3) sub: 58.89 6.23 4.98 286 4.16-4.54 (m, H4', H5') 2.00-2.62 (m, 2xCOCH35 3.86 (s, CH3O) 1.12-1.80 (m, 4xCH2) 0.78-1.04 (m, 2xCH3) EXAMPLE 54
To a solution of 2.0 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 30 ml of chloroform were added 0.95 ml of triethylamine and 1.08 g of 4-n-propoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for one hour and then at 50 -60 C for 30 minutes. The reaction liquid was cooled and washed with a 0.1-N aqueous solution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate.The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography on silica gel (elution solvent: chloroform). The resultant purified oily substance was dried at room temperature under reduced pressure whereby 2.1 g (77.8%) of 3-(4-n-propoxybenzoyl)-2'-deoxy-3',5'di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance.
V(#maxEtOH, nm): 220,288
NMR 8(ppm, CDCI3):
Uridine moiety: 7.78 (d, H6), 6.24 (broad-t, H1'), 5.16-5.28 (m, H3')
4.24-4.52 (m, H4', H5'), 2.24-2.46 (m, 2xCOCH3), 1.20-1.92 (m,
6 x CH2), 0.82-1.10 (m, 2 x CH3)
Benzoyl moiety: 7.86 (d, H2, H6), 6.92 (d, H3, H5), 3.99 (t, CH2O), near 1.7 (m, CH2), near
1.0 (m, CH3)
Elementary analysis (as C31H41FN2O9):
Calc. (%): C 61.58 H 6.83 N 4.63
Found (%): C 61.35 H 6.98 N 4.43
EXAMPLE 55
To a solution of 2.0 g of 2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine in 30 ml of chloroform were added 1.0 ml of triethylamine and 0.98 g of 2-methoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for 5 hours.The reaction liquid was treated in the same manner as described in Example 54 whereby 2.1 g (79.8%) of 3-(2-methoxybenzoyl)-2'-deoxy-3',5'-di
O-n-pentanoyl-5-fluorouridine were obtained as an oily substance.
UV(EtOH, nm): 259, 322
NMR b(ppm, CDCI3):
Uridine moiety: 7.69 (d, H6), 6.16 (broad-t, H1,), near 2.4 (m, H2,), 5.14-5.28 (m, H3,), 4.18-4.40 (m, H4,, H6,), 2.18-2.46 (m, 2 x COCH2), 1.14-1.80 (m 4 x CH2), 0.84-0.98 (m, 2 x CH3) Benzayl moiety: 8.06 (dd, H6), 7.52 (td, H4), 7.04 (t, H5), 6.92 (d, H3), 3.78 (s, CH3O) Elementary analysis (as C27H33FN2O9): Calc. (%): C 59.12 H 6.06 N 5.11
Found (%):C 58.68 H 6.02 N 4.80
EXAMPLE 56
To a solution of 2.0 g of 2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine in 30 ml of chloroform were added 1.0 ml of triethylamine and 1.2 g of 2,3-dimethoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for 30 minutes and then at 50-60 C for 2 hours. The reaction liquid was cooled and then treated in the same manner as described in Example 54 whereby 4.6 g (79.3%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 50.
EXAMPLE 57
To a solution of 4.1 g of 2'-deoxy-3',5'-di-0-n-pentanoyl-5-fluorouridine in 10 ml of pyridine were added 4.3 g of 4-n-butoxybenzoyl chloride. The mixture was subjected to reaction at 50-60 C for 12 hours. The reaction liquid was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was subjected, as in Example 50, to the column chromatography and the treatment with an active carbon whereby 4.6 g (78.0%) of 3-(4-n-butoxybenzoyl)-2'-deoxy-3',5'-di-O-npentanoyl-5- fluorouridine were obtained as an oily substance.
UV (#maxEtOH, nm):221,289
NMR b(ppm, CDCI3):
Uridine moiety: 7.76 (d, H6), 6.27 (broad-t, H,'), near 2.4 (m, H2,), 5.16-5.32 (m, H3,), 4.20-4.58 (m, H4,, H5,), 2.04-2.69 (m, 2 x COCH2), 1.15-1.96 (m,
4xCH2), 0.82-1.12 (m, 2xCH3)
Benzoyl moiety: 7.88 (d, H2, H6), 6.95 (d, H3, H5), 4.06 (t, CH2O), near 1.7 (m, 2xCH2),
near 1.0 (m, CH3)
Elementary analysis (as C30H39FN209): Calc. (%): C 61.01 H 6.66 N 4.74
Found (%):C 61.00 H 6.74 N 5.16
EXAMPLE 58 To a solution of 4.1 g of 2'-deoxy-3',5')di-0-n-pentanoyl-5-fluorouridine in 20 ml of dioxane were added under ice cooling 2.1 ml of triethylamine and 2.1 9 of 4-n-butoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for 30 minutes and then at 5060oC for 2 hours. The reaction liquid was treated in the same manner as described in Example 50 whereby 5.0 g (84.6%) of 3 (4-n-butoxybenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 57.
EXAMPLE 59
To a solution of 2.0 g of 2'-deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine in 40 ml of diethyl ether were added 0.95 ml of triethylamine and 0.93 g of 3-methoxybenzoyl chloride. The. mixture was subjected to reaction at room temperature for 10 hours. The reaction liquid was cooled and then treated in the same manner as described in Example 54 whereby 1.6 g (61.5%) of 3-(3-methoxybenzoyl)-2'deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine were obtained as an only substance.
UV (-maxEtOH, nm): 220,261,318
NMR #(ppm, CDCl3):
Uridine moiety: 7.76 (d, H6), 6.24 (broad-t, H,'), near 2.4 (m, H2,), 5.14-5.28 (m, H3'), 4.26-4.44 (m, H4,, H6,), 2.18-2.50 (m 2 x COCH2), 1.20-174 (m, 6 x CH2), 0.82-0.96 (m, 2 x CH3)
Benzoyl moiety: 7.12-7.50 (m, aromatic H), 3.86 (s, CH3O) Elementary analysis (as C29H37FN2O9): Calc. (%): C 60.41 H 6.47 N 4.86
Found (%): C 60.15 N 6.52 N 4.71
EXAMPLE 60
To a solution of 4.4 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 30 ml of acetonitrile were aded 3.5 ml of triethylamine and 3.4 g of 4-methoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for 6 hours.The reaction liquid was concentrated under reduced pressure and the residue as dissolved in ethyl acetate.
The ethyl acetate solution was treated in the same manner as described in Example 54 whereby 4.5 g (78.0%) of 3-(4-methoxybenzoyl)-2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine were obtained as an oily substance.
UV (#maxEtOH, nm): 221,287
NMR (ppm, CDCI3):
Uridine moiety: 7.75 (d, H6), 6.24 (broad-t, H,'), near 2.4 (m, H2,), 5.08-5.34 (m, H3,), 4.18-4.54 (m, H4,, H5,), 2.04-2.84 (m, 2 X COCH2), 1.18-1.90 (m, 6 x CH2), 0.76-1.06 (m, 2 x CH3)
Benzoyl moiety: 7.87 (d, H2, H6), 6,93 (d, H3, h5), 3.86 (s, CH3O)
Elementary analysis (as C29H37FN209): Calc. (%): C 6-0.41 H 6.47 N 4.86
Found (%): C 60.78 H 6.59 N 4.69
EXAMPLE 61
To a solution of 4.4 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 30 ml of acetonitrile were added 3.5 ml of triethylamine and 4.0 g of 2,3-dimethoxybenzoyl chloride.The mixture was subjected to reaction at room temperature for 2 hours and then at 50-60 C for one hour. The reaction liquid was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The ethyl acetate solution was trated in the same manner as described in Example 54 whereby 3.9 g (64.3%) of 3-(2,3-dimethoxybenzoyl)-2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluoruridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 52.
EXAMPLE 62
To a solution of 4.4 g of 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine in 20 ml of dioxane were added 2.1 ml of triethylamine and 2.2 g of 4-n-propoxybenzoyl chloride. The mixture was subjected to reaction at room temperature for 30 minutes and then at 600C for 30 minutes. The reaction liquid was cooled and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a 0.1-N aqueous solution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by' distillation under reduced pressure and the residue was purified by column chromatography on silica gel (elution solvent: chloroform).The resultant purified oily substance was dried at room temperature under reduced pressure whereby 5.1 g (84.3%) of 3-(4-n-propoxybenzoyl-2'-deoxy-3' ,5'-di-O-n-pentanoyl-5- fluorouridine were obtained as an oily substance. The physical characteristics of this substance were identical with those of the oily substance obtained in Example 54.
EXAMPLES 63-70 In the same manner as described in Example 62, 2'-deoxy-3',5'-di-0-n-alkylcarbonyl-5- fluorouridine derivatives are prepared. The structures, yields and physical characteristics of the prepared derivatives are shown in Table 9.
TABLE 9
In General Elementary analysis UV Formula I Empirical formula EtOH NMR (CDCl3) # (ppm) Ex. (R)m Yield Calc. (%) C, H, N #max (%) Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety 63 3,5-di- 74.3 C28H33FN2O10 217 7.76 (d, H6) 6.24 (broad-t, H1') 6.96-7.08 (m, H2, H6) methoxy 58.13 6.10 4.84 near 2.4 (m, H2') 5.15-5.30 (m, H3) 6.68-6.76 (m, H4) (3) Oily 57.91 6.25 5.09 274 4.20-4.44 (m, H4',H5') 2.16-2.52 (m, 2xCOCH1) 3.82 (s, 2xCH3O) sub 1.16-1.76 (m, 4xCH2) 0.80-1.04 (m, 2xCH3) 335 64 4-ethoxy 79.8 C30H39FN2O9 220 7.78 (d, H6) 6.28 (broad-t, H2') 7.88 (d, H2, H6) (4) 61.01 6.66 4.74 near 2.4 (m, H2') 5.14-5.32 (m, H3') 6.95 (d, H3, H5') Oily 60.82 6.84 4.98 289 4.22-4.58 (m, H4', H5') 2.04-2.63 (m, 2xCOCH3) 4.13 (q, CH2O) sub 1.14-1.86 (m, 6xCH2) 0.78-1.04 (m, 2xCH3) near 1.4 (m, CH3) 65 4-n-butoxy 78.0 C32H43FN2O9 220 7.75 (d, H6) 6.29 (broad-t, H1') 7.87 (d, H2, H5) (4) 82.12 7.00 4.53 near 2.4 (m, H2') 5.16-5.34 (m, H3') 6.95 (d, H3, H5) 4.07 (t, CH2O) Oily 82.27 7.38 4.78 289 4.22-4.60 (m, H4', H5') 2.06-2.70 (m, 2xCOCH2) near 1.7 (m, 2xCH2) sub 1.16-1.92 (m, 6xCH2) 0.80-1.16 (2xCH3) near 1.0 (m, CH3) 66 2-methoxy 7.85 C29H37FN2O9 259 7.69 (d, H6) 6.18 (broad-t, H1') 8.06 (dd, H6) 60.41 6.47 4.86 near 2.4 (m, H2') 5.14-5.30 (m, H3') 7.52 (td, H4) (4) Oily 60.51 6.17 4.87 322 4.18-4.52 (m, H4', H5'), 2.14-2.44 (m, COCH2) 7.03 (t, H5) sub 1.14-1.80 (m, 6xCH2) 0.80-0.96 (2xCH3) 3.78 (s, CH3O) 67 3-methoxy 71.1 C27H32FN2O6 220 7.76 (d, H6) 6.25 (broad-t, H1') 7.12-7.48 59.12 6.06 5.11 261 near 2.4 (m, H2') 5.15-5.30 (m, H3) (m, aromatic H) (3) Oily 59.26 6.16 5.40 318 4.24-4.46 (m, H4', H5') 2.18-2.46 (m, 2xCOCH2) 3.86 (s, CH3O) sub 1.12-1.80 (m, 4xCH2) 0.82-1.02 (m, 2xCH3) 68 2-ethoxy 61.5 C30H39FN2O9 259 7.69 (d, H5) 6.28 (broad-t, H1') 8.09 (dd, H6) 61,01 6.66 4.74 near 2.4 (m, H2') 5.15-5.30 (m, H3') 7.55 (td, H4) (4) Oily 61.22 6.84 4.56 324 4.18-4.54 (m, H4', H5') 2.04-2.68 (m, 2xCOCH2) 7.04 (t, H5) sub 1.14-1.86 (m, 6xCH2) 0.80-1.04 (m, 2xCH3) 6.92 (d, H3) 4.02 (q, CH2O) near 1.3 (m, CH3) TABLE 9 (Continued)
In general Elementary analysis UV Formula I Empirical formula EtOH NMR (CDCL3) # (ppm) Ex. (R)m Yield Calc. (%) C, H, N #max No. (%) Found (%) C, H, N (nm) Uridine moiety Benzoyl moiety 69 4-ethoxy 73.3 C28H35FN2O9 220 7.76 (d, H6) 6.28 (broad-t, H1') 7.88 (d, H2, H6) 59.78 6.27 4.98 near 2.4 (m, H2') 5.14-5.30 (m, H3') 8.95 (d, H3, H5) (3) Oily 59.61 6.27 5.21 288 4.20-4.56 (m, H4', H5') 2.04-2.68 (2xCOCH2) 4.14 (q, CH2O) sub 1.12-1.82 (m, 4xCH2) 0.78-1.06 (m, 2xCH3) 1.35 (t, CH3) 70 4-n-propoxy 76.4 C29H37FN2O9 220 7.78 (d, H6') 6.26 (broad-t, H1') 7.86 (d, H2, H6) 60.41 6.47 4.86 near 2.4 (m, H2') 5.16-5.20 (m, H3') 6.92 (d, H3, H5) Oily 60.73 6.21 4.89 289 4.20-4.58 (m, H4', H5') 2.25-2.46 (m, 2xCOCH2) 4.00 (t, CH2O) sub 1.16-1.96 (m, 4xCH2) 0.82-1.10 (m, 2xCH3) near 1.7 (m, CH2) near 1.0 (m, CH3) EXAMPLE 71
Using 2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine and 4-methoxybenzoyl chloride, the reaction and after-treatments were carried out in the same manner as described in Example 60.The resultant oily substance was recrystallized from ethanol whereby 3-(4-methoxybenzoyl)-2'-deoxy-3',5'di-0-n-hexanoyl-5-fluorouridine having a melting point of 81-82 C was obtained (yield: 75.0%) as white needle crystals.
UV (#maxEtOH, nm): 221,287
NMR #(ppm, CDCl3):
Uridine moiety: 7.75 (d, H6), 6.24 (broad-t, H1), near 2.4 (m, H2,), 5.08-5.34 (m, H3,), 4.18-4.54 (m, H4', H5'), 2.04-2.64 (m, 2 x COCH2), 1.16-1.90 (m,
6 x CH2), 0.76-1.06 (m, 2 x CH3)
Benzoyl moiety: 7.87 (d, H2, H6), 6.93 (d, H3, H5), 3.86 (s, CH2O) Elementary analysis (as C29H37FN2O9):
Calc. (%): C, 60.41; H, 6.47; N, 4.86
Found (%):C, 60.30; H, 6.73; N, 4.80
EXAMPLES 72-74
The oily substances obtained in Examples 53, 64 and 69 were recrystallized from ethanol in the same manner as described in Example 71 whereby 3-(4-methoxybenzoyl)-2'-deoxy-3',5'-di-O-n-
pentanoyl-5-fluorouridine having a melting point of 84-85 C (yield: 74.0%), 3-(4-ethoxybenzoyl)-2'
deoxy-3',5'-di-O-n-haxanoyl-5-fluorouridine having a melting point of 90-91 C OC (yield: 75.0%) and 3
(4-ethoxybenzoyl)-2'-deoxy-di-O-n-pantanoyl-5-fluorouridine having a melting point of 88-89 C
(yield: 86.0%) were obtained, respectively, as white needle crystals. The physical characteristics of these substances were identical in UV-adsorption spectra, NMR spectra and elementary analytical data with those of the corresponding oily substances obtained in Examples 53, 64 and 69.
EXAMPLE 75
To a solution of 3.0 g of 2'-deoxy-di-O-n-pantanoyl-5-fluorouridine in 30 ml of dry dioxane were added 2.0 ml of triethylamine and 1.6 g of 3,4-methylenedioxybenzoyl chloride. The mixture was subjected to reaction at 700C for one hour. The reaction liquid was cooled and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with a 0.1-N aqueous solution of caustic soda and then with a saturated aqueous solution of edible salt and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was dissolved in a small amount of chloroform and filtered to remove insoluble matter.
The filtrate was purified by column chromatography on silica gel (elution solvent: chloroform) whereby 1.2 g (29.0%) of 3-(3,4-methylenedioxybenzoyl)-2'-deoxy-di-O-n-pantanoyl-5-fluorouridine were obtained as an oily substance.
UV (,AEmTxH, nm): 206, 236, 278, 321
NMR (ppm, CDCI3):
Uridine moiety: 7.78 (d, H6), 6.28 (broad-t, H1,), near 2.4 (m, H2,), 5.18-5.32 (m, i 13), 4.24-4.56 (m, H4,, H5'). 2.20-2.52 (m, 2 x COCH2) 1.18-1.84 (m, 4 x CH2), 0.88-1.00 (m, 2 x CH3)
Benzoyl moiety: 7.52 (dd, H6), 7.38 (d, H5). 6.86 (d, H2), 6.08 (s, CH2)
EXAMPLE 76 Using 2'-deoxy-di-O-n-hexanoyl-5-fluorouridine and 3,4-methylenedioxybenzoyl chloride, the reaction and aftertreatments were carried out in the same manner as described in Example 75 whereby 1.3 g (32.0%) of 3-(3,4-methylenedioxybenzoyl)-2'-deoxy-di-O-n-hexanoyl-5 fluorouridine were obtained.
UV (#maxEtOH, nm): 206, 236, 278, 321
NMR #(ppm, CDCl3):
Uridine moiety: 7.74 (d, H6), 6.26 (broad-t, H1'), 5.18-5.28 (m, H3,) 4.24-4.42 (m, H4,, H5,), 2.18-2.50 (m, 2 x COCH2), 1.18-1.76 (m, 6 x GH2), 0.82-0.98 (m, 2 x CH3)
Benzoyl moiety: 7.50 (dd, H6), 7.36 (d, H5), 6.86 (d, H2), 6.06 (s, OH2) The preparation of the anti-tumor agents of the present invention will now be illustrated in more detail by way of the following typical preparation examples.
(A) Hard capsule preparations: 3-(4-methoxybenzoyl)-2'-deoxy-3',5'-di-O-n-hexanoyl-5- fluoridine 100mg
milk sugar 160mg
crystalline cellulose 27 mg
hydroxypropylcellulose of a low degree of substitution 10 mg
magnesium stearate 3 mg
total 300 mg
Capsules (No. 2) are formed according to a conventional method so that each capsule may contain the above dose of ingredients. In general 3-9 capsules per day can be administered orally to adult
patients.
Recipe 2: The compound of the present invention 80 mg
cane sugar esters of fatty acids 20 mg
milk sugar 165 mg
crystalline cellulose 24 mg
hydroxypropylcellulose of a low degree of substitution 8 mg
magnesium stearate 3 mg
total 300 mg
The following compounds can be used as the compounds of the present invention for the above
recipe:'
3-(4-methoxybenzoyl)-2'-deoxy-di-O-n-hexanoyl-5-fluorouridine
3-(2,3-methoxybenzoyl)-2'-deoxy-di-O-n-propionyl-5-fluorouridine
Capsules are formed according to a conventional method so that each capsule may contain the
above dose of ingredients. In general, 3-9 capsules can be administered orally to adult patients.
Recipe 3:
The compound of the present invention 80 mg
polyethylene glycol 6000 20 mg
milk sugar 161 mg
crystalline cellulose 21 mg
hydroxypropylcellulose 8 mg
carboxymethylcellulose 5 mg
talc 5 mg
total 30C mg
The following compounds can be used as the compound of the present invention for the above
recipe:
3-(4-methoxybenzoyl)-2'-deoxy-di-O-n-hexanoyl-5-fluorouridine
3-(4-ethoxybenzoyl)-2'-deoxy-di-O-n-pentanoyl-5-fluorouridine
First, pills are formed according to a usual method, using the compound of the present invention,
polyethylene glycol 6000, milk sugar, crystalline cellulose and hydroxypropylcellulose. The pills are then
incorporated with carboxymethylcellulose and talc and the mixture is worked up according to a
conventional method to capsules (No. 2) in such a manner that each capsule may contain the above
dose of ingredients.As a rule, 3-9 capsules per day can be administered orally to adult patients.
(B) Soft Capsuie preparations
Recipe:
the compound of the present invention 50 mg
polyethylene glycol 400 250 mg
propylene glycol 10 mg
bleached beeswax 10 mg
total 320 mg
The following compounds can be used as the compound of the present invention for the above recipe:
3-(4-methoxybenzoyl)-2'-deoxy-di-O-n-hexanoyl-5-fluorouridine
3-(3-benzoylbenzoyl)-2'-deoxy-di-O-n-palmitoyl-5-fluorouridine
3-(2-methylbenzoyl)-2'-deoxy-di-O-n-pentanoyl-5-fluorouridine 3-(3-methylbenzoyl)-2'-deoxy-3',5'-di-0-n-hexanoyl-5-fluorouridine
3-benzoyl-2'-deoxy-3',5'-di-O-n-hexanoyl-5-fluorouridine 3-(4-n-propoxybenzoyl)-2'-deoxy-3',5'-di-O-n-pentanoyl-5-fl uorouridine
Capsules are formed according to a conventional method so that each capsule may contain the above dose of ingredients.As a rule, 3-9 capsules per day can be administered orally to adult patients.
(C) Syrup preparations
Recipe 1: A vial containing the under-mentioned ingredients
3-(4-methoxybenzoyl)-2'-deoxy-di-O-n-hexanoyl-5
fluorouridine 10 mg
Carboxymethylcellulose calcium 4 mg
white sugar 486 mg
total 500 mg
Recipe 2: An ampoule containing the under-mentioned ingredients
polyethylene glycol 400 3000 mg
purified water 1000 mg
total 4000 mg
On oral administration, the solution in the ampoule is added to the vial and the mixture is well shaken. The resultant syrup corresponds to a unit dose and can be administered orally 3-9 times per day.
It is understood that the preceding representative examples may be varied within the scope of the present specification both as to reactants and reaction conditions, by one skilled in the art to chieve essentially the same results.
As many widely different embodiments of this invention may be made without departing from the spirit and scope thereof, it is to be construed that this invention is not limited to the specific embodiments thereof except as defined in the appended claims.
Claims (32)
1. 2'-Deoxy-3',5'di-O-alkylcarbonyl-5-fluorouridine derivatives of the general formula:
wherein R is an alkyl group, an alkoxy group or a halogen atom, m is zero or an integer of 1 to 3, and n is an integer of 1 to 14, with the proviso that when m is 2 or 3, the groups R may be the same or different and that when m is 2 and the adjacent two R groups are alkoxy groups, the two alkyl moieties of the alkoxy groups may be combined to form together with the two adjacent oxa bridging members in alkylenedioxy group.
2.2'-Deoxy-3',5'-di-O-n-alkylcarbonyl-5-fluorouridine derivatives as claimed in claim 1, wherein in the general formula (I) is a methyl, methoxy, ethoxy, or propoxy group, or a fluorine athom.
3. 2'-Deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives as claimed in claim 1, wherein R in the general formula (I) is a methoxy group and m is 2.
4. 4.2'-Deoxy-3',5'-di-O-n-alkylcarbonyl-5-fluorouridine derivatives as claimed in any one of the preceding claims wherein n is 3, 4 or 5.
5. 3-Benzoyl-2'-deoxy-3',5'-di-0-pentanoyl-5-fluorouridine.
6. 3-Benzoyl-2'-deoxy-3',5'-di-0-hexanoyl-5-fluorouridine.
7. 3-(2,3 or 4-Methyl)-benzoyl-2'-deoxy-3',5'-di-O-butanoyl-5-fluorouridine.
8. 3-(2,3 or 4-Methyl)-benzoyl-2'-deoxy-3',5'-di-O-pentanoyl-5-fluorouridine.
9. 3-(2,3 or 4-Methyl)-benzoyl-2'-deoxy-3',5'-di-0-hexanoyl-5-fluorouridine.
10. 3-(2,3 or 4-Methyl)-benzoyl-2'-deoxy-3',5'-di-O-pentanoyl-5-fluorouridine.
11. 3-(2,3 or 4-Methyl)-benzoyl-2'-deoxy-3',5'-di-O-hexanoyl-5-fluorouridine.
12.3-(2,3-Dimethyl)-benzoyl-2'-deoxy-3',5'-di-O-pentanoyl or -hexanoyl-5-fluorouridine.
13. 3-(2,3-Dimethoxy)-benzoyl-2'-deoxy-3',5'-di-O-pentanoyl or-hexanoyl-5-fluorouridine.
14. 3-(2,3 or 4-Ethyl)-benzoyl-2'-deoxy-3',5'-di-O-pen tanoyl or -hexanoyl-S4luorouridine.
15. 3-(2,3 or 4-Ethoxy)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or -hexanoyl-5-fluorouridine.
16. 3-(2,3 or 4-P ropoxy)-benzoyl-2'-deoxy-3' ,5-di-0-pentanoyl or -hexanoyl-5-fluorouridine.
17. 3-(2,3 or 4-Fluoro)-benzonyl-2'-deoxy-3',5'-di-O-pentanoyl or -hexanoyl-5-fluorouridine.
18. 3-(2,4-Dichloro)-benzoyl-2'-deoxy-3',5'-di-0-pentanoyl or-hexanoyl-5-fluorouridine.
19. A process for the preparation of 2'-deoxy-3',5'-di-0-alkylcarbonyl-5-fluorouridine derivatives of the general formula
wherein R, m and n are as defined in claim 1 which comprises reacting a 2'-deoxy-3',5-di-0alkylcarbonyl-5-fluorouridine of the general formula:
wherein n is as defined above, with a benzoyi halide of the general formula:
wherein R and m are as defined above and Hal is a halogen atom.
20. A process as claimed in claim 19 wherein Hal in the general formula (III)i is a chlorine atom.
21. A process as claimed in claim 19 or claim 20 wherein the reaction is carried out in the presence of an acid-binding agent.
22. A process as claimed in claim 21 wherein the acid-binding agent is an aliphatic tertiary amine, an aromatic tertiary amine o a heterocyclic tertiary amine.
23. A process as claimed in claim 22 wherein the tertiary amine is triethylamine.
24. A process as claimed in any one of claims 1 9 to 23 wherein the reaction is carried out in the presence of an organic solvent.
25. A process as claimed in claim 24 wherein the solvent is diethyl ether, dioxane, chloroform, ethyl acetate, acetonitrile, pyridine, dimethylformamide or dimethylsulfoxide.
26. A process as claimed in any one of claims 19 to 21, 23 or 25 wherein the reaction is carried out under ice cooling or at a temperature up to 700C in dioxane in the presence of triethylamine.
27. A process as claimed in claim 24 substantially as hereinbefore described with reference to any one of the Examples.
28. A 2'-Deoxy-3',5'-di-o-alkylcarbonyl-5-fluorouridine derivative as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 1 9 to 27.
29. An anti-tumor agent containing as an active ingredient thereof one or more 2'-deoxy-3',5-di
O-alkylcarbonyl-5-fluorouridine derivatives as claimed in any one of claims 1 to 18, or claim 28.
30. An anti-tumor agent as claimed in claim 29 which includes pharmaceutically acceptable carrier or excipient.
31. An anti-tumor agent as claimed in claim 30 wherein the carrier is polyethylene glycol or a cane sugar ester of a fatty acid.
32. An anti-tumor agent as claimed in claim 29 substantially as hereinbefore described.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1740880A JPS56115799A (en) | 1980-02-15 | 1980-02-15 | 2'-deoxy-3',5'-di-o-alkylcarbonyl-5-fluorouridine derivative, its preparation, and antitumor agnet containing the same |
JP11210280A JPS5735596A (en) | 1980-08-13 | 1980-08-13 | Ester derivative of deoxyfluorouridine |
JP55126776A JPS5751000A (en) | 1980-09-11 | 1980-09-11 | Ester derivative of alkoxybenzoyldeoxyfluorouridine |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2072164A true GB2072164A (en) | 1981-09-30 |
GB2072164B GB2072164B (en) | 1983-12-21 |
Family
ID=27281812
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8104375A Expired GB2072164B (en) | 1980-02-15 | 1981-02-12 | 2'-deoxy-3',5'-di-o-alkylcarbonyl-5-fluorouridine derivatives a process for the preparation of the derivatives and antitumor agents containing the derivatives |
Country Status (7)
Country | Link |
---|---|
AT (1) | AT374203B (en) |
CH (1) | CH646715A5 (en) |
DE (1) | DE3105111A1 (en) |
ES (1) | ES499443A0 (en) |
FR (1) | FR2476086A1 (en) |
GB (1) | GB2072164B (en) |
IT (1) | IT1210989B (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0082668A1 (en) * | 1981-12-18 | 1983-06-29 | Beecham Group Plc | 5-(2-Halogenovinyl)-2'-deoxyuridine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in treating viral infections |
EP0129984A1 (en) * | 1983-05-23 | 1985-01-02 | Taiho Pharmaceutical Company Limited | Novel 2'-deoxy-5-substituted uridine derivatives, processes for preparing the same and antitumor agent containing the same |
EP0180897A2 (en) * | 1984-10-30 | 1986-05-14 | Otsuka Pharmaceutical Co., Ltd. | 5-Fluorouracil derivatives |
US4864021A (en) * | 1984-10-30 | 1989-09-05 | Otsuka Pharmaceutical Co., Ltd. | 5-fluorouracil derivatives |
US5047521A (en) * | 1986-04-30 | 1991-09-10 | Otsuka Pharmaceutical Co., Ltd. | 5-fluorouracil derivatives |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5924999B2 (en) * | 1978-06-10 | 1984-06-13 | 富山化学工業株式会社 | Method for producing a novel 5-fluoro-2'-deoxy-β-uridine derivative |
JPS5535057A (en) * | 1978-09-05 | 1980-03-11 | Funai Corp | 2'-deoxy-5-fluorouridine derivative, its preparation, and antitumor agent comprising it |
-
1981
- 1981-02-12 GB GB8104375A patent/GB2072164B/en not_active Expired
- 1981-02-12 DE DE19813105111 patent/DE3105111A1/en active Granted
- 1981-02-13 ES ES499443A patent/ES499443A0/en active Granted
- 1981-02-13 IT IT8119758A patent/IT1210989B/en active
- 1981-02-13 FR FR8102922A patent/FR2476086A1/en active Granted
- 1981-02-13 CH CH96481A patent/CH646715A5/en not_active IP Right Cessation
- 1981-02-13 AT AT0069181A patent/AT374203B/en not_active IP Right Cessation
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0082668A1 (en) * | 1981-12-18 | 1983-06-29 | Beecham Group Plc | 5-(2-Halogenovinyl)-2'-deoxyuridine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in treating viral infections |
EP0129984A1 (en) * | 1983-05-23 | 1985-01-02 | Taiho Pharmaceutical Company Limited | Novel 2'-deoxy-5-substituted uridine derivatives, processes for preparing the same and antitumor agent containing the same |
EP0180897A2 (en) * | 1984-10-30 | 1986-05-14 | Otsuka Pharmaceutical Co., Ltd. | 5-Fluorouracil derivatives |
EP0180897A3 (en) * | 1984-10-30 | 1987-08-19 | Otsuka Pharmaceutical Co., Ltd. | 5-fluorouracil derivatives |
EP0323441A2 (en) * | 1984-10-30 | 1989-07-05 | Otsuka Pharmaceutical Co., Ltd. | 5-Fluorouracil derivatives |
US4864021A (en) * | 1984-10-30 | 1989-09-05 | Otsuka Pharmaceutical Co., Ltd. | 5-fluorouracil derivatives |
EP0323441A3 (en) * | 1984-10-30 | 1990-08-16 | Otsuka Pharmaceutical Co., Ltd. | 5-fluorouracil derivatives |
US4983609A (en) * | 1984-10-30 | 1991-01-08 | Otsuka Pharmaceutical | 5-fluorouracil derivatives |
EP0436902A1 (en) * | 1984-10-30 | 1991-07-17 | Otsuka Pharmaceutical Co., Ltd. | 5-Fluorouracil derivatives |
US5047521A (en) * | 1986-04-30 | 1991-09-10 | Otsuka Pharmaceutical Co., Ltd. | 5-fluorouracil derivatives |
Also Published As
Publication number | Publication date |
---|---|
CH646715A5 (en) | 1984-12-14 |
GB2072164B (en) | 1983-12-21 |
FR2476086A1 (en) | 1981-08-21 |
FR2476086B1 (en) | 1984-01-06 |
DE3105111C2 (en) | 1993-08-12 |
IT1210989B (en) | 1989-09-29 |
ES8206550A1 (en) | 1982-08-16 |
ATA69181A (en) | 1983-08-15 |
AT374203B (en) | 1984-03-26 |
DE3105111A1 (en) | 1981-12-24 |
ES499443A0 (en) | 1982-08-16 |
IT8119758A0 (en) | 1981-02-13 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19960212 |