DK174238B1 - 5-Fluoruracilderivater, deres fremstilling og lægemidler indeholdende sådanne forbindelser - Google Patents
5-Fluoruracilderivater, deres fremstilling og lægemidler indeholdende sådanne forbindelser Download PDFInfo
- Publication number
- DK174238B1 DK174238B1 DK198504967A DK496785A DK174238B1 DK 174238 B1 DK174238 B1 DK 174238B1 DK 198504967 A DK198504967 A DK 198504967A DK 496785 A DK496785 A DK 496785A DK 174238 B1 DK174238 B1 DK 174238B1
- Authority
- DK
- Denmark
- Prior art keywords
- group
- groups
- hydroxy
- lower alkyl
- pyridyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 98
- 238000002360 preparation method Methods 0.000 title claims description 50
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 title claims description 12
- 229940079593 drug Drugs 0.000 title description 2
- 239000003814 drug Substances 0.000 title description 2
- -1 carboxy - Chemical class 0.000 claims description 651
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 125000003545 alkoxy group Chemical group 0.000 claims description 52
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 125000004423 acyloxy group Chemical group 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000002252 acyl group Chemical group 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000005633 phthalidyl group Chemical group 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 9
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 9
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 9
- 108090000623 proteins and genes Proteins 0.000 claims description 8
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 4
- 125000004957 naphthylene group Chemical group 0.000 claims description 4
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- JQFVVLQYCVLBJT-UHFFFAOYSA-N (4-benzoyloxy-5-chloropyridin-2-yl) 3-[5-fluoro-2,6-dioxo-3-(oxolan-2-yl)pyrimidine-1-carbonyl]benzoate Chemical compound O=C1N(C(=O)C=2C=C(C=CC=2)C(=O)OC=2N=CC(Cl)=C(OC(=O)C=3C=CC=CC=3)C=2)C(=O)C(F)=CN1C1CCCO1 JQFVVLQYCVLBJT-UHFFFAOYSA-N 0.000 claims description 2
- MUNIBABZZFUPTI-UHFFFAOYSA-N (6-benzoyloxy-3-cyanopyridin-2-yl) 3-[5-fluoro-2,6-dioxo-3-(oxolan-2-yl)pyrimidine-1-carbonyl]benzoate Chemical group O=C1N(C(=O)C=2C=C(C=CC=2)C(=O)OC=2C(=CC=C(OC(=O)C=3C=CC=CC=3)N=2)C#N)C(=O)C(F)=CN1C1CCCO1 MUNIBABZZFUPTI-UHFFFAOYSA-N 0.000 claims description 2
- 235000008331 Pinus X rigitaeda Nutrition 0.000 claims description 2
- 235000011613 Pinus brutia Nutrition 0.000 claims description 2
- 241000018646 Pinus brutia Species 0.000 claims description 2
- FRQIPGQTGGEWEB-UHFFFAOYSA-N [5-chloro-2-oxo-1-(oxolan-2-yl)pyridin-4-yl] 3-[5-fluoro-2,6-dioxo-3-(oxolan-2-yl)pyrimidine-1-carbonyl]benzoate Chemical compound O=C1N(C(=O)C=2C=C(C=CC=2)C(=O)OC=2C(=CN(C(=O)C=2)C2OCCC2)Cl)C(=O)C(F)=CN1C1CCCO1 FRQIPGQTGGEWEB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- QQUCICQQEABXRU-UHFFFAOYSA-N (6-acetyloxy-3-cyanopyridin-2-yl) 4-[5-fluoro-2,6-dioxo-3-(oxolan-2-yl)pyrimidine-1-carbonyl]furan-3-carboxylate Chemical compound CC(=O)OC1=CC=C(C#N)C(OC(=O)C=2C(=COC=2)C(=O)N2C(N(C3OCCC3)C=C(F)C2=O)=O)=N1 QQUCICQQEABXRU-UHFFFAOYSA-N 0.000 claims 1
- 229930194542 Keto Natural products 0.000 claims 1
- ZGHSOASCFCKMHR-UHFFFAOYSA-N [3-cyano-6-(furan-2-carbonyloxy)pyridin-2-yl] 4-[5-fluoro-2,6-dioxo-3-(oxolan-2-yl)pyrimidine-1-carbonyl]furan-3-carboxylate Chemical compound O=C1N(C(=O)C=2C(=COC=2)C(=O)OC=2C(=CC=C(OC(=O)C=3OC=CC=3)N=2)C#N)C(=O)C(F)=CN1C1CCCO1 ZGHSOASCFCKMHR-UHFFFAOYSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 150000001733 carboxylic acid esters Chemical group 0.000 claims 1
- 125000004427 diamine group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 229920002472 Starch Polymers 0.000 description 8
- 150000004820 halides Chemical class 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 235000008504 concentrate Nutrition 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 229960002949 fluorouracil Drugs 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- DCMUJUQQBAFVLJ-UHFFFAOYSA-N oxolan-2-yl acetate Chemical compound CC(=O)OC1CCCO1 DCMUJUQQBAFVLJ-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 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 5
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000008177 pharmaceutical agent Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 4
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 3
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- ZEZJPIDPVXJEME-UHFFFAOYSA-N 2,4-Dihydroxypyridine Chemical compound OC=1C=CNC(=O)C=1 ZEZJPIDPVXJEME-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 229940110456 cocoa butter Drugs 0.000 description 3
- 235000019868 cocoa butter Nutrition 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- XDMDYELGPVRCSZ-UHFFFAOYSA-N (5-chloro-2-trimethylsilyloxypyridin-4-yl)oxy-trimethylsilane Chemical compound C[Si](C)(C)OC1=CC(O[Si](C)(C)C)=C(Cl)C=N1 XDMDYELGPVRCSZ-UHFFFAOYSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000006185 3,4-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C(=C1[H])C([H])([H])[H])C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 description 2
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 2
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound 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 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000006096 absorbing agent Substances 0.000 description 2
- 150000001266 acyl halides Chemical class 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 125000001124 arachidoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000000732 arylene group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- FDQSRULYDNDXQB-UHFFFAOYSA-N benzene-1,3-dicarbonyl chloride Chemical compound ClC(=O)C1=CC=CC(C(Cl)=O)=C1 FDQSRULYDNDXQB-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
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- MHSVXHXNSXETER-UHFFFAOYSA-N methyl 2-[(4-hydroxy-2-oxopyridine-1-carbonyl)amino]acetate Chemical compound COC(=O)CNC(=O)N1C=CC(O)=CC1=O MHSVXHXNSXETER-UHFFFAOYSA-N 0.000 description 1
- ZGONRPXUNVTWTA-UHFFFAOYSA-N methyl 2-isocyanatoacetate Chemical compound COC(=O)CN=C=O ZGONRPXUNVTWTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 125000004373 methylthiopropyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 101150032584 oxy-4 gene Proteins 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000010665 pine oil Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000020374 simple syrup Nutrition 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
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- SYRHIZPPCHMRIT-UHFFFAOYSA-N tin(4+) Chemical compound [Sn+4] SYRHIZPPCHMRIT-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- PIPKLZQVSBPFNN-UHFFFAOYSA-N trimethyl-(6-trimethylsilyloxypyridin-2-yl)oxysilane Chemical compound C[Si](C)(C)OC1=CC=CC(O[Si](C)(C)C)=N1 PIPKLZQVSBPFNN-UHFFFAOYSA-N 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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Description
DK 174238 B1 I i
Opfindelsen angår hidtil ukendte 5-fluoruracil-denvater, fremgangsmåder til fremstilling deraf og farmaceutiske præparater indeholdende sådanne forbindelser 5 I FR-A-2 428 052 er der beskrevet 5-fluor- (β- uridm eller 2'-deoxy-fi-undin) derivater, der kan anvendes som carcinostatiske midler I Chem Abstr 101 55487 y er der beskrevet 2'-deoxy-5-fluoruridin-etherdenvater, der udviser anticarcinogen virkning 10 I GB-A-2 066 812 er der beskrevet 5'-acylundinderiva-ter, der har kraftig antitumorvirkning med lav toksicitet I GB-A-2 072 164 er der beskrevet 2’-deoxy-3',5'-di-O-alkylcarbonyl-5-fluoruridinderivater, der er nyttige som antitumormidler 15 5-Fluoruracildenvaterne ifølge opfindelsen er hidtil ukendte forbindelser, der ikke tidligere er beskrevet i litteraturen og har antitumorvirkning
Man har udført undersøgelser i forsøg på at forbedre antitumorvirkningen af kendte 5-fluoruracil-20 og 2'-deoxy-5-fluorundinforbindelser og beslægtede forbindelser og på at gøre dem mindre toksiske, og som en følge heraf er det ifølge opfindelsen lykkedes at fremstille en klasse af hidtil ukendte 5-fluoruracil-denvater og 5-fluoruridmderivater, som er substitu-25 eret i 3'- eller 5'-stilling med phenyl-lavere alkyl-oxygrupper, evt med specifikke substituenter, og beslægtede forbindelser Ifølge opfindelsen har det også vist sig, at de således fremstillede forbindelser har en fortrinlig antitumorvirkning og er meget nyttige 30 som antitumormidler
Ifølge opfindelsen tilvejebringes der forbindelser med formlen o o
35 X II II
R -O-C-Y-C-o (Ib) 2 DK 174238 B1 hvori Rx er en pyridylgruppe, eventuelt med 1 til 4 substituenter valgt blandt hydroxyqrupper, oxogrupper, halogenatomer, amino-, carboxy-/ cyano-, nitro-, carba-5 inoyl-, lavere alkylcarbamoyl- og carboxy-lavere alkyl-carbamoylgrupper, phenyl-carbamoyl, eventuelt substitueret med 1 til 3 substituenter valgt blandt halogenatomer, lavere alkoxy- og lavere alkylgrupper på phenyl-nngen, lavere alkoxycarbonyl-lavere alkylcarbamoyl-, 10 lavere alkyl-, lavere alkenyl-, lavere alkoxycarbonyl-, tetrahydrofuranyl-, tetrahydropyranyl-, lavere alkoxy-lavere alkyl-, lavere alkylthio-lavere alkyl-, phenyl-lavere alkoxy-lavere alkyl-, phthalidyl- og acyloxy-grupper, hvori acylet af acyloxygruppen er udvalgt fra 15 gruppen bestående af (i) Ci-Cjo alkanoylgrupper eventuelt substitueret med substituenterne udvalgt fra gruppen bestående af halogenatom, hydroxygruppe, lavere alkoxygruppe, aryloxygruppe, aryl-20 grupper eventuelt substitueret med 1 til 3 substituenter udvalgt fra gruppen bestående af halogenatom, lavere alkylgruppe, lavere alkoxygruppe, carboxygruppe, lavere alkoxy-carbonylgruppe, nitrogruppe og cyanogruppe 25 på arylringen, phenyl-lavere alkoxycarbonyl- gruppe og lavere alkylcarbamoylgruppe, (il) arylcarbonylgrupper eventuelt substitueret med lavere alkylendioxygrupper eller med l til 3 substituenter udvalgt fra gruppen 30 bestående af halogenatom, lavere alkylgrup pe, lavere alkoxygruppe, carboxygruppe, lavere alkoxycarbonylgruppe, nitrogruppe, cyanogruppe, phenyl-lavere alkoxycarbonylgruppe, hydroxygruppe, guanidylgruppe, phe-35 nyl-lavere alkoxygruppe, aminogruppe og aminogruppe substitueret med lavere alkylgruppe, 3 DK 174238 B1 I (m) thienylcarbonyl, furanylcarbonyl, thiazolyl- carbonyl, quinolylcarbonyl, pyrazinylcarbonyl eller pyndylcarbonyl, (iv) kulsyreestergrupper såsom aryloxycarbonyl- 5 grupper, forgrenede eller ligekædede eller cykliske alkoxycarbonylgrupper, (v) substituerede eller ikke substituerede cyc-loalkylcarbonylgrupper, (vi) lavere alkenyl (eller lavere alkynyl)carbo- 10 nylgrupper, og (vn) lavere alkenyl (eller lavere alkynyl)oxycar- bonylgrupper, Y er udvalgt fra gruppen bestående af phenylengruppe, naphthylengruppe, pyndindiylgruppe, pyrazindiylgruppe, 15 furandiylgruppe og 4-pyndon-1-lavere alkyl-diylgruppe, og a er en kendt 5-fluoruracil-afledt gruppe, som er bundet ved hjælp af en ester- eller amidbinding til den carbonylgruppe, hvortil denne substituent α er knyttet, og som er valgt blandt 20 (i) en gruppe dannet ud fra et 5-fluoruracilderivat med formlen 0 25 (1-la)
/NT
l β 30 hvori β betegner et hydrogenatom, tetrahydrofuranyl, lavere alkylcarbamoyl, phthalidyl, lavere alkoxy-lavere 4 DK 174238 B1 alkyl eller lavere alkanoyloxy-lavere alkoxycarbonyl, og (11) en gruppe dannet ud fra et 5-fluoruracildenvat med formlen
H V'A
10 R 6' A
hvori R betegner en lavere alkoxycarbonylgruppe, R betegner en lavere alkoxygruppe eller gruppen -0-N=CH—A))
15 \J
Forbindelserne med formlen (1-la) er beskrevet i J Med Chem 25, 1219, 1982, Cancer Chemother Pharmacol , i, 203-208, 1978 og den offentliggjorte japanske 20 patentansøgning nr 37787/1975 (har endnu ikke været udsat for prøvning)
Forbindelsen med formlen (1-lc) er beskrevet i EPC patentansøgningen offentliggjort under nr 99091
Fordelagtige forbindelser ifølge opfindelsen er 25 angivet i krav 2-8
Opfindelsen angår også en fremgangsmåde til fremstilling af forbindelserne ifølge opfindelsen som angivet i krav 9
Opfindelsen angår desuden forbindelserne ifølge 30 opfindelserne til anvendelse til behandling af cancer Opfindelsen angår endvidere et farmaceutisk præparat, der er ejendommeligt ved, at det omfatter en forbindelse ifølge opfindelsen og en farmaceutisk acceptabel bærer 35 Gennem beskrivelsen er udtrykkene "lavere alkyl" 5 .
DK 174238 B1 og "lavere alkoxy", anvendt i sig selv eller indeholdt i forskellige funktionelle grupper, tiltænkt at eksemplificere henholdsvis ligekædede eller forgrenede 0,-0,- X b alkylgrupper/ såsom methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, osv., og ligekædede 5 eller forgrenede C^-Cg-alkoxygrupper, såsom methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyl-oxy, hexyloxy, osv. Endvidere er udtrykket "halogen" , anvendt i sig selv eller indeholdt i forskellige funktionelle grupper, gennem beskrivelsen tiltænkt at eksemr· 10 plificere fluor, chlor, brom, 3od, osv. Endvidere menes der med udtrykket "lavere alkylendioxy", anvendt i sig selv eller indeholdt i forskellige funktionelle grupper, gennem beskrivelsen,C^-C^-alkylendioxygrupper, såsom methylendioxy, ethylenxioxy, tnmethylenxioxy, tetrame-15 thylendioxy, osv.
Med hensyn til substituenterne i substituerede phenyl-lavere alkylgrupper er eksempler på lavere alkylgrupper ligekædede eller forgrenede C^-Cg-alkylgrup-per, såsom methyl, ethyl, propyl, isopropyl, butyl, 20 tert-butyl, pentyl, hexyl, osv; eksempler på lavere alkoxygrupper er ligekædede eller forgrenede C^-Cg-al-koxygrupper, såsom methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, osv., eksempler på halogenatomer er fluor, chlor, brom og jod; 25 eksempler på lavere alkoxycarbonylgrupper er ligekædede eller forgrenede C2-C^-alkoxycarbonylgrupper, såsom methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyoxycarbonyl, osv. Eksempler på 30 phenyl-lavere alkylgrupper, der eventuelt er substitueret med de ovennævnte substituenter eller med carboxy-eller di (lavere alkyl) aminogrupper på phenylnngen er phenylalkylgrupper, hvori phenylgruppen, der eventuelt er substitueret med en til tre af de ovennævnte substi-35 tuenter, er bundet til en C^-Cg-alkylengruppe såsom methylen, ethylen, tnmethylen, 1-methylethylen, tetra-methylen, 2-methyltnmethylen, pentamethylen, hexame-thylen, osv. Eksempler derpå er følgende: 6 DK 174238 B1 benzyl, 2-methylbenzyl, 2-methylbenzvlf 4-merhyIbenzyl, 2-ethylber»2yl, 3-ethvlbenzyl, 4- ethylbenzvl, 2-propvlbenzyl, 3-propylbenzyl, 4- 5 propylbenzyl, 2-butylbenzyi, 3-buryibenzyi, 4- butylbenzyl, 2-tert-butylbenzyl, 3-tert-butylbenzyl, 4-tert-butylbenzyl, 2-pentylbenzyl, 3-pentylbenzyl, 4-pentylbenzyl, 2-hexylbenzyl, 3-hexylbenzyl, 4-hexyl- benzyl, 2,3-dimethylbenzyl, 2,4-dimethylbenzyl, 2,5- dimethylbenzyl, 2,6-dimethylbenzyl, 3,4-diraethylbenzyl, 3,5-dimethylbenzyl, 2,3,4-tnmethylbenzyl, 2,4,5- tnmethylbenzyl, 2,3,5-trimethylbenzyl, 2,4,6-tri-15 methylbenzyl, 3,4,5-tnmethylbenzyl, 2,3-diethylbenzyl, 2,4-diethylbenzyl, 2,5-diethylbenzyl, 2,6-diethvlbenzyl, 2,4,6-triethylbenzyl, 2,4-dipropylbenzyl, 3,4,5-tri-20 ethylbenzyl, 3-methyl-4-ethylbenzyl, 1-phenylethyl, 2- phenylethyl, 2-phenyl-l-methyl-ethyl, 1-(2-methyl-phenyl)ethyl, 2-(2-methylphenyl)ethyl, 2-(3-methyl- phenyl)ethyl, 2-(4-methylphenyl)ethyl, 1-(2,4-dimethyl-25 phenyl)ethyl, 2-(2,4-dimethylphenyl)ethyl, 1-(2,4,6-tnmethylphenyl)ethyl, 2-(2,4,6-trimethylphenyl)ethyl, 3- phenylpropyl, 3-(4-methylphenyl)propyl, 4-phenylbutyl, 4- (2-methylphenyl)butyl, 5-phenylpentyl, 5-(3-methyl-30 phenyl)pentyl, 6-phenylhexyl, 6-(4-methylphenyl)hexyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2,3-dimethoxybenzvl, 2,4-dimethoxybenzyl, 2,5-di-35 mernoxyoenzyl, 3-meimoxy-4-ennoxybenzyi, 2,6-cunethoxy-benzyl, 3,4-dimethoxynenzyl, 3,5-dimeT:hoxyDenzyl, 2,3,4-trimethoxybenzyl, 2,4,5-trxmethoxvbenzyl, 2,3,5-tri- DK 174238 B1 7 methoxybenzyl, 2,4,6-trimethoxyoenzyl, 3,4,5-trunethoxy- benzvl, 2-ethoxybenzyl, 4-propoxybenzyl, 3-butoxybenzyl, 2-tert-butoxybenzy1, 3-pentyloxybenzyl, 4-hexyloxybenzyl, 5 2,3-diethoxybenzyl, 1-(4-methoxyphenyl)ethyl, 2-(3,4-di- methoxyphenyl)ethyl, 3-(4-methoxyphenyl)propyl, 4-(2- methoxyphenyl)butyl, 5-(4-methoxyphenyl)pentyl, 6-(4- methoxyphenyl)hexyl, 6-(3,4,5-tripentyloxyphenyl)hexyl, 10 2-fluorobenzyl, 3-fluorbenzyl, 4-fluorbenzyl, 2,3-di- fluorbenzyl, 2,4-difluorbenzyl, 2,5-difluorbenzyl, 2-fluor-3-chlorbenzyl, 2-fluor-3-brorbenzyl, 2,6-di- fluorbenzyl, 2,3,4-trifluorbenzvl, 2,4,5-tnfIuor- 15 benzyl, 2,3,5-trifluorbenzyl, 2,4,6-trifluorbenzyl, 3,4,5-tnfluornenzyl, 1-{2-fluorphenyl)ethyl, 2-(2- fluorphenyl)ethyl, 3-(3-fluorphenyl)propyl, 4-(2-fluor- 2Q phenyl)butyl, 5-(2-fluorphenyl)pentyl, 6-(3-fluorphenyl)- hexyl, 2-brombenzyl, 3-brombenzyl, 4-brombenzyl, 2,3-di- brombenzyl, 2-brom-3-fluorbenzyl, 2-fluor-4-brombenzyl, 2,4-dibrombenzyl, 2,5-dibrombenzyl, 2,6-dibrombenzyl, 25 2,3,4-tnbrombenzyl, 2,4,5-tribrombenzyl, 2,3,5-tnbrom- benzyl, 2,4,6-tnbrombenzyl, 3,4,5-tribrombenzyl, 1- (2-bromphenyl)ethyl, 2-(2-bromphenyl)ethyl, 3-(2-brom- phenyl) propyl, 4-(3-bromphenyl)-butyl, 5-(2-bromphenyl)-30 pentyl, 6-(4-bromphenyl)hexyl, 2-chlorbenzyl, 3-chlor- benzyl, 4-chlorbenzyl, 2,3-dichlorbenzyl, 2,4-dichlor- benzyl, 2,5-dichlorbenzyl, 2,6-dichlorbenzyl, 2-brom-4- chlorbenzyl, 2-fluor-4-chlorbenzyl, 2,3,4-tnchlorben-35 zyl, 2,4,5-tnchlorbenzyl, 2,3,5-trichlorbenzyl, 2,4,6-trichlorbenzyl, 3,4,5-tnchlorbenzyl, 1-(4-chlorphenyl)- 8 DK 174238 B1 ethyl, 2-(4-chlorphenyl)ethyl, 3-(2-chlorphenyl)propyl, 4-(4-chlorphenyl)butyl, 5-(3-chlorphenyl)pentyl, 6-(4-chlorphenyl)hexyl, 2-(3,4-dxchlorphenyl)ethyl, 2-5 xodbenzyl, 3-xodbenzyl, 4-iodbenzyl, 3,4-dnodbenzyl, 3,4,5-trxiodbenzyl, 2-(3-xodphenyl(ethyl, 6-(2-xod-pheny1)hexyl, 2-carboxybenzyl, 3-carboxybenzyl, 4-car-boxybenzyl, 2,3-dxcarboxybenzyl, 2,4-dxcarboxybenzyl, 10 2,5-dxcarboxybenzyl, 2,6-dxcarboxybenzyl, 3,4-dxcarboxyben- zyl, 3,5-dxcarbaxybenzyl, 2,3,4-trxcarboxybenzyl, 2,4,6-trx-carboxybenzyl, 3,4,5-trxcarboxybenzyl, 1-(4-carboxy- phenyl)ethyl, 2-(4-carboxyphenyl)ethyl, 2-(2,6-dxcarboxy-^ phenyl)ethyl, 3-(3-carboxyphenyl)propyl, 5-(2,4,6-trx-carboxyphenyl)pentyl, 6-(4-carboxyphenyl)hexyl, 6-(3,5-dxcarboxyphenyl)hexyl, 4-methoxvcarbonylbenzyl, 3- methoxycarbonylbenzyl, 2-methoxycarbonylbenzyl, 4- ethoxycarbonylbenzyl, 3-ethoxycarbonylbenzyl, 2-ethoxycarbonylbenzyl, 4-propoxycarbonylbenzvl, 4-butoxycarbonylbenzyl, 4-pentyloxycarDonyibenzyi, 25 4-hexyloxycaxbonylbenzyl, 3,4-dimethoxycarbonylbenzyl, 2.4- dxmethoxycanDonylbenzyl, 3,5-dimethoxycarbonvlbenzyl, 2.3.4- trxmethoxycarconylbenzyl, 3.4.5- trxmethoxycaroonvlbenzyl, 30 2-(4-methoxycarbonylphenyl)ethyl, 6-(4-methoxycarbonylphenyl) hexyl, 2-(Ν,Ν-dxmethylamxno)benzyl, 3-(Ν,Ν-dxmethylamxno)benzyl, ^ 4-(Ν,Ν-dxmethylamxno)benzyl, 4-(N-methyl, N-ethylamxno)benzyl, 2,4-dx (Ν,Ν-dxmethylamxno)benzyl, 2.4.6- tri(Ν,Ν-dimethylamxno)benzyl, osv.
9 DK 174238 B1
Eksempler på acyl i acyloxygrupper som angivet i beskrivelsen og kravene og specielt beskrevet som den af Rx repræsenterede substituent i pyridylgruppen er mangfoldige og omfatter de følgende 5 arylcarbonylgrupper, der eventuelt er substitueret med lavere alkylendioxygrupper eller med 1 til 3 substitu-enter valgt blandt halogenatomer, lavere alkyl-, lavere alkoxy-, carboxy-, lavere alkoxycarbonyl-, nitro-, cyano-, phenyl-lavere alkoxycarbonyl-, hydroxy-, 10 guanidyl-, phenyl-lavere alkoxy- og ammogrupper og aminogrupper substitueret med lavere alkylgrupper
Eksempler på acyldelene omfattet i punkterne (i) til (vii) er som følger 10 DK 174238 B1 (i) C^-C^Q-alkanoylgrupper, der eventuelt er substitueret med substituenterne valgt blandt halogen-atomer, hydroxy-, lavere alkoxy-, aryloxy-, substituerede eller usubstitueredearyl-, phenyl-lavere alkoxycar-5 bonyl- og lavere alkylcarbamoylgrupper.
Usubstituerede Cl“C20 -alkanoylgrupper, så som formyl, acetyl, propionyl, butyryl, isobutyryl, pentano-yl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, 10 pentadecanoyl, hexadecanoyl, heptadecanoyl, ocatadeca-noyl, nonadecanoyl, eicosanoyl, osv.; Cj-Cg-alkanoyl-grupper substitueret med 1 til 3 halogenatomer så -som monochloracetyl, monobromacetyl, dichloracetyl, tnchloracetyl, 3-chlorpropionyl, 4-chlorbutyryl, 5-15 chlorpentanoyl, 6-chlorhexanoyl, osv.; C2-Cg-alkanoyl-grupper substitueret med hydroxygrupper, såsom hydroxy-acetyl, 3-hydroxypropionyl, 5-hydroxypentanoyl, 4-hydroxybutanoyl, 6-hydroxyhexanoyl, osv.; C2-Cg-alka-noylgrupper substitueret med C^-Cg-alkoxygrupper, såsom 20 methoxyacetyl, ethoxyacetyl, 3-propoxypropionyl, 6-he-xyloxyhexanoyl, 3-methoxypropionyl, osv.; C2-Cg-alka-noylgrupper substitueret med phenoxy eller naphthyloxy-grupper, såsom phenoxyacetyl, 2-phenoxypropionyl, 3-phenoxypropionyl, 4-phenoxybutyryl, 5-phenoxypentanoyl, 25 6-phenoxyhexanoyl, a-naphthyloxyacetyl, osv.; C2~C6~ alkanoylgrupper substitueret med arylgrupper, der eventuelt er substitueret med 1 til 3 substituenter valgt blandt halogenatomer, lavere alkyl-, lavere alkoxy-, carboxy-, lavere alkoxycarbonyl-, nitro- og cyanogrup-30 per på arylrmgen (phenylrmgen, naphthyl ringen, osv.), DK 174238 B1 11 såsom a-phenylacetyl, 2-phenylpropionyl, 3-phenylpropio-nyl, 4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexa-noyl, a-(2-chlorphenyl)acetyl, a-(4-methylphenyl)acetyl, a-(3,4,5-tnmethoxyphenyl)acetyl, a-(3,4-dime-5 thoxyphenyl)acetyl, 6-(4-carboxyphenyl)hexanoyl, 4—(4— ethoxycarbonylphenyl)pentanoyl, a- (4-mtrophenyl) -acetyl, a-(4-cyanophenyl)acetyl, a-naphthylacetyl, β-naph-thylacetyl, osv.; C^-C20-alkanoylgrupper substitueret med phenyl-Cj-C^-lavere alkoxycarbonylgrupper, såsom 10 α-benzyloxycarbonylacetyl, 2-benzvloxycarbonylpropionyl, 3-benzyloxycarbonylpropionyl, 4-ber.zyloxycsrbonylbutyryl, 5-benzyloxycarbonylpentanoyl, 6-benzyloxycarbonylhexanoyl, 3-(α-phenethyloxycarbonyl)propionyl, 3-(β-phenethyl-15 oxycarbonyl)propionyl, 5-(benzyloxycarbonyl)hexanoyl, 7-(benzyloxycarbonyl)heptanoyl, 8-(α-phenethyloxycarbonyl)- octanoyl, 9-(β-phenethyloxycarbonyl)nonanoyl, 10-(benzyl- oxycarbonyl)decanoyl, 11-(β-phenethyloxycarbonyl)- 20 tridecanoyl, 15-(benzyloxycarbonyl)pentadecanoyl, 17-(benzyloxycarbonyl)heptadecanoyl, 20-(benzyloxycarbonyl) eicosanoyl, osv.; C^-C2ø-alkanoylgrupper substitueret med C2~C^-lavere alkylcarbamoylgrupper, såsom 25 methylcarbamoylacetyl, ethylcarbomoylacetyl, propylcar-bamoylacetyl, butylcarbamoylacetyl, tertbutylcarbomoyl-acetyl, pentylcarbamoylacetyl, hexylcarbamoylacetyl, methylcarbamoylpropionyl, ethylcarbamoylbutyryl, propyl-carbamoylpentanoyl, ethylcarbamoylhexanoyl, ethylcarba-30 moylheptanoyl, methylcarbamoyloctanoyl, ethylcarbamoyl-nonanoyl, methylcarbamoyIdecanoyl, methylcarbamoyltridecanoyl , ethylcarbamoylpentadecanoyl, methylcarbamoyl-heptadecanoyl, methylcarbamoyleicosanoyl, osv.; 12 DK 174238 B1 (11) arylcarbonylgrupper, der eventuelt er substitueret med lavere alkylendioxygrupper eller med 1 til 3 substituenter valgt blandt halogenatomer, lavere alkyl-, lavere alkoxy-, carboxy-, lavere alkoxycarbonyl-, 5 nitro-, cyano-, phenyl-lavere alkoxycarboxy-, hydroxy-, guanidyl-, phenyl-lavere alkoxy- og aminogrupper og aminogrupper substitueret med lavere alkylgrupper på arylringen.
arylcarbonylgrupper, såsom phenylcarbonyl, naph-10 thylcarbonyl, osv., der eventuelt er substitueret med lavere alkylendioxygrupper eller med 1 til 3 substituenter valgt blandt halogenatomer, lavere alkyl-, lavere alkoxy-, carboxy-, lavere alkoxycarbonyl-, natro-, cyano-, phenyl-lavere alkoxycarbonyl-, hydroxy-, guanidyl-, 15 phenyl-lavere alkoxy- og aminogrupper og aminogrupper substitueret med lavere alkylgrupper, såsom benzoyl, α-napnthylcaroonyl, β-napnthylcarDonyl, 2-metnylbenzoyl, 3-methylbenzoy1, 4-methylbenzoy1, 2,4-dimethylben2oy1, 20 3,4,5-tnmethylbenzoyl, 4-ethylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2,4-dimethoxybenzoyl, 3,4,5-trimethoxybenzoyl, 4-ethoxybenzoyl, 2-methoxy-4- ethoxybenzoyl, 2-propoxybenzoyl, 3-propoxybenzoyl, 25 4-propoxybenzoyl, 2,4-dipropoxybenzoyl, 3,4,5-tnpropoxy- benzoyl, 2-carboxybenzoyl, 3-carboxybenzoyl, 4-carboxy- benzoyl, 2-chlorbenzoyl, 3-chlorbenzoyl, 4-chlor- benzoyl, 2,3-dichlorbenzoyl, 2,4,6-tnchlorbenzoyl, 2-brombenzoyl, 4-fluorbenzoyl, 2-methoxycarbonyl- benzoyl, 3-methoxycarbonylbenzoyl, 4-methoxycarbonyl- benzoyl, 2-ethoxycarbonylbenzoyl, 3-ethoxycarbonyl- benzoyl, 4-ethoxycarbonylbenzoyl, 2-propoxycarbonyl-35 benzoyl, 3-propoxycarbonylbenzoyl, 4-propoxycarbonyl- DK 174238 B1 13 benzoyl, 2-isopropoxycarbonylbenzoyl, 3-isopropoxy-carbonylbenzoyl, 4-isopropoxycarbonylbenzoyl, 2-butoxy-carbonylbenzoyl, 3-butoxycarbonylbenzoyl, 4-butoxy-carbonylbenzoyl, 2-tert-butoxycarbonylbenzoyl, 3-tert-5 butoxycarbonylbenzoyl, 4-tert-butoxycarbonylbenzoyl, 2- pentyloxycarbonylbenzoyl, 3-pentyloxycarbonylbenzoyl, 4-pentyloxycarbonylbenzoyl, 2-hexyloxycarbonylbenzoyl, 3- hexyloxycarbonylbenzoyl, 4-hexyloxycarbonylbenzoyl, 3.5- dimethoxycarbonylbenzoyl, 3,4,5-trrmethoxycarbonyl-10 benzoyl, f$-inethyl-a-naphthylcarbonyl, a-methoxy-β- naphthylcarbonyl, β-chlor—α-naphthylcarbonyl, 2-cyano-benzoyl, 4-cyanobenzoyl, 2-mtrobenzoyl, 4-mtrobenzoyl, 2-benzyloxycarbonylbenzoyl, 3-benzyloxycarbonylbenzoyl, 4- benzyloxycarbonylbenzoyl, 3-(α-phenethyloxycarbonyl)-benzoyl, 4- (β-phenethyloxycarbonyl)benzoyl, 4-(3-phenyl-propoxycarbonyl)benzoyl, 4-(6-phenylhexyloxycarbonyl)-benzoyl, 2-hydroxybenzoyl, 3-hydroxybenzoyl, 2,3-dihydroxybenzoyl, 3,4-dihydroxybenzoyl, 3.4.5- trlhydroxybenzoy1, 4-hydroxybenzoyl, 20 2-guanidylbenzoyl, 3-guanidylbenzoyl, 4-guanidylbenzoyl, 2-(benzyloxy)benzoyl, 3-(benzyloxy)benzoyl, 4-{benzyl-oxy)benzoyl, 2-(α-phenethyloxy)benzoyl, 3-(α-phenethyl-oxy)benzoyl, 4-(α-phenethyloxy)benzoyl, 2-($-phenethyl-oxy)benzoyl, 3-(β-phenethyloxy)benzoyl, 4-(β-phenethyl-
n C
oxy)benzoyl, 4-(3-phenylpropoxy)benzoyl, 4-(4-phenyl- 14 DK 174238 B1 butoxy)benzoyl, 4-(5-phenylpentyloxy)benzoyl, 4-{6-phenylhexyloxy) benzoyl, 2-araxnobenzoyl, 3-ammobenzoyl, 4-aminobenzoyl, 2-methylamxnobenzoyl, 3-methylamxno-benzoyl, 4-methylaminobenzoyl, 2-ethylamxnobenzoyl, 5 3-propylamxnobenzoyl, 4-butylamxnobenzoyl, 3-pentyl-amxnobenzoyl, 4-hexylamxnobenzoyl, 2-{N,N-dxmethyl-aru.no)benzoyl, 3-(Ν,Ν-dxmethylamxno)benzoyl, 4-(N,N-dxme-chylainxno) benzoyl, 3-{N-methyl-N-ethylanu.no)benzoyl, 4- (Ν,Ν-dxethylamxno) benzoyl, 3- <N,N-åxpropylamxno) -10 benzoyl, 4-(N,N-dxbutylamxno)benzoyl, 4-(Ν,Ν-dipentyl-anxno)benzoyl, 4-(N,Ν-dxhexylamxno)benzoyl, 3-benzyl-oxycarbonyl-1-naphthylcarbonyl, 6-(β-phenethyloxy-carbonyl)-1-naphthylcarbonyl, 4-benzyloxycarbonyl-2-naphthylcarbonyl, 5-(a-phenethyloxycarbonyl)-2-naphthyl-carbonyl, 2-hydroxy- 1-naphthylcarbonyl, 3-hydroxy-l-naphthylcarbonyl, 4-hydroxy-l-naphthylcarbonyl, 5-hydroxy-l-naphthylcarbonyl, 6-hydroxy-l-naphthylcarbonyl, 7-hydroxy-l-naphtylcarbonyl, 8-hydroxy-1-naphthylcarbonyl, l-hydroxy-2-naphthylcarbonyl, 4-hydroxy-2-20 naphthylcarbonyl, 5-hydroxy-2-naphthylcarbonyl, 7- hydroxy-2-naphthylcarbonyl, 2-guanidyl-l-naphtylcarbonyl, 3-guanxdyl-l-naphthylcarbonyl, 5-guanidyl-l-naphthyl-carbonyl, 6-guanxdyl-l-naphthylcarbonyl, 8-guanxdyl-l-naphthylcarbonyl, 1-guanxdyl-2-naphthylcarbonyl, 4-25 guanxdyl-2-naphthylcarbonyl, 6-guanidyl-2-naphthyl- DK 174238 B1 15 carbonyl, 8-guanidyl-2-naphthylcarbonyl, 2-ammo-l-naphthylcarbonyl, 3-ammo-l-naphthylcarbonyl, 4-ammo- 1- naphthylcarbonyl, 6-amino-l-naphthylcarbonyl, 4-anano- 2- naphthylcarbonyl, 5-ammo-l-naphthylcarbonyl, 7-amino-5 2-naphthylcarbonyl, 8-anuno-2-naj5hthylcarbonyl, 3-(N,N~ dimethylammo)-2-naphthylcarbonyl, 4-(N-methyl-N-ethyl- amino)-l-naphthylcarbonyl, 6-(N,N-dimethylamino)-l- napnrnyicaraonyl, 7-(N-methyl-N-ethylamino)-2-naphthyl- caroonyl, 8- (N-methyl-N-ethvlanu.no) -1-naonrhvicaroonvl, 10 3,4-methylendioxybenzoyl, 3,4-ethylendioxybenzoyl, 2,3- methylendioxybenzoyl, osv.
(nx) 5- eller 6-ledede umættede heteronng-car-bonylgrupper med nitrogen-, svovl- eller oxygenatomer som heteroatornet.
15 Thienylcarbonyl, furanylcarbonyl, thiazolylcar- bonyl, quinolylcarbonyl, pyrazinylcarbonyl, pyndylcar-bonyl, osv., såsom 2-thienylcarbonyl, 3-thienylcarbonyl, 2-furanylcarbonyl, 3-furanylcarbonyl, 4-thiazolylcar-bonyl, 2-qumolylcarbonyl, 2-pyrazinylcarbonyl, 2-p.yn-20 dylcarbonyl, 3-pyndylcarbonyl, 4-pyridylcarbonyl, osv.
(iv) Kulsyreestergrupper, såsom aryloxycarbonyl-grupper, ligekædede eller forgrenede eller cycliske alkoxycarbonylgrupper.
Aryloxycarbonylgrupper, der eventuelt er sub-25 stitueret med 1 til 3 substituenter valgt blandt halogenatomer, lavere alkylgrupper og lavere alkoxygrupper på arylnngen (phenylringen, naphthylnngen, osv.), såsom phenoxycarbony1, a-naphthyloxycarbonyl, β-naphthyloxy-carbonyl, 2-methylphenoxycarbonyl, 3-methylphenoxycar-30 bonyl, 4-methylphenoxycarbonyl, 2,4-dimethylphenoxy- carbonyl, 3,4,5-tnmethylphenoxycarbonyl, 4-ethylphenoxy-carbonyl, 2-methoxyphenoxycarbonyl, 3-methoxyphenoxy-carbonyl, 4-methoxyphenoxycarbonyl, 2,4-dimethoxyphenoxy-carbonyl, 3,4,5-tnmethoxyphenoxycarbonyl, 4-ethoxy- 16 DK 174238 B1 phenoxycarbonyl, 2-propoxyphenoxycarbonyl, 3-propoxy-phenoxycarbonyl, 4-propoxyphenoxycarbonyl, 2,4-dipro-poxyphenoxycarbonyl, 3,4,5-tripropoxyphenoxycarbonyl, 2-chlorphenoxycarbonyl, 3-chlorphenoxycarbonyl, 4-chlor-5 phenoxycarbonyl, 2,3-dichlorphenoxycarbonyl, 2,4, 6-tn-chlorphenoxycarbonyl, 2-bromphenoxycarbonyl, 4-fluor-phenoxycarbonyl, β-methyl-a-naphthyloxycarbonyl, a-me-thoxy-(3-naphthyloxycarbonyl, β-chlor-a-naphthyloxycar-bonyl, osv.; ligekædede, forgrenede eller cycliske 10 alkoxycarbonylgrupper med 1 til 8 carbonatomer i alkoxy-delen såsom methoxycarbonyl, ethoxycarbonyl, propoxy-carbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexylcarbonyl, cyclo-propyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyl-15 oxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycar-bonyl, cyclooctyloxycarbonyl, osv.
(v) Substituerede eller usubstituerede cycloal-kylcarbonylgrupper.
Cycloalkylcarbonylgrupper, der eventuelt er sub-20 stitueret med halogenatomer, hydroxy-, lavere alkoxy-eller lavere alkylgrupper og har 3 til 8 carbonatomer i cycloalkylnngen, såsom cyclopropylcarbonyl, cyclobutyl-carbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, 2-chlorcyclo-25 hexylcarbonyl, 3-hydroxycyclopentylcarbonyl, 3-methyl-cyclohexylcarbonyl, 4-methoxycyclohexylcarbonyl, osv.
(vi) Lavere alkenylcarbonylgrupper (eller lavere alkynylcarbonylgrupper).
Carbonylgrupper med C2~Cg-alkenyl eller alkynyl-30 grupper, såsom vinylcarbonyl, allycarbonyl, 2-butenyl-carbonyl, 3-butenylcarbonyl, 1-methylallylcarbonyl, 2-pentenylcarbonyl, 3-hexenylcarbonyl, ethynylcarbonyl, propynylcarbonyl, 2-butynylcarbonyl, l-methyl-3-pentynyl-carbony1, 4-hexyny1carbonyl, osv.
35 (vn) Lavere alkenyl- eller alkynyloxycarbonyl- grupper.
Carbonylgrupper med C2~Cg-alkenyloxy- eller -alkynyloxygrupper, såsom vmyloxycarbonyl, allyloxy- DK 174238 B1 17 carbonyl, 2-butenyloxycarbonyl, 3-butenyloxycarbonyl, 2-hexenyloxycarbonyl, 1-methylallyloxycarbonyl, 2-pentenyloxycarbonyl/ 3-hexenyloxycarbonyl, ethynyloxy-carbonyl, propynyloxycarbonyl/ 2-butynyloxycarbonyl, 5 l-methyl-3-pentynyloxycarbonyl, 4-hexynyloxycarbonyl, osv.
Substituenterne på den substituerede pyndylgrup-10 pe betegnet RX er eksemplificeret nedenfor.
Eksempler på lavere alkylcarbamoylgrupper er alkylcarbamoylgrupper med en eller to C-^-Cg-alkylgrup-per, såsom N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, 15 N-isopropylcarbamoyl, N-butylcarbamoyl, N-tert-butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl, N,N-dimethylcarbamoyl, 2o N/N-diethylcarbamoyl/ N,N-dipropy1carbamoyl, N-isopropyl-N-methylcarbamoyl, N-ethyl- N-methylcarbamoyl, N-methyl-N-pentyl-carbamoyl, N-propyl-N-pentylcarbamoyl, N,N-dipentylcarbamoyl, 25 N-ethyl-N-hexylcarbamoyl, N-hexyl-N-pentylcarbamoyl, N,N*-dihexylcarbamoyl og lignende.
Eksempler på phenylcarbamoylgrupper, der eventuelt har 1 til 3 substituenter valgt blandt halogen, lavere alkyl og lavere alkoxy på phenylnngen,er carba-30 moylgrupper med en eller to phenylgrupper, som eventuelt kan have 1 til 3 substituenter valgt blandt halogen, C^-Cg-alkoxy og C^-Cg-alkyl på phenylrmgen, såsom N-(2-chlorphenyl) carbamoyl, N-(3,5-dichlor)phenylcarba-moyl, N-(3-methoxyphenyl)carbamoyl, N-(4-propoxypheny1)-35 carbamoyl, N-(2-methylphenyl)carbamoyl, N-(4-ethylphe-nyl)carbamoyl, N-(3-isopropylphenyl)carbamoyl, N-(4-hexylphenyl)carbamoyl, N-phenylcarbamoyl, N,N-diphenyl-carbamoyl og lignende.
18 DK 174238 B1
Eksempler på lavere alkenylgrupper er Cj'-Cg-alkenylgrupper, såsom vinyl, allyl, 2-butenyl, 3-bute-nyl, 1-methylallyl, 2-pentenyl, 2-hexenyl og lignende.
Eksempler på lavere alkoxycarbonylgrupper er 5 carbonylgrupper med C^-Cg-alkoxygrupper, såsom methoxy-carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy-carbonyl, tert-butoxycarbonyl, butoxycarbonyl, pentyl-oxycarbonyl, hexyloxycarbonyl og lignende.
Eksempler på tetrahydrofuranylgrupper er 2-te-10 trahydrofuranyl, 3-tetrahydrofuranyl og lignende.
Eksempler på lavere alkoxy-lavere alkylgrupper er alkoxyalkylgrupper, hvori alkoxydelen og alkyIdelen hver indeholder 1 til 6 carbonatomer, såsom methoxyme-thyl, 3-methoxypropyl, 4-ethoxybutyl, 6-propoxyhexyl, 15 5-isopropoxypentyl, l,l-dimethyl-2-butoxyethyl, 2-me-thyl-3-tert-butoxypropyl, 2-pentyloxyethyl, 2-hexyloxy-ethyl og lignende.
Eksempler på phenyl-lavere alkoxy-lavere alkylgrupper er alkoxyalkylgrupper, som er substitueret med 20 phenylgrupper, og hvori alkoxydelen og alkyldelen hver indeholder 1 til 6 carbonatomer, såsom benzyloxymethyl, 2-benzyloxyethyl, 5-(2-phenylpentyloxy)-pentyl, 6-benzyloxyhexyl, 4-hexyloxyhexyl, 25 phenylmethoxymethyl, 2-phenylethoxymethyl, 2-(phenyl-methoxy)ethyl, 2-(phenylmethoxy)propyl, 4-(phenyl-methoxy)butyl, 5-(phenylmethoxy)pentyl, 6-{phenylmethoxy) hexyl , 2-(2-phenylethoxy)ethyl, 2-(4-phenyl- 30 butoxy)ethyl, 4-(4-phenylbutoxy)butyl, 6-phenyl-methoxyhexyl og lignende.
Eksempler på lavere alkoxycarbonyl-lavere alkyl-carbamoylgrupper er carbamoylgrupper, der er substitueret med en alkoxycarbonylalkylgruppe, hvori alkoxygrup-35 pen og alkyldelen hver indeholder 1 til 6 carbonatomer, såsom methoxycarbonylmethylcarbamoyl, DK 174238 B1 19 3- methoxycarbonylpropylcarbamoyl, ethoxycarbonylmethylcarbamoyl, propoxycarbonylmethylcarbamoy1, lsooropoxvcarbonylmethylcarbamoyl, 5 butoxycarbonylmethylcarbamoyl, tert-butoxycarbonylmethylcarbamoyl, pentyloxycarbonylmethylcarbamoyl, hexyloxycarbonylmethylcarbamoyl, 2-methoxycarbonylethylcarbamoyl, 2-methoxyc arbony1-1 -m ethy1-ethy1carbamoyl, 4- methoxycarbonylbutylcarbamoyl, 2-methoxycarbonyl-l,1-dimethylethylcarbamoy1, 15 5-methoxycarbonylpentylcarbamoyl, 6-methoxycarbonylhexylcarbamoy1, 2-ethoxycarbonylethylcarbamoyl, 4- ethoxycarbonylbutylcarbamoy1, 20 6-propoxycarbonylhexylcarbamoyl, 5- isopropoxycarbonylpentylcarbamoyl, 1, l-dimethyl-2-butoxycarbonylethylcarbamoyl, 2-methy1-3-tert-butoxycarbonylpropylcarbamoy1, 25 2-pentyloxycarbonylethylcarbamoyl, hexyloxycarbonylethylcarbamoyl og lignende.
Eksempler på carboxy-lavere alkylcarbamoylgrupper er carboxy-C^-Cg-alkylcarbamoylgrupper, såsom 30 N-(carboxymethyl)carbamoyl, N-(2-carboxyethyl)carbamoyl, N- (3-carboxypropyl)carbamoyl, N-(2-methyl-2-carboxyethyl) -carbamoyl, N-(4-carboxybutyl)carbamoyl, N-(2-methyl-3-carboxypropyl)carbamoyl, N-(2,2-dimethyl-2-carboxyetbyl)-35 carbamoyl, N-(5-carboxypentyl)carbamoyl, K-(6-carboxyhexyl) - DK 174238 B1 20 carbamoyl og lignende.
Eksempler på tetrahydropyranylgrupper er 2-tetra-hydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl og lignende.
5 Eksempler på lavere alkylthio-lavere alkylgrupper er C^-Cg-alkylthio-C^-Cg-alkylgrupper, såsom methylthiomethyl, ethylthiomethyl, propylthiomethyl, butylthiomethyl, tert-butylthiomethyl, pentylthiomethyl, 10 hexylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, methylthiopentyl, methylthiohexyl, ethylthioethyl, ethylthiobutyl, propylthiohexyl og lignende.
15 Pyridinrmgen er fortrinsvis substitueret ved 1 eller flere vilkårlige af 2- til 6-stillingerne med en til fire substituenter valgt blandt hydroxy, halogen, ammo, carboxyl, cyano, nitro, oxo, lavere alkyl, lavere alkenyl, lavere alkoxycarbonyl, carbamoyl og acyloxy 20 blandt substituenterne eksemplificeret ovenfor, eller fortrinsvis substitueret i 1-stillmg med carbamoyl, lavere alkylcarbamoyl, phenylcarbamoyl, der eventuelt har 1 til 3 substituenter valgt blandt halogen, lavere alkoxy og lavere alkyl på phenylnngen, tetrahydrofura-25 nyl, phthalidyl, lavere alkoxy-lavere alkyl, phenyl-lavere alkoxy-lavere alkyl og lavere alkoxycarbonyl-lavere alkylcarbamoyl blandt substituenterne exemplifi-seret ovenfor.
Foretrukne eksempler på gruppen med formlen (Y) 30
O O
II II
dVS RX-0-C-Y-C- er dem der er repræsenteret ved formlen DK 174238 B1
Rxl·^· N i^RX5 5 xl hvori R er hydroxy eller acyloxy, hvor acylet i yO y4 acyloxy er som defineret ovenfor, R og R er hver hydrogen, halogen, amino, carboxyl, carbamoyl, cyano, nitro, lavere alkyl, lavere alkenyl eller lavere alkoxycarbonyl, R og R er hver hydrogen, hydroxy 10 eller acyloxy, hvor acylet i acyloxy er som defineret ovenfor, når mindst en af Rxl, Rx3 og Rx5 er fri hydroxy kan strukturen i 1-stilling på pyndinringen være N på grund af keto-enol tautomensmen,
15 H
idet hydrogenet bundet til nitrogenet eventuelt er substitueret med en substituent valgt blandt lavere alkyl, tetrahydrofuranyl, tetrahydropyranyl, lavere alkoxy-lavere alkyl, phthalidyl, carbamoyl, lavere alkoxycarbo-20 nyl-lavere alkylcarbamoyl, phenyl-lavere alkoxy-lavere alkyl, phenylcarbamoyl,som kan have 1 til 3 substitu-enter valgt blandt halogen, lavere alkoxy og lavere alkyl på phenylringen, lavere alkylcarbamoyl, carboxy-la-vere alkylcarbamoyl, lavere alkylthio-lavere alkyl og vi x 3 25 lavere alkenyl, forudsat at mindst en af R , R og x5 R betegner en hydroxygruppe og at hydrogenet på den ene hydroxylgruppe betegnet med Rxl, Rx3 eller Rx5 er
O O
substitueret med en gruppe , hvori Y er som 30 defineret ovenfor.
Mere foretrukne grupper med formlen (Y) er dem, x4 der har formlen (Y-a), hvori R er halogen, ammo, carboxyl, carbamoyl, cyano, nitro, lavere alkyl, lavere alkenyl eller lavere alkoxycarbonyl.
35 De mest foretrukne grupper med formlen (Y) er vd dem, der har formlen (Y-a), hvori R er halogen eller cyano.
22 DK 174238 B1
Eksempler på pyridylgrupperne med Rx og eventuelt med de ovennævnte forskellige substituenter er som følger.
2-pyndyl, 3-pyridyl, 4-pyndyl, 5 2-hydroxy-3-pyridyl, 2-hydroxy-4-pyridyl/ 2-hydroxy-5-pyridyl, 2-hydroxy-6-pyridyl, 2-hydroxy-5-chlor —3-pyridyl, 2-hydroxy-5-chlor — 4-pyndyl, 10 4-hydroxy-5-chlor-—2-pyridyl, 2-hydroxy-5-chlor —6-pyridyl, 2-hydroxy-5-fluor —4-pyndyl, 4-hydroxy-5-fluor —2-pyridyl, 15 2-hydroxy-5-fluor-6-pyridyl, 2-hydroxy-5-brom —4-pyndyl, 4-hydroxy-5~brom—2-pyridyl, 2-hydroxy-5-brom —6-pyridyl, 20 2-hydroxy-5-iod —4-pyndyl, 4-hydroxy-S-iod -2-pyndyl, 2-hydroxy-5-iod«—6-pyridyl, i 2-hydroxy-3-brom —4-pyrxdyl, 25 4-hydroxy-3-brom—2-pyndyl, 2-hydroxy-3-chlor —4-pyndyl, 4-hydroxy-3-chlor —2-pyndyl, 2-hydroxy-3-chlor -6-pyridyl, 30 2-hydroxy-4-chlor—6-pyridyl, 1- (2-tetrahydrofuranyl) -1, 2-dihydro-2-oxo-3-pyndyl, 1- (2-tetrahydrofuranyl) -1,2-dihydro-2-oxo-4-pyndyl, 1- (2-tetrahydrofuranyl) -1,2-dihydro-2-oxo-5-pynayl, 35 1-(2-tetrahydrofuranyl)-1,2-dihydro-2-oxo-6-pyridyl, 23.
DK 174238 B1 1- (3-tetrahydrofuranyl) -l,2-dxhydro-2-oxo-4-pyrxdyl, 1- (2-tetrahydrofuranyl)-1,2-dxhydro-2-oxo-5-chlor- 4-pyridyl, 1-(2-tetrahydrofuranyl)-1,2-dxhydro-2-oxo-5-chlor_ 5 6-pvrxdyl, 1-(2-tetrahydrofuranyl)-1,2-dihydro~2-oxo-5-fluor— 4-pyrxdyl, 1-(2-tetrahydrofuranyl)-1,2-dihydro-2-oxo-5-brom-10 4-pyridyl, 1-(2-tetrahydrofuranyl)-1,2-dihydro-2-oxo-5-iod— 4-pyrxdyl, 1-(3-tetrahydrofuranyl)-1,2-dxhydro-2-oxo-5-chlor— 15 4-pyridyl, 1-(2-tetrahydrofuranyl)-1,2-dxhydro-2-oxo-3-chlor— 4-pyridyl, 1-ethoxymethyl-l,2-dxhydro-2-oxo-3-pyrxdyl, 20 1-ethoxymethyl-l,2-dxhydro-2-oxo-4-pyrxdyl, 1-ethoxymethyl-l,2-dxhydro-2-oxo-5-pyrxdyl, 1-ethoxymethyl-l,2-dxhydro-2-oxo-6-pyrxdyl, 1-methoxymethyl-l,2-dihydro-2-oxo-4-pyridyl, 25 1"(2-methoxyethyl)-l,2-dxhydro-2-oxo-4-pyrxdyl, 1-ethoxymethyl-l,2-dxhydro-2-oxo-5-chlor —3-pyridyl, 1-ethoxymethyl-l,2-dxhydro-2-oxo-5-chlor -4-pyridyl, 1-ethoxymethyl-l,2-dxhydro-2-oxo-5-chlor—6-pyridyl, 30 1-ethoxymethyl-l,2-dihydro-2-oxo-5-fluor —4-pyridyl, 1-ethoxymethyl-l, 2-dihydro-2-oxo-5-broni —4-pyrxdyl, 1-ethoxymethyl-l,2-dihydro-2-oxo-5-iod —4-pyrxdyl, 1-methoxymethyl-l, 2-dxhydro-2-oxo-5-chlor—4-pyrxdyl, DK 174238 B1 24 1-(2-methoxyethyl)-1,2-dxhydro-2-oxo-5-chlor —4-pyrxdyl, 1- (2-ethoxymethyl)-1,2-dihydro-2-oxo-3-chlor —4~pyridyl, 5 2-acetyioxy-5-chior «—4-pyridyl, 2- acetyloxy-5-fluor,— 4-pyrxdyl, 2-acetyloxy~5-broin —4-pyrxdyl, 2-acetyloxv-5-iod —4-pyrxdyl, 10 2-acetyloxy-5-methyl-4-pyrxdyl, 2-acetyloxy-5-cyano-4-pyrxdyl, 2-acetyloxy-5-nxtro-4-pyrxdyl, 2-acetyloxy-5-carboxy-4-pyrxdyl, 15 2-propanoyloxy-5-chlor—4-pyrxdyl, 2-butanoyloxy-5-chlor —4-pyndyl, 2-xsobutanoyloxy-5-chlor 4-pyridyl, 2- pentanoyloxy-5-chlor —4-pyridyl, 20 2-hexanoyloxy-5-chlor —4-pyrxdyl, 3- acetyloxy-5-chlor —4-pyndyl, 2-acetyloxy-3-chlor —4-pyrxdyl, 4- acetyloxy-5-chlor -2-pyrxdyl, 25 4-acetyloxy-5-fluor —2-pyndyl, 4-acetyloxy-5-brom -2-pyrxdyl, 4-acetyloxy-5-iod —2-pyrxdylr 4-acetyloxy-5-methyl-2-pyndyl, 30 4-acetyloxy-5-cyano-2-pyrxdyl, 4-acetyloxy~5-nxtro-2-pyridyl, 4-acetyloxy-5-carboxy-2-pyndyl, 6-acetyloxy-5-chlor—2-pyrxdyl, 4-propanoyloxy-5-chlor —2-pyridyl, DK 174238 B1 25 4-butanoyloxy-5-chlor —2-pyrxdyl, 4-xsobutanoyloxy-5-chlor —2-pyridyl, 5 4-pentanoyloxy-5-chlor —2-pyrxdyl, 4-hexanoyloxy-5-chlor—2-pyricyl, 4-acetyloxy-3-chlor —2-pyridyl, 10 3-acetyloxy-5-chlor —2-pyrxdyl, 2-acetyloxy-4-pyridy1, 2-propanoyloxy-4-pyrxdyl, 2-hexanoyloxy-4-pyrxdyl, 15 4-acetyloxy-2-pyrxdyl, 4-propanoyloxy-2-pyridyl, 4-hexanoyloxy-2-pyrxdyl, 2-methoxycarbonyloxy-5-chlor —4-pyndyl, 20 2-methaxycarbonyloxy-6-chlor — 4-pyrxdyl, 2-ethoxycarbonyloxy-3-chlor —4-pyndyl, 2-ethoxycarbonyloxy-5-chlor —4-pyndyl, 2-ethoxycarbonyloxy-5-fluor — 4-pyndyl, 25 2-ethoxycarbonyloxy-5-brom 4-pyrxdyl, 2-ethoxycarbonyloxy-6-chlor —4-pyrxdyl, 2-ethoxycarbonyloxy-5-chlor —3-pyrxdyl/ 2-ethoxycarbonylox> -5-chlor — 6-pyndyl, 30 2-propoxycarbonyloxy-5-chlor —4-pyrxdyl, 2-hexyloxycarbonyloxy-5-chlor —4-pyrxdyl, 2- benzoyloxy-4-pyrxdyl, 3- benzoyloxy-4-pyrxdyl, 35 4-benzoyloxy-2-pyndyl, DK 174238 B1 26 3- benzoyloxy-2-pyridyl, 2-(2-methylbenzoyl)oxy-4-pyndyl, 2- (3-netn\ Ibenzoyl) oxy-4-pyndyl, 2-(4-methylbenzoyl)oxy-4-pyndyl, 5 2-(4-ethylbenzoyl) oxy-4-pyndyl, 2- (2-chlorbenzoyl) oxy-4-pyridyl, 2- (3-chlorbenzoyl) oxy-4-pyndyl, 2-(4-chlorbenzovl)oxy-4-pyridyl, 2- (4-fluorbenzoyl) oxy-4-pyndyl, 10 2- (4-tert-butylbenzoyl) oxy-4-pyndyl, 2- (4-hexyIbenzoyl)oxy-4-pyndyl, 4- (2-methylbenzoyl)oxy-2-pyndyl, 4-(4-ethylbenzoyl)oxy-2-pyridyl, 4-(3-chlorbenzoyl)οχγ-2-pyndyl, 15 4-(4-fluorbenzoyl)oxy-2-pyridyl, 4- (4-tert-butylbenzoyl) oxy-2-pyndyl, 2-benzoyloxy-5-chlor —4-pyndyl, 2-benzoyloxy-5-fluor —4-pyridyl, 2-benzoyloxy-5-brom -4-pyndyl, 20 2-benzoyloxy-5-iod—4-pyndyl, 2-benzoyloxy-5-methyl-4-pyridyl, 2-benzoy loxy-5-cyano-4-pyndyl, 2-benzoyloxy-5-nitro-4-pyridyl, 2-benzoyloxy-5-carboxy-4-pyridyl, 25 3-benzoyloxy~5-chlor —4-pyridyl, 2-benzoyloxy-3-chlor — 4-pyndyl, 2- (2-methylbenzoyl) oxy-5-chlor —4-pyndyl, 2- (3-methvlbenzoyl) oxy-5-chlor —4-pyndyl, 2-(4-methylbenzoyl) oxy-5-chlor —4-pyridyl, DK 174238 B1 27 2-(3,4,5-tnmethylbenzoyl) oxy-5-chlor —4-pyndyl, 2-(4-ethylbenzoyl)oxy-5-chlor -4-pyndyl, 5 2-(4-tert-butylbenzoyl)oxy-5-fluor —4-pyndyl, 2- (4-hexylbenzoyl)oxy-5-brom — 4-pyndyl, 2- (2-chlor cenzoyl) oxy-5~chlor-4-pyndyl, 2- (3-chlor benzoyl) oxy-5-chlor-4-pyridyl, 10 2- (4— chlorbenzoyl) oxy-5-chlor-4-pyndyl, 2- (4-fluorbenzoyl)oxy-5-chlor-4-pyridyl, 2- (2,4-dichlorbenzoyl) oxy-5- chlor-4-pyndyl, 2-(3,4,5-trichlorbenzoyl) oxy-5-chlor-4-pyndyl, 2- (2-methoxybenzoyl) oxy-5-chlor —4-pyndyl, 2- (3-inethoxybenzoyl) oxy-5-chlor -4-pyndyl, 2-(4-methoxybenzoyl) oxy-5-chlor —4-pyndyl, 2- (3,4,5-triiriethoxybenzoyl) oxy-5-chlor —4-pyndyl, 20 4-benzoyloxy-5-chlor—2-pyndyl, 4-benzoyloxy-5-fluor —2-pyridyl, 4-benzoyloxy-5-brom —2-pyndyl, 4-benzoyloxy-5-iod -2-pyridyl, 25 4-benzoyloxy-5-methyl-2-pyridyl, 4-benzoyloxy-5-cyano-2-pyndyl, 4-benzoyloxy-5-nitro-2-pyridyl, 4-benzoyloxy-5-carboxy-2-pyndyl, 30 3-benzoyloxy-5-chlor -2-pyridyl, 6-benzoyloxy-5-chlor —2-pyridyl, 28 DK 174238 B1 6-(2,4-dichlorbenzoyloxy)-3-cyano-2~pyridyl, 6-(3,4,5-trimethoxybenzoyloxy)-3-cyano-2-pyridyl, 6-(4-fluorbenzoyloxy)-3~chlor-2-pyridvl, 5 6-benzoyloxy-3-cyano-2-pyridyl, 4- (4-methylbenzoyl) oxy-5-chlor —2-pyridyl, 4- (2,4-dimethylbenzoyl) oxy-5-chlox -2-pyndyl, 4-(3,4,5-trimethylbenzoyl)oxy-5-chlor — 2-pyridyl, 10 4-(2-chlorbenzoyl)oxy-5-chlor-2-pyrxdyl, 4- (2,4-dichlorbenzoyl]oxy-5-chlor-2-pyridyl, 4-(4-methoxybenzoyl)oxy-5-chlor —2-pyridyl, 1-phthalidyl-l ,2-dihydro-2-oxo-3-pyndyl, 15 1-phthalidyl-l, 2-dihydro-2-oxo-4-pyndyl, 1-phthalidyl-l, 2-dihydro-2-oxo-5-pyndyl, 1-phthalidyl-l, 2-dihydro-2-oxo-6-pyndyl, 1-carbomethoxymethylcarbamoyl-l,2-dihydro-2-oxo-3-20 pyndyl, 1-carbomethoxymethylcarbamoyl-l,2-dihydro-2-Oxo-4-pyridyl, 1-carbomethoxymethylcarbamoyl-l,2-dihydro-2-oxo-5-25 pyndyl, 1-carbomethoxymethylcarbamoyl-l,2-dihydro-2-oxo-6-pyndyl, 1- carboethoxymethylcarbamoyl-l,2-dihydro-2-oxo-4-pyridyl, 30 2-hydroxy-5-’inethyl-3-pyridyl, 2- hydroxy-5-methyl-4-pyndyl, 2-hydroxy-5-methyl-6-pyndyl, DK 174238 B1 29 2-hydroxy-5-ethyl-4-pyndyl, 2-hydroxy-3-methyl-4-pyridyl, 5 2-hydroxy-3-cyano-4-pyridyl, 2-hydroxy-3-cyano-5-pyndyl, 2-hydroxy- 3.-cyano- 6 -pyr idy 1, 2-hydroxy-5-cyano-6-pyndyl, 10 2-hydroxy-3-nitro-4~pyndyl, 2-hydroxy-3-mtro-5-pyridyl, 2-hydroxy-5-mtro-6-pyndyl, 2-hydroxy-6-mtro-4-pyridyl, 15 2-hydroxy-5-carboxy-3-pyridyl, 2-hydroxy-5-carboxy-4-pyndyl, 2-hydroxy-5-carboxy-6-pyridyl, 2-hydroxy-3-carboxy-4-pyndyl, 20 2-hydroxy-5-ethoxycarbonyl-3-pyndyl, 2-hydroxy-5-e thoxyca rbony1-4-pyridyl, 2-hydroxy-5-ethoxycarbonyl-6-pyridyl/ 2-hydroxy-3-ethoxycarbonyl-4-pyridyl, 25 2-hydroxy-3,5-dichlor —4-pyndyl, 2-hydroxy-3,5-dichlor —6-pyridyl, 2-hydroxy-3,5-dibrom —4-pyndyl, 2-hydroxy-3,5-dibrom —6-pyridyl, 50 2-hydroxy-3-ammo-4-pyndyl, 2-hydroxy-3-ammo-5-pyndyl, 30 2-hydroxy-3-anuno-6-pyridyl, DK 174238 B1 2-hydroxy-3-carbamoyl-4-pyndyl, 2-hydroxy-3-carbamoyl-5-pyridyl, 5 2-hydroxy-3-carbamoyl-6-pyrxdyl, 2,4-dxhydroxy-G-pyridyl, 2,6-dihydroxy-4-pyridyl, 1,2-dxhydro-2-oxo-4-pyrxdyl, 10 l,6-dxhydro-6-oxo-2-pyrxdyl, 1-(benzyloxymethyl)-5-chlor—1,2-dxhydro-2-oxo-4-pyrxdyl, 1- (benzyloxymethyl) -5-fluor —1,2-dxhydro-2-oxo-6-pyridyl, 1-(β-phenethyloxymethyl)-5~brom —1,2-dxhydro-2-oxo-4-15 pyrxdyl, 1- (2-benzyloxyethyl) -5-chlor —1 ,2-dxhydro-2-oxo-4-pyndyl, 5-chlor -4- [p- (Ν,Ν-dimethylamxno) benzoyloxy]-2-pyrxdyl, 20 5-brom -4- [p- (Ν,Ν-dxmethylamxno)benzoyloxy]-2-pyrxdyl, 5-chlor -4- [p- (N, N-dxmethylamxno) benzoyloxy] -3-pyrxdyl, 5-chlor —4-[p-(N-methyl,N-ethylamxno)benzoyloxy]-2-pyrxdyl, 2^ 5-f luor -4- [o- (Ν,Ν-dxmethylamxno) benzoyloxy] -2-pyrxdyl, 5-f luor —4-hexanoyloxy-2-pyndy 1, 5-brom —4-hexanoyloxy-2-pyndyl, 5-iod — 4-hexanoyloxy~2-pyndyl, 30 5-f luor —4-octadecanoyloxy-2-pyrxdyl, 5-chlor —4-octadecanoyloxy-2-pvrxdyl, 5-brom —4-octadecanoyloxy-2-pyndyl, DK 174238 B1 31 5-io<3 — 4-octadecanoyloxy-2-pyndyl, 5-fluor -4- (2-furoyloxy) -2-pyndyl, 5 5-chlor -4-(2-furoyloxy)-2-pyridyl, 5-brom -4- (2-furoyloxy) -2-pyndyl, 5-iod -4- (2-furoyloxy) -2-pyndyl, 5-chlor —4-(3-furoyloxy)-2-pyridyl, 10 5-brom —4-(3-furoyloxy)-2-pyridyl, 5-fluor —4-(2-thenoyloxy)-2-pyndyl, 5-chlor -4-(2-thenoyloxy)-2-pyridyl, 5-brom -4-(2-thenoyloxy)-2-pyridyl, 15 5-iod -4-(2-thenoyloxy)-2-pyndyl r 5-chlor -4-(3-thenoyloxy)-2-pyridyl, 5-iod -4-(3-thenoyloxy)-2-pyridylf 4- (1-naphthoyloxy)-2-pyridyl, 20 4-(2-naphthoyloxy)-2-pyndyl, 5- (1-naphthoyloxy)-2-pyndyl, 5- (2-naphthoyloxy) -2-pyndyl, 25 6- (2-naphthoyloxy)-2-pyndyl, 3-cyano-6-(2-thenoyloxy)-2-pyridyl, 3- cyano-6- (3-thenoyloxy) -2-pyndyl, 4- cyano-6-(2-thenoyloxy) -2-pyndyl, 30 3—cyan o—6— (2-furoyloxy) -2-pyndyl og lignende.
DK 174238 B1 32
Arylengrupperne betegnet Y i pyridyloxycarbo-nylarylencarbonylgruppen med formlen (Y) omfatter dem, der er dannet udfra aromatiske carbonhydnder eller 5- eller 6-ledede aromatiske heterocycler indeholdende 5 et eller to heteroatomer, som er ens eller forskellige og valgt blandt nitrogen og oxygen, ved fjernelse af to hydrogenatomer, der hver er bundet til to forskellige carbonatomer. Eksempler på sådanne arylengrupper er phenylengrupper, såsom 1,2-phenylen, 1,3-phenylen, 10 l,4~phenylen og lignende; naphthylengrupper, såsom 1,2-naphthylen, 1,3-naphthylen, 1,4-naphthylen, 1,5-naphthy-len, 1,6-naphthylen, 1,7-naphthylen, 1,8-naphthylen og lignende; pyndmdiylgrupper, såsom 2,4-pyridindiyl, 2,5-pyridmdiyl, 2,6-pyridindiyl, 3,4-pyridindiyl, 3,5-15 pyndindiyl og lignende; pyrazindiylgrupper^såsom 2,3-pyrazmdiyl, 2,6-pyrazindiyl, 2,5-pyrazindiyl og lignende; furandiylgrupper^såsom 2,3-furandiyl, 3,4-fu-randiyl, 2,5-furandiyl og lignende; 4-pyndon-l-lavere alkyl-diylgrupper såsom 4-pyndon-l-methyl-2,3-diyl, 20 4-pyridon-l-methyl-2,5-diyl, 4-pyndon-l-methyl-2,6-diyl og lignende.
Med hensyn til formlen (lb) omfatter substituenten a 5-fluoruracil-afledte grupper, forsåvidt de kan omdannes til 5-fluoruracil in vivo og forsåvidt de kan 25 danne en ester- eller amidbinding sammen med carbonyl-gruppen, hvortil substituenten α er bundet, dvs egnede 5-fluoruracil-afledte grupper omfatter f eks dem, der dannes fra 5-fluoruraciIderivaterne med formlerne il-la) og (1-lc) 30 (χ) Forbindelser med formlen DK 174238 B1 33 ΗΝ'ίΤ'*' (1-la)
xJ
ι hvori β betegner et hydrogenatom, en tetrahydrofuranyl-, lavere alkylcarbamoyl-, phthalidyl-, lavere alkoxy-lavere alkyl- eller lavere alkanoyloxy-lavere alkoxycarbonyl-10 gruppe.
Forbindelserne med formlen (1-la) er beskrevet i J. Med. Chem. 25, 1219, 1982, Cancer Chemother.
Pharmacol., 1, 203-208, 1978 og den offentliggjorte japanske patentansøgning nr. 37787/1975(har endnu ikke 15 været udsat for prøvning).
Med hensyn til formlen (1-la) kan
O O
x II I
R -0-C-Y-C- gruppen bindes i 3- eller 1-stilling af 5-fluoruracilnngen ved en amidbinding.
d . ·Ρ * 20 (n) Forbindelser med formlen
25 I
O"^ N'T
H V-‘ 30 hvori R6'A betegner en lavere alkoxycarbonylgruppe, A betegner en lavere alkoxygruppe eller gruppen -°-N'CH-0
Forbindelsen med formlen (1-lc) er beskrevet i 35 EPC patentansøgningen offentliggjort under nr. 99091.
DK 174238 B1 34
Med hensyn til formlen (1-lc) kan gruppen O O
x II II , R „ R-O-C-Y—C- bindes i 1- eller 3-stillmg til 5-fluorura- cilrmgen ved en amidbinding.
5 Med hensyn til forbindelserne med formlerne 6 # A 7 Ά (l-la) og (1-lc) er grupperne betegnet &, R og R eksemplificeret nedenfor
Eksempler på lavere alkylcarbamoylgrupper er 10 alkylcarbamoylgrupper med en eller to C^-Cg-alkylgrup-per, såsom N-rnethylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-tert-butylcarbamoyl, 15 N-pentylcarbamoyl, N-hexylcarbamoyl, N/N-dimethylcarbamoyl, Ν,Ν-diethylcarbamoyl, Ν,Ν-dipropylcarbamoyl, N-isopropyl-N-methylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-methyl-N-pentyl-carbamoyl, 20 N-propyl-N-pentylcarbamoyl, N,N-dipentylcarbamoyl, N-ethyl-N-hexylcarbamoyl, N-hexyl-N-pentylcarbamoyl, i Ν,Ν-dihexylcarbamoyl og lignende.
Eksempler på lavere alkoxy-lavere alkylgrupper er alkoxyalkylgrupper, hvori alkoxydelen og alkyldelen hver indeholder 1 til 6 carbonatomer, såsom methoxymethyl, 3-methoxypropyl, 4-ethoxybutyl, 6-propoxyhexyl, 5-isopropoxypentyl, 30 l,l-dunethyl-2-butoxyethyl, 2-methyl-3-tert-butoxypropyl, 2-pentyloxyethyl, 2-hexyloxyethyl og lignende.· DK 174238 B1 35
Eksempler på lavere alkanoyloxy-lavere alkoxy-carbonylgrupper er alkanoyloxy-alkoxycarbonylgrupper, hvori alkanoyIdelen og alkoxydelen hver indeholder 1 til 6 carbonatomer, såsom acetyloxy-5 methoxycarbonyl, 4-(formyloxy)butoxycarbonyl, 6-(propionyloxy)hexyloxycarbonyl, 5-{isobutyryloxy)- pentyloxycarbonyl, 6-(hexanoyloxy)hexyloxycarbonyl, 2-(hexanoyloxy)ethoxycarbonyl, 2-(acetyloxy)ethoxy- 10 carbonyl, acetyloxymethoxycarbonyl og lignende.
Eksempler på lavere alkoxycarbonylgrupper er carbonylgrupper med Cj-Cg-alkoxygrupper, såsom methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, butoxycarbonyl, 15 pentyloxycarbonyl, hexyloxycarbonyl og lignende.
Forbindelserne ifølge opfindelsen indeholdende substituenten med formlen (Y) omfatter keto-enol-tauto-merer. Opfindelsen omfatter disse tautomerer.
Forbindelserne med formlen 20
O O
II II
Rx-0-C-Y-C-a (lb) 25 hvori Rx, Y og α er som defineret ovenfor, kan fremstilles ved fremgangsmåderne vist i de følgende reaktionsskemaer (a) og (b) DK 174238 B1 36
Reaktionsskema (a) ff ff x n —8
5 X-C-Y-C-α + R -O-R
( 34 ) ( 26 )
10 V
X « li R-O-C-Y-C-a ( lb ) 15
Q
hvori X er et halogenatom, R er hydrogen eller en tri (lavere alkyl) silylgruppe, og Qi, R og Y er som defineret tidligere Først fremstilles syrehalogenider (34a) og (34c) 20 ved indføring af en acylgruppe XCO-Y-CO- i 3-stillingen i forbindelserne med formlerne (1-la) og (1-lc) i overensstemmelse med de følgende reaktionsskemaer (i1) og <i2)
Reaktionsskema (i^) 25
™ jj + XCO-Y-COX
( 21 )
30 I
β (l-la) O 0 O p _> χ-ϋ-ν-ϊ-/γ 35 0^- β (34a) DK 174238 B1 37 hvori X er et halogenatom, og β og Y er som defineret tidligere
Reaktionsskema (i2) 5
A + XCO-Y-COX
ak„JrH
Η Y'A < 21 > 10 (1-lc) O O o
--> xi-V-S-NjS<R5'A
t Lh
15 NXl'A
H R (34c) hvori X er et halogenatom, og hvor R6 A, R7 A og Y er 20 som tidligere defineret
Reaktionen, ved hvilken acyl (XCO-Y-CO-) indføres . i 3-stillmgen af pynmidmdelen (acylenng) , kan ~ udføres ved en sædvanlig fremgangsmåde, f eks syreha-logenidprocessen Ved syrehalogenidmetoden lades et 25 acylhalogenid (XCO-Y-COX) reagere med forbindelserne (1-la) og (1-lc) i et passende opløsningsmiddel i tilstedeværelse af et syreoptagende middel til opnåelse af de ønskede forbindelser 34a og 34c Eksempler på egnede syreoptagende midler er natnumhydrogencarbonat, 30 natriumcarbonat, kaliumcarbonat, pyndm, tnethylamm, osv. Eksempler på egnede opløsningsmidler er benzen, chloroform, methylenchlond, carbontetrachlorid, dioxan, tetrahydrofuran, osv. Acylhalogenidet anvendes i en mængde på mindst ca. 1 mol, fortrinsvis 1 til ca. 3 DK 174238 B1 38 mol, pr mol af forbindelserne (1-la) og (1-lc)
Reaktionstemperaturen er sædvanligvis -30 til 100°C, fortrinsvis stuetemperatur til ca 80°C Reaktionen tager ca 20 minutter til ca 20 timer Derefter om-5 sættes de opnåede forbindelser (34a) og (34c) med forbindelsen (26) til opnåelse af (Ib) Når den anvendte forbindelse (26) er en forbindel-
Q
se, hvori R er hydrogen, kan reaktionen udføres på samme måde som ved fremstillingen af forbindelserne 10 (34a) og (34c) Når den anvendte forbindelse (26) er en forbm- g delse, hvori R er en tri(lavere alkyl)silylgruppe, udføres reaktionen under anvendelse af et opløsningsmiddel, som ikke vil påvirke reaktionen ugunstigt, 15 under tørre betingelser, fortrinsvis under vandfri betingelser. Eksempler på foretrukne opløsningsmidler er halogenerede carbonhydnder, såsom dichlormethan og chloroform, aromatiske carbonhydnder, såsom benzen og toluen, og aprotiske opløsningsmidler, såsåm dioxan, 20 acetomtril, acetone og tetrahydrofuran. Sædvanligvis anvendes mindst ca. et mol, fortrinsvis 1 til 3 mol, af forbindelsen (26) pr mol af syrehalogeniderne (34a) og (34c) Reaktionen udføres ved ca 0 til ca 100°C, fortrinsvis ved stuetemperatur til ca. 80°C i g 25 1 til 6 timer, fortrinsvis ca. 2 timer. Når R er hydrogen, er det ønskeligt at anvende en base, såsom tnethylamm, trimethylamm, dimethylanilm eller g pyndin, til reaktionen. Hvis R er tri (lavere alkyl)si-lyl, er det endvidere ønskeligt at anvende en Lewissyre, 30 såsom tin(XV)chlond, zmkchlorid eller alumimumchlo- nd.
Forbindelserne (26) der skal anvendes til den nærværende reaktion, er sædvanligvis dem, der er kendte, men de omfatter nogle hidtil ukendte forbindelser. Så-35 danne forbindelser kan let fremstilles ved den følgende fremgangsmåde. Forbindelsen substitueret med 2-tetra- DK 174238 B1 39 hydrofuranyl i 1-stillingen af pyndinringen kan fremstilles udfra et tilsvarende kendt pyridinderivat med et hydrogenatom i 1-stillingen ved tilsætning af hexa-methyldisilazan til derivatet, refluksning af blandingen 5 i ca. 2 til ca. 20 timer, og dernæst fjernelse af overskydende silazan fra reaktlonsblandingen, opløsning af remanensen‘i et halogeneret carbonhydnd, såsom dichlor-methan og chloroform, eller i et aprotisk opløsningsmiddel, såsom dioxan og acetonitnl, tilsætning af 10 2-acetoxytetrahydrofuran til opløsningen i en mængde på mindst ca. 1 mol til 2 mol pr. mol af pyndmderivatet og en Lewissyre, såsom tin(IV)chlond, zinkchlond eller aluminiumchlond, og omsætning af blandingen ved ca. 0 til ca. 100°C, fortrinsvis omkring stuetemperatur^ 15 i ca. 1 til ca. 10 timer. Når 2-acetoxytetrahydrofuran anvendt til reaktionen erstattes af et aroylhalogemd, lavere alkanoylhalogenid, aroyloxycarbonylhalogenid, lavere alkoxycarbonylhalogenid, 2-halogenphthalidallyl-halogenid, phenyl-lavere alkoxy-lavere alkylhalogenid 20 eller lavere alkoxy-lavere alkylhalogenid, har den opnåede forbindelse substituenten af aryloxy-, lavere alkanoyloxy-, aroyloxycarbonyloxy- eller lavere alkoxy-carbonyloxygruppen i 2- οσ/eller 4-stillmgen af pyrxdin-ringen eller phthalidyl-, allyl-, phenyl-lavere alkoxy-25 lavere alkyl- eller lavere alkoxy-lavere alkylgruppen i 1-stillmgen af pyndinringen. Yderligere kan forbindelsen substitueret med N-(lavere alkoxycarbonyl-lavere alkyl)aminocarbonyl i 1-stillingen af pyndinringen fremstilles udfra et tilsvarende pyridinderivat med et 30 hydrogenatom i 1-stillingen ved tilsætning af mindst ca. 1 mol af et lavere alkoxycarbonyl-lavere alkyliso-cyanat pr. mol af derivatet i et opløsningsmiddel, såsom dioxan, dichlormethan, chloroform, acetonitnl, acetone eller pyndm, og omsætning af blandingen ved 35 ca. 0 til ca. 100°C i ca. 10 minutter til ca. 1 time, fortrinsvis ca. 30 minutter.
DK 174238 B1 40
Reaktionsskema (b)
rx-oXyXx + aH
5 (36) { 22 ) sl·
O O
I! II
10 RX-0-C-Y-C-a (lb) hvori Rx, Y og α er som defineret tidligere, og X er et halogenatom 15 Denne reaktion kan udføres på samme måde som reaktionen ifølge skemaerne (i1) og (i2)
Forbindelserne (lb) ifølge opfindelsen har en fremragende anticancervirknmg og lav toksicitet.
For eksempel har de svagere bivirkninger, såsom 20 tab af legemsvægt. Forbindelserne ifølge opfindelsen er derfor meget nyttige som antitumormidler til behandling af cancerlidelser hos mennesker og dyr.
Undersøgelser har vist, at anticancervirknmgen af forbindelserne (1) ifølge opfindelsen kan øges yder- 25 ligere, når de anvendes i kombination med et pyndmde-nvat med formlen (X) nedenfor.
30 Å- (X)
N
HO
DK 174238 B1 41 1 3 hvori et af Y og Y er et hydrogenatom, den anden er 2 hydroxyl, Y er et hydrogenatom, et halogenatom, lavere alkyl, cyano eller nitro, og hydroxylgruppen i 2-, 4-og/eller 6-stillingen kan være acyleret.
5 Nogle af forbindelserne med formlen (X) er kendte.
De andre kan let fremstilles ved en kendt fremgangsmåde (Tnv. Chem. Rec. 73, 704 (1954) . Acyleringen af hydroxyl-gruppen eller grupperne i 2-, 4- og/eller 6-stilling kan udføres på samme måde som i reaktionsskemaet (b) el-10 ler (c).
De ønskede produkter ifølge opfindelsen anvendes x form af almindelig acceptable farmaceutiske præparater, som fremstilles ved anvendelse af fortyndingsmidler og excipienter, såsom fyldstoffer, kvældningsmidler, binde-15 midler, befugtnmgsmidler, desintegreringsmidler, overfladeaktive stoffer, smøremidler og lignende. Enhedsformer til administration af disse farmaceutiske midler ifølge opfindelsen kan være forskellige og vælges til imødekommelse af forskellige terapeutiske formål. Typiske 20 former for farmaceutiske præparater er f.eks. tabletter, piller, pulverpræparater, væskepræparater, suspensionspræparater, emulsionspræparater, granulatpræparater, kapsler, suppositorier, injektionspræparater (væskeformige, suspensioner eller andre), salver ^ og lignende.
Ved formulering til tabletter kan de bærere, der er kendte som bærere indenfor dette område, anvendes i vid udstrækning, f.eks. excipienter, såsom lactose, raffineret sukker, natriumchlond, glucose, urinstof, stivelse, calciumcarbonat, kaolin, krystallinsk cellulose, kiselsyre og andre; bindemidler, såsom vand, ethanol, propanol, simpel sirup, glucoseopløsning, stivelsesopløsning, gelatineopløsning, carboxymethylcellulose, shellac, methylcellulose, kaliumphosphat, polyvmylpyrrolidon 35 og andre ; desintegreringsmidler, såsom tørret stivelse, DK 174238 B1 42 natriumalgmat, agar-agar-pulver, laminarlapulver, natnumhydrogencarbonat, calciumcarbonat, en fedtsyreester af polyoxyethylensorbitan, natnumlaurylsulfat, monoglycend af stearinsyre, stivelse, lactose og andre; desintegrermgsmhibitorer, såsom raffineret sukker, ^ smørende cacaosmør, hydrogenerede olier og andre; absorb-tionsaccelleratorer, såsom kvaternære ammoniumbaser, natnumlaurylsulfat og andre; befugtningsmidler, såsom glycerol, stivelse og andre; adsorptionaccelleratorer, såsom stivelse, lactose, kaolin, bentonit, colloidal 10 kiselsyre og andre; og smøremidler, såsom renset talkumpulver, stearinsyresalte, borsyrepulver, polyethylengly-col og andre. Om nødvendigt kan tabletterne desuden overtrækkes med sædvanlige filmovertræk for at omforme dem til overtrukne tabletter, f.eks. tabletter over-15 trukket med sukker, gelatinef lim, entenske film og film, eller dobbelt - eller multilagede tabletter og andre. Ved formgivning til piller, kan bærere, der er kendte indenfor dette område, i vid udstrækning anvendes, f.eks. excipienter, såsom glucose, lactose, stivelse, cacaosmør, 20 hydrogenerede vegetabilske olier, kaolin, talkum og andre, bindemidler, såsom pulveriseret gummi arabicum, pulveriseret tragacanth gummi, gelatine, ethanol og andre; desintegreringsmidler, såsom laminaria, agar-agar- pulver og andre. Ved formning til suppositorier kan de 2 5 materialer, der er kendte indenfor dette område, i vid udstrækning anvendes, f.eks. polyethylenglycol, cacaosmør, højere alkoholer, estere af højere alkoholer, gelatine, semisyntetiserede glycender og andre. Kapsler fremstillet på sædvanlig måde ved blanding af forbindelsen ifølge opfindelsen med de ovennævnte forskellige bærere og indkapsling af blandingen i hårde gelatinekapsler, bløde gelatinekapsler, osv. Ved fremstilling af injectionspræparater steriliseres de fremstillede opløsninger, emulsioner og suspensioner, og de er for-35 trmsvis isotoniske med blod. Ved fremstilling af opløs- DK 174238 B1 43 nxnger, emulsioner og suspensioner, kan de fortyndingsmidler, der er kendte indenfor dette område, anvendes x vid udstrækning, f.eks. vand, ethanol, propylenglycol, ethoxyleret isostearylalkohol, polyoxyleret isostearyl-alkohol, polyoxyethylensorbitanfedtsyreester og andre.
5 Ved fremstilling af isotoniske opløsninger kan en tilstrækkelig mængde natriumchlond, glucose eller glycerol tilsættes for at gøre opløsningen isotonisk med blodet.
De farmaceutiske blandinger til mjectionspræparater kan endvidere om nødvendig indeholde sædvanlige opløsende 10 midler, pufferopløsninger, analgetiske midler eller lignende. De farmaceutiske midler ifølge opfindelsen kan endvidere indeholde farvestoffer, konserveringsmidler, parfumestoffer, krydderier, sødestoffer osv., samt om nødvendigt andre medikamenter. Ved formulering til pasta-, IS creme- og gelpræparater, kan fortyndingsmidler, såsom hvid vaseline, paraffiner, glycerol, cellulosederivater, polyethylglycoler, siliconer, bentonit og liqnende anvendes .
Den mængde af det ønskede produkt ifølge opfin-20 delsen, der skal indeholdes som aktiv komponent i det farmaceutiske middel, er ikke underlagt særlige begrænsninger og kan vælges fra et bredt område, sædvanligvis kan 1 til 70 vægt% anvendes.
Administrationsve;]en af det ovennævnte farmaceu-25 tiske middel er ikke underlagt særlige begrænsninger, og midlet kan administreres ved en passende metode for de respektive typer af administreringsformer, afhængigt af patientens alder, køn oo andre betingelser, patientens tilstand m.m. F.eks. administreres tabletter, pil-30 ler, væske-, suspensions-, emulsions- og oranulatpræ-parater og kapsler oralt; m]ectionspræparater administreres intravenøst alene eller som en blanding med sædvanlige mjicerbare transfusionsvæsker, såsom en glucoseopløsning, en ammosyreopløsning eller anden 35 opløsning; og om nødvendigt administreres mjectionspræ- DK 174238 B1 44 paraterne alene intramuskulært, mtrakutant,subkutant eller intraperitonealt; og suppositorierne administreres i rectum.
Dosen af de ønskede produkter ifølge opfindelsen kan vælges passende afhængigt af administrennqsvejen, 5 patientens alder, køn og andre betingelser, oq symptomernes alvorlighed. Almindeligvis kan de farmaceutiske midler ifølge opfindelsen administreres i en mængde på ca. 0,5 til ca. 20 mg/kg af legemsvægten/dag beregnet som forbindelsen ifølge opfindelsen (aktiv komponent), 10 i 1 til 4 delte doser.
Opfindelsen vil blive beskrevet mere detaljeret i de følgende referenceeksempler, eksempler, farmaceutiske test og fremstillmgseksempler.
I forbindelse med NMR-data i referenceeksemplerne 15 og eksemplerne anvendes tallene, der er givet som fodtegn til højre for symbolerne "C", "H" eller "N", til anqivelse af placeringen i forbindelsen. Udtrykket "Cg-H", refererer for eksempel til hydrogenet bundet til carbonatomet i 6-stillingen. Ligeledes betegner 20 l,C3' 4' 5'“H "' f»eks. hydrogenatomerne bundet til car-bonatomerne i 3'-, 4'- og 5'-stillingerne. Også refererer eksempelvis til hydrogenet bundet til carbonatomet i 1-stillingen. "N^H" refererer eksempelvis til hydrogenet bundet til nitrogenatoraet i 3-stillrng 25 af 5-fluoruracilrmgen.
Referenceeksempel 1
Fremstilling af 5-chlor-4-hydroxy-l-(2-tetrahydrofura-nyl) -2 (IH) -pyndon.
30 10 ml hexamethyldisilazan tilsattes til 1,00 g 5-chlor-4-hydroxy-2 (IH)-pyndon, og blandingen blev refluxet i 6 timer. Overskydende hexamethylsisilazan blev dernæst afdrevet, og den olieagtige remanens blev opløst i 50 ml dichlormethan. Til opløsningen tilsattes 35 1,00 g 2-acetoxytetrahydrofuran og 0,1 ml tm(IV)chlo-rid, og blandingen blev omrørt natten over ved stuetem- DK 174238 B1 45 peratur. Reaktionsblandingen blev neutraliseret med tnethylamin, og opløsningsmidlet blev afdrevet. Methanol tilsattes til remanensen, og blandingen blev omrørt ved stuetemperatur i 2 timer. Opløsningsmidlet blev af-5 drevet, og remanensen placeret på en silicagelkolonne og elueret med 2% methanol”chloroform til opnåelse af I, 07 g af titelforbindelsen med et udbytte på 73,5%.
Smp. 170-173°C 10 1H-NMR(DMSO-dg)6: II, 6 (IH, bs, OH) 7,59 (IH, s, Cg-H) 15 6,09-5,99 (IH, q, ^ ^ ) 5,76 (IH, s, C3-H) 20 ,0 .
4,39-3,73 (2H, m, X V ) 2,42-1,82 (4H, m, (°Y )
H
Referenceeksempel· 2
Fremstilling af 5-chlor-l-ethoxymethyl-4-hydroxy-2(IH)-30 pyndon.
Ved at følge den almene fremgangsmåde ifølge referenceeksempel 1 og anvendelse af chlormethylethyl-ether istedet for 2-acetoxytetrahydrofuran, fremstilledes 5-chlor-l-ethoxyrrethyl~4-hydroxy-2 (IH) -pyridon i et udbytte på 39%.
DK 174238 B1 46
Snp. 217-219°C 1H-NMR (DKSO-d _) 6 :
O
11,63 (IH, bs, OH) 5 7,87 (IH, s, Cg-H) 5,75 (IH, s, C3-H) 5,16 (2H, s, N-CH2-0-) 10 3,49 (2H, g, J = 7Hz, -OCH2 CH3) 1,09 (3H, t, J = 7Hz, -OCH2 CH_3)
Referenceeksempel 3 15 Fremstilling af 2-benzoyloxy-5-chlor-4-hydroxypyndm.
Titelforbindelsen blev fremstillet i et udbytte på 51% idet man fulgte den almene fremgangsmåde ifølge referenceeksempel 1 og anvendte benzoylchlond istedet for 2-acetoxytetrahydrofuran. Titelforbindelsen bliver 20 blød ved 184°C.
^H-NMR (DMSO-dg) 6 ϊ 8,27 (IH, s, Cg-H) 25 8.,16-8,07 (2H, m, ^J^-CO- > 7,78-7,51 (3H, m, ) 30 6,91 (IH, s, C3-H)
Referenceeksempel 4
Fremstilling af 4-hydroxy-l-{3-ph thal idyl) -2 (IH) -pyn-35 don.
10 ml hexamethyldisilazan tilsattes til 1,00 g 4-hydroxy-2-(IH)-pyndon, og blandingen blev refluxet i 6 timer. Reaktionsblandingen blev opkoncentreret under DK 174238 B1 47 reduceret tryk, og koncentratet blev opløst x 20 ml acetonxtril. Til denne opløsning tilsattes 2,29 g 3-bromphthalid, og blandingen blev omrørt natten over ved stuetemperatur. Methanol tilsattes til reaktions-5 blandingen, og den opnåede blanding blev omrørt ved stuetemperatur i 15 minutter. Reaktionsblandingen op-koncentreredes dernæst under reduceret tryk, og koncentratet førtes til en silicagelkolonne og blev elueret med 1% methanol-chloroform, til opnåelse af 0,62 g af 10 titelforbindelsen med et udbytte på 30%.
Smp. 239-241°C 1H“NMR(DMSO-dg)δ: 11,05 (IH, bs, OH)
yV
8,29-7,52 (5H, m, Γ|ΐ O ) 6,99 (IH, d, J = 8Hz, Cg-H) 5,88 (IH, dd, J3*5 = 2Hz, J5*g = 8Hz, C5-H) 5,65 (IH, d, J = 2Hz, C-j-H) 2g Referenceeksempel 5
Fremstilling af l-carbomethoxymethylcarbamoyl-4-hydroxy-2(lH)-pyridon.
2,49 g carbomethoxymethylisocyanat tilsattes til en suspension af 2,00 g 4-hydroxy-2(IH)-pyridon i 60 ml 30 dioxan, og blandingen blev omrørt ved 90°C i 30 minutter. Opløsningsmidlet blev afdrevet, og ether blev tilsat til remanensen. Det således dannede bundfald blev filtreret fra til opnåelse af 2,20 g af titelforbindelsen med et udbytte på 54%.
DK 174238 B1 48
Snip. 124 ^ 126 eC 1H-’NMR(DMSO-dc) 6 :
O
11,52 (IH, bs, OH) 5 10,82 (IH, t, J = 6Hz, ~CONHCH2-) 8,20 (IH, d, J = 8Hz, Cg-H) 6,17 (IH, dd, J5*6 = 8Hz, = 2Hz, Cg-H) 10 5,74 (IH, d, J = 2Hz, C-j-H) 4,15 (2H, d, J = 6Hz, -CONHCHj-) 3,68 (3H, s, -COOCH3) 15
Referenceeksempel 6
Fremstilling af l-benzoyloxymethyl-5-chlor-4-hydroxy-2 (IH) -pyndon.
Ved at følge den almene fremgangsmåde ifølge referenceeksempel 1 og anvendelse af benzyloxymethyl-20 chlond istedet for 2-acetoxytetrahydrofuranet og desuden at anvende acetonitnl som opløsningsmiddel istedet for dichlormethan fremstilledes titelforbindelsen med et udbytte på 57%.
Snp. 165-167°C 25 1H-NMR(DMSO—dc)fi:
O
11,65 (IH, bs, OH) 7,92 (IH, s, Cg-H) 30 7,31 (5H, s, phenyl-H) 5,77 (IH, s, C3-H) 5,27 (2H, s, -NCH20-) 35 4,55 (2H, s, -OCH2-^^> ) DK 174238 B1 49
Referenceeksempel 7
Fremstilling af 2,4-bis(trimethylsilyloxy)-5-chlor-pyridin.
50 ml hexamethyldisilazan tilsattes til 9,6 g 5 5-chlor-4~hydroxy-2 (IH) -pyndon, og blandingen blev omrørt natten over på et oliebad ved 140°C. Uopløseligt materiale blev fjernet ved filtrering, og filtratet blev destilleret under reduceret tryk til opnåelse af 14,4 g af titelforbindelsen, der kogte ved 120°C/7 mmHg.
10 Udbytte 75%.
Referenceeksempel 8
Fremstilling af 2-acetoxy-5-chlor-4~hydroxypyridm.
15 2,09 ml acetylbromid og 0,10 ml tin (IV)chlorid tilsattes til en opløsning af 5,00 g 2,4-bis(trimethylsi-lyloxy)-5-chlorpyridin i 250 ml tørt dichlormethan, og blandingen blev omrørt ved stuetemperatur i 3,5 timer. Reaktionsblandmgen blev neutraliseret med triethyl*· 20 amm, og opløsningsmidlet afdrevet. Remanensen anbragtes på en silicagelkolonne og blev elueret med 40% ethyl-acetat-benzen som eluenngsmiddel til opnåelse af 2,07 g af titelforbindelsen med et udbytte på 64%.
Smp. 270-272°C 25 1 H-NMR(DMSO-d-)6:
O
11,90 (IH, bs, OH) 8,20 (IH, s, C6-H) 30 6,69 (IH, s, C3-H) 2,27 (3H, s, COCH3) DK 174238 B1 50
Eksempel 1
Fremstilling af 3-[3-(1,2-dihydro-2-oxo-4-pyridyloxy-carbonyl)benzoyl]-5-fluor-l-{2-tetrahydrofuranyl)uracil 1,00 g isophthaloylchlorid og 0,70 ml tnethyl-5 amm sattes til en opløsning af 1,00 g 5-fluor-1-(2-tetrahydrofuranyl)uracil i 30 ml tørret dioxan. Blandingen blev refluxet i 2 timer. Der tilsattes 1,00 ml triethylamm, og blandingen blev refluxet i 2 timer.
Der tilsattes desuden 0,60 g 4-hydroxy-2(IH)-pyridon, 10 og blandingen blev refluxet i 3 timer. Opløsningsmidlet blev afdrevet og 30 ml ethylacetat og 30 ml vand blev tilsat til remanensen. Det uopløselige materiale blev fjernet ved filtrering. Ethylacetatfasen blev skilt fra, tørret over vandfrit natriumsulfat og opkoncentreret.
15 Koncentratet blev udsat for silicagelkolonnechromatogra-fi til udførelse af gradienteluenrø med anvendelse af chloroform og blandinger af methanol (indtil 2%) og chloroform. Fraktionerne svarende til titelforbindelsen blev opsamlet og opkoncentreret til opnåelse af 0,40 g 20 af et pulver i et udbytte på 18%.
1H-NMR(DMSO-dg)6: 11,74 (IH, bs, -NH-, forsvandt ved tilsætning af 02^ 8,63-8,41 (3H, m, ^2*4*6_Η i benzoylrinqen) 2 5 8,14 (IH, d# J - 7Hz, Cg-H) 7,84 (IH, t, J = 8Hz, C^-H i benzoylringen) 7,51 (IH, d, J = BHz, Cg-H i pyridinxxngen) 30 6,34-6,26 (2H, m, C3 ,,-H i pyridinrxngen) 5,93 (IH, t, J = 4Hz, Cx,-H) 4,41-4,20 og: 3,92-3,72 (hver IH, m, C4,-H) 2,27-1,92 (4H, m, C2,*3,-H) 35 DK 174238 B1 51
Eksempel 2
Fremstilling af 3-[4-(l,2-dihydro-2-oxo-4-pyridyloxy-carbonyl)benzoyl]-5-fluor-l-(2-tetrahydrofuranyl)uracil Titelforbindelsen blev fremstillet på samme måde 5 som i eksempel 1 .
1H-NMR (DMSO-dg) 4: 11,73 (IH, bs, -NH-, forsvandt ved tilsætning sf r2o) 8,28 (4H, s, phenyl-H) 10 8,14 (IH, d, J = 7Hz, Cg-H) 7,52 (IH, d, J = 8Hz, Cg-H i pyridmringen) 6,33-6,25 (2H, m, Cg g-H i pyridmringen) 5,92 (IH, bt, J = 4Hz, C.,-H) 15 4,49-4,26 og 4.03-3.77 ( hver IH, m, C^.-H)
Eksempel 3 20 Fremstilling af 3- (3- (2-benzoyloxy-5-chlor-4-pyndyloxy-carbonyl)benzoyl]-5-fluor-l-(2-tetrahydrofuranyl)uracil Titelforbindelsen blev fremstillet på samme måde som i eksempel 1.
25 1H-NMR(CDC13)6:
8,·69-8,L6 (6H, m, , CO—og Cg-H
-CO
i pyridmringen) 30 7,81-7,45 (5H, m, V^-CO- , CO—^ Cg-H) -co' DK 174238 B1 52 7,41 (IH, s, C^-H i pyridinringen) 6,00-5,90 (lm, Clt-H) 4,42-3,87 (2H, m, C4,-H) 5 2,55-1,89 (4H, m, C2I#3,-H)
Eksempel 4
Fremstilling af 3- [3-(4-benzoyloxy-5-chlor-2-pyndyloxy-10 carbonyl)benzoyl]-5-fluor-1-(2-tetrahydrofuranyl)uracil Titelforbindelsen blev fremstillet på samme måde som i eksempel 1.
1H-NMR(CDC13)6:
15 8,66-8,17 (6H, , CO-og Cg-H
i pyridinringen) 20 7,79-7,41 (5H, m, ^~CO- , og Cg-H)
-CO
7,38 (1H# s, C^-H i pyridinringen) 6,02-5,90 (lin, Clt-H) 25 4,45-3,87 (2H, m, C4,-H) 2,55-1,89 (4H, m, C2,#3,-H)
Eksempel 5 30 Fremstilling af 3-[2-(2-acetoxy-5-chlor-4-pyridyloxy-carbonyl)benzoyl]-5-fluor-1-(2-tetrahydrofuranyl)uracil 5,53 ml tnethylamm og 1,52 g lsophthaloylchlo-rid blev sat til en opløsning af 1,00 g 1-(2-tetrahydrofuranyl) -5-f luoruracil i 50 ml tørret dioxan. Blandingen 3 5 blev refluxet 1 time. Reaktionsblandmgen blev filtreret _______ . .. i DK 174238 B1 53 og filtratet blev opkoncentreret. Koncentratet blev opløst i 50 ml acetonitril. Til opløsningen sattes 3,46 ml tnethylamin og 1,40 g 2-acetoxy-5-chlor-4-hydroxypyri-dm. Blandingen omrørtes ved stuetemperatur i 2 timer.
5 Reaktionsblandingen blev filtreret og opkoncentreret. Koncentratet blev renset ved silicagelkolonnechromato-grafi med anvendelse af chloroform som eluenngsmiddel til opnåelse af 530 mg af titelforbindelsen i et udbytte på 20%.
10 i ^H-NMRtCDCl^6: 8,68-8,22 (3H, m, )
-CO
15 8,47 (IH, S, Cg-H x pyridinringen) 7,72 (IH, t, J = 8Hz, >
-CO
20 7,54 (IH, d, J = 6Hz, Cg-H) 7,27 (IH, s, C^-H i pyridinrnngen) 5,98-5,90 (lm, Cj.-H) 25 4,29-4,04 (2H, m, C^,-H) 2,35 (3H, s, C0CF3) 2,43-1,89 (4H, m, C2,*3,-H) DK 174238 B1 54
Eksempel 6
Fremstilling af 3-[3-(4-acetoxy-5-chlor-2-pyridyloxy-carbonyl)benzoyl]-5-fluor-1-(2-tetrahydrofuranyl)uracil Titelforbindelsen blev fremstillet på samme måde 5 som i eksempel 5.
^H-NMR(CDClg)δ: 8,65-8,19 (4H, m, -^^-co- og C6"H i pyridin- co 10 ringen) 7,70 (IH, t, J = 8Hz, (Q-CO- )
-CO
15 7,53 (IH, d, J = 6Hz, Cg-H) 7,18 (IH, s, C^-H x pyridrnringen) 6,02-5,90 (IH, ri, C^.-H) 20 4,45-3,87 (2H, m, C4,-H) 2,44-1,90 (7H, m, COCHj °9 Cj.^.-H)
Eksempel 7 25 Fremstilling af 5-fluor-3-[3-([2-(2-methylbenzoyloxy)-4-pyndyloxycarbonyl) benzoyl ] -1- (2-tetrahydrofuranyl) uracil Titelforbindelsen blev fremstillet på samme måde som i eksempel 5.
DK 174238 B1 55 1H-NMR (CDC13) 6: 8.67- 7,21 (12H, in, phenyl-H, i pyridmringen og C«'») 5 6,00-5,90 (IH, m, Clt-H) 4,40-3,90 (2H, ro, C4,-H) 2,69 <3H, s, CH3) 2,60-1,95 (4H, m, C2,-3,-H) 10
Eksempel 8
Fremstilling af 3-[3- (2-benzoyloxy-4~pyndyloxycarbonyl) -benzoyl]-5-fluor-l-(2-tetrahydrofuranyl)uracil
Titelforbindelsen blev fremstillet på samme måde 15 som i eksempel 5.
iH-NMR(CDCl3)6 : 8.67- 8,18 (6H, m, og 09 20
Cg-H i pyridmringen) 25 7,79-7,40 (5H, m, 05
CO
Cg-K) 7,34-7,23 (2H, m, C3 g-H i pyridinrmgen) 30 6,00-5,90 (lHf m, CJt-H) 4,45-3,87 (2H, m, C4,-H) 2,55-1,89 <4H, m, DK 174238 B1 56
Eksempel 9
Fremstilling af 3-(3(l-benzyloxymethyl-5-chlor-l,2-dihydro-2-oxo-4-pyridyloxycarbonyl)benzoyl]-5-fluor-1-(2-tetrahydrofuranyl)uracil 5 Titelforbindelsen blev fremstillet på samme måde som i eksempel 5.
1H-NMR(CDC13)5: 8,65-8,21 (3H, m, ) 10 co' 7,79-7,51 (3H, m, , Cg-H, og Cg-H i
CO
py ndinr ingen) 15 7,34 (5H, s, -CH2) 6.65 (IH, s, C^-H i pyridmrmgen) 5,98-5,91 (IH, m, Cj.-H) 20 5,42 (2H, s, NCH20-) 4.66 (2H, s, -0CH2-^ ) 25 4,27-3,85 (2H, m, C4,-H) 2,57-1,90 (4H, m, C2I#3,-») DK 174238 B1 57
Eksempel 10
Fremstilling af 3-[3-[5-chlor-l,2-dihydro-2-oxo-l-(2-tetrahydrofuranyl) -4-pyndyloxycarbonyl] benzoyl] -5-fluor-1-(2-tetrahydrofuranyl)uracil 5 Titelforbindelsen blev fremstillet på samme måde som i eksempel 5.
1H-NMR(CDC13)6: 8,92-8,20 (3H, m, -^3~co )
10 CO
7,79-7,54 (3H, m, / Cg-H og Cg-H i
CO
py ndinr ingen) 15 6,58 (IH, s, C3-H i pyndinnngen) 6,18-5,91 (2H, m, C^-H i furanylgruppen x 2) 4,33-3,87 (4H, m, Ο^,-Η χ furanylgruppen x 2) 20 2,67-1,78 (8H, m, Cji.3ι~H χ furanylgruppen x 2) x 2)
Eksempel n 25 Fremstilling af 5-fluor-3-[3-[4-(2-naphthoyloxy)-2- pyridyloxycarbonyl]benzoyl]-1-{2-tetrahydrofuranyl)-uracil
Titelforbindelsen blev fremstillet på samme måde som i eksempel 5, DK 174238 B1 58 1H-NMMCDC13)6: 8,75-7,20 (15H, m, naphthyl-H, phenyl-H, Η χ pyrid in ringen og Cg-B) 5.97- 5,90 (1E, ro, C1?-E) 4.52- 3,85 (2H, m, C4,-H) 2.52- 1,78 (4H, m, C2,#3,-H) 10
Eksempel 12
Fremstilling af 3-[3-[3-chlor-6-(4-fluorbenzoyloxy)-2-pyridyloxycarbonyl]benzoyl]-5-fluor-1-(2-tetra-hydrofuranyl)uracil 15 Titelforbindelsen blev fremstillet på samme måde som i eksempel 5.
1H-NMR(CDC13)6: 8,67-8,13 (5H, m, CO , -CO—^^-F ) 20 co 8,00 (IH, d, J = 8Hz, C^-H i pyridinringen) 7,70 (IH, t, J = 8Hz, ^^-CO )
-CO
7,54 (IH, d, J = 6Hz, Cg-H) 30 7,31-7,07 (3H, m, -CO-^^-F , Cg-H x pyridmnngen) 5.97- 5,89 (IH, m, C1,-H) 35 4>,34-3,84 (2H, m, C4',-H) 2,47-1,86 (4H, m, C2,-H, Cg.-H) DK 174238 B1 59
Eksempel 13
Fremstilling af 3-[3-(6-benzoyloxy-3-cyano-2-pyridyl-oxycarbonyl)benzoyl]-5-fluor-l-(2-tetrahydrofuranyl)-uracil 5 Titelforbindelsen blev fremstillet på samme måde som i eksempel 5.
1H-NMR(CDCl3)i: 8,69-8,12 (6H, in, co , -CO-og 10 CO ' C^-H i pyndinringen) 7,79-7,38 (6H, m, , Cg-H,
CO
Cg-H i pyndmringen) 5,96-5,87 UH, m, C^-H) 20 4,30-3,80 (2H, mr C4,-H) 2,50-1,85 (4H, m, C2,-H, C3,-H)
Eksempel 14
Fremstilling af 3- [-3-[3-cyano-6- (3,4,5-tnmethoxy-25 benzoy loxy) -2-pyndyloxycarbonyl] benzoyl] -5-f luor-1-(2-tetrahydrofuranyl)uracil
Titelforbindelsen blev fremstillet på samme måde som i eksempel 5.
30 1H-NWR(CDC13)6: 8,69-8,21 (4H, m, —, C^-H χ pyndin-
CO
ringen) 35 7,73 {1H# t, J - 8Hz, £^“co )
-CO
DK 174238 B1 60 7,54 (IH, d, J = 6Hz, Cg-H) ch3° 7,44 (2H, s, CH30 -Cv-00' ) ch3o 7,42 (IH, d, J = 8Hz, C^-H i pyridmrmgen)
CH O
5,97-5,90 (IH, m, C1(-H) -3 4,34-3,81 (11H, m, C4,-H og
Ch3° 2,50-1,87 (4H, m, C2,-H, C3,-H)
Eksempel 15 15 Fremstilling af 3-[3-[3-cyano-6-(2-furoyloxy)-2-pyndyl-oxycarbonyl]benzoyl]-5-fluor-l-(2-tetrahydrofuranyl)-uracil
Titelforbindelsen blev fremstillet på samme måde som i eksempel 5.
20 1 ^H-NMR(GDC13)δ: 8,68-8,20 (4H, m, —c0 · C4-H 1 pyridin-
CO
25 ringen) 7,81-7,40 (5H, m, ^^“c0 r Cg-H, C5_H 1 "co _s pyridinrmgen og IJ Jl^ ) 30 ^0 æ~ 6,61 (IH, dd, J = 2Hz, J = 4Hz, |j Π ) ^ co- 35 5,98-5,88 (IH, ιη,-Ο^-Η) 4,27-3,84 (2H, m, C4,-H) 2,36-1,86 (4H, m, Cj.-H, C3,-H) DK 174238 B1 61
Eksempel 16
Fremstilling af 3-[4-(6-benzoyloxy-3~cyano-2-pyridyl-oxycarbonyl)-3-furoyl]-5-fluor-l-(2-tetrahydrofuranyl)-uracil 5 Titelforbindelsen blev fremstillet på samme måde som i eksempel 5.
^-NMRCCDCl^ 6: 8,39 (28, s, Y _ ) 10 8,25-8,11 (3H, m, ^ - C^H x pyridmnnaen) 15 7,69-7,22 (5H, ir, -ø- CO f Cg-H oa Cg-H i 2o pyndinringen) 5,92-5,82 (IH, m, Cj.-H) 4,22-3,71 (2H, m, C4,-H) 2,33-1,68 (4H, m, C2,-H, C3;-H) 25
Eksempel 17
Fremstilling af 3-[3-[3-cyano-6-(2-thenoyloxy)-2-pyndyl-oxycarbonyl]benzoyl]-5-fluor-l-(2-tetrahydrofuranyl)uracil 30 Titelforbindelsen blev fremstillet på samme måde som i eksempel 5.
1H-NMR(CDCl3)fi: 8,66-8 j 18 (4H, m, co , C^-H i pyridin- DK 174238 B1 62 co 5 ringen) 8,03 (IH, dd, J = 1H2, J = 4Hz, J jj^ ) 10 7,81-7,64 (2H, m, ^jV-CO- og - Π jf ) -OΓ K s A co- 7,53 (IH, d, J = 6Hz, Cg-H) 7,44 (IH, d, J = 8Hz, C,--H i pyndinringen) 15 7,26-7,14 (IH, m, ^ jj^ ) 6,00-5,90 (IH, m, C,,-H) 20 ’ 1 4,28-3,87 (2H, m, C4,-H) 2,50-1,89 (4H, m, C2,-H, C3,-H)
Eksempel 18 25 Fremstilling af 3~[3-[3-cyano-6-(2,4-dichlorbenzoyloxy)-2-pyndyloxycarbonyl] benzoylI-5-f luor-1- (2-tetrahydro- furaryl)uraci]
Titelforbindelsen blev fremstillet nå samme måde som i eksempel 5.
1H-NMR(CDC13)δ: 8,67-8,21 (4H, in, CQ » i pyndmringen) DK 174238 B1 63 5 8,09 (IH, d, J « 9Hz, CO-^^-Cl ) 7,73 (IH, t, J - 8Hz, fe™ ,
-CO
7,57-7j33 (4H, m, Cg-H, Cg-H i pyndmringen 15 og CO—Cl ) 6,01-5,90 (IH, m, Οχι-Η) 4,35-3,82 (2H, m, C-.-H) 20 q 2,50-1,80 (4H, m, C2,-H, Cg.-B)
Eksempel 19
Fremstilling af 3-[5-(6 *benzoyloy.y-3-cyano-2-pyndyloxy-25 carbonyl)-3-nicotinoyl]-5-fluor-1-(2-tetrahydrofuranyl)-uracil
Titelforbindelsen blev fremstillet tå samme måde som i eksempel 5.
1H-NMR(CDC13) ¢: DK 174238 B1 64 Αγ<=ο- 9,57-8,84 (3H, m, JLJJ^ > 5 -OC n 8,27 {IH, d, J = 8Hz, ” Jjji > 8,25-8,12 (2H, mf -OC-^^ ) 7,70-7,42 (4H, m, Cg-H og -OC·-^— ) NC-^jAn 15 7,40 (IH, d, J = 8Hz, [|l^ ) 5,94-5,88 (IH, m, Οχι-Η) 4,34-3,71 (2H, in, C4,-H) 20 2,50-1,88 (4H, m, C3,-H)
Eksempel 20 25 Fremstilling af 3-[3-(l,-2-dihydro-2-oxo-6-pyndyloxy-carbonyl)benzoyl]-5-fluor-l-(2-tetrahydrofuranyl)uracil Isophthaloylchlorid (1,50 g) og 6,0 ml tnethyl-amm blev sat til en opløsning af 1,00 g 5-fluor-l-(2-tetrahydrofuranyl)uracil i 50 ml dioxan. Blandingen blev 30 refluxet i 1,5 timer. Det opnåede bundfald blev fjernet ved filtrering, og filtratet blev opkoncentreret. Til koncentratet sattes 50 ml methylenchlorid, og dertil sattes 10 ml af en opløsning af 1,50 g 2,6-bis (tnme-thylsilyloxy)pyridm i methylenchlorid. Man lod bian-35 tingen henstå ved stuetemperatur i 3 timer. Opløsnings- DK 174238 B1 65 midlet blev afdrevet, og remanensen blev udsat for sili-cagelkolonnechromatografi med anvendelse af 2% methanol-chloroform som eluermgsmiddel til opnåelse af 0,30 g af titelforbindelsen i et udbytte på 14%.
5 1H-NMR(CDCl3)i: 8,66-8,19 (3H, m, >
-CO
10 7,83-7,62 (2H, m, ^^-co- og C4-H x -oc pyndin ringen) 15 7,52 UH, d, J = 6Hz, Cg-H) 6,77 og 6,68 ( hver IH, d, J = 8Hz, i pyndinnngen) 20 5,99-5,92 (IH, zn, C^.-H) 4,30-3,88 (2H, m, C4,-H) 2,44-1,89 (4H, m, C2,«3,-H)
25 Farmakologisk test I
(a) Sarcoma-180, der var dyrket i en ICR-muse ascites, blev fortyndet med en fysiologisk saltopløsning og transplanteret subcutant ind i rygqen af η ICP mus i en mængde på 2 x 10 i hver. Fra 24 timer 30 efter transplanteringen blev en testforbindelse suspenderet i en 5%1 s opløsning af oummiarabicum indaivet oralt i hver mus en gang dagligt i de 7 efterfølgende dage.
DK 174238 B1 66
Den faste tumor blev fjernet fra stedet under huden på musens ryg på den tiende dag efter transplanteringen til måling af tumorens vægt. Forholdet (T/C) mellem vægten af tumor (T), skåret ud fra gruppen af mus 5 behandlet med testforbmdelse^ og vægten af tumor (C) fra gruppen af mus, der ikke var behandlet dermed, blev bestemt. Dosen, der oav 50%'s tumonnhibering (EDt-g-værdien) ved hvilken τ/C er 0,5, blev bestemt fra dosis-responskurven for dosis og forholdet (T/C).
10 Resultaterne er vist i tabel 1.
I tabel 1 nedenfor er resultaterne anqivet sammen med værdien opnået ved anvendelse af et anticancer-præparat indeholdende 5-fluor-1-(2-tetrahydrofuranyl)-uracil og uracil i et vægtforhold fra 1 til 4 som kon-15 trol.
Tabel 1
Testforbindelse ED^q (m9/^g)
Forbindelse ifølge eksempel 1 10 20 Forbindelse ifølge eksempel 3 25
Forbindelse .ifølge eksempel 4 18
Forbindelse ifølge eksempel 10 28
Forbindelse ifølge eksempel 15 18
Kontrol 30 25
Præparateksempel 1
Forbindelse ifølge eksempel 2 0,25 mg
Stivelse 130 mg 30 Magnesiumstearat 20 mg
Lactose 50 mg
Totalt Ca. 200 mg
Der fremstilledes tabletter, som hver havde den ovennævnte sammensætning, på sædvanlig måde.
DK 174238 B1 67
Præparateksempel 2
Forbindelse ifølge eksempel 1 12,5 mg
Polyethylenglycol (molekylvægt: 4000) 0,3 g ^ Natnumchlond 0,9 g
Polyoxyethylen-sorbitan-monooleat 0,4 g
Natriummethabisulfit 0,1 g
Methylparaben 0,18 g
Propylparaben 0,02 g
Destilleret vand til injektion 100 ml
Parabenerne, natriummethabisulfitet og natnum-chlondet blev opløst i det destillerede vand under omrøring ved 80°C. Den opnåede opløsning blev afkølet til 40°C. Forbindelsen ifølge opfindelsen, polyethylengly-colen og polyoxyethylen-sorbitan-monooleatet blev op-15 løst i opløsningen i den nævnte rækkefølge. Til opløsningen sattes destilleret vand til justering af mængden til den ønskede værdi. Blandingen blev dernæst ledet gennem filterpapir til sterilisation og placeret i ampuller i en mængde på 1 ml pr. ampul til opnåelse 20 af et injektionspræparat.
Claims (16)
1 Forbindelse, kendetegnet ved, at den har formlen 5 0 0 II II Rx-0-C-Y-C-a (lb) hvori R'* er en pyridylgruppe, eventuelt med 1 til 4 10 substituenter valgt blandt hydroxygrupper, oxogrupper, halogenatomer, ammo-, carboxy-, cyano-, nitro-, carbamoyl-, lavere alkylcarbamoyl- og carboxy-lavere alkylcarbamoylgrupper, phenyl-carbamoyl, eventuelt substitueret med 1 til 3 substituenter valgt blandt 15 halogenatomer, lavere alkoxy- og lavere alkylgrupper på phenylnngen, lavere alkoxycarbonyl-lavere alkylcarba-moyl-, lavere alkyl-, lavere alkenyl-, lavere alkoxycarbonyl-, tetrahydrofuranyl-, tetrahydropyranyl-, lavere alkoxy-lavere alkyl-, lavere alkylthio-lavere 20 alkyl-, phenyl-lavere alkoxy-lavere alkyl-, phthalidyl-og acyloxygrupper, hvori acylet af acyloxygruppen er udvalgt fra gruppen bestående af (i) alkanoylgrupper eventuelt substitueret med substituenterne udvalgt fra gruppen 25 bestående af halogenatom, hydroxygruppe, lavere alkoxygruppe, aryloxygruppe, aryl-grupper eventuelt substitueret med 1 til 3 substituenter udvalgt fra gruppen bestående af halogenatom, lavere alkylgruppe, lavere 30 alkoxygruppe, carboxygruppe, lavere alkoxy- carbonylgruppe, nitrogruppe og cyanogruppe på arylrmgen, phenyl-lavere alkoxycarbonyl-gruppe og lavere alkylcarbamoylgruppe, (n) arylcarbonylgrupper eventuelt substitueret 35 med lavere alkylendioxygrupper eller med 1 DK 174238 B1 til 3 substituenter udvalgt fra gruppen bestående af halogenatom, lavere alkylgrup-pe, lavere alkoxygruppe, carboxygruppe, lavere alkoxycarbonylgruppe, nitrogruppe, 5 cyanogruppe, phenyl-lavere alkoxycarbonyl gruppe, hydroxygruppe, guanidylgruppe, phenyl -lavere alkoxygruppe, aminogruppe og aminogruppe substitueret med lavere alkyl-gruppe, 10 (m) thienylcarbonyl, furanylcarbonyl, thiazolyl- carbonyl, quinolylcarbonyl, pyrazinylcarbo-nyl eller pyndylcarbonyl, (iv) kulsyreestergrupper såsom aryloxycarbonyl-grupper, forgrenede eller ligekædede eller 15 cykliske alkoxycarbonylgrupper, (v) substituerede eller ikke substituerede cyc-loalkylcarbonylgrupper, (vi) lavere alkenyl (eller lavere alkynyl)carbo-nylgrupper, og 20 (vn) lavere alkenyl (eller lavere alkynyl)oxycar- bonylgrupper, Y er udvalgt fra gruppen bestående af phenylengruppe, naphthylengruppe, pyndmdiylgruppe, pyrazindiylgruppe, furandiylgruppe og 4-pyridon-1-lavere alkyl-diylgruppe, 25 og a er en kendt 5-fluoruracil-afledt gruppe, som er bundet ved hjælp af en ester- eller amidbinding til den carbonylgruppe, hvortil denne substituent ot er knyttet, og som er valgt blandt 30 (i) en gruppe dannet ud fra et 5-fluoruracilderivat med formlen DK 174238 B1 O I I
5 I β hvori β betegner et hydrogenatom, tetrahydrofuranyl, lavere alkylcarbamoyl, phthalidyl, lavere alkoxy-lavere alkyl eller lavere aIkanoyloxy-lavere alkoxycarbonyl, 10 og (n) en gruppe dannet ud fra et 5-fluoruracilderivat med formlen 0 ,F 15 οΚΛτ* (1'1c) « V'A g 0 JV hvori R betegner en lavere alkoxycarbonylgruppe, 20. betegner en lavere alkoxygruppe eller gruppen
25. Forbindelse ifølge krav 1, kendeteg net ved, at acylet i acyloxygruppen som substituen-ten i den af Rx repræsenterede pyndylgruppe er valgt blandt arylcarbonylgrupper, der eventuelt er substitueret med lavere alkylendioxygrupper eller med 1 til 3 30 substituenter valgt blandt halogenatomer, lavere alkyl-, lavere alkoxy-, carboxyl-, lavere alkoxycarbonyl-, nitro-, cyano-, phenyl-lavere alkoxycarbonyl-, hydroxy-, guanidyl-, phenyl-lavere alkoxy- og amino-grupper og ammogrupper substitueret med lavere alkyl-35 grupper DK 174238 B1
3 Forbindelse ifølge krav 2, kendetegnet ved, at gruppen 0 0 5. il li RX«O-C-Y-C- er en gruppe med formlen 10 L li (Y-a) / K \ v5 Exl \Rx5 y 1 15 hvori R er hydroxy eller acyloxy, hvor acylet i y2 y/ acyloxy er som defineret i krav 1, R og R er hver hydrogen, halogen, amino, carboxy, carbamoyl, cyano, nitro, lavere alkyl, lavere alkenyl eller lavere y "3 y C alkoxycarbonyl, R og R er hver hydrogen, hydroxy 20 eller acyloxy, hvor acylet i acyloxy er som defineret i krav 1, når mindst en af R5^, Rx^ og Rx^ er frit hydroxy, kan strukturen af 1-stillmgen i pyndinnngen være H som følge af keto-enol tautomensmen, hvor det til 30 nitrogenet knyttede hydrogen eventuelt er substitueret med en substituent valgt blandt lavere alkyl, tetrahy-drofuranyl, tetrahydropyranyl, lavere alkoxy-lavere alkyl, phthalidyl, carbamoyl, lavere alkoxycarbonyl -lavere alkylcarbamoyl, phenyl-lavere alkoxy-lavere 35 alkyl, phenyl carbamoyl, der kan have 1 til 3 substitu- DK 174238 B1 enter valgt blandt halogen, lavere alkoxy og lavere alkyl på phenylnngen, lavere alkylcarbamoyl, carboxy-lavere alkylcarbamoyl, lavere alkylthio-lavere alkyl og vi x3 lavere alkenyl, forudsat at mindst en af R , R og Y C 5. betegner en hydroxygruppe, og at hydrogenet i en af hydroxygrupperne betegnet Rxl, Rx3 og Rx5 er substitueret med en gruppe
0 O 10. ii II -C-Y-C- hvon Y er som defineret ovenfor
4 Forbindelse ifølge krav 3, kendeteg- 15. e t ved, at a er en gruppe dannet ud fra et 5- fluoruracilderivat med formlen 0 i I (1"la) 20 o'S.^ β hvori S betegner et hydrogenatom, tetrahydrofuranyl, lavere alkylcarbamoyl, phthalidyl, lavere alkoxy-lavere 25 alkyl eller lavere alkanoyloxy-lavere alkoxycarbonyl.
5 Forbindelse ifølge krav 3, kendeteg net ved, at a er en gruppe dannet ud fra et 5-fluor-uracildenvat med formlen okArK H \r7'A 35 DK 174238 B1 hvori R6 A betegner en lavere alkoxycarbonylgruppe, 7' A R betegner en lavere alkoxygruppe eller gruppen
6 Forbindelse ifølge ethvert af kravene 4 og 5, kendetegnet ved, at gruppen
10. O II II RX-0-C-Y-C- er en gruppe med formlen 15 R*3 T jj (Y-a) y 1 \ χ5
20 RX1 XRX3 γΐ hvori R er hydroxy eller acyloxy, hvor acylet i Y O y Λ acyloxy er som defineret i krav 1, R og R er hver hydrogen, halogen, amino, carboxy, carbamoyl, cyano, 25 nitro, lavere alkyl, lavere alkenyl eller lavere alkoxycarbonyl, R og R er hver hydrogen, hydroxy eller acyloxy, under den forudsætning, at mindst en af Rxl, Rx3 og Rx5 betegner en hydroxygruppe, og at hydrogenet i en af hydroxygrupperne betegnet Rxl, Rx3 yC 30 eller R er substitueret med gruppen O O II II -C-Y-C- 35 DK 174238 B1 hvori Y er som defineret ovenfor
7 Forbindelse ifølge krav 6, kendeteg- x 1 net ved, at R er hydroxy, benzoyloxy, C,-Cg alka- y O noyloxy eller furoyloxy, R er et hydrogenatom, en af 5. og R^ er et hydrogenatom og den anden af R og R er hydroxy, benzoyloxy, C,-Cg-alkanoyloxy eller furoyloxy, og R er en cyanogruppe eller et halogen- xl x3 atom, under den forudsætning, at mindst en af R , R X5 og R er hydroxy, og at hydrogenet i den ene hydroxy-10 gruppe betegnet Rxl, Rx3 eller RxS er substitueret med gruppen O O Il II
15 -C-Y-C- hvori Y er som defineret ovenfor
8 Forbindelse ifølge krav 1, kendetegnet ved, at den er valgt blandt 3- [3- (6-benzoyloxy- 20 3-cyano-2-pyndyloxycarbonyl)benzoyl] -1- (2-tetrahydro-furanyl)-5-fluoruracil, 3-[3-(4-benzoyloxy-5-chlor~2- pyridyloxycarbonyl)benzoyl] -1- (2-tetrahydrofuranyl) -5-fluoruracil,3- [3- (6-furoyloxy-3-cyano-2-pyridyloxycar-bonyl) benzoyl] -1- (2-tetrahydrofuranyl) -5-fluoruracil, 25 3- [4- (6-furoyloxy-3-cyano-2-pyridyloxycarbonyl) -3-furoyl] -1- (2-tetrahydrofuranyl) - 5-fluoruracil, 3- [4-(6-acetyloxy-3-cyano-2-pyridyloxycarbonyl) -3-furoyl] -1-(2-tetrahydrofuranyl)-5-fluoruracil og 3-{3-[5-chlor- 1,2-dihydro-2-oxo-l- (2-tetrahydrofuranyl) -4-pyridyloxy-30 carbonyl] benzoyl}-1- (2-tetrahydrofuranyl) -5-fluorura-cil
9 Fremgangsmåde til fremstilling af en forbindelse som angivet i krav l, nemlig en forbindelse med formlen 35 DK 174238 B1 O O II II Rx-0-C-Y-C-a (lb) 5 hvori RX,,Y og a er som defineret i krav 1, kende -tegnet ved, at man a) omsætter en forbindelse med formlen O O 10. ii « X-C-Y-C-a (34) hvori X er et halogenatom, og Y og a er som defineret ovenfor, med en forbindelse med formlen 15 Rx-0-R® (26) Y ΰ hvori R er som defineret ovenfor, og R er hydrogen eller en tri(lavere alkyl)silylgruppe, eller b) omsætter en forbindelse med formlen
20. O II II RX-0-C-Y-C-X (22) '·'· hvori Rx og Y er som defineret ovenfor, og X er et 25 halogenatom, med en forbindelse med formlen «Η (36) hvori ot er som defineret ovenfor.
10 Forbindelse med formlen (lb) ifølge krav 1 til anvendelse til behandling af cancer. 30 11 Farmaceutisk præparat, kendetegnet ved, at det omfatter en forbindelse med formlen (lb) ifølge krav 1 og en farmaceutisk acceptabel bærer.
Applications Claiming Priority (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP22993884 | 1984-10-30 | ||
JP59229938A JPS61106593A (ja) | 1984-10-30 | 1984-10-30 | 2′−デオキシ−5−フルオロウリジン誘導体 |
JP25458784 | 1984-11-30 | ||
JP25458784 | 1984-11-30 | ||
JP719085 | 1985-01-17 | ||
JP719085 | 1985-01-17 | ||
JP5978885 | 1985-03-25 | ||
JP5978885 | 1985-03-25 | ||
JP9829585 | 1985-05-09 | ||
JP9829585 | 1985-05-09 | ||
JP19258285 | 1985-08-30 | ||
JP19258285 | 1985-08-30 | ||
JP19522385 | 1985-09-03 | ||
JP19522385 | 1985-09-03 |
Publications (3)
Publication Number | Publication Date |
---|---|
DK496785D0 DK496785D0 (da) | 1985-10-29 |
DK496785A DK496785A (da) | 1986-05-01 |
DK174238B1 true DK174238B1 (da) | 2002-10-07 |
Family
ID=27563394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK198504967A DK174238B1 (da) | 1984-10-30 | 1985-10-29 | 5-Fluoruracilderivater, deres fremstilling og lægemidler indeholdende sådanne forbindelser |
Country Status (5)
Country | Link |
---|---|
EP (3) | EP0436902B1 (da) |
KR (1) | KR920006824B1 (da) |
DE (3) | DE3588036T2 (da) |
DK (1) | DK174238B1 (da) |
HK (1) | HK1003112A1 (da) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4864021A (en) * | 1984-10-30 | 1989-09-05 | Otsuka Pharmaceutical Co., Ltd. | 5-fluorouracil derivatives |
DK169520B1 (da) * | 1986-07-25 | 1994-11-21 | Otsuka Pharma Co Ltd | 5-fluoruracilderivater, fremgangsmåde til deres fremstilling, anticancerpræparat indeholdende et sådant derivat og anvendelse af et sådant derivat til fremstilling af et præparat til behandling af cancer |
AU610913B2 (en) * | 1987-07-31 | 1991-05-30 | Taiho Pharmaceutical Co., Ltd. | 2'-deoxy-5-fluorouridine derivatives |
KR920002143B1 (ko) * | 1988-07-11 | 1992-03-12 | 다이호 야꾸힝고오교 가부시끼가이샤 | 5-치환 우리딘 유도체 및 그의 제조 중간체 |
NL194430C (nl) | 1989-01-05 | 2002-04-04 | Otsuka Pharma Co Ltd | Niet-injecteerbaar farmaceutisch preparaat met anti-kankerwerking. |
US5166327A (en) * | 1990-07-31 | 1992-11-24 | Yuki Gosei Kogyo Co., Ltd. | Process for producing 3'-deoxy-3-'-fluorothymidine |
GB9322795D0 (en) * | 1993-11-05 | 1993-12-22 | Wellcome Found | Novel compounds |
DK2495243T3 (da) * | 2009-10-27 | 2017-03-27 | Delta-Fly Pharma Inc | Nye 5-fluorouracilderivater |
AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5924999B2 (ja) * | 1978-06-10 | 1984-06-13 | 富山化学工業株式会社 | 新規な5−フルオロ−2′−デオキシ−β−ウリジン誘導体の製造法 |
JPS5535057A (en) * | 1978-09-05 | 1980-03-11 | Funai Corp | 2'-deoxy-5-fluorouridine derivative, its preparation, and antitumor agent comprising it |
US4340728A (en) * | 1979-11-28 | 1982-07-20 | Fuji Kagaku Kogyo Kabushiki Kaisha | Nucleoside derivatives and process for preparing same |
GB2072164B (en) * | 1980-02-15 | 1983-12-21 | Funai Pharmaceutical Ind Ltd | 2'-deoxy-3',5'-di-o-alkylcarbonyl-5-fluorouridine derivatives a process for the preparation of the derivatives and antitumor agents containing the derivatives |
GB2117766B (en) * | 1982-03-24 | 1985-08-29 | Nat Res Dev | Pharmaceutical compositions |
JPS5929699A (ja) * | 1982-08-11 | 1984-02-16 | Funai Corp | 2′−デオキシ−5−フルオロウリジンのエ−テル誘導体およびその製造方法並びにこれを含有する抗腫瘍剤 |
AU548712B2 (en) * | 1983-05-23 | 1986-01-02 | Taiho Pharmaceutical Co., Ltd. | 2:-deoxy-5-substituted uridine derivatives |
-
1985
- 1985-10-29 EP EP90124970A patent/EP0436902B1/en not_active Expired - Lifetime
- 1985-10-29 DE DE3588036T patent/DE3588036T2/de not_active Expired - Lifetime
- 1985-10-29 DE DE3588103T patent/DE3588103T2/de not_active Expired - Lifetime
- 1985-10-29 DK DK198504967A patent/DK174238B1/da not_active IP Right Cessation
- 1985-10-29 DE DE8585113724T patent/DE3583726D1/de not_active Expired - Lifetime
- 1985-10-29 EP EP89102313A patent/EP0323441B1/en not_active Expired - Lifetime
- 1985-10-29 EP EP85113724A patent/EP0180897B1/en not_active Expired - Lifetime
- 1985-10-30 KR KR1019850008045A patent/KR920006824B1/ko not_active IP Right Cessation
-
1998
- 1998-03-16 HK HK98102172A patent/HK1003112A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
EP0323441A3 (en) | 1990-08-16 |
KR860003242A (ko) | 1986-05-21 |
DE3588103D1 (de) | 1996-05-30 |
EP0323441A2 (en) | 1989-07-05 |
EP0436902B1 (en) | 1995-06-28 |
DK496785A (da) | 1986-05-01 |
DE3588103T2 (de) | 1996-10-17 |
DE3583726D1 (de) | 1991-09-12 |
EP0436902A1 (en) | 1991-07-17 |
EP0180897A3 (en) | 1987-08-19 |
HK1003112A1 (en) | 1998-10-09 |
DE3588036D1 (de) | 1995-08-03 |
EP0323441B1 (en) | 1996-04-24 |
DE3588036T2 (de) | 1995-11-16 |
EP0180897B1 (en) | 1991-08-07 |
DK496785D0 (da) | 1985-10-29 |
KR920006824B1 (ko) | 1992-08-20 |
EP0180897A2 (en) | 1986-05-14 |
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Legal Events
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B1 | Patent granted (law 1993) | ||
PUP | Patent expired |