NO161493B - Analogifremgangsmaate ved fremstilling av terapeutisk aktive 1,6-nafthyridinderivater. - Google Patents
Analogifremgangsmaate ved fremstilling av terapeutisk aktive 1,6-nafthyridinderivater. Download PDFInfo
- Publication number
- NO161493B NO161493B NO853329A NO853329A NO161493B NO 161493 B NO161493 B NO 161493B NO 853329 A NO853329 A NO 853329A NO 853329 A NO853329 A NO 853329A NO 161493 B NO161493 B NO 161493B
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- carbon atoms
- dihydro
- naphthyridine
- general formula
- Prior art date
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- VSOSXKMEQPYESP-UHFFFAOYSA-N 1,6-naphthyridine Chemical class C1=CN=CC2=CC=CN=C21 VSOSXKMEQPYESP-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 title claims description 11
- 238000002360 preparation method Methods 0.000 title claims description 3
- -1 alkyl radical Chemical class 0.000 claims abstract description 45
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims abstract description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000001301 oxygen Substances 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- ZQKMVHXJWJNEQG-UHFFFAOYSA-N 1h-1,6-naphthyridin-2-one Chemical class C1=NC=CC2=NC(O)=CC=C21 ZQKMVHXJWJNEQG-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- QGMYIPJEQYWPSE-UHFFFAOYSA-N ethyl 2-methyl-5-propan-2-yloxy-4-[2-(trifluoromethyl)phenyl]-3,4-dihydro-1H-1,6-naphthyridine-2-carboxylate Chemical compound C(C)OC(=O)C1(NC2=CC=NC(=C2C(C1)C1=C(C=CC=C1)C(F)(F)F)OC(C)C)C QGMYIPJEQYWPSE-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 150000003254 radicals Chemical class 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000004950 trifluoroalkyl group Chemical group 0.000 claims description 2
- 210000004204 blood vessel Anatomy 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 239000005864 Sulphur Substances 0.000 abstract 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract 1
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- 229910052757 nitrogen Inorganic materials 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
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- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 5
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 230000008602 contraction Effects 0.000 description 5
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- 230000008025 crystallization Effects 0.000 description 5
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KVPKWOWFDGOPOB-UHFFFAOYSA-N benzyl 2-methyl-5-propan-2-yloxy-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound C1=2C(OC(C)C)=NC=CC=2NC(C)=C(C(=O)OCC=2C=CC=CC=2)C1C1=CC=CC=C1C(F)(F)F KVPKWOWFDGOPOB-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 3
- 229960004166 diltiazem Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000028161 membrane depolarization Effects 0.000 description 3
- 229960001597 nifedipine Drugs 0.000 description 3
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
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- 210000003540 papillary muscle Anatomy 0.000 description 3
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- 125000001424 substituent group Chemical group 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- ZEZJPIDPVXJEME-UHFFFAOYSA-N 2,4-Dihydroxypyridine Chemical compound OC=1C=CNC(=O)C=1 ZEZJPIDPVXJEME-UHFFFAOYSA-N 0.000 description 2
- HOVXHSHAXPTANC-UHFFFAOYSA-N 2-methyl-5-propan-2-yloxy-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Chemical compound C1=2C(OC(C)C)=NC=CC=2NC(C)=C(C(O)=O)C1C1=CC=CC=C1C(F)(F)F HOVXHSHAXPTANC-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000700198 Cavia Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
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- 230000029936 alkylation Effects 0.000 description 2
- ACZJZGLXRPZSLI-UHFFFAOYSA-N diethyl 2,6-dimethyl-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1C(F)(F)F ACZJZGLXRPZSLI-UHFFFAOYSA-N 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- HUQQGWQOVHUQMX-UHFFFAOYSA-N ethyl 2-methyl-5-oxo-4-[2-(trifluoromethyl)phenyl]-4,6-dihydro-1h-1,6-naphthyridine-3-carboxylate Chemical compound CCOC(=O)C1=C(C)NC=2C=CNC(=O)C=2C1C1=CC=CC=C1C(F)(F)F HUQQGWQOVHUQMX-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 230000000297 inotrophic effect Effects 0.000 description 2
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 2
- FABRLWWYXLJYPC-UHFFFAOYSA-N methyl 2-methyl-5-oxo-4-phenyl-4,6-dihydro-1h-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(C)NC=2C=CNC(=O)C=2C1C1=CC=CC=C1 FABRLWWYXLJYPC-UHFFFAOYSA-N 0.000 description 2
- IKSXWGZRDWATLC-UHFFFAOYSA-N methyl 4-(2-fluorophenyl)-2-methyl-5-oxo-4,6-dihydro-1h-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(C)NC=2C=CNC(=O)C=2C1C1=CC=CC=C1F IKSXWGZRDWATLC-UHFFFAOYSA-N 0.000 description 2
- CUIWILCDCJQRSV-UHFFFAOYSA-N methyl 4-(2-fluorophenyl)-2-methyl-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)F)OC(C)C)C CUIWILCDCJQRSV-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- HJPRDQORMYXGNT-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methyl-5-propan-2-yloxy-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound CN(CCOC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)C(F)(F)F)OC(C)C)C)C HJPRDQORMYXGNT-UHFFFAOYSA-N 0.000 description 1
- ZDVRPKUWYQVVDX-UHFFFAOYSA-N 2-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=CC=C1C=O ZDVRPKUWYQVVDX-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- HCKWJKWXDJQZPG-UHFFFAOYSA-N 2-methylpropyl 2-methyl-5-propan-2-yloxy-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound C(C(C)C)OC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)C(F)(F)F)OC(C)C)C HCKWJKWXDJQZPG-UHFFFAOYSA-N 0.000 description 1
- XETVXLXTDFVQLH-UHFFFAOYSA-N 2-methylsulfanylethyl 2-methyl-4-(3-nitrophenyl)-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound CSCCOC(=O)C1=C(NC2=CC=NC(=C2C1C1=CC(=CC=C1)[N+](=O)[O-])OC(C)C)C XETVXLXTDFVQLH-UHFFFAOYSA-N 0.000 description 1
- ZSXSEOURRIMBLA-UHFFFAOYSA-N 3-(dimethylamino)propyl 2-methyl-4-(3-nitrophenyl)-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound CN(CCCOC(=O)C1=C(NC2=CC=NC(=C2C1C1=CC(=CC=C1)[N+](=O)[O-])OC(C)C)C)C ZSXSEOURRIMBLA-UHFFFAOYSA-N 0.000 description 1
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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- AVSRSZCPQDWEEU-UHFFFAOYSA-N ethyl 2-methyl-4-(2-methylphenyl)-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound C(C)OC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)C)OC(C)C)C AVSRSZCPQDWEEU-UHFFFAOYSA-N 0.000 description 1
- MXEAMWZLFSOMFP-UHFFFAOYSA-N ethyl 2-methyl-5-(2-methylpropoxy)-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound C(C)OC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)C(F)(F)F)OCC(C)C)C MXEAMWZLFSOMFP-UHFFFAOYSA-N 0.000 description 1
- BMWIWSPMAOLLQZ-UHFFFAOYSA-N ethyl 2-methyl-5-propan-2-yloxy-4-thiophen-2-yl-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound CCOC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1cccs1 BMWIWSPMAOLLQZ-UHFFFAOYSA-N 0.000 description 1
- MQBRVNPLIQTRDE-UHFFFAOYSA-N ethyl 4-(2,3-dichlorophenyl)-2-methyl-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound C(C)OC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C(=CC=C1)Cl)Cl)OC(C)C)C MQBRVNPLIQTRDE-UHFFFAOYSA-N 0.000 description 1
- VCCOEMCFIYFRPA-UHFFFAOYSA-N ethyl 4-(2-chlorophenyl)-5-methoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound C(C)OC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)Cl)OC)C VCCOEMCFIYFRPA-UHFFFAOYSA-N 0.000 description 1
- YMADKVDPPPEXHH-UHFFFAOYSA-N ethyl 4-(2-cyanophenyl)-2-methyl-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound CCOC(=O)C1=C(C)NC2=CC=NC(OC(C)C)=C2C1C1=CC=CC=C1C#N YMADKVDPPPEXHH-UHFFFAOYSA-N 0.000 description 1
- CAVVBKNLBLFAFO-UHFFFAOYSA-N ethyl 5-butoxy-2-methyl-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound C(C)OC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)C(F)(F)F)OCCCC)C CAVVBKNLBLFAFO-UHFFFAOYSA-N 0.000 description 1
- CKLPUQLPXQOAJX-UHFFFAOYSA-N ethyl 5-methoxy-2-methyl-4-(3-nitrophenyl)-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound C(C)OC(=O)C1=C(NC2=CC=NC(=C2C1C1=CC(=CC=C1)[N+](=O)[O-])OC)C CKLPUQLPXQOAJX-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- HUKPMUKCYXQYNF-UHFFFAOYSA-N methyl 2-methyl-4-(2-nitrophenyl)-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)[N+](=O)[O-])OC(C)C)C HUKPMUKCYXQYNF-UHFFFAOYSA-N 0.000 description 1
- XNNDQMXXPKMBGV-UHFFFAOYSA-N methyl 2-methyl-4-(3-nitrophenyl)-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(NC2=CC=NC(=C2C1C1=CC(=CC=C1)[N+](=O)[O-])OC(C)C)C XNNDQMXXPKMBGV-UHFFFAOYSA-N 0.000 description 1
- FLCZQWGPAKTSIT-UHFFFAOYSA-N methyl 2-methyl-4-phenyl-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(C)NC2=CC=NC(OC(C)C)=C2C1C1=CC=CC=C1 FLCZQWGPAKTSIT-UHFFFAOYSA-N 0.000 description 1
- CINNTLODRMZKKS-UHFFFAOYSA-N methyl 4-(2-bromophenyl)-2-methyl-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)Br)OC(C)C)C CINNTLODRMZKKS-UHFFFAOYSA-N 0.000 description 1
- CBQHZXCQFINDTR-UHFFFAOYSA-N methyl 4-(2-bromophenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound BrC1=C(C=CC=C1)C1C(=C(NC2=CC=NC(=C12)OCC)C)C(=O)OC CBQHZXCQFINDTR-UHFFFAOYSA-N 0.000 description 1
- HOSCHJTVYALXHU-UHFFFAOYSA-N methyl 4-(2-bromophenyl)-5-methoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)Br)OC)C HOSCHJTVYALXHU-UHFFFAOYSA-N 0.000 description 1
- LTAGJUFCZXKBGK-UHFFFAOYSA-N methyl 4-(2-chloro-6-fluorophenyl)-2-methyl-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1F)Cl)OC(C)C)C LTAGJUFCZXKBGK-UHFFFAOYSA-N 0.000 description 1
- FMFXXNLKXNZQMM-UHFFFAOYSA-N methyl 4-(3-chloro-2-fluorophenyl)-2-methyl-5-propan-2-yloxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C(=CC=C1)Cl)F)OC(C)C)C FMFXXNLKXNZQMM-UHFFFAOYSA-N 0.000 description 1
- KGJJDIFEODINJP-UHFFFAOYSA-N methyl 4-(3-chloro-2-fluorophenyl)-5-methoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound COC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C(=CC=C1)Cl)F)OC)C KGJJDIFEODINJP-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- MWXFBQMLEBUEQN-UHFFFAOYSA-N propan-2-yl 2-methyl-5-propan-2-yloxy-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-1,6-naphthyridine-3-carboxylate Chemical compound C(C)(C)OC(=O)C1=C(NC2=CC=NC(=C2C1C1=C(C=CC=C1)C(F)(F)F)OC(C)C)C MWXFBQMLEBUEQN-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 230000005477 standard model Effects 0.000 description 1
- 230000002966 stenotic effect Effects 0.000 description 1
- DWCSXQCXXITVKE-UHFFFAOYSA-N triethyloxidanium Chemical class CC[O+](CC)CC DWCSXQCXXITVKE-UHFFFAOYSA-N 0.000 description 1
- QDNCLIPKBNMUPP-UHFFFAOYSA-N trimethyloxidanium Chemical group C[O+](C)C QDNCLIPKBNMUPP-UHFFFAOYSA-N 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
- C07D213/78—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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Liquid Crystal Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse angår en analogifremgangsmåte for fremstilling av terapeutisk aktive 1,6-nafthyridinderivater av generell formel:
hvor R^ er fenyl, eventuelt substituert med halogenatomer eller cyano, nitro, trifluoralkyl, C^- C^ alkoxy, 2,3-methylen-dioxy; eller er thienyl, benzoxadiazolyl, piperidinyl eller pyridyl, R~ er rettkjedet eller forgrenet alkylradikal inne-. 3 holdende opp til 4 carbonatomer, eller et benzylradikal; R er et hydrogenatom, et rettkjedet eller forgrenet alkylradikal eller et alkoxycarbonylradikal inneholdende opp til 4 carbonatomer; R 4 er et rettkjedet eller forgrenet alkylradikal inneholdende opp til 4 carbonatomer, og R<5> er et carboxyl- eller alkoxycarbonylradikal av generelle formel III
hvori R 7 er hydrogen, et rettkjedet eller forgrenet alkylradikal med 1-4 carbonatomer, benzyl, trans-cinnamyl, cyclo-propylmethyl, 2-piperidinoethyl, N-benzylpiperidinyl, N-benzyl-pyrrolidinylmethyl eller et alkoxyalkyl- eller alkylthio-alkylradikal av generelle formel IV
hvori X er svovel eller oxygen, n er 2 eller 3 og R g er alkyl med 1-4 carbonatomer eller fenyl, eller R 7 er et ammoalkyl-radikal av generell formel VI
9 10
hvori R og R , som kan være like eller forskjellige, er hydrogen, alkyl med fra 1-4 carbonatomer eller benzyl, og n er 2 eller 3, såvel som farmakologisk akseptable salter derav.
En særlig foretrukket forbindelse er ethyl-(-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluormethylfenyl)-1,6-nafthyridincarboxylat og dets farmakologisk akseptable salter.
Analogifremgangsmåten ifølge oppfinnelsen er kjenne-tegnet ved at et 1,6-nafthyridinonderivat av generell formel:
hvori R , R og R har de ovenfor angitte betydninger og R har samme betydning som R 5, bortsett fra en carboxylgruppe, alkyleres på kjent måte.
Forbindelsene av generell formel (VII) kan f.eks. fremstilles som beskrevet i BRD patentsøknad P 33 27 650, ved at enten
a) et dihydropyridin av generell formel:
13 4 5 hvori R , R , R og R har de ovenfor angitte betydninger, omsettes med s-triazin i nærvær av en base, b) et 1,4-dihydropyridin av generell formel (VIII) omsettes med et dialkylformamid-dialkylacetal av generell formel: 12
hvori R -substituentene kan være like eller forskjellige og er methyl- eller ethylradikaler, og hver av R^-substituentene er et alkylradikal inneholdende opp til 4 carbonatomer eller de to R^-substituenter sammen betegner et alkylenradikal inneholdende opp til 3 carbonatomer, og at den erholdte forbindelse av generell formel: 13 4 5 12
hvori R , R , R , R og R har de ovenfor angitte betydninger, omsettes med ammoniakk, eller c) 2,4-dihydroxypyridin omsettes med en forbindelse av generell formel: 15 41 hvori R og R har de ovenfor angitte betydninger, og R er et rettkjedet eller forgrenet alkylradikal inneholdende opp til 4 carbonatomer, i nærvær av ammoniakk.
Forbindelsene av generell formel (XI) er kjente eller kan fremstilles ved fremgangsmåter kjent fra litteraturen (se Org. Reactions, 15, 204 et seq./1967). 2,4-dihydroxypyridin er kommersielt tilgjengelig.
1,4-dihydropyridinene av generell formel (VIII) anvendt ved fremgangsmåte a) og b), er kjente (se f.eks. Chem. Rev., 82, 223/1982) eller kan fremstilles på analog måte.
For utførelse av fremgangsmåte a) oppvarmes 1,4-dihydro-pyridinderivatet med s-triazin i et inert organisk løsnings-middel i nærvær av en sterk base, f.eks. et alkalimetall-alkoholat eller natriumhydrid, til en temperatur på fra 50 til 160°C, og fortrinnsvis fra 100 til 150°C. Som løsnings-midler er særlig polare løsningsmidler foretrukket, slik som dimethylsulfoxyd, dimethylformamid, ethylenglycol-dimethylether eller lavere alkoholer, slik som ethanol.
For utførelse av reaksjonen ifølge fremgangsmåtevariant b) omsettes det egnede 1,4-dihydropyridinderivat med en ekvi-valent eller overskytende mengde av dialkylformamid-dialkylacetal, fortrinnsvis i nærvær av et aprotisk løsningsmiddel slik som dimethylformamid, dimethylsulfoxyd eller hexamethyl-fosforsyretriamid under oppvarming. Spesielt foretrukne formamidacetaler innbefatter dimethylformamid-dimethylacetal og dimethylformamid-diethylacetal.
Mellomproduktet av generell formel (X) erholdt ifølge fremgangsmåtevariant b) omdannes til en forbindelse av generell formel (VII) ved omsetning med ammoniakk i nærvær av fortrinnsvis et protisk løsningsmiddel, ved omgivende temperatur eller ved en forhøyet temperatur, fortrinnsvis kokepunktet for det anvendte løsningsmiddel. Som løsnings-middel er særlig foretrukket lavere alkoholer, slik som methanol eller ethanol.
Reaksjon c) utføres fortrinnsvis i et inert organisk løsningsmiddel, spesielt lavere alkoholer slik som methanol, ethanol eller isopropanol. Det er også hensiktsmessig å arbeide ved forhøyede temperaturer, fortrinnsvis ved koke-temperaturen for det anvendte løsningsmiddel. Reaksjons-produktene kan isoleres og renses etter kjente separasjons-prosesser slik som krystallisering og/eller kromatografi.
Fremstilling av 1,6-nafthyridinderivatene av generell formel (I) finner sted ifølge oppfinnelsen etter konven-sjonelle prosesser beskrevet innen litteraturen for 0-alkylering av lactamer (se Adv. Heterocyclic Chem., 12, 185-212/1970). Egnede alkyleringsmidler innbefatter alkylhalogenider og alkylsulfonater, dialkylsulfater og trialkyl-oxoniumsalter.
For omsetning med alkylhalogenider anvendes forbindelsene av generell formel (VII) i form av deres metallsalter, fortrinnsvis deres alkalimetall- eller sølvsalter, som enten fremstilles separat eller som dannes in situ ved hjelp av egnede baser, slik som metallhydrider, carbonater eller alkoxyder, i aprotiske løsningsmidler.
Som egnede løsningsmidler, avhengig av det anvendte alkyleringsmiddel, kan det anvendes praktisk talt alle inerte organiske løsningsmidler slik som åpen-kjedede, cykliske eller også aromatiske hydrocarboner, f.eks. n-pentan, n-hexan, cyclohexan, benzen eller toluen, halogenerte hydrocarboner slik som diklormethan eller 1,2-diklorethan, ethere slik som diethylether eller 1,2-dimethoxyethan, såvel som dipolare aprotiske løsningsmidler slik som dimethylformamid, hexa-methylfosforsyretriamid og dimethylsulfoxyd. Avhengig av det anvendte løsningsmiddel kan temperaturområdet varieres fra mellom -20°C og kokepunktet for det angjeldende løsnings-middel.
På grunn av den ambidente karakter av lactamanionet
vil det ved alkyleringen hyppig oppnås blandinger av 0- og N-alkyleringsprodukter, avhengig av reaksjonsbetingelsene og det anvendte alkyleringsmiddel (se J. Org. Chem., 32, 4040
et seq./1967). Den erholdte produktblanding kan separeres ved kromatografiske metoder og/eller ved krystallisering.
1,6-nafthyridinderivatene av generell formel (I) hvori R 2 er et methyl- eller ethylradikal, erholdes fortrinnsvis ved omsetning av 1,6-nafthyridinonene av generell formel (VII)
med trimethyl- eller triethyloxoniumsalter, spesielt tri-methyloxonium-tetrafluorborat, i et aprotisk løsningsmiddel. Fremstilling av O-propyl-, O-isopropyl-, 0-butyl-, 0-sek-butyl-, 0-isobutyl- og 0-benzylforbindelsene utføres på den annen side fortrinnsvis ved alkylering av alkalimetall-saltene med egnede alkyl- eller benzylhalogenider.
Da forbindelsene av generell formel (I) ifølge oppfinnelsen har et chiralt senter ved C4, kan de foreligge enten som racemiske blandinger eller i form av enantiomerene.
Forbindelsene av generell formel (I) er meget effek-tive calciumantagonister. I motsetning til kjente calciumantagonister vil en cardiodepresjon (negativ inotrop,
negativ kronotrop virkning) ved terapeutiske konsentrasjoner ikke være forventet.
På basis av sin blodkarspasmolytiske virkning er de spesielt anvendbare når det gjelder cerebrale, cardiale og perifere blodkarsykdommer slik som myocardial ischaemia, cerebralt infarkt, pulmonar trombose og arteriosclerose og andre stenotiske indikasjoner, spesielt fordi en negativ inotrop bivirkning hovedsakelig er fraværende sammenlignet med kjente forbindelser med lignende virkningsprofil. Derfor er 1,6-nafthyridinderivatene ifølge oppfinnelsen verdifulle midler for å bekjempe hjerte-sirkulasjonsmortalitet.
En ytterligere side ved oppfinnelsen angår således anvendelse av 1,6-nafthyridinderivatene av generell
formel (I) for å bekjempe blodkarsykdommer.
De etterfølgende eksempler illustrerer oppfinnelsen.
Eksempel 1
Methyl-(-)- 4-( 2- fluorfenyl)- 1, 4- dihydro- 5- isopropoxy- 2-methyl- 1, 6- nafthyridin- 3- carboxylat
1,1 g (37 mmol) natriumhydrid (80% i paraffinolje)
ble suspendert i 70 ml tørt dimethylformamid, og en løsning av 10 g (32 mmol) methyl-(-)-4-(2-fluorfenyl)-1,4,5,6-tetra-hydro-2-methyl-5-oxo-l,6-nafthyridin-3-carboxylat i 100 ml dimethylformamid ble dråpevis tilsatt ved omgivende temperatur under omrøring. Etter at gassutviklingen hadde avtatt ble reaksjonsblandingen ytterligere omrørt i 30 minutter ved
omgivende temperatur. 5,9 g (35 mmol) isopropyljodid i 30 ml dimethylformamid ble deretter tilsatt. Omrøringen ble fortsatt i 20 minutter ved omgivende temperatur, løs-ningsmidlet ble fordampet av i en rotasjonsfordamper, og det oljeaktige residuum ble omrørt med 100 ml vann. Den resulterende lysebrune, krystallinske masse ble filtrert fra under sug, vasket med ether og tørket.
For rensing av det urene produkt ble dette krystallisert fra en blanding av 400 ml ethylacetat og 50 ml methanol,
idet O-alkyleringsproduktet var tilbake i sterkt anriket form i modervæsken som en lettløselig komponent. Denne ble først kromatografert over silicagel med diklormethan/methanol (9:1 v/v), hvorved utgangsmaterialet som fremdeles var til stede, derved ble fullstendig separert. Ytterligere kromato-graf i over silicagel med toluen/ethylacetat (3:1 v/v) ga praktisk talt rent methyl-(-)-4-(2-fluorfenyl)-1,4-dihydro-5-isopropoxy-2-methyl-l,6-nafthyridin-3-carboxylat (R^ = 0,3). Krystallisering fra n-hexan/diisopropylether ga sluttelig TLC-rene krystaller med smp. 164-165°C.
Methyl-(-)-4-(2-fluorfenyl)-1,4,5,6-tetrahydro-2-methyl-5-oxo-l,6-nafthyridin-3-carboxylat anvendt som utgangsmateriale, ble fremstilt som følger: En løsning av 31,5 g (120 mmol) dimethyl-4-(2-fluor-fenyl)-1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylat i 260 ml dimethylformamid ble dråpevis tilsatt under nitrogenatmosfære til en suspensjon av 3,8 g (130 mmol) natriumhydrid (80% i paraffinolje) i 60 ml tørt dimethylformamid. Etter at gassutviklingen var nedsatt, ble reaksjonsblandingen ytterligere omrørt i 10 minutter ved omgivende temperatur, hvorpå 10,0 g (120 mmol) s-triazin i 260 ml dimethylformamid ble dråpevis tilsatt. Reaksjonsblandingen ble oppvarmet til 110°C i 16 timer, og etter avkjøling ble den fordampet i vakuum. Det mørke residuum ble omrørt med 600 ml aceton, filtrert, og filtratet ble fordampet i vakuum. Det urene produkt ble kokt med 300 ml methanol, krystallene dannet etter avkjøling, ble filtrert fra og omkrystallisert fra methanol for ytterligere rensing. Det ble erholdt methyl-(-)-
4-(2-fluorfenyl)-1,4,5,6-tetrahydro-2-methyl-5-oxo-l,6-nafthyridin-3-carboxylat i form av lyse, beigefarvede krystaller med smp. 315-316°C (spaltn.).
Følgende forbindelser ble erholdt på analog måte: methyl-(-)- 4-( 2- bromfenyl)- 1, 4- dihydro- 5- isopropoxy- 2-methyl- 1, 6- nafthyridin- 3- carboxylat (l.a); smp. 201-202°C, omkrystallisert fra diisopropylether, methyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- nitro-fenyl)- 1, 6- nafthyridin- 3- carboxylat (l.b); smp. 170°C, omkrystallisert fra diisopropylether/methanol, methyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4- fenyl- 1, 6-nafthyridin- 3- carboxylat (l.c); smp. 132-133°C, omkrystallisert fra n-hexan, methyl-(-)- 4-( 3- klor- 2- fluorfenyl)- 1, 4- dihydro- 5- isopropoxy-2- methyl- l, 6- nafthyridin- 3- carboxylat (l.d); smp. 166-167°C, omkrystallisert fra n-hexan, methyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 3- nitro-fenyl)- 1, 6- nafthyridin- 3- carboxylat (l.e); smp. 174-175°C, omkrystallisert fra n-hexan, methyl-(-)- l, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- trifluor-methylfenyl)- 1, 6- nafthyrldin- 3- carboxylat (l,f); smp. 199-200°C, omkrystallisert fra diisopropylether, methyl-(-)- 4-( 2- klor- 6- fluorfenyl)- 1, 4- dihydro- 5- isopropoxy-2- methyl- l, 6- nafthyridin- 3- carboxylat (l.g); smp. 194-195°C, omkrystallisert fra diisopropylether, methyl-(-)- 1, 4- dihydro- 2- methyl- 5- propoxy- 4-( 2- trifluor-methylfenyl)- 1, 6- nafthyridin- 3- carboxylat (l.h); smp. 151-152°C, omkrystallisert fra n-hexan/diisopropylether, methyl-(-)- 4-( 2- bromfenyl)- 5- ethoxy- l, 4- dihydro- 2- methyl- l, 6-nafthyridin- 3- carboxylat (l.i)j smp. 203-204°C, omkrystallisert fra toluen/ethylacetat, ethyl-(-)- 5- butoxy- l, 4- dihydro- 2- methyl- 4-( 2- trifluormethyl-fenyl)- 1, 6- nafthyridin- 3- carboxylat (l.j); smp. 107-109°C, omkrystallisert fra n-hexan,
2- methoxyethyl'- (-) - 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4- ( 3-nitrofenyl)- 1, 6- nafthyridin- 3- carboxylat (l.k)j smp. 174-175°C, omkrystallisert fra diisopropylether,
ethyl- (-) - 1 , 4- dihydro- 5- isopropoxy- 2- methyl- 4- ( 2^ trifluor-methylf enyl) - 1, 6- naf thyrjdin- 3- carboxylat (1.1);
smp. 102-103°Cf omkrystallisert fra n-hexan, isopropyl-(-)- l, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- tri-fluormethylfenyl)- 1, 6- nafthyridin- 3- carboxylat (1.m);
smp. 111-112°C, omkrystallisert fra n-hexan, isobutyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- tri-fluormethylfenyl)- 1, 6- nafthyridin- 3- carboxylat (l.n);
smp. 115-116°C, omkrystallisert fra n-hexan, ethyl-(-)- 4-( 2, 3- diklorfenyl)- 1, 4- dihydro- 5- isopropoxy- 2-methyl- 1, 6- nafthyridin- 3- carboxylat (l.o); smp. 272-273°C, omkrystallisert fra diisopropylether,
ethyl-(-)- 5- sek- butoxy- l, 4- dihydro- 2- methyl- 4-( 2- trifluor-methylf enyl) - 1, 6- nafthyridin- 3- carboxylat- hydroklorid (l.p); smp. 148-150°C, omkrystallisert fra diisopropylether/ethylacetat,
ethyl-(-)- 1, 4- dihydro- 5- isobutoxy- 2- methyl- 4-( 2- trifluor-methylf enyl) - 1, 6- nafthyridin- 3- carboxylat (l.q);
smp. 118-119°C, omkrystallisert fra petroleumether
(kp. 60-80°C),
t- butyl-(-)- 1/ 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- trifluor-methylf enyl) - 1, 6- nafthyridin- 3- carboxylat (l.r);
smp. 209°C, omkrystallisert fra n-hexan/diisopropylether. ethyl-(-)- 2- ethyl- l, 4- dihydro- 5- isopropoxy- 8- methyl- 4- fenyl-1, 6- nafthyridin- 3- carboxylat (l.s); smp. 176-177°C, omkrystallisert fra n-hexan/diisopropylether, 2-( N- benzyl- N- methylamino)- ethyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4—( 3- nitrofenyl)- 1, 6— nafthyrldin- 3-carboxylat- dihydroklorid (l.t); smp. 148-150°C, omkrystallisert fra ethylacetat/acetonitril,
2- dimethylaminoethyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl-4-( 3- nitrofenyl)- 1, 6- nafthyridln- 3- carboxylat- dihydroklorid (l.u); smp. 148-150°C, omkrystallisert fra diisopropylether, 2- methylthioethyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 3- nitrofenyl)- 1, 6- nafthyridin- 3- carboxylat (l.v)>
smp. 154-155°C, omkrystallisert fra diisopropylether/ethylacetat,
2- ( N- benzyl- N- methylamino)- ethyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- trifluormethylfenyl)- 1, 6- nafthyridin-3- carboxylat- dihydroklorid (l.w); smp. 163-165°C (spaltn.), omkrystallisert fra acetonitril,
diethyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- trifluor-methylf enyl )- l , 6- nafthyridin- 3, 8- dicarboxylat (1.x);
smp. 140-141°C, omkrystallisert fra n-hexan,
ethyl-(-)— 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- trifluor-methylf enyl) - 1, 6- nafthyridin- 3- carboxylat- hydroklorid (l.y); smp. 137°C, omkrystallisert fra ethylacetat,
ethyl-(-)- 1) 4- dihydro- 5- isopropoxy- 4-( 2- methoxyfenyl)-2-methyl- 1, 6- nafthyridin- 3- carboxylat (l.z); smp. 145-146°C, omkrystallisert fra n-hexan/diisopropylether,
ethyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- thienyl)-1, 6- nafthyridin- 3- carboxylat (l.aa); smp. 110-111°C, omkrystallisert fra n-hexan,
ethyl-(-)- 4-( 2- cyanofenyl)- 1, 4- dihydro- 5- isopropoxy- 2- methyl-1, 6- nafthyridin- 3- carboxylat (l.ab); smp. 182-183°C, omkrystallisert fra n-hexan/diisopropylether,
ethyl- (-) - 5*- benzyloxy- l, 4- dihydro- 2- methyl- 4- ( 2- trif luor-methylf enyl) - 1, 6- nafthyridin- 3- carboxylat (l.ac);
smp. 14 2-143°C, omkrystallisert fra n-hexan/diisopropylether ,
ethyl-(-)- 2- ethyl- l, 4- dihydro- 5- isopropoxy- 8— methyl- 4-( 2-trifluormethylfenyl)- 1, 6- nafthyrldin- 3- carboxylat (l.ad);
smp. 112-113°C, omkrystallisert fra n-hexan,
benzyl—(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- trifluor-methylf enyl) - 1 , 6- nafthyridin- 3- carboxylat (l.ae).j smp. 126-127°C, omkrystallisert fra n-hexan,
2- dimethylaminoethyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl-4- ( 2- trifluormethylfenyl)- 1, 6- nafthyridin- 3- carboxylat (l.af); smp. 104-105°C, omkrystallisert fra n-hexan,
3- dimethylaminopropyl-(-)- 1, 4- dihydro— 5- isopropoxy- 2- methyl-4- ( 3- nitrofenyl)- 1, 6- nafthyridin- 3- carboxylat (l.ag);
smp. 134-136°C, omkrystallisert fra n-hexan/diisopropylether ,
ethyl-(-)- 4-( 2- difluormethoxyfenyl)- 1/ 4- dihydro- 5- isopropoxy- 2- methyl- l, 6- nafthyridin- 3- carboxylat (l.ah), 2- dibenzylamlnoethyl-(-)- 1, 4- dihydro- 5- lsopropoxy- 2- methyl-4-( 2- trifluormethylfenyl)- 1, 6- nafthyrldin- 3- carboxylat
(l.ai),
ethyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-(2-methyl-fenyl)- l, 6- nafth yridin- 3- carboxylat (l.aj); smp. 122-124°C, omkrystallisert fra n-hexan/diisopropylether,
2- dimethylaminoethyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl-4- ( 3- nitrof enyl) ^- 1, 6- naf thyr idin- 3- car bo xylat (l.ak)j smp. 91-93°C, omkrystallisert fra n—hexan/diisopropyl-
ether.
Eksempel 2
Methyl-(4-.)- 1, 4- dihydro- 5- methoxy- 2- methyl- 4- fenyl- 1, 6-nafthyridin- 3— carboxylat 5 g (17 mmol) methyl-(-)-1,4,5,6-tetrahydro-2-methyl-5- oxo-4-fenyl-1,6-nafthyridin-3-carboxylat og 5 g (34 mmol) trimethyloxoniumtetrafluorborat i 200 ml 1,2-diklorethan ble omrørt i 1,5 time ved omgivende temperatur under en nitrogenatmosfære. Reaksjonsblandingen ble ristet ut med 50 ml vann, og den organiske fase ble fraskilt og fordampet på en rotasjonsfordamper. Etter omkrystallisering av residuet fra isopropanol ble tetrafluorboratet av den ønskede forbindelse erholdt. Denne ble omrørt med en mettet, vandig løsning av kaliumhydrogencarbonat og diethylether, og den etheriske løsning ble fraskilt, tørket over vannfritt natriumsulfat og fordampet på en rotasjonsfordamper. Krystallisering av den frie base fra 50 ml n-hexan/diisopropylether (2:1 v/v) ga farveløse krystaller med smp. 210-212°C.
Methyl-(-)-l,4,5,6-tetrahydro-2-methyl-5-oxo-4-fenyl-1,6-nafthyridin-3-carboxylat anvendt som utgangsmateriale,
ble fremstilt analogt med eksempel 1 under anvendelse av methyl-1,4-dihydro-2,6-dimethyl-4-fenylpyridin-3,5-dicarboxylat.
Følgende forbindelser ble erholdt på analog måte: ethyl-(-)- 4-( 2- klorfenyl)- l, 4- dihydro- 5- methoxy- 2- methyl-1, 6- nafthyridin- 3- carboxylat (2.a); smp. 173-174°C, omkrystallisert fra n-hexan/diisopropylether, ethyl-(-)- l, 4- dihydro- 5- methoxy- 2- methyl- 4-( 3- nitrofenyl)-1, 6- nafthyridin- 3- carboxylat (2 .b); smp. 184-186°C, omkrystallisert fra diisopropylether/ethanol, ethyl- (-)- 4-( 2- fluorfenyl)- 1, 4- dihydro- 5- methoxy- 2- methyl-1/ 6- nafthyridin- 3- carboxylat (2.c); smp. 148-150°C, omkrystallisert fra n-hexan,
ethyl-(-)- l, 4- dihydro- 5- methoxy- 2- methyl- 4-( 2- trifluor-methylf enyl)- 1 , 6- nafthyridin- 3- carboxylat (2.d);
smp. 118-120°C, omkrystallisert fra n-hexan, methyl-(-)- 4-( 3- klor- 2- fluorfenyl)- 1, 4- dihydro- 5- methoxy- 2-methyl- 1, 6- nafthyridin- 3- carboxylat (2.e); smp. 214-216°C, omkrystallisert fra diisopropylether/methanol, methyl-(-)- 4—( 2- bromfenyl)- 1, 4- dihydro- 5- methoxy- 2- methyl-1, 6- nafthyridin- 3- carboxylat (2.f); smp. 204-205°C, omkrystallisert fra diisopropylether/methanol
Ek sempel 3
(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- trifluormethyl-fenyl)- 1, 6- nafthyridin- 3- carboxylsyre
3,0 g (6,2 mmol) benzyl-(-)-1,4-dihydro-5-isopropoxy-2- methyl-4-(2-trifluormethylfenyl)-1,6-nafthyridin-3-carboxylat ble hydrogenert ved normaltrykk og ved omgivende temperatur under anvendelse av 1,5 g 10% palladium på aktivt carbon i 100 ml ethanol. Opptaket av hydrogen ble avsluttet etter 30 minutter. Katalysatoren ble filtrert fra, løs-ningsmidlet ble destillert av i vakuum, og det farveløse, krystallinske residuum ble omkrystallisert fra diisopropylether/ethylacetat. Det ble erholdt (-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluormethylfenyl)-1,6—nafthyridin-3- carboxylsyre i form av farveløse krystaller med et smelte-punkt på 164-166°C (spaltn.).
Benzyl-(-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluormethylfenyl)-1,6-nafthyridin-3-carboxylat anvendt som utgangsmateriale, ble fremstilt analogt med eksempel 1 under anvendelse av dibenzyl-l,4-dihydro-2,6-dimethyl-4-(2-trifluormethylfenyl)-pyridin-3,5-dicarboxylat.
Eksempel 4 ( se forbindelse 1. 1)
Ethyl-(-)- 1, 4- dihydro- 5- isopropoxy- 2- methyl- 4-( 2- trifluor-methylf enyl) - 1 , 6- nafthyridin- 3- carboxylat
1,3 g (43 mmol) natriumhydrid (80% i paraffinolje) ble suspendert i 200 ml tørt dimethylformamid, og 12,5 g
(33 mmol) ethyl-(-)- 1,4,5,6-tetrahydro-2-methyl-5-oxo-4-(2-tri-fluormethylfenyl)-1,6-nafthyridin-3-carboxylat ble tilsatt i porsjoner ved omgivende temperatur og under omrøring. Etter at gassutviklingen var avtatt, ble reaksjonsblandingen ytterligere omrørt i 15 minutter ved omgivende temperatur. 7,2 g (43 mmol) isopropyljodid ble deretter tilsatt. Omrøringen ble fortsatt i 3 dager ved omgivende temperatur. Løsnings-midlet ble fordampet fra i vakuum, og etter tilsetning av 500 ml vann ble residuet behandlet i et ultralydbad i 30 minutter. Den resulterende, krystallinske masse ble filtrert fra og tørket ved 50°C.
For rensing av det urene produkt ble dette oppløst i ethylacetat og kromatografert over silicagel med toluen/ethylacetat (3:1 v/v). Løsningsmidlet av fraksjonene med R f = 0/4 ble fordampet i vakuum, og residuet ble omrørt for krystallisering med n-hexan. Produktet ble filtrert fra og omkrystallisert fra 60 ml n-hexan. Farveløse krystaller ble erholdt med smp. 102-103°C.
Ethyl-(-)-1,4,5,6-tetrahydro-2-methyl-5-oxo-4-(2-tri-fluormethylfenyl)-1,6-nafthyridin-3-carboxylat anvendt som utgangsmateriale, ble fremstilt som følger: En løsning av 79,2 g (0,2 mol) diethyl-1,4-dihydro-2,6-dimethyl-4-(2-trifluormethylfenyl)-pyridin-3,5-dicarboxylat i 400 ml dimethylformamid ble dråpevis tilsatt under en nitrogenatmosfære, til en suspensjon av 6,0 g
(0,2 mol) natriumhydrid (80% i.paraffinolje) i 100 ml tørt dimethylformamid. Etter at gassutviklingen var avtatt, ble reaksjonsblandingen ytterligere omrørt i 10 minutter ved omgivende temperatur, hvorpå 16,2 g (0,2 mol) s-triazin i
300 ml dimethylformamid ble dråpevis tilsatt. Reaksjonsblandingen ble oppvarmet til 110°C i 16 timer under omrør-ing og ble etter avkjøling fordampet i vakuum. Residuet ble omrørt med 1,5 1 aceton, filtrert og filtratet ble fordampet i vakuum. Residuet ble kromatografert over silicagel med diklormethan/methanol (9:1 v/v). Fraksjonen med R^ = 0,4 5 ble omrørt med 200 ml kloroform, og de lyse, beigefarvede krystaller ble filtrert fra. For ytterligere rensing ble disse omkrystallisert fra ethanol, og farveløse krystaller ble erholdt med smp. 261°C.
Diethyl-l,4-dihydro-2,6-dimethyl-4-(2-trifluormethyl-fenyl)-pyridin-3,5-dicarboxylat anvendt som utgangsmateriale, ble fremstilt som følger: 50 g (0,29 mol) 2-trifluormethyl-benzaldehyd og 76 g (0,58 mol) ethylacetoacetat i 30 ml vandig ammoniakk ble kokt i 16 timer med 200 ml ethanol. Etter utfelling og av-kjøling ble produktet filtrert fra og vasket med kald ethanol. Det ble erholdt lyse, beigefarvede krystaller med smp. 142-143°C.
De etterfølgende sammenligningsforsøk viser den farma-kologiske effektivitet av forbindelsene av generell formel (I):
a) Isolert glattmuskel
Isolert glattmuskel fra kaniner (blodkarringer,
A. basilaris, A. coronaria, A. saphena) ble festet i et organbad på en slik måte at isometriske kontraksjoner kunne måles. Kontraksjonen ble initiert med en kaliumdepolariser-ing i tyrodløsning. Forsøksprotokollen var en kjent standard-modell for bestemmelse av forbindelser som blokkerer calcium-kanalene som åpnes ved calciumdepolariseringen (Fleckenstein, 1983). Som det fremgår fra etterfølgende tabell I, virker noen forbindelser semi-maksimalt relakserende i det nano-molare område. Denne styrke overskred betydelig den av de tidligere kjente calciumantagonister diltiazem og nifedipin.
b) Isolert papillærmuskel
Papillærmuskel fra venstre ventrikkel av marsvin ble
festet som i tilfellet med de isolerte kar, i et organbad for
måling av isometrisk kontraksjon og ble stimulert elektrisk nred feltstimulering med en frekvens på 250/min. (stimuler-ingsperiode 10 msek., supramaksimal amplitude). Den etter-følgende tabell II viser at forbindelsene utviser sin calciumantagonistvirkning selektivt på glatt-karmuskelen, og på myocardiumet utvises overraskende, i det terapeutiske område (1-100 nmolar) ingen negativ, men tvert imot delvis en positiv inotrop virkning. Det kan imidlertid ikke utelukkes at dimethylsulfoxydet anvendt som løsningsmiddel, har bidratt til den observerte positive inotrope virkning. Forbindelsen ifølge eksempel lc) utviser, ved den terapeutiske konsentrasjon på 3 x 10 _7mol/l, en maksimal økning av kontraktiliteten på 36%, og ved en konsentrasjon på 4 x 10 - 9 mol/l var denne +18%.
TABELL I
Tabell I viser konsentrasjoner (IC^q, mol/1) av forbindelser (I) som bevirker semi-maksimal inhibering av K<+->depolariseringskontraksjonen i blodkarringer i et organbad. Av sammenligningsgrunner er IC^-verdiene for calcium-antagonistene diltiazem og nifedipin også angitt.
TABELL II
Forandringer av kontraksjonsamplituden på isolert papillærmuskel fra marsvin (stimuleringsfrekvens 250/min., stimul-eringstid 10 msek, stimuleringsam.plitude 10-20 V feltstimulering). IC = inhiberende konsentrasjon, ^C^qq til-svarer maksimal virkning. A% = maksimal nedsettelse av kontraktiliteten. De inhiberende konsentrasjoner av diltiazem og nifedipin er gitt for sammenligning.
Tabell II viser de maksimale virkninger på kontraktiliteten når det gjelder de nødvendige konsentrasjoner (IC^0Q = inhiberende konsentrasjon). Ut fra dette fremgår det at sammenligningsforbindelsene, selv i tilfellet med betydelig lavere konsentrasjoner (ic^oq)' utviser en høyere nedsettelse av kontrakt il i teten. Konsentrasjonen IC,_~
J 100 ligger langt utenfor det terapeutiske område for forbindelsene ifølge oppfinnelsen slik at en negativ inotrop virkning ikke finnes for disse. Ut fra dette følger at den terapeutiske sikkerhet for forbindelsene fremstilt ifølge oppfinnelsen, er betydelig øket i sammenligning med de kjente forbindelser.
Claims (2)
1. Analogifremgangsmåte for fremstilling av terapeutisk aktive 1,6-nafthyridinderivater av generell formel:
hvor R1 er fenyl, eventuelt substituert med halogenatomer eller cyano, nitro, trifluoralkyl, C^-C^ alkoxy, 2,3-methylen-dioxy; eller er thienyl, benzoxadiazolyl, piperidinyl eller pyridyl, R~ er rettkjedet eller forgrenet alkylradika. l inne-3 holdende opp til 4 carbonatomer, eller et benzylradikal; R er et hydrogenatom, et rettkjedet eller forgrenet alkylradikal eller et alkoxycarbonylradikal inneholdende opp til 4 carbonatomer; R<4> er et rettkjedet eller forgrenet alkylradikal inneholdende opp til 4 carbonatomer, og R 5 er et carboxyl- eller alkoxycarbonylradikal av generell formel III
hvori R 7 er hydrogen, et rettkjedet eller forgrenet alkylradikal med 1-4 carbonatomer, benzyl, trans-cinnamyl, cyclo-propylmethyl, 2-piperidinoethyl, N-benzylpiperidinyl, N-benzyl-pyrrolidinylmethyl eller et alkoxyalkyl- eller alkylthio-alkylradikal av generelle formel IV
hvori X er svovel eller oxygen, n er 2 eller 3 og R g er alkyl med 1-4 carbonatomer eller fenyl, eller R 7 er et ammoalkyl-radikal av generell formel VI 9 10
hvori R og R , som kan være like eller forskjellige, er hydrogen, alkyl med fra 1-4 carbonatomer eller benzyl, og n er 2 eller 3, såvel som farmakologisk akseptable salter derav,
karakterisert ved at et 1,6-nafthyridinonderivat av generell formel:
hvori R 1 , R 3 og R <4> har de ovenfor angitte betydninger og R<51 >har samme betydning som R 5, bortsett fra en carboxylgruppe, alkyleres på kjent måte.
2. Fremgangsmåte ifølge krav 1 for fremstilling av ethyl-(-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluormethyl-fenyl)-1,6-nafthyridincarboxylat og dets farmakologisk akseptable salter,
karakterisert ved at tilsvarende utgangsmateria-aler anvendes.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843431303 DE3431303A1 (de) | 1984-08-25 | 1984-08-25 | 1,6-naphthyridin-derivate, verfahren zu deren herstellung und deren verwendung |
| DE19853502790 DE3502790A1 (de) | 1985-01-29 | 1985-01-29 | 1,6-naphthyridin-derivate, verfahren zu deren herstellung und deren verwendung |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO853329L NO853329L (no) | 1986-02-26 |
| NO161493B true NO161493B (no) | 1989-05-16 |
| NO161493C NO161493C (no) | 1989-08-23 |
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ID=25824189
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO853329A NO161493C (no) | 1984-08-25 | 1985-08-23 | Analogifremgangsmaate ved fremstilling av terapeutisk aktive 1,6-nafthyridinderivater. |
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| Country | Link |
|---|---|
| US (1) | US4711901A (no) |
| EP (1) | EP0173933B1 (no) |
| KR (1) | KR890000706B1 (no) |
| AT (1) | ATE48276T1 (no) |
| AU (1) | AU576887B2 (no) |
| BG (1) | BG43691A3 (no) |
| CA (1) | CA1263118A (no) |
| DE (1) | DE3574471D1 (no) |
| DK (1) | DK165247C (no) |
| ES (1) | ES8604960A1 (no) |
| FI (1) | FI80697C (no) |
| GR (1) | GR852040B (no) |
| HU (1) | HU194879B (no) |
| IE (1) | IE58364B1 (no) |
| IL (2) | IL75987A (no) |
| NO (1) | NO161493C (no) |
| NZ (1) | NZ213218A (no) |
| PH (4) | PH21177A (no) |
| PL (1) | PL146668B1 (no) |
| RO (1) | RO92245B (no) |
| SU (1) | SU1395143A3 (no) |
| YU (2) | YU45000B (no) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3431303A1 (de) * | 1984-08-25 | 1986-02-27 | Goedecke Ag | 1,6-naphthyridin-derivate, verfahren zu deren herstellung und deren verwendung |
| DE3906460C1 (no) * | 1989-03-01 | 1990-11-15 | Goedecke Ag, 1000 Berlin, De | |
| DE3906406C1 (no) * | 1989-03-01 | 1990-10-25 | Goedecke Ag, 1000 Berlin, De | |
| DE102006026585A1 (de) | 2006-06-07 | 2007-12-13 | Bayer Healthcare Aktiengesellschaft | Substituierte 4-Aryl-1,4-dihydro-1,6-naphthyridine und ihre Verwendung |
| DE102006026583A1 (de) | 2006-06-07 | 2007-12-13 | Bayer Healthcare Aktiengesellschaft | Aryl-substituierte hetero-bicyclische Verbindungen und ihre Verwendung |
| DE102007009494A1 (de) | 2007-02-27 | 2008-08-28 | Bayer Healthcare Ag | Substituierte 4-Aryl-1, 4-dihydro-1,6-naphthyridinamide und ihre Verwendung |
| ES2828704T3 (es) * | 2014-08-01 | 2021-05-27 | Bayer Pharma AG | Procedimiento para la preparación de (4S)-4-(4-ciano-2-metoxifenil)-5-etoxi-2,8-dimetil-1,4-dihidro-1,6-naftiridin-3-carboxamida y su purificación para su uso como principio activo farmacéutico |
| PL3337801T3 (pl) * | 2015-08-21 | 2019-10-31 | Bayer Pharma AG | Sposób wytwarzania (4S)-4-(4-cyjano-2-metoksyfenylo)-5-etoksy-2,8-dimetylo-1,4-dihydro-1,6-naftyrydyno-3-karboksyamidu i odzyskiwania (4S)-4-(4-cyjano-2-metoksyfenylo)-5-etoksy-2,8-dimetylo-1,4-dihydro-1,6-naftyrydyno-3-karboksyamidu za pomocą metod elektrochemicznych |
| MX367960B (es) * | 2015-08-21 | 2019-09-12 | Bayer Pharma AG | Procedimiento para la preparacion de (4s)-4-(4-ciano-2-metoxifenil o)-5-etoxi-2,8-dimetilo-1,4-dihidro-1,6-naftiridina-3-carboxamida y su purificacion para su uso como principio activo farmaceutico. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4304914A (en) * | 1980-07-07 | 1981-12-08 | Usv Pharmaceutical Corporation | Naphthyridone derivatives |
| DE3327650A1 (de) * | 1983-07-30 | 1985-02-14 | Gödecke AG, 1000 Berlin | 1,6-naphthyridinon-derivate, verfahren zu deren herstellung und deren verwendung bei der bekaempfung von gefaesserkrankungen |
-
1985
- 1985-07-31 IL IL8575987Q patent/IL75987A/xx not_active IP Right Cessation
- 1985-08-01 IL IL75987A patent/IL75987A0/xx not_active IP Right Cessation
- 1985-08-15 SU SU853936405A patent/SU1395143A3/ru active
- 1985-08-21 RO RO119914A patent/RO92245B/ro unknown
- 1985-08-21 BG BG8571530A patent/BG43691A3/xx unknown
- 1985-08-22 FI FI853233A patent/FI80697C/fi not_active IP Right Cessation
- 1985-08-22 GR GR852040A patent/GR852040B/el unknown
- 1985-08-23 ES ES546366A patent/ES8604960A1/es not_active Expired
- 1985-08-23 DK DK384485A patent/DK165247C/da not_active IP Right Cessation
- 1985-08-23 EP EP85110646A patent/EP0173933B1/de not_active Expired
- 1985-08-23 DE DE8585110646T patent/DE3574471D1/de not_active Expired - Fee Related
- 1985-08-23 AU AU46626/85A patent/AU576887B2/en not_active Ceased
- 1985-08-23 HU HU853212A patent/HU194879B/hu not_active IP Right Cessation
- 1985-08-23 PL PL1985255118A patent/PL146668B1/pl unknown
- 1985-08-23 PH PH32684A patent/PH21177A/en unknown
- 1985-08-23 NZ NZ213218A patent/NZ213218A/en unknown
- 1985-08-23 CA CA000489290A patent/CA1263118A/en not_active Expired
- 1985-08-23 NO NO853329A patent/NO161493C/no unknown
- 1985-08-23 IE IE208585A patent/IE58364B1/en not_active IP Right Cessation
- 1985-08-23 AT AT85110646T patent/ATE48276T1/de not_active IP Right Cessation
- 1985-08-23 YU YU1348/85A patent/YU45000B/xx unknown
- 1985-08-24 KR KR1019850006133A patent/KR890000706B1/ko not_active IP Right Cessation
-
1986
- 1986-07-30 US US06/891,712 patent/US4711901A/en not_active Expired - Lifetime
- 1986-10-03 PH PH34327A patent/PH23411A/en unknown
- 1986-10-03 PH PH34326A patent/PH23379A/en unknown
-
1987
- 1987-06-17 PH PH35419A patent/PH24762A/en unknown
-
1988
- 1988-01-26 YU YU14588A patent/YU47010B/sh unknown
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