JPS6316398B2 - - Google Patents
Info
- Publication number
- JPS6316398B2 JPS6316398B2 JP58130756A JP13075683A JPS6316398B2 JP S6316398 B2 JPS6316398 B2 JP S6316398B2 JP 58130756 A JP58130756 A JP 58130756A JP 13075683 A JP13075683 A JP 13075683A JP S6316398 B2 JPS6316398 B2 JP S6316398B2
- Authority
- JP
- Japan
- Prior art keywords
- fluoro
- deoxyuridine
- formula
- integer
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical class C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 230000000259 anti-tumor effect Effects 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical class C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 8
- 238000007796 conventional method Methods 0.000 description 8
- 230000004083 survival effect Effects 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000001727 in vivo Methods 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
- 108090000371 Esterases Proteins 0.000 description 5
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- -1 alkali metal salts Chemical class 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 231100001274 therapeutic index Toxicity 0.000 description 4
- MXHRCPNRJAMMIM-ULQXZJNLSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-tritiopyrimidine-2,4-dione Chemical class O=C1NC(=O)C([3H])=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 MXHRCPNRJAMMIM-ULQXZJNLSA-N 0.000 description 3
- TXWCDJYEKHLJSO-MYINAIGISA-N 1-[(2s,4s,5r)-2-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO)O[C@@]1(F)N1C(=O)NC(=O)C=C1 TXWCDJYEKHLJSO-MYINAIGISA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 238000006911 enzymatic reaction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960002949 fluorouracil Drugs 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HMKVXSDEPPJDSX-GFSQRUHRSA-N 1-[(2r,4s,5r)-4-butanoyl-4-hydroxy-5-(1-hydroxy-2-oxopentyl)oxolan-2-yl]-5-fluoropyrimidine-2,4-dione Chemical compound C1[C@](C(=O)CCC)(O)[C@@H](C(O)C(=O)CCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 HMKVXSDEPPJDSX-GFSQRUHRSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- ASOJCIZYYRUYIM-UHTJTAKZSA-N 5-fluoro-1-[(2r,4s,5r)-4-hexadecanoyl-4-hydroxy-5-(1-hydroxy-2-oxoheptadecyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@](C(=O)CCCCCCCCCCCCCCC)(O)[C@@H](C(O)C(=O)CCCCCCCCCCCCCCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ASOJCIZYYRUYIM-UHTJTAKZSA-N 0.000 description 2
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound 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 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 208000007093 Leukemia L1210 Diseases 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000003842 bromide salts Chemical class 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 2
- 239000003240 coconut oil Substances 0.000 description 2
- 235000019864 coconut oil Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012457 nonaqueous media Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- VMPHSYLJUKZBJJ-UHFFFAOYSA-N trilaurin Chemical compound CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)COC(=O)CCCCCCCCCCC VMPHSYLJUKZBJJ-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- PPUUEVYUHGROKR-BEKQNFRLSA-N 5-fluoro-1-[(2r,4s,5r)-4-hexanoyl-4-hydroxy-5-(1-hydroxy-2-oxoheptyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@](C(=O)CCCCC)(O)[C@@H](C(O)C(=O)CCCCC)O[C@H]1N1C(=O)NC(=O)C(F)=C1 PPUUEVYUHGROKR-BEKQNFRLSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical class CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical class NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 150000004075 acetic anhydrides Chemical class 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- PWAXUOGZOSVGBO-UHFFFAOYSA-N adipoyl chloride Chemical compound ClC(=O)CCCCC(Cl)=O PWAXUOGZOSVGBO-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
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- 229940110456 cocoa butter Drugs 0.000 description 1
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- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
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- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 1
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- 150000002314 glycerols Chemical class 0.000 description 1
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
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- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 229940093609 tricaprylin Drugs 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
産業上の利用分野
本発明は新規な５−フルオロ−2′−デオキシウ
リジン誘導体その製造法およびそれを有効成分と
して含有する抗腫瘍剤に関する。
更に詳細には本発明は、著しく低用量で高水準
の抗腫瘍効果を示し、かつ安全係数が大で生体内
での５−フルオロ−2′−デオキシウリジンの徐放
化性能にすぐれている新規な５−フルオロ−2′−
デオキシウリジン誘導体その製造法およびそれを
有効成分として含有する抗腫瘍剤に関する。
従来技術
５−フルオロ−2′−デオキシウリジンは、５−
フルオロウラシルの代識産物のひとつとして制癌
活性を有することが知られている化合物である。
その制癌活性は、in vitroのマウス由来の樹立細
胞株の増殖阻害活性において、同一モル濃度で５
−フルオロウラシルの100倍以上、同じく５−フ
ルオロウラシルの代謝産物である５−フルオロウ
リジンの10−100倍と報告されている〔Cancer
Research、Cancer、35、1121（1975）、Proc.
Amer.Ass.Cancer Research、71（1976）、
Cancer Research、18、730（1958）〕。
しかしながら、担癌動物を用いたin vivoの実
験では５−フルオロ−2′−デオキシウリジンの効
果は十分でなく、in vitroの結果とは逆に、５−
フルオロウラシルおよび５−フルオロウリジンに
対してその制癌効果が劣ることが報告されている
〔Cancer Research、19、494（1959）、Proc.Soc.
Exp.Biol.N.Y.、97、470（1958）、Proc.Soc.Exp.
Biol.、N.Y.、104、127（1960）、Ann.N.Y.Acad.
Sci.、76、575（1958）〕。
この原因としては、５−フルオロ−2′−デオキ
シウリジンの制癌効果は、５−フルオロ−2′−デ
オキシウリジンと腫瘍細胞の接触時間に大きく依
存するのに対し、生体内に投与された５−フルオ
ロ−2′−デオキシウリジンの半減期は著しく短く
腫瘍細胞との接触時間が十分に得られないことに
よると考えられている〔Cancer Research、32、
1045（1972）、Clin.Pharmacol.ther.、５、581
（1964）、Cancer Research、38、3479（1978）、
Bull.Cancer（Paris）、66、67（1979）、Bull.
Cancer（Paris）、66、75（1979）、Europ.J.
Cancer、16、1087（1980）〕。
この様な欠点を改善するために、現在まで種々
の５−フルオロ−2′−デオキシウリジン誘導体の
研究がなされている。例えば、３−アシル−５−
フルオロ−2′−デオキシウリジン（特開昭54−
163586号公報）、3′，5′−ジアシル−５−フルオ
ロ−2′−デオキシウリジン（日本薬学会第100年
会講演要旨集p.321（1980））、３位及び3′，5′位の
両者をアシル化した５−フルオロ−2′−デオキシ
ウリジン（特開昭56−113795、56−113796、56−
113797号公報）、５−フルオロ−2′−デオキシウ
リジンの3′，5′−ジエステル類（特開昭58−
49315号公報）などが知られている。しかしなが
ら、これらの誘導体は体内貯留性を向上させる目
的で導入した高脂溶性基の影響で中枢神経系への
毒性および溶血作用が懸念される。また水溶性の
低下によつて注射剤等の剤形への応用が困難であ
るなどの問題点を有する。
発明の目的
そこで本発明者らは上述の知見に基づいて生体
内に投与後、徐々に５−フルオロ−2′−デオキシ
ウリジンを放出することによつて高い抗腫瘍活性
を発現し、かつ副作用の少ない５−フルオロ−
2′−デオキシウリジンの誘導体を得るべく、５−
フルオロ−2′−デオキシウリジンの3′および5′部
位を生理条件下で電荷を有する様々な基によつて
エステル化したマスク型化合物について鋭意検索
した結果、末端にカルボキシル基を有するアルキ
ル基によつてエステル化した化合物が著しく低用
量で高水準の抗腫瘍効果を示し、かつ安全係数が
大で、生体内での５−フルオロ−2′−デオキシウ
リジンの徐放化性能にすぐれていることを見い出
し、本発明を完成するに至つた。
しかして本発明の目的は、優れた抗腫瘍効果を
示す新規な５−フルオロ−2′−デオキシウリジン
誘導体、その製造法、及びそれを有効成分とする
抗腫瘍剤を提供することにある。
発明の構成及び効果
本発明においては一般式〔〕
〔式中、ｎ、ｍは同じでも異なつてもよく１〜18
の整数を表わす。〕
で表わされる５−フルオロ−2′−デオキシウリジ
ン誘導体又はその薬理学的に許容される塩が提供
される。
上記式〔〕においてｎ、ｍは同じでも異なつ
ていてもよく１〜18の整数を示す。
本発明の化合物は3′位、5′位の置換基の末端に
あるカルボキシル基の塩であつてもよく、このよ
うな塩としては例えばナトリウム塩、カリウム塩
などのアルカリ金属の塩；カルシウム塩、マグネ
シウム塩、アルミニウム塩などの２価もしくは３
価の金属塩：アンモニウム塩、テトラメチルアン
モニウム塩、モノメチルアンモニウム塩、ジメチ
ルアンモニウム塩、トリメチルアンモニウム塩、
モルホリウム塩、ピペリジニウム塩などの有機塩
などが挙げられる。
本発明化合物の具体例としては、例えば、3′，
5′−ジマロニル−５−フルオロ−2′−デオキシウ
リジン、3′，5′−ジスクシニル−５−フルオロ−
2′−デオキシウリジン、3′，5′−ジグルタリル−
５−フルオロ−2′−デオキシウリジン、3′，5′−
ジアデイピル−５−フルオロ−2′−デオキシウリ
ジン、3′，5′−ジピメリル−2′−デオキシウリジ
ン、3′，5′−ジスベロイル−５−フルオロ−2′−
デオキシウリジン、3′，5′−ジアゼラオイル−５
−フルオロ−2′−デオキシウリジンなどがある。
本発明の化合物で一般式〔〕においてｎ、ｍ
が同じ場合、すなわち下記式〔−１）
〔式中、ｎは１〜18の整数を示す。m′はｎと同
じ整数を示す。〕
で表わされる５−フルオロ−2′−デオキシウリジ
ン誘導体は、５−フルオロ−2′−デオキシウリジ
ンと一般式〔〕
HOOC−（CH2）o−COOH ………〔〕
〔式中、ｎは１〜18の整数を示す。〕
で表わされる化合物の反応性誘導体を塩基の存在
下で反応させることによつて製造することができ
る。
本発明の化合物で一般式〔〕においてｎ、ｍ
が異なる場合、すなわち下記式〔−２〕
〔式中、ｎは１〜18の整数を示す。m″はｎと異
なり１〜18の整数を示す。〕
で表わされる５−フルオロ−2′−デオキシウリジ
ン誘導体は、一般式〔〕
〔式中、Ｒは保護基を有するヒドロキシル基を示
す。〕
で表わされる化合物と一般式〔〕
HOOC−（CH2）o−COOH ………〔〕
〔式中、ｎは１〜18の整数を示す。〕
で表わされる化合物の反応性誘導体を塩基の存在
下で反応させ、次いで保護基を脱離させた後一般
式〔〕
HOOC−（CH2）n″−COOH ………〔〕
〔式中、m″はｎと異なり１〜18の整数を示す。〕
で表わされる化合物の反応性誘導体を塩基の存在
下で反応させることによつて製造することができ
る。
一般式〔〕、〔〕で表わされる化合物の反応
性誘導体としては、対応する酸塩化物、酸臭化物
などの酸ハロゲン化物、酸無水物、混合酢無水
物、活性化エステル又は活性化酸アミド等が挙げ
られる。なかでも酸塩化物、酸臭化物などの酸ハ
ロゲン化物が好ましい。かかる反応性誘導体を反
応せしめる際に用いる塩基しては例えば、トリメ
チルアミン、トリエチルアミン、トリブチルアミ
ン、ピリジン、Ｎ−メチルモルホリン、２，６−
ルチジン、Ｎ，Ｎ−ジメチルアミノピリジンなど
の有機塩基類；炭酸アルカリ、酢酸アルカリなど
の無機塩基類が挙げられる。なかでもピリジン、
トリエチルアミンが好ましい。反応溶媒として
は、塩基として有機塩基類を用いるときは、有機
塩基類がそのまま溶媒として使用される。有機塩
基類のほかには例えば、エチルエーテル、テトラ
ヒドロフラン、ジオキサンなどのエーテル類；塩
化メチレン、四塩化炭素などのハロゲン化炭化水
素類；ベンゼン、トルエン等の芳香族炭化水素類
などの非極性溶媒が好ましい溶媒として挙げられ
る。反応せしめる際の使用量は、一般式〔〕、
〔〕で表わされる化合物の反応性誘導体は、５
−フルオロ−2′−デオキシウリジンに対して２倍
モル以上用いられ、また塩基は等モル以上用いら
れる。反応温度は、反応の初期には氷冷下で行
い、次いで室温で反応を行うのが好ましい。反応
時間は、反応する化合物の種類、量等によつて異
なるが、通常１〜５時間程度である。
本発明で用いる前記式〔〕で表わされる化合
物においてＲは保護基を有するヒドロキシル基を
示すが、保護基としては例えばトリフエニルメチ
ル基、トリフエニルメトキシアセチル基等の立体
障害性の高い保護基が挙げられる。前記式〔〕
の化合物は通常の方法で製造することができる。
保護基の脱離は、酸性あるいはアルカリ性の通
常の加水分解条件で行うことができる。例えば、
酢酸水溶液、塩酸水溶液などの酸性条件下、ある
いはアンモニア性メタノール溶液などのアルカリ
性条件下で行うことができる。
反応後に目的物を単離精製するには、通常の方
法、例えば再結晶、薄層クロマトグラフイー、カ
ラムクロマトグラフイー等の手段によつて行うこ
とができる。
かくして本発明の５−フルオロ−2′−デオキシ
ウリジン誘導体が得られるが、更に必要に応じ
て、薬理学的に許容される塩を得るために塩生反
応に付してもよい。塩生成反応は通常の方法によ
つて行われ、例えば水酸化ナトリウム、水酸化カ
リウム、炭酸ナトリウム、アンモニア、トリメチ
ルアミン、モノエタノールアミン、モルホリンな
どを５−フルオロ−2′−デオキシウリジン誘導体
と通常の方法で中和反応せしめることによつて行
われる。
本発明によれば、一般式〔〕で示される化合
物は、その抗腫瘍効果をマウス白血病細胞L1210
を移殖した担癌マウスの延命効果で調べると、５
−フルオロ−2′−デオキシウリジンが抗腫瘍効果
を示す用量の10分の１〜100分の１という極めて
低用量で強い延命効果を示しまた安全係数も高い
ことが明らかとなつた。また一般式〔〕で示さ
れる化合物は、エステラーゼを用いたin vitroの
系で、酵素反応によつて徐々に５−フルオロ−
2′−デオキシウリジンを放出することが示され、
その放出速度は中鎖および短鎖の脂肪族アシル基
を3′および5′部位に導入した従来の５−フルオロ
−2′−デオキシウリジン誘導体に比べ著しく緩慢
で生体内半減期のきわめて短い５−フルオロ−
2′−デオキシウリジンと抗腫細胞の接触時間を長
くするという点ですぐれた性質を有することが明
らかとなつた。
例えば、本発明の3′，5′−ジアデイピル−５−
フルオロ−2′−デオキシウリジンは、マウス白血
病細胞L1210を移植した担癌マウスの生存日数を
30％増加させるに要する投与量（ILS30）が同じ
延命効果を示す５−フルオロ−2′−デオキシウリ
ジンの約1/100（0.5mg／Kg／日）と極めて低用量
でよく、また最大延命効果を示すのに要する投与
量（ILSmax）が５−フルオロ−2′−デオキシウ
リジンの約1/10（10mg／Kg／日）と少ない。
さらに、ILSmax／ILS30で示される治療係数
が親化合物である５−フルオロ−2′−デオキシウ
リジンの10倍と安全性も高い。
またエステラーゼを用いた加水分解の実験で、
例えば本発明の3′，5′−ジアデイピル−５−フル
オロ−2′−デオキシウリジンおよび3′，5′−ジス
クシニル−５−フルオロ−2′−デオキシウリジン
は、エステル鎖部分の炭素数が等しい従来の3′，
5′−ジヘキサノイル−５−フルオロ−2′−デオキ
シウリジンおよび3′，5′−ジブチリル−５−フル
オロ−2′−デオキシウリジンとの比較で、酵素反
応によつて親化合物である５−フルオロ−2′−デ
オキシウリジンを放出する速度がそれぞれ1/120
０、1/1500ときわめて遅い。このことは生体内で
の半減期がきわめて短い５−フルオロ−2′−デオ
キシウリジンを生体内で徐々に放出することによ
つて長時間にわたつて腫瘍細胞と５−フルオロ−
2′−デオキシウリジンを接触させられると考えら
れ、本発明の化合物の高い抗腫瘍効果を裏付けて
いる。
本発明の５−フルオロ−2′−デオキシウリジン
誘導体は上述のとおり、優れた抗腫瘍効果を有す
るものであり、従つて本発明によれば一般式
〔〕で表わされる５−フルオロ−2′−デオキシ
ウリジン誘導体を有効成分とする抗腫瘍剤が提供
される。
本発明の５−フルオロ−2′−デオキシウリジン
誘導体は、経口的にあるいは皮下、筋肉内、静脈
内、経皮、直腸内等の非経口内に投与される。経
口投与の剤型としては、例えば錠剤、丸剤、顆粒
剤、散剤、液剤、懸濁剤、カプセル剤などが挙げ
られる。
錠剤の形態にするには、例えば乳糖、デンプ
ン、結晶セルロース、ヒドロキシプロピルセルロ
ースなどの賦形剤；カルボキシメチルセルロー
ス、メチルセルロース、ポリビニルピロリドンな
どの結合剤；アルギン酸ナトリウム、炭酸水素ナ
トリウム、ラウリル硫酸ナトリウムなどの崩壊剤
等を用いて通常の方法により成形することができ
る。丸剤、散剤、顆粒剤も同様に上記の賦形剤等
を用いて通常の方法によつて成形することができ
る。液剤、懸濁剤は例えばトリカプリリン、トリ
アセチン、トリラウリンなどのグリセリンエステ
ル類；ココナツツ油、分画ココナツツ油などの植
物油；エタノールなどのアルコール類などを用い
て通常の方法によつて成形される。カプセル剤は
顆粒剤、散剤などをハードゼラチンカプセルに充
填することによつて、あるいは液剤をソフトゼラ
チンカプセルに充填することによつて成形され
る。
皮下、筋肉内、静脈内投与の剤型としては、水
性あるいは非水性溶液剤、懸濁剤などの形態にあ
る注射剤がある。非水溶性溶液剤、懸濁剤は、例
えばプロピレングリコール、ポリエチレングリコ
ール、オリーブ油、オレイン酸エチルなどが用い
られ、これらに必要に応じて防腐剤、安定剤など
が添加される。注射剤は通常バクテリア保留フイ
ルターをとおす濾過、殺菌剤の配合等の処理を適
宜行うことによつて無菌化される。
経皮投与の剤型としては、例えば軟膏剤、クリ
ーム剤などが挙げられ、軟膏剤はヒマシ油、オリ
ーブ油などの脂肪油、ワセリン等を用いて通常の
方法により成形され、クリーム剤は脂肪油あるい
はジエチレングリコール、ソルビタンモノ脂肪酸
エステルなどの乳化剤等を用いて通常の方法によ
つて成形される。
直腸投与のためには、ゼラチンソフトカプセル
あるいはカカオ脂等を用いた坐剤などが用いられ
る。
本発明の５−フルオロ−2′−デオキシウリジン
誘導体又はその薬理学的に許容される塩の投与量
は、患者の年令、性別、疾患の程度、剤型などに
よつて異なるが、通常0.3〜500mg／Kg／日、好ま
しくは10〜100mg／Kg／日である。
本発明の５−フルオロ−2′−デオキシウリジン
誘導体又はその薬理学的に許容される塩は２種以
上を適宜選択して併用投与することも出来る。
以下本発明を実施例により更に詳細に説明す
る。
実施例 １
3′，5′−ジアデイピル−５−フルオロ−2′−デ
オキシウリジンの合成
（ｎ＝ｍ＝４）
５−フルオロ−2′−デオキシウリジン250mg
（1.01ｍmole）を10mlの無水ピリジンに溶解し、
氷冷撹拌下、アデイポイルクロリド800mg（4.37
ｍmole）を約３時間かけて加え、室温で一夜撹
拌した。反応混合物を50mlの氷水中に注ぎ１時間
撹拌の後、2N塩酸を加えPHを400とし、20mlの酢
酸エチルで３回抽出した。酢酸エチルを減圧下室
温で留去して得られた粗生成物をクロロホルムに
溶かし、シリカゲルカラムクロマトグラフイーに
付し、クロロホルム−エタノール（95：５）〜
（90：10）溶出部分を集め濃縮して3′，5′−ジア
デイピル−５−フルオロ−2′−デオキシウリジン
を得た。収率40％であつた。
UV：λmax 209nｍ、268nｍ
NMR（δTMS CDCl3-D3COD）：
1.5−1.8（ｍ、8H〕、2.1−2.5（ｍ、10H）
4.2−4.4（ｍ、3H）、5.1−5.3（ｍ、1H）、
6.3（ｔ、1H）、7.9（ｄ、1H、Ｊ＝6.5Hz）．
m.p.：44−45℃
実施例 ２
3′，5′−ジグルタリル−５−フルオロ−2′−デ
オキシウリジンの合成
（ｎ＝ｍ＝３）
５−フルオロ−2′−デオキシウリジン220mg
（0.89ｍmole）を３mlの無水ピリジンに溶解し、
室温で無水グルタル酸280mg（2.46ｍmole）を加
え、室温で一夜さらに80℃で３時間撹拌した。反
応混合物を30mlの氷水中に注ぎ１時間撹拌の後
2N−塩酸を加えPHを4.00とし、15mlの酢酸エチ
ルで３回抽出した。酢酸エチルを減圧下室温で留
去して得られた粗生成物をクロロホルムに溶かし
シリカゲルカラムクロマトグラフイーに付し、ク
ロロホルム−エタノール（93：７）〜（88：12）
溶出部分を集め濃縮して3′，5′−ジグルタリル−
５−フルオロ−2′−デオキシウリジンを得た。収
率70％であつた。
形状−油状
UV：λmax 209nｍ、268nｍ
NMR（δTMS C3COD）：
1.7−2.2（ｍ、4H）、2.2−2.7（ｍ、10H）、
4.2−4.5（ｍ、3H）、5.2−5.4（ｍ、1H）、
6.25（ｔ、1H）、7.92（ｄ、1H、Ｊ＝6.5Hz）．
実施例 ３
3′，5′−ジスクシニル−５−フルオロ−2′−デ
オキシウリジンの合成
（ｎ＝ｍ＝２）
５−フルオロ−2′−デオキシウリジン500mg
（2.02ｍmole）を６mlの無水ピリジンに溶解し、
室温で無水コハク酸500mg（5.00ｍmole）を加え
室温で一夜撹拌した。反応混合物を60mlの氷中に
注ぎ１時間撹拌の後2N−塩酸を加えPHを4.00と
し30mlの酢酸エチルで３回抽出した。酢酸エチル
を減圧下室温で留去して得られた粗生成物をクロ
ロホルムに溶かしシリカゲルカラムクロマトグラ
フイーに付し、クロロホルム−エタノール（90：
10）〜（85：15）溶出部分を集め濃縮して3′，
5′−ジスクシニル−５−フルオロ−2′−デオキシ
ウリジンを得た。収率80％であつた。
UV：λmax 209nｍ、268nｍ
NMR（δTMS C3COD）：
2.5−2.7（ｍ、10H）、4.2−4.4（ｍ、3H）、
5.2−5.4（ｍ、1H）、6.25（ｔ、1H）、
7.92（ｄ、1H、Ｊ＝6.5Hz）．
m.p.：116−117℃
実施例 ４
５−フルオロ−2′−デオキシウリジン誘導体の
抗腫瘍活性
本発明の化合物3′，5′−ジアデイピル−５−フ
ルオロ−2′−デオキシウリジンについて、マウス
白血病L1210に対する抗腫瘍効果を親化合物の５
−フルオロ−2′−デオキシウリジンおよび長鎖脂
肪族アシル基を配した3′，5′−ジパルミトイル−
５−フルオロ−2′−デオキシウリジン（特開昭58
−49315号公報に記載された化合物）と比較した。
移植７日目のマウス白血病L1210腹水腫瘍細胞
105個をBDFマウス（〓６週、Ca24ｇ、１群：５
匹）の腹腔内に移植し、実験に供した。
腫瘍細胞移植24時間後より、１日１回５日間薬
剤を連続腹腔内投与した。
薬剤の抗腫瘍効果は、薬剤投与群の生存期間を
対照群（薬剤無投与）のそれに対する増加割合で
示した。
すなわち、対照群に比し30％生存期間を延長さ
せるに要する薬剤投与量をILS30とし、最大延命
率（Max.ILS（％））を示すに要する投与量を
ILSmaxとして表わした。また、ILSmax.／
ILS30を治療係数としてその薬剤の安全性を示す
指標とした。
結果は第１表および第１図に示したとおりであ
る。
INDUSTRIAL APPLICATION FIELD The present invention relates to a novel 5-fluoro-2'-deoxyuridine derivative, a method for producing the same, and an antitumor agent containing the same as an active ingredient. More specifically, the present invention provides a novel drug that exhibits a high level of antitumor effect at a significantly low dose, has a large safety factor, and has excellent sustained release performance of 5-fluoro-2'-deoxyuridine in vivo. 5-Fluoro-2'-
This invention relates to a method for producing a deoxyuridine derivative and an antitumor agent containing it as an active ingredient. Prior art 5-fluoro-2'-deoxyuridine is 5-fluoro-2'-deoxyuridine.
It is a compound known to have anticancer activity as one of the substitute products of fluorouracil.
Its anticancer activity was shown to be 5% at the same molar concentration in the growth inhibitory activity of established cell lines derived from mice in vitro.
-It is reported to be more than 100 times more than fluorouracil and 10-100 times more than 5-fluorouridine, which is also a metabolite of 5-fluorouracil [Cancer
Research, Cancer, 35 , 1121 (1975), Proc.
Amer. Ass. Cancer Research, 71 (1976),
Cancer Research, 18 , 730 (1958)]. However, in in vivo experiments using tumor-bearing animals, the effect of 5-fluoro-2'-deoxyuridine was not sufficient, contrary to the in vitro results.
It has been reported that its anticancer effect is inferior to that of fluorouracil and 5-fluorouridine [Cancer Research, 19 , 494 (1959), Proc.Soc.
Exp.Biol.NY, 97 , 470 (1958), Proc.Soc.Exp.
Biol., NY, 104 , 127 (1960), Ann.NYAcad.
Sci., 76 , 575 (1958)]. The reason for this is that the anticancer effect of 5-fluoro-2'-deoxyuridine largely depends on the contact time between 5-fluoro-2'-deoxyuridine and tumor cells; -Fluoro-2'-deoxyuridine has an extremely short half-life, which is thought to be due to insufficient contact time with tumor cells [Cancer Research, 32 ,
1045 (1972), Clin.Pharmacol.ther., 5 , 581
(1964), Cancer Research, 38 , 3479 (1978),
Bull. Cancer (Paris), 66 , 67 (1979), Bull.
Cancer (Paris), 66 , 75 (1979), Europ.J.
Cancer, 16 , 1087 (1980)]. In order to improve these drawbacks, various 5-fluoro-2'-deoxyuridine derivatives have been studied to date. For example, 3-acyl-5-
Fluoro-2'-deoxyuridine
163586), 3',5'-diacyl-5-fluoro-2'-deoxyuridine (Proceedings of the 100th Annual Meeting of the Pharmaceutical Society of Japan, p.321 (1980)), 3rd place and 3',5' place 5-fluoro-2'-deoxyuridine (JP-A-113795, 56-113796, 56-
113797), 3',5'-diesters of 5-fluoro-2'-deoxyuridine (Japanese Patent Application Laid-open No. 11379-
Publication No. 49315) are known. However, these derivatives are concerned about toxicity to the central nervous system and hemolytic effects due to the effects of highly lipophilic groups introduced for the purpose of improving retention in the body. In addition, it has problems such as difficulty in applying it to dosage forms such as injections due to decreased water solubility. Purpose of the Invention Based on the above-mentioned findings, the present inventors have developed a method that gradually releases 5-fluoro-2'-deoxyuridine after in vivo administration, thereby exhibiting high antitumor activity and reducing side effects. less 5-fluoro-
In order to obtain a derivative of 2'-deoxyuridine, 5-
As a result of intensive searches for mask-type compounds in which the 3' and 5' moieties of fluoro-2'-deoxyuridine are esterified with various groups that are charged under physiological conditions, we found that the 3' and 5' moieties of fluoro-2'-deoxyuridine are esterified with various charged groups under physiological conditions. The compound esterified with this method shows a high level of antitumor effect at a significantly low dose, has a large safety factor, and has excellent sustained release performance of 5-fluoro-2'-deoxyuridine in vivo. This finding led to the completion of the present invention. Therefore, an object of the present invention is to provide a novel 5-fluoro-2'-deoxyuridine derivative exhibiting excellent antitumor effects, a method for producing the same, and an antitumor agent containing the same as an active ingredient. Structure and effects of the invention In the present invention, the general formula [] [In the formula, n and m may be the same or different and are 1 to 18
represents an integer. ] A 5-fluoro-2'-deoxyuridine derivative or a pharmacologically acceptable salt thereof is provided. In the above formula [], n and m may be the same or different and represent an integer of 1 to 18. The compound of the present invention may be a salt of the carboxyl group at the end of the substituent at the 3' or 5' position, and examples of such salts include alkali metal salts such as sodium salts and potassium salts; calcium salts; , divalent or trivalent salts such as magnesium salts, aluminum salts, etc.
Valent metal salts: ammonium salts, tetramethylammonium salts, monomethylammonium salts, dimethylammonium salts, trimethylammonium salts,
Examples include organic salts such as morpholium salts and piperidinium salts. Specific examples of the compounds of the present invention include, for example, 3',
5'-dimalonyl-5-fluoro-2'-deoxyuridine, 3',5'-disuccinyl-5-fluoro-
2′-deoxyuridine, 3′,5′-diglutaryl-
5-Fluoro-2'-deoxyuridine, 3',5'-
Diadipyr-5-fluoro-2'-deoxyuridine, 3',5'-dipimelyl-2'-deoxyuridine, 3',5'-disuberoyl-5-fluoro-2'-
Deoxyuridine, 3',5'-diazeroyl-5
-Fluoro-2'-deoxyuridine, etc. In the compound of the present invention, n, m in the general formula []
If they are the same, that is, the following formula [-1] [In the formula, n represents an integer of 1 to 18. m' indicates the same integer as n. ] The 5-fluoro-2'-deoxyuridine derivative represented by 5-fluoro-2'-deoxyuridine has the general formula [] HOOC-(CH 2 ) o -COOH ...... [] [where n is Indicates an integer from 1 to 18. ] It can be produced by reacting a reactive derivative of the compound represented by the following in the presence of a base. In the compound of the present invention, n, m in the general formula []
are different, that is, the following formula [-2] [In the formula, n represents an integer of 1 to 18. m'' is an integer from 1 to 18, unlike n.] The 5-fluoro-2'-deoxyuridine derivative represented by the general formula [] [In the formula, R represents a hydroxyl group having a protecting group. ] Compounds represented by the general formula [] HOOC-(CH 2 ) o -COOH ...... [] [In the formula, n represents an integer of 1 to 18. ] A reactive derivative of the compound represented by is reacted in the presence of a base, and then the protective group is removed, followed by the general formula [] HOOC-(CH 2 ) n ″-COOH ...... [ ] [In the formula, Unlike n, m'' represents an integer from 1 to 18. ] It can be produced by reacting a reactive derivative of the compound represented by the following in the presence of a base. Reactive derivatives of the compounds represented by the general formulas [] and [] include corresponding acid halides such as acid chlorides and acid bromides, acid anhydrides, mixed acetic anhydrides, activated esters, and activated acid amides. can be mentioned. Among these, acid halides such as acid chlorides and acid bromides are preferred. Examples of bases used in reacting such reactive derivatives include trimethylamine, triethylamine, tributylamine, pyridine, N-methylmorpholine, 2,6-
Examples include organic bases such as lutidine and N,N-dimethylaminopyridine; and inorganic bases such as alkali carbonate and alkali acetate. Among them, pyridine,
Triethylamine is preferred. As a reaction solvent, when an organic base is used as a base, the organic base is used as it is as a solvent. In addition to organic bases, for example, ethers such as ethyl ether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as methylene chloride and carbon tetrachloride; and nonpolar solvents such as aromatic hydrocarbons such as benzene and toluene. These are listed as preferred solvents. The amount used in the reaction is based on the general formula [],
The reactive derivative of the compound represented by [ ] is 5
-Fluoro-2'-deoxyuridine is used in an amount of twice or more in mole or more, and the base is used in an equimolar or more amount. Regarding the reaction temperature, it is preferable to carry out the reaction under ice cooling at the initial stage of the reaction, and then to carry out the reaction at room temperature. The reaction time varies depending on the type and amount of the compound to be reacted, but is usually about 1 to 5 hours. In the compound represented by the above formula [] used in the present invention, R represents a hydroxyl group having a protecting group, and the protecting group may include a highly sterically hindered protecting group such as a triphenylmethyl group or a triphenylmethoxyacetyl group. Can be mentioned. The above formula []
The compound can be produced by conventional methods. The protective group can be removed under normal acidic or alkaline hydrolysis conditions. for example,
This can be carried out under acidic conditions such as an aqueous acetic acid solution or aqueous hydrochloric acid solution, or under alkaline conditions such as an ammoniacal methanol solution. After the reaction, the target product can be isolated and purified by conventional methods such as recrystallization, thin layer chromatography, column chromatography, etc. In this way, the 5-fluoro-2'-deoxyuridine derivative of the present invention is obtained, but if necessary, it may be further subjected to a halogenetic reaction to obtain a pharmacologically acceptable salt. The salt-forming reaction is carried out by a conventional method, for example, by reacting sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia, trimethylamine, monoethanolamine, morpholine, etc. with a 5-fluoro-2'-deoxyuridine derivative by a conventional method. This is done by causing a neutralization reaction. According to the present invention, the compound represented by the general formula [] shows its antitumor effect on murine leukemia cells L1210.
When examining the survival effect of transplanted tumor-bearing mice, it was found that 5
It has been revealed that -fluoro-2'-deoxyuridine has a strong survival effect and a high safety factor at an extremely low dose of 1/10 to 1/100 of the dose that exhibits antitumor effects. In addition, the compound represented by the general formula [] is gradually produced by enzymatic reaction in an in vitro system using esterase.
It has been shown to release 2'-deoxyuridine,
Its release rate is significantly slower than that of conventional 5-fluoro-2'-deoxyuridine derivatives in which medium-chain and short-chain aliphatic acyl groups are introduced into the 3' and 5' sites, and its in vivo half-life is extremely short. Fluoro-
It has been revealed that it has excellent properties in terms of prolonging the contact time between 2'-deoxyuridine and antitumor cells. For example, the 3',5'-diadipyr-5-
Fluoro-2'-deoxyuridine increases the survival time of tumor-bearing mice transplanted with murine leukemia cells L1210.
The dose required to increase the survival rate by 30% (ILS 30 ) is approximately 1/100 (0.5 mg/Kg/day) of 5-fluoro-2'-deoxyuridine, which has the same survival effect, which is extremely low. The dose required to show efficacy (ILSmax) is about 1/10 (10 mg/Kg/day) of 5-fluoro-2'-deoxyuridine. Furthermore, it is highly safe, with a therapeutic index expressed by ILSmax/ILS 30 that is 10 times that of the parent compound, 5-fluoro-2'-deoxyuridine. In addition, in a hydrolysis experiment using esterase,
For example, the 3',5'-diadeipyl-5-fluoro-2'-deoxyuridine and 3',5'-disuccinyl-5-fluoro-2'-deoxyuridine of the present invention have the same number of carbon atoms in the ester chain moiety. 3′,
In comparison with 5'-dihexanoyl-5-fluoro-2'-deoxyuridine and 3',5'-dibutyryl-5-fluoro-2'-deoxyuridine, the parent compound 5-fluoro- The rate of releasing 2′-deoxyuridine is 1/120, respectively.
0, extremely slow at 1/1500. This means that by gradually releasing 5-fluoro-2'-deoxyuridine, which has an extremely short half-life in vivo, 5-fluoro-2'-deoxyuridine can interact with tumor cells over a long period of time.
It is believed that 2'-deoxyuridine can be contacted, supporting the high antitumor effect of the compounds of the present invention. As mentioned above, the 5-fluoro-2'-deoxyuridine derivative of the present invention has an excellent antitumor effect, and therefore, according to the present invention, the 5-fluoro-2'-deoxyuridine derivative represented by the general formula [] An antitumor agent containing a deoxyuridine derivative as an active ingredient is provided. The 5-fluoro-2'-deoxyuridine derivative of the present invention is administered orally or parenterally, such as subcutaneously, intramuscularly, intravenously, transdermally, or rectally. Examples of dosage forms for oral administration include tablets, pills, granules, powders, solutions, suspensions, and capsules. For tablet form, excipients such as lactose, starch, microcrystalline cellulose, hydroxypropylcellulose; binders such as carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone; and disintegrating agents such as sodium alginate, sodium bicarbonate, sodium lauryl sulfate, etc. It can be molded by a conventional method using a chemical agent or the like. Pills, powders, and granules can also be formed using the above-mentioned excipients and the like in a conventional manner. Solutions and suspensions are formed by conventional methods using, for example, glycerin esters such as tricaprylin, triacetin, and trilaurin; vegetable oils such as coconut oil and fractionated coconut oil; and alcohols such as ethanol. Capsules are formed by filling hard gelatin capsules with granules, powders, etc., or by filling soft gelatin capsules with liquid preparations. Dosage forms for subcutaneous, intramuscular, and intravenous administration include injections in the form of aqueous or nonaqueous solutions, suspensions, and the like. As the non-aqueous solutions and suspensions, propylene glycol, polyethylene glycol, olive oil, ethyl oleate, etc. are used, and preservatives, stabilizers, etc. are added to these as necessary. Injectable preparations are usually sterilized by appropriate treatments such as filtration through a bacteria retention filter and addition of a sterilizing agent. Examples of dosage forms for transdermal administration include ointments and creams. Ointments are formed using fatty oils such as castor oil or olive oil, petrolatum, etc. by a conventional method, and creams are formed using fatty oils or It is molded by a conventional method using an emulsifier such as diethylene glycol or sorbitan monofatty acid ester. For rectal administration, gelatin soft capsules or suppositories using cocoa butter or the like are used. The dosage of the 5-fluoro-2'-deoxyuridine derivative or its pharmacologically acceptable salt of the present invention varies depending on the patient's age, sex, degree of disease, dosage form, etc., but is usually 0.3 ~500 mg/Kg/day, preferably 10-100 mg/Kg/day. Two or more 5-fluoro-2'-deoxyuridine derivatives or pharmacologically acceptable salts thereof of the present invention can be appropriately selected and administered in combination. The present invention will be explained in more detail below with reference to Examples. Example 1 Synthesis of 3',5'-diadeipyl-5-fluoro-2'-deoxyuridine (n=m=4) 250 mg of 5-fluoro-2'-deoxyuridine
(1.01 mmole) in 10 ml of anhydrous pyridine,
Adipoyl chloride 800 mg (4.37
mmole) was added over about 3 hours and stirred at room temperature overnight. The reaction mixture was poured into 50 ml of ice water and stirred for 1 hour, then 2N hydrochloric acid was added to adjust the pH to 400, and the mixture was extracted three times with 20 ml of ethyl acetate. The crude product obtained by distilling off ethyl acetate at room temperature under reduced pressure was dissolved in chloroform and subjected to silica gel column chromatography, and chloroform-ethanol (95:5) to
(90:10) The eluted portion was collected and concentrated to give 3',5'-diadipyr-5-fluoro-2'-deoxyuridine. The yield was 40%. UV: λmax 209nm, 268nm NMR (δ TMS CDCl3-D3COD ): 1.5-1.8 (m, 8H), 2.1-2.5 (m, 10H) 4.2-4.4 (m, 3H), 5.1-5.3 (m, 1H), 6.3 (t, 1H), 7.9 (d, 1H, J = 6.5Hz). mp: 44-45°C Example 2 Synthesis of 3',5'-diglutaryl-5-fluoro-2'-deoxyuridine (n = m=3) 5-fluoro-2'-deoxyuridine 220 mg
(0.89 mmole) was dissolved in 3 ml of anhydrous pyridine,
280 mg (2.46 mmole) of glutaric anhydride was added at room temperature, and the mixture was stirred overnight at room temperature and further at 80° C. for 3 hours. Pour the reaction mixture into 30 ml of ice water and stir for 1 hour.
2N-hydrochloric acid was added to adjust the pH to 4.00, and the mixture was extracted three times with 15 ml of ethyl acetate. The crude product obtained by distilling off ethyl acetate at room temperature under reduced pressure was dissolved in chloroform and subjected to silica gel column chromatography to obtain a mixture of chloroform-ethanol (93:7) to (88:12).
The eluted portion was collected and concentrated to give 3′,5′-diglutaryl-
5-fluoro-2'-deoxyuridine was obtained. The yield was 70%. Shape - Oily UV: λmax 209nm, 268nm NMR (δ TMS C3COD ): 1.7-2.2 (m, 4H), 2.2-2.7 (m, 10H), 4.2-4.5 (m, 3H), 5.2-5.4 (m, 1H) ), 6.25 (t, 1H), 7.92 (d, 1H, J=6.5Hz). Example 3 Synthesis of 3',5'-disuccinyl-5-fluoro-2'-deoxyuridine (n=m=2) 500 mg of 5-fluoro-2'-deoxyuridine
(2.02 mmole) in 6 ml of anhydrous pyridine,
500 mg (5.00 mmole) of succinic anhydride was added at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 60 ml of ice, stirred for 1 hour, and then 2N hydrochloric acid was added to adjust the pH to 4.00, followed by extraction three times with 30 ml of ethyl acetate. The crude product obtained by distilling off ethyl acetate at room temperature under reduced pressure was dissolved in chloroform and subjected to silica gel column chromatography.
10) ~ (85:15) Collect the eluted portion and concentrate 3′,
5'-disuccinyl-5-fluoro-2'-deoxyuridine was obtained. The yield was 80%. UV: λmax 209nm, 268nm NMR (δ TMS C3COD ): 2.5-2.7 (m, 10H), 4.2-4.4 (m, 3H), 5.2-5.4 (m, 1H), 6.25 (t, 1H), 7.92 (d , 1H, J=6.5Hz). mp: 116-117°C Example 4 Antitumor activity of 5-fluoro-2'-deoxyuridine derivative The compound 3',5'-diadipyr-5-fluoro-2'-deoxyuridine of the present invention was tested against murine leukemia L1210. The antitumor effect of the parent compound 5
-Fluoro-2'-deoxyuridine and 3',5'-dipalmitoyl with long chain aliphatic acyl group-
5-Fluoro-2'-deoxyuridine
-49315). Mouse leukemia L1210 ascites tumor cells on day 7 of transplantation
10 5 BDF mice (〓6 weeks, Ca24g, 1 group: 5
It was transplanted into the abdominal cavity of a mouse and used for experiments. Starting 24 hours after tumor cell transplantation, the drug was continuously administered intraperitoneally once a day for 5 days. The antitumor effect of a drug was expressed as the percentage increase in survival time in the drug-administered group compared to that in the control group (no drug administered). In other words, the drug dose required to extend the survival period by 30% compared to the control group is defined as ILS 30 , and the dose required to show the maximum survival rate (Max.ILS (%)) is defined as ILS 30.
Expressed as ILSmax. Also, ILSmax./
ILS 30 was used as a therapeutic index to indicate the safety of the drug. The results are shown in Table 1 and Figure 1.
【表】
第１表、第１図からわかるように本発明の化合
物のひとつである3′，5′−ジアデイピル−５−フ
ルオロ−2′−デオキシウリジンは５−フルオロ−
2′−デオキシウリジンの1/10乃至1/100という極
めて低用量で高い抗腫瘍効果を示し、また治療係
数も10倍高かつた。また3′，5′−ジパルミトイル
−５−フルオロ−2′−デオキシウリジンと比べて
も治療係数は４倍高かつた。
実施例 ５
５−フルオロ−2′−デオキシウリジン誘導体の
エステラーゼによる加水分解速度
本発明の化合物3′，5′−ジアデイピル−５−フ
ルオロ−2′−デオキシウリジン、3′，5′−ジグル
タリル−５−フルオロ−2′−デオキシウリジンお
よび3′，5′−ジスクシニル−５−フルオロ−2′−
デオキシウリジンについて、ブタ肝臓より抽出し
たエステラーゼを用いて酵素的加水分解による親
薬物の放出速度を3′，5′−ジプロピオール−５−
フルオロ−2′−デオキシウリジン、3′，5′−ジブ
チリル−５−フルオロ−2′−デオキシウリジン、
3′，5′−ジヘキサノイル−５−フルオロ−2′−デ
オキシウリジンおよび3′，5′−ジオクタノイル−
５−フルオロ−2′−デオキシウリジンと比較し
た。
薬剤を10μｇ／mlの濃度で等張りん酸緩衝液
（PH7.00）に溶解し、37℃でブタ肝臓より抽出し
たエステラーゼ（シグマ社製）を酵素濃度
0.03units／ml〜150units／mlとなるように加えた
後、経時的にサンプル（10μ）をHPLCカラム
に注入して酵素反応によつて放出された５−フル
オロ−2′−デオキシウリジン量を測定した。
各酵素濃度において、加えた５−フルオロ−
2′−デオキシウリジン誘導体の1/2量が、親薬物
に変換されるのに要した時間（ｔ1/2）を酵素に
よる加水分解速度の指標として示した。
結果は第２表の通りである。[Table] As can be seen from Table 1 and Figure 1, 3',5'-diadeipyl-5-fluoro-2'-deoxyuridine, one of the compounds of the present invention, is 5-fluoro-2'-deoxyuridine.
It showed a high antitumor effect at an extremely low dose of 1/10 to 1/100 of 2'-deoxyuridine, and the therapeutic index was 10 times higher. The therapeutic index was also four times higher than that of 3',5'-dipalmitoyl-5-fluoro-2'-deoxyuridine. Example 5 Hydrolysis rate of 5-fluoro-2'-deoxyuridine derivatives by esterase Compounds of the present invention 3',5'-diadeipyl-5-fluoro-2'-deoxyuridine, 3',5'-diglutaryl-5 -Fluoro-2'-deoxyuridine and 3',5'-disuccinyl-5-fluoro-2'-
For deoxyuridine, the release rate of the parent drug by enzymatic hydrolysis was determined using esterase extracted from pig liver.
Fluoro-2'-deoxyuridine, 3',5'-dibutyryl-5-fluoro-2'-deoxyuridine,
3',5'-dihexanoyl-5-fluoro-2'-deoxyuridine and 3',5'-dioctanoyl-
It was compared with 5-fluoro-2'-deoxyuridine. The drug was dissolved in isotonic phosphate buffer (PH7.00) at a concentration of 10 μg/ml, and esterase (manufactured by Sigma) extracted from pig liver at 37°C was added to the enzyme concentration.
After adding 0.03 units/ml to 150 units/ml, the sample (10μ) was injected into an HPLC column over time to measure the amount of 5-fluoro-2'-deoxyuridine released by the enzymatic reaction. did. At each enzyme concentration, added 5-fluoro-
The time (t1/2) required for 1/2 amount of the 2'-deoxyuridine derivative to be converted into the parent drug was shown as an index of the rate of hydrolysis by the enzyme. The results are shown in Table 2.
【表】【table】
【表】
第２表からわかるように本発明の化合物はエス
テル鎖部分の炭素数が等しい直鎖アルキルエステ
ルとの比較で酵素反応によつて親薬物を放出する
速度が1/1200−1/15000ときわめて遅く、生体に
投与後生体内の酵素系で徐々に５−フルオロ−
2′−デオキシウリジンを放出する性質を有するこ
とが明らかである。
実施例 ６
錠剤の製造
本発明の化合物（3′，5′−ジアデイピル−５−フ
ルオロ−2′−デオキシウリジン 50mg
乳 糖 50mg
コーンスターチ 30mg
エチルセルロース 10mg
カルボキシメチルセルロースカルシウム 57mgステアリン酸マグネシウム ３mg
計 200mg
実施例 ７
カプセル剤の製造
本発明の化合物（3′，5′−ジグルタリル−５−フ
ルオロ−2′−デオキシウリジン 100mg
乳 糖 97mg
結晶セルロース 50mgステアリン酸マグネシウム ３mg
計 250mg
実施例 ８
顆粒剤の製造
本発明の化合物（3′，5′−ジスクシニル−５−フ
ルオロ−2′−デオキシウリジン 50mg
乳 糖 587mg
エチルセルロース 10mg
コーンスターチ 250mg
カルボキシメチルセルロースカルシウム 100mgステアリン酸マグネシウム ３mg
計 1000mg
実施例 ９
注射剤の製造
本発明の化合物（3′，5′−ジアデイピル−５−
フルオロ−2′−デオキシウリジン）を水溶液（PH
6.00−7.50）に溶解し１ml中に0.3mg〜100mgを含
む注射剤を得た。[Table] As can be seen from Table 2, the compound of the present invention releases the parent drug at a rate of 1/1200 to 1/15000 through an enzymatic reaction compared to a straight chain alkyl ester with the same number of carbon atoms in the ester chain portion. 5-Fluoro-
It is clear that it has the property of releasing 2'-deoxyuridine. Example 6 Manufacture of tablets Compound of the present invention (3',5'-diadipyr-5-fluoro-2'-deoxyuridine 50mg Lactose 50mg Corn starch 30mg Ethylcellulose 10mg Carboxymethyl cellulose calcium 57mg Magnesium stearate 3mg Total 200mg Example 7 Capsules Production of the compound of the present invention (3',5'-diglutaryl-5-fluoro-2'-deoxyuridine 100 mg Lactose 97 mg Crystalline cellulose 50 mg Magnesium stearate 3 mg Total 250 mg Example 8 Production of the compound of the present invention (3',5'-diglutaryl-5-fluoro-2'-deoxyuridine) 3',5'-disuccinyl-5-fluoro-2'-deoxyuridine 50mg Lactose 587mg Ethylcellulose 10mg Cornstarch 250mg Carboxymethylcellulose calcium 100mg Magnesium stearate 3mg Total 1000mg Example 9 Production of injection Compound of the present invention (3', 5′-diadipir-5-
fluoro-2′-deoxyuridine) in an aqueous solution (PH
6.00-7.50) to obtain an injection containing 0.3 mg to 100 mg per ml.
第１図は、５−フルオロ−2′−デオキシウリジ
ン誘導体（５−フルオロ−2′−デオキシウリジ
ン、3′，5′−ジパルミトイル−５−フルオロ−
2′−デオキシウリジン、3′，5′−ジアデイピル−
５−フルオロ−2′−デオキシウリジン）の抗腫瘍
活性（投与量に対するILS値の変化）を示したも
のである。
Figure 1 shows 5-fluoro-2'-deoxyuridine derivatives (5-fluoro-2'-deoxyuridine, 3',5'-dipalmitoyl-5-fluoro-
2′-deoxyuridine, 3′,5′-diadipyr-
This figure shows the antitumor activity (change in ILS value with respect to dose) of 5-fluoro-2'-deoxyuridine).
Claims (1)
整数を示す。〕 で示される５−フルオロ−2′−デオキシウリジン
誘導体又はその薬理学的に許容される塩。 ２ ５−フルオロ−2′−デオキシウリジンと一般
式〔〕 HOOC−（CH2）o−COOH ………〔） 〔式中、ｎは１〜18の整数を示す。〕 で表わされる化合物の反応性誘導体を塩基の存在
下で反応させ、次いで必要に応じて塩生成反応に
付すことを特徴とする 一般式〔−１〕 〔式中、ｎは１〜18の整数を示す。m′はｎと同
じ整数を示す。〕 で表わされる５−フルオロ−2′−デオキシウリジ
ン誘導体又はその薬理学的に許容される塩の製造
法。 ３ 一般式〔〕 〔式中、Ｒは保護基を有するヒドロキシル基を示
す。〕 で表わされる化合物と 一般式〔〕 HOOC−（CH2）o−COOH ………〔〕 〔式中、ｎは１〜18の整数を示す。〕 で表わされる化合物の反応性誘導体を塩基の存在
下で反応させ、次いで保護基を脱離させた後 一般式〔〕 HOOC−（CH2）n″−COOH ………〔〕 〔式中、m″はｎと異なり、１〜18の整数を示
す。〕 で表わされる化合物の反応性誘導体を塩基の存在
下で反応させ、次いで必要に応じて塩生成反応に
付すことを特徴とする。 一般式〔−２〕 〔式中、ｎは１〜18の整数を示す。m″はｎと異
なり１〜18の整数を示す。〕 で表わされる５−フルオロ−2′−デオキシウリジ
ン誘導体又はその薬理学的に許容される塩の製造
法。 ４ 下記式〔〕 〔式中、ｎ、ｍは同じでも異つてもよく１〜18の
整数を示す。〕 で示される５−フルオロ−2′−デオキシウリジン
誘導体又はその薬理学的に許容される塩を有効成
分とする抗腫瘍剤。[Claims] 1. The following formula [] [In the formula, n and m may be the same or different and represent an integer of 1 to 18. ] A 5-fluoro-2'-deoxyuridine derivative or a pharmacologically acceptable salt thereof. 2 5-Fluoro-2'-deoxyuridine and the general formula [] HOOC-(CH 2 ) o -COOH ...... [) [In the formula, n represents an integer of 1 to 18]. ] General formula [-1] characterized in that a reactive derivative of the compound represented by is reacted in the presence of a base, and then subjected to a salt-forming reaction if necessary. [In the formula, n represents an integer of 1 to 18. m' indicates the same integer as n. ] A method for producing a 5-fluoro-2'-deoxyuridine derivative or a pharmacologically acceptable salt thereof. 3 General formula [] [In the formula, R represents a hydroxyl group having a protecting group. ] A compound represented by the general formula [] HOOC-(CH 2 ) o -COOH ...... [] [In the formula, n represents an integer of 1 to 18. ] After reacting a reactive derivative of the compound represented by the following in the presence of a base, and then removing the protecting group, the general formula [] HOOC-(CH 2 ) n ″-COOH ...... [ ] [In the formula, m″ is different from n and represents an integer from 1 to 18. ] It is characterized by reacting a reactive derivative of the compound represented by the following in the presence of a base, and then subjecting it to a salt-forming reaction if necessary. General formula [-2] [In the formula, n represents an integer of 1 to 18. m'' is an integer of 1 to 18, unlike n.] A method for producing a 5-fluoro-2'-deoxyuridine derivative or a pharmacologically acceptable salt thereof represented by the following formula [] [In the formula, n and m may be the same or different and represent an integer of 1 to 18. ] An antitumor agent containing a 5-fluoro-2'-deoxyuridine derivative or a pharmacologically acceptable salt thereof as an active ingredient.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58130756A JPS6023398A (en) | 1983-07-20 | 1983-07-20 | 5-fluoro-2'-deoxyuridine derivative, its preparation and antineoplastic agent containing said derivative as active component |
| DE8484902821T DE3481191D1 (en) | 1983-07-20 | 1984-07-19 | ANTINEOPLASTIC AGENT. |
| EP84902821A EP0151189B1 (en) | 1983-07-20 | 1984-07-19 | Antineoplastic agent |
| PCT/JP1984/000368 WO1985000608A1 (en) | 1983-07-20 | 1984-07-19 | Antineoplastic agent |
| US06/717,275 US4757139A (en) | 1983-07-20 | 1984-07-20 | 5-fluoro-2'-deoxyuridine derivative, processes for preparing same and antitumor composition containing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58130756A JPS6023398A (en) | 1983-07-20 | 1983-07-20 | 5-fluoro-2'-deoxyuridine derivative, its preparation and antineoplastic agent containing said derivative as active component |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6023398A JPS6023398A (en) | 1985-02-05 |
| JPS6316398B2 true JPS6316398B2 (en) | 1988-04-08 |
Family
ID=15041897
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58130756A Granted JPS6023398A (en) | 1983-07-20 | 1983-07-20 | 5-fluoro-2'-deoxyuridine derivative, its preparation and antineoplastic agent containing said derivative as active component |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6023398A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61189215A (en) * | 1985-02-18 | 1986-08-22 | Teijin Ltd | Oily pharmaceutical composition of 5-fluoro-2'-deoxyuridine ester |
-
1983
- 1983-07-20 JP JP58130756A patent/JPS6023398A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6023398A (en) | 1985-02-05 |
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