NO811420L - 6- (PYRIDINYL) -4-SUBSTITUTED-3 (2H) -PYRIDAZINONES SUITABLE AS CARDIOTONIC AGENTS AND PROCEDURES FOR THEIR PREPARATION - Google Patents
6- (PYRIDINYL) -4-SUBSTITUTED-3 (2H) -PYRIDAZINONES SUITABLE AS CARDIOTONIC AGENTS AND PROCEDURES FOR THEIR PREPARATIONInfo
- Publication number
- NO811420L NO811420L NO811420A NO811420A NO811420L NO 811420 L NO811420 L NO 811420L NO 811420 A NO811420 A NO 811420A NO 811420 A NO811420 A NO 811420A NO 811420 L NO811420 L NO 811420L
- Authority
- NO
- Norway
- Prior art keywords
- pyridinyl
- oxo
- dihydro
- acid
- ethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title claims description 17
- 239000000496 cardiotonic agent Substances 0.000 title description 8
- FIULGFJIHJJXMT-UHFFFAOYSA-N [C]1[N]C=CC=C1 Chemical class [C]1[N]C=CC=C1 FIULGFJIHJJXMT-UHFFFAOYSA-N 0.000 title 1
- 239000002253 acid Substances 0.000 claims description 56
- -1 4-pyridinyl Chemical group 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 54
- 150000003839 salts Chemical class 0.000 claims description 50
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 35
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 30
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 10
- 239000012458 free base Substances 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 8
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 6
- 150000001450 anions Chemical class 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- XEEVLJKYYUVTRC-UHFFFAOYSA-L oxomalonate(2-) Chemical compound [O-]C(=O)C(=O)C([O-])=O XEEVLJKYYUVTRC-UHFFFAOYSA-L 0.000 claims description 4
- AJKVQEKCUACUMD-UHFFFAOYSA-N 2-Acetylpyridine Chemical compound CC(=O)C1=CC=CC=N1 AJKVQEKCUACUMD-UHFFFAOYSA-N 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- 239000012320 chlorinating reagent Substances 0.000 claims description 2
- 150000002429 hydrazines Chemical class 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 239000000243 solution Substances 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 238000007792 addition Methods 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 18
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 235000011054 acetic acid Nutrition 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000003177 cardiotonic effect Effects 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 7
- 239000004310 lactic acid Substances 0.000 description 7
- 235000014655 lactic acid Nutrition 0.000 description 7
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- KZBNMPJVBPMBCG-UHFFFAOYSA-N diethyl 2-hydroxy-2-(2-oxo-2-pyridin-4-ylethyl)propanedioate Chemical compound CCOC(=O)C(O)(C(=O)OCC)CC(=O)C1=CC=NC=C1 KZBNMPJVBPMBCG-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 229940098779 methanesulfonic acid Drugs 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- DVWKXUYQVXPLQT-UHFFFAOYSA-N 2-methyl-3-oxo-6-pyridin-4-ylpyridazine-4-carboxamide Chemical compound C1=C(C(N)=O)C(=O)N(C)N=C1C1=CC=NC=C1 DVWKXUYQVXPLQT-UHFFFAOYSA-N 0.000 description 5
- WJVSAPVTDKNDAS-UHFFFAOYSA-N ethyl 2-methyl-3-oxo-6-pyridin-4-ylpyridazine-4-carboxylate Chemical class CN1C(=O)C(C(=O)OCC)=CC(C=2C=CN=CC=2)=N1 WJVSAPVTDKNDAS-UHFFFAOYSA-N 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
- LPRDIYKZZIDTPV-UHFFFAOYSA-N 3-pyridin-4-yl-1h-pyridazin-6-one Chemical compound N1C(=O)C=CC(C=2C=CN=CC=2)=N1 LPRDIYKZZIDTPV-UHFFFAOYSA-N 0.000 description 4
- FBOQGQULUAPQCC-UHFFFAOYSA-N 3-pyridin-4-yl-4,5-dihydro-1h-pyridazin-6-one Chemical compound N1C(=O)CCC(C=2C=CN=CC=2)=N1 FBOQGQULUAPQCC-UHFFFAOYSA-N 0.000 description 4
- PXVULGBZWDSEGI-UHFFFAOYSA-N 4-amino-2-methyl-6-pyridin-4-ylpyridazin-3-one Chemical compound C1=C(N)C(=O)N(C)N=C1C1=CC=NC=C1 PXVULGBZWDSEGI-UHFFFAOYSA-N 0.000 description 4
- GPVUOJQVQCQENB-UHFFFAOYSA-N 5-amino-3-pyridin-4-yl-1h-pyridazin-6-one Chemical compound N1C(=O)C(N)=CC(C=2C=CN=CC=2)=N1 GPVUOJQVQCQENB-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- JFGAMCHVJAGCJO-UHFFFAOYSA-N ethyl 6-oxo-3-pyridin-4-yl-1h-pyridazine-5-carboxylate Chemical compound N1=C(O)C(C(=O)OCC)=CC(C=2C=CN=CC=2)=N1 JFGAMCHVJAGCJO-UHFFFAOYSA-N 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Chemical compound Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 description 4
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 210000003540 papillary muscle Anatomy 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WMQUKDQWMMOHSA-UHFFFAOYSA-N 1-pyridin-4-ylethanone Chemical compound CC(=O)C1=CC=NC=C1 WMQUKDQWMMOHSA-UHFFFAOYSA-N 0.000 description 3
- AVPTZFZCDCYPOY-UHFFFAOYSA-N 2-methyl-3-oxo-6-pyridin-4-ylpyridazine-4-carbohydrazide Chemical compound C1=C(C(=O)NN)C(=O)N(C)N=C1C1=CC=NC=C1 AVPTZFZCDCYPOY-UHFFFAOYSA-N 0.000 description 3
- PMUZKPNRBITVHX-UHFFFAOYSA-N 6-oxo-3-pyridin-4-yl-1h-pyridazine-5-carbohydrazide Chemical compound N1C(=O)C(C(=O)NN)=CC(C=2C=CN=CC=2)=N1 PMUZKPNRBITVHX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- NNBYTRDSKTZTGA-UHFFFAOYSA-N 1-(2-methylpyridin-3-yl)ethanone Chemical compound CC(=O)C1=CC=CN=C1C NNBYTRDSKTZTGA-UHFFFAOYSA-N 0.000 description 2
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 2
- FUSNOPLQVRUIIM-UHFFFAOYSA-N 4-amino-2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-n-[3-(trifluoromethyl)phenyl]pyrimidine-5-carboxamide Chemical compound O=C1NC(C)(C)CN1C(N=C1N)=NC=C1C(=O)NC1=CC=CC(C(F)(F)F)=C1 FUSNOPLQVRUIIM-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- 230000036772 blood pressure 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
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- LKPGARDGOQJLHL-UHFFFAOYSA-N diethyl 2-hydroxy-2-(2-oxo-2-pyridin-2-ylethyl)propanedioate Chemical class CCOC(=O)C(O)(C(=O)OCC)CC(=O)C1=CC=CC=N1 LKPGARDGOQJLHL-UHFFFAOYSA-N 0.000 description 2
- DBKKFIIYQGGHJO-UHFFFAOYSA-N diethyl 2-oxopropanedioate Chemical compound CCOC(=O)C(=O)C(=O)OCC DBKKFIIYQGGHJO-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000002837 heart atrium Anatomy 0.000 description 2
- 239000012493 hydrazine sulfate Substances 0.000 description 2
- 229910000377 hydrazine sulfate Inorganic materials 0.000 description 2
- LIAWOTKNAVAKCX-UHFFFAOYSA-N hydrazine;dihydrochloride Chemical compound Cl.Cl.NN LIAWOTKNAVAKCX-UHFFFAOYSA-N 0.000 description 2
- 208000021822 hypotensive Diseases 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- LRPCLTPZMUIPFK-UHFFFAOYSA-N methane;sulfuric acid Chemical compound C.OS(O)(=O)=O LRPCLTPZMUIPFK-UHFFFAOYSA-N 0.000 description 2
- HTAWQGONZIWLRC-UHFFFAOYSA-N methylhydrazine;dihydrochloride Chemical compound Cl.Cl.CNN HTAWQGONZIWLRC-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- DASXLYSUTRIHGW-UHFFFAOYSA-N 1-(3-ethylpyridin-4-yl)ethanone Chemical compound CCC1=CN=CC=C1C(C)=O DASXLYSUTRIHGW-UHFFFAOYSA-N 0.000 description 1
- DIASEPULVQSMAS-UHFFFAOYSA-N 1-(5-methylpyridin-3-yl)ethanone Chemical compound CC(=O)C1=CN=CC(C)=C1 DIASEPULVQSMAS-UHFFFAOYSA-N 0.000 description 1
- NKCHJKQEKHAFEA-UHFFFAOYSA-N 2-(2-hydroxyethyl)-3-oxo-6-pyridin-4-ylpyridazine-4-carbohydrazide Chemical compound OCCN1C(=O)C(C(=O)NN)=CC(C=2C=CN=CC=2)=N1 NKCHJKQEKHAFEA-UHFFFAOYSA-N 0.000 description 1
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- ZHNFLHYOFXQIOW-LPYZJUEESA-N quinine sulfate dihydrate Chemical compound [H+].[H+].O.O.[O-]S([O-])(=O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 ZHNFLHYOFXQIOW-LPYZJUEESA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse angår 6-(pyridinyl)-4.-substituerte-3 (2H )-pyridazinoner, som kan anvendes som kardiotoniske midler, deres fremstilling, samt deres anvendelse som kardiotoniske midler. The present invention relates to 6-(pyridinyl)-4.-substituted-3 (2H )-pyridazinones, which can be used as cardiotonic agents, their preparation, and their use as cardiotonic agents.
Haginiwa et al. (Yakugaku Zasshi 98 (1), 67-71 (1 978), Chem Abstr. 88, 170,096v (1 978) omsatte 4(2H)-pyridazinon med pyridin 1-oksydert og platinisert Pd-C-katalysator og fikk fremstilt 6 - (2-pyridinyl)-3(2H ) -pyri - daz inon. Haginiwa et al. (Yakugaku Zasshi 98 (1), 67-71 (1 978), Chem Abstr. 88, 170,096v (1 978) reacted 4(2H)-pyridazinone with pyridine 1-oxidized and platinized Pd-C catalyst and obtained 6 - (2-pyridinyl)-3(2H ) -pyri-dazinone.
Yoshitomi Pharmaceutical Ind, Ltd, Japansk patent-søknad nr. 1 9-987/79, publisert 15 februar 1 979, og basert på søknad nr. 85.192/77 innsendt 15 juli 1977, beskriver blandt annet fremstillingen av 4-, 5 -dihydro-6-(4--pyr idinyl) - 3 (2H)-pyridazinon ved at man i to timer koker under tilbake-løp en etanolisk oppløsning av 3-(isonikotinoyl)propionsyre (samme som y - oxo- y- (4--pyr idinyl ) smør syre ) og hydraz inhydrat. 4-, 5-dihydro-6-(4--pyr idinyl )-3 (2H ) -pyridazinon og de nærstående 4., 5-dihydro-6-(4-- eller 3- eller 2 -pyridinyl )-5-R-3 (2H ) - pyridazinoner hvor R er H eller lavere alkyl, sies på side 2' i den engelske oversettelse .at "det ikke bare kan brukes som medisiner som hypotensider og antitrombemidler fordi de har farmakologisk virkning såsom at de er hypotensive, Yoshitomi Pharmaceutical Ind, Ltd, Japanese Patent Application No. 19-987/79, published February 15, 1979, and based on Application No. 85,192/77 filed July 15, 1977, describes, among other things, the preparation of 4-, 5-dihydro -6-(4--pyridinyl)-3 (2H)-pyridazinone by refluxing an ethanolic solution of 3-(isonicotinoyl)propionic acid (same as y-oxo-y- (4- -pyr idinyl ) butyric acid ) and hydraz inhydrate. 4-, 5-dihydro-6-(4--pyridinyl)-3(2H)-pyridazinone and the related 4.,5-dihydro-6-(4-- or 3- or 2-pyridinyl)-5- R-3 (2H ) - pyridazinones where R is H or lower alkyl, it is said on page 2' of the English translation that "it can not only be used as medicines such as hypotensives and antithrombotics because they have pharmacological effects such as being hypotensive,
ved at de hindrer koagulering av blodplater og at de er membranstabiliserende, men at de også kan brukes som mellomprodukter for syntese av slike medisiner". in that they prevent the coagulation of blood platelets and that they are membrane stabilisers, but that they can also be used as intermediates for the synthesis of such medicines".
Foreliggende oppfinnelse angår 2-R-4--R 1 -6-PY-3(2H)-pyridaz inoner med formel I The present invention relates to 2-R-4--R 1 -6-PY-3(2H)-pyridaz inones of formula I
eller deres syreaddisjonssalter, hvor PY er 4-- eller 3-pyridinyl eller 4-- eller 3-pyridinyl med en eller to lavere-alkyl substituenter, R er hydrogen, lavere-alkyl eller lavere-hydroksyalkyl, og R<1>er amino, karbamyl, karboksy, amino- or their acid addition salts, wherein PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl with one or two lower alkyl substituents, R is hydrogen, lower alkyl or lower hydroxyalkyl, and R<1> is amino , carbamyl, carboxy, amino-
karbamyl eller lavere-karbaloksy. Forbindelser med formel I hvor R' er -NH^(amino) og nevnte salter er anvendbare carbamyl or lower-carboxy. Compounds of formula I where R' is -NH 2 (amino) and said salts are useful
som kardiotoniske midler slik dette ble bestemt ved hjelp av standard-kardiotoniske bedømmelsesmetoder. Foretrukkede utførelser er de hvor R' er amino, PY er 4-pyridinyl eller 3-pyridinyl og R er hydrogen, metyl, etyl eller 2-hydroksyetyl. Også andre forbindelser med formel I unntatt de hvor R<1>er karboksy eller de hvor R<1>er lavere-karbaloksy når R er hydrogen, kan brukes sam kardiotoniske midler, mens forbindelser med formel I hvor R<1>er karboksy eller hvor R' as cardiotonic agents as determined by standard cardiotonic assessment methods. Preferred embodiments are those where R' is amino, PY is 4-pyridinyl or 3-pyridinyl and R is hydrogen, methyl, ethyl or 2-hydroxyethyl. Also other compounds of formula I except those where R<1> is carboxy or those where R<1> is lower-carboxy when R is hydrogen, can be used together with cardiotonic agents, while compounds of formula I where R<1> is carboxy or where R'
er lavere-karbaloksy når R er hydrogen, kan brukes som mellomprodukter f. eks. for fremstilling av de tilsvarende forbindelser hvor R<1>er karbamyl. Videre kan man bruke forbindelser hvor R' er karbamyl eller aminokarbamyl som mellomprodukter for fremstilling av forbindelse med formel I hvor R' er amin. Foretrukkede forbindelser med formel I hvor is lower-carboxy when R is hydrogen, can be used as intermediates e.g. for the preparation of the corresponding compounds where R<1> is carbamyl. Furthermore, compounds where R' is carbamyl or aminocarbamyl can be used as intermediates for the preparation of compounds of formula I where R' is amine. Preferred compounds of formula I wherein
R' er forskjellige fra amin, er de hvor R er hydrogen,R' are different from amine, are those where R is hydrogen,
metyl eller etyl, R' er karbamyl eller aminokarbamyl og PYmethyl or ethyl, R' is carbamyl or aminocarbamyl and PY
er 4--pyridinyl eller 3-pyridinyl.is 4-pyridinyl or 3-pyridinyl.
Forbindelser med formel I hvor R er hydrogenCompounds of formula I where R is hydrogen
kan eksistere i tautomeriske former, d.v.s. som 4--R'-6-PY-3 (2H )-pyridazinoner med formel I og/éller som 4--R 1 ^6 -PY-3-pyridazinoler med formel IA, slik dette er vist nedenfor: can exist in tautomeric forms, i.e. as 4--R'-6-PY-3 (2H )-pyridazinones of formula I and/or as 4--R'-6-PY-3-pyridazinols of formula IA, as shown below:
Strukturelle preferenser for kjente 3(2H)-pyridazinoner eller 3-pyridazinoler synes å indikere at formel I er den foretrukkede tautomeriske struktur, og man har følgelig foretrukket å bruke navn basert på denne struktur I, skjønt det er underforstått at begge typer strukturer Structural preferences for known 3(2H)-pyridazinones or 3-pyridazinols seem to indicate that formula I is the preferred tautomeric structure, and consequently it has been preferred to use names based on this structure I, although it is understood that both types of structures
inngår i oppfinnelsen.included in the invention.
Man kan reagere di-(lavere-alkyl) hydroksy (2-oxo - 2-PY-etyl )propandioat (II) med et hydrazinsalt med formel RNHN^.nH An (III) slik at man får fremstilt et lavere-alkyl 2, 3-dihydro-2-R-3-okso-6-PY-4--pyridazinkarboksylat (Ia: I You can react di-(lower-alkyl) hydroxy (2-oxo - 2-PY-ethyl )propanedioate (II) with a hydrazine salt of the formula RNHN^.nH An (III) so that a lower-alkyl 2 is produced, 3-dihydro-2-R-3-oxo-6-PY-4--pyridazinecarboxylate (Ia: I
hvor R<1>er lavere-karbaloksy). Videre kan man reagere Ia med hydrazinhydrat eller vannfritt hydrazin og få frem- where R<1> is lower-carboxy). Furthermore, one can react Ia with hydrazine hydrate or anhydrous hydrazine and obtain
stilt 2, 3-dihydr o-2-R-3-okso-6-PY-4--pyridazinkarboksyl syre-hydrazid (Ib:I hvor R<1>er aminokarbamyl), og hvor PY og R stilted 2, 3-dihydr o-2-R-3-oxo-6-PY-4--pyridazinecarboxylic acid hydrazide (Ib:I where R<1>is aminocarbamyl), and where PY and R
er som definert ovenfor i forbindelsen med formel I, fortrinnsvis 4-~Pyridinyl og hydrogen eller metyl, henholdsvis, n ;er 1 eller 2, x er 1, 2 eller 3, og An er et anion av en sterk uorganisk syre eller av en organisk sulfonsyre. is as defined above in the compound of formula I, preferably 4-~Pyridinyl and hydrogen or methyl, respectively, n is 1 or 2, x is 1, 2 or 3, and An is an anion of a strong inorganic acid or of a organic sulfonic acid.
Man kan omdanne et lavere-alkyl 2,3-dihydro-2-R-3-oxo-PY-4.-pyridazinkarboksylat (Ia) til 2,3-dihydro-2-R-3-okso-6-PY-4--Pyridazinkarboksamid (Ic:I, hvor R' er karbamyl) enten ved en direkte reaksjon med ammoniakk eller via den tilsvarende 2, 3-dihydro -2 -R-3-oxo-6 -PY-4.-pyr idazin - karboksyl syre (ld:I hvor R' er karboksy), ved å hydrolysere esteren til syre og deretter reagere denne med et klorerings-middel for fremstilling av syrekloridet som så omsettes med ammoniakk til nevnte karboksamid (Ic hvor R' er karbamyl), One can convert a lower-alkyl 2,3-dihydro-2-R-3-oxo-PY-4.-pyridazine carboxylate (Ia) into 2,3-dihydro-2-R-3-oxo-6-PY-4 --Pyridazinecarboxamide (Ic:I, where R' is carbamyl) either by a direct reaction with ammonia or via the corresponding 2, 3-dihydro-2-R-3-oxo-6-PY-4.-pyridazine-carboxyl acid (ld:I where R' is carboxy), by hydrolysing the ester to acid and then reacting this with a chlorinating agent to produce the acid chloride which is then reacted with ammonia to said carboxamide (Ic where R' is carbamyl),
og hvor R og PY hår samme betydning som angitt ovenfor, fortrinnsvis hydrogen eller metyl, og 4-pyridinyl, henholdsvis. and where R and PY have the same meaning as stated above, preferably hydrogen or methyl, and 4-pyridinyl, respectively.
Man kan fremstille forbindelser med formel leOne can prepare compounds of formula Ie
(I hvor R' er amino) ved å reagere 2-R-6-PY-3(2H)-pyridazinon med hydrazin. Man kan også reagere 2,3-dihydro-2-R-3-oxo-6-PY-4--pyridazinkarboksamid (Ic) med en reagens som er i stand til å omdanne karbamyl til amino, hvorved man får fremstilt 4.-amino-2-R-6-PY-3 (2H )-pyridazinon (le) eller reagere 2,3-dihydro - 2 -R -oxo -6 -PY-4--pyr ida z in kar bok syl syre -hydraz id (Ib ) med en reagens som . er i stand til å omdanne karboksyl syre-hydrazidet til amino, hvor R og PY har samme betydning som angitt ovenfor for forbindelser med formel I. Omdannelsen av Ic til le utføres fortrinnsvis ved å bruke vandig alkali-metall-hypohalit, fortrinnsvis hypobromit eller hypoklor.it. (I where R' is amino) by reacting 2-R-6-PY-3(2H)-pyridazinone with hydrazine. You can also react 2,3-dihydro-2-R-3-oxo-6-PY-4--pyridazinecarboxamide (Ic) with a reagent capable of converting carbamyl to amino, whereby 4 is produced.- amino-2-R-6-PY-3 (2H )-pyridazinone (le) or react 2,3-dihydro - 2 -R -oxo -6 -PY-4--pyr ida z in kar bok syl syre -hydraz id (Ib ) with a reagent which . is capable of converting the carboxylic acid hydrazide to amino, where R and PY have the same meanings as given above for compounds of formula I. The conversion of Ic to Ie is preferably carried out using aqueous alkali metal hypohalite, preferably hypobromite or hypochlorite .it.
Omdannelsen av Ib til le utføres fortrinnsvis ved å bruke salpetersyre. The conversion of Ib to Le is preferably carried out using nitric acid.
Foreliggende oppfinnelse angår videre di-(lavere-alkyl)hydroksy(2-oxo-2-PY-etyl ) propandioater med formel The present invention further relates to di-(lower-alkyl)hydroxy(2-oxo-2-PY-ethyl)propanedioates of the formula
II II
eller syreaddisjonssalter av disse forbindelser, hvor PY er som definert i forbindelsen med formel I, fortrinnsvis 4-pyridinyl eller 3-pyridinyl og R i er lavere-alkyl, fortrinnsvis etyl eller metyl. or acid addition salts of these compounds, where PY is as defined in the compound of formula I, preferably 4-pyridinyl or 3-pyridinyl and R i is lower alkyl, preferably ethyl or methyl.
Man kan reagere acetylpyridin med formelOne can react acetylpyridine with formula
PY-COCH^(IV) med di-(lavere-alkyl) oxomalonat for å få fremstilt di -(lavere-alkyl)hydroksy(2-oxo-2-PY-etyl)propan - dioat (II) hvor PY er som definert i formel I ovenfor, fortrinnsvis 4--pyridinyl. PY-COCH^(IV) with di-(lower-alkyl)oxomalonate to obtain di-(lower-alkyl)hydroxy(2-oxo-2-PY-ethyl)propane-dioate (II) where PY is as defined in formula I above, preferably 4-pyridinyl.
En kardiotonisk sammensetning for å øke hjertets kontraktilitet innbefatter et farmasøytisk akseptabelt inert bærestoff og som en aktiv komponent, en effektiv mengde av den kardiotoniske forbindelsen 2-R-4--R 1 -PY-3 (2H ) -pyridazinon med formel I, d.v.s. hvor R' er amino, karbamyl, aminokarbamyl eller lavere-karbaloksy, R er hydrogen, lavere-alkyl eller lavere-hydroksyalkyl, men bare lavere-alkyl eller lavere-hydroksyalkyl når R' er lavere-karbaloksy, og PY er som definert ovenfor i formel I, eller et farmasøytisk akseptabelt syreaddisjonssalt av slike forbindelser. Foretrukne kardiotoniske forbindelser er de hvor PY er 4--pyridinyl eller 3-pyridinyl. A cardiotonic composition for increasing cardiac contractility comprises a pharmaceutically acceptable inert carrier and, as an active component, an effective amount of the cardiotonic compound 2-R-4--R 1 -PY-3 (2H )-pyridazinone of formula I, i.e. where R' is amino, carbamyl, aminocarbamyl or lower-carboxy, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, but only lower-alkyl or lower-hydroxyalkyl when R' is lower-carboxy, and PY is as defined above in formula I, or a pharmaceutically acceptable acid addition salt of such compounds. Preferred cardiotonic compounds are those wherein PY is 4-pyridinyl or 3-pyridinyl.
For å øke hjertets kontraktilitet hos en pasient som krever en slik behandling, kan man oralt eller parenteralt tilføre i fast eller flytende doseringsform en effektiv mengde av den kardiotoniske forbindelsen 2-R-4.-R"-6-PY-3 (2H ) - pyridazinon eller et farmasøytisk akseptabelt syreaddisjonssalt av en slik forbindelse. In order to increase the contractility of the heart in a patient requiring such treatment, an effective amount of the cardiotonic compound 2-R-4.-R"-6-PY-3 (2H ) can be administered orally or parenterally in solid or liquid dosage form - pyridazinone or a pharmaceutically acceptable acid addition salt of such a compound.
Med begrepet "lavere-alkyl" slik det brukes her,With the term "lower alkyl" as used herein,
f. eks. i forbindelse med betydningen av R (formlene I, Ia,e.g. in connection with the meaning of R (the formulas I, Ia,
Ib, Ic, Id, le eller III), i forbindelse med betydningen av R (formel II) eller som en substituent for PY (formel I, Ib, Ic, Id, le or III), in conjunction with the meaning of R (formula II) or as a substituent for PY (formula I,
Ia, Ib, Ic, Id, le eller II),,forståes alkylradikaler medIa, Ib, Ic, Id, le or II),, are understood as alkyl radicals
fra 1':• til 6 karbonatomer som kan forefinnes i rette eller grenete kjeder, så som metyl, etyl, n-propyl, isopuopyl, n-butyl, 2-butyl, isobutyl. from 1':• to 6 carbon atoms which may be present in straight or branched chains, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl.
Med symbolet PY slik det brukes her, f. eks. som 6-substituenten i forbindelser med formlene I, Ia, Ib, Ic, With the symbol PY as used here, e.g. as the 6-substituent in compounds of formulas I, Ia, Ib, Ic,
Id, le eller II, forståes 4-- eller 3-pyridinyl eller 4--Id, Ie or II, is understood as 4-- or 3-pyridinyl or 4--
eller 3-pyridinyl med en eller to "lavere-alkyl" substituenter, f. eks. 2-metyl-4-pyridinyl, 2,6-dimetyl-4-pyridinyl, 3-metyl-4.-pyridinyl, 2-metyl-3-pyr idinyl, 6-metyl-3-pyr idinyl (alternativt kalt 2-metyl-5-pyridinyl, 2,3-dimetyl-4-pyridinyl, 2,6-dimetyl-4--pyridinyl, 2-etyl-4--pyridinyl, 2-isopropyl-4--pyridinyl, 2-n-butyl-4--pyridinyl, 2-n-hexyl-4--pyridinyl, 2, 6-dimetyl-4--pyridinyl, 2, 6-dimetyl-3-pyridinyl, 2, 6-diisopropyl-4--pyridinyl, 2, 6-di-n-hexyl-4--pyridinyl, o.l. or 3-pyridinyl with one or two "lower alkyl" substituents, e.g. 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4.-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively called 2-methyl -5-pyridinyl, 2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl- 4--pyridinyl, 2-n-hexyl-4--pyridinyl, 2, 6-dimethyl-4--pyridinyl, 2, 6-dimethyl-3-pyridinyl, 2, 6-diisopropyl-4--pyridinyl, 2, 6-di-n-hexyl-4-pyridinyl, etc.
Med begrepet "lavere-hydroksyalkyl" slik det brukes her, f. eks. i forbindelse med betydningen av R i formléne I, Ia, Ib, Ic, Id, le eller III, forståes hydroksyalkyl-radikaler med fra 2. til 6 karbonatomer, og som har sin hydroksy-gruppe og sin frie valentbinding (eller en tilknyttende binding) på forskjellige karbonatomer, og hvor nevnte gruppe kan være rett eller grenet, så som 2-hydroksyetyl ,-■ < 2-hydroksypropyl, 3-hydroksypropyl, 2-hydroksy-2-metylpropyl, 2-hydroksy-1, 1-dimetyletyl, 4--hydr oksybutyl, 5 -hydro ksyamyl, 6-hydroksyhexyl, o.l. With the term "lower hydroxyalkyl" as used herein, e.g. in connection with the meaning of R in the formulas I, Ia, Ib, Ic, Id, le or III, hydroxyalkyl radicals with from 2 to 6 carbon atoms, and which have their hydroxy group and their free valence bond (or an associated bond ) on different carbon atoms, and where said group can be straight or branched, such as 2-hydroxyethyl ,-■ < 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-1, 1-dimethylethyl, 4-hydroxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl, etc.
Med begrepet "lavere-karbaloksy", slik det brukes her, f. eks. i forbindelse med betydningen av R' i formlene I og Ia, forståes karbaloksy-radikaler hvor alkoksydelen kan være rett eller grenet og kan inneholde fra 1 til 6 karbonatomer, f. eks. karbometoksy, karbetoksy, karbo-n-propoksy, karbisopropoksy, karbo-n-butoksy, karbo-tert.-butoksy og karbo -n -hexoksy. With the term "lower carboxy" as used herein, e.g. in connection with the meaning of R' in the formulas I and Ia, carbolic radicals are understood where the alkoxy part can be straight or branched and can contain from 1 to 6 carbon atoms, e.g. carbomethoxy, carbethoxy, carbo-n-propoxy, carbisopropoxy, carbo-n-butoxy, carbo-tert-butoxy and carbo-n-hexoxy.
Forbindelse ifølge foreliggende oppf innel se o. med formlene I, Ia, Ib, Ic, le og II kan brukes både i form av den frie basen og i form av syreaddisjonssalter, og begge formler inngår i oppfinnelsen. Syreaddisjonssaltene vil vanligvis være mer hensiktsmessig å bruke i praksis, og gir samme virkning som baseformen. De syrer som brukes for å fremstille syreaddisjonssalter innbefatter fortrinnsvis de som når de kombineres med den frie basen, gir farmasøytisk akseptable salter, d.v.s. salter hvis anioner er relativt ufarlige i dyreorganismen når de brukes i farmasøytiske doser av saltene, slik at de fordelaktige kardiotoniske egen-skaper som forefinnes i den frie base ikke blir tilside- Compounds according to the present invention see etc. with the formulas I, Ia, Ib, Ic, le and II can be used both in the form of the free base and in the form of acid addition salts, and both formulas are part of the invention. The acid addition salts will usually be more appropriate to use in practice, and give the same effect as the base form. The acids used to prepare acid addition salts preferably include those which, when combined with the free base, give pharmaceutically acceptable salts, i.e. salts whose anions are relatively harmless in the animal organism when used in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties found in the free base are not disregarded
satt av andre effekter som kan tilskrives anionene. Ved gjennomføring av oppfinnelsen kan man således bruke den frie baseformen, men man kan også bruke farmasøytisk akseptable salter, og disse kan man avlede fra mineralsyrer så som saltsyre,; svovelsyre, fosforsyre. og sulfaminsyre, samt organiske syrer som eddiksyre, sitronsyre, melkesyre, tartar-syre, metansulfonsyre, etansulfonsyre, benzensulfonsyre,p-toluensulfonsyre, cyklohexylsulfaminsyre, kininsyre, o.1., hvor man får hydrokloridet, sulfatet, fosfatet, sulfamatet, acetatet, sitratet,lictatet, tartratet, metansulfoantet, etan-sulfonatet, benzensulfonatet, p-toluensulfonsatet, cyklo-hexyl sulf amatet og kinatet, henholdsvis. set by other effects attributable to the anions. When carrying out the invention, the free base form can thus be used, but pharmaceutically acceptable salts can also be used, and these can be derived from mineral acids such as hydrochloric acid; sulfuric acid, phosphoric acid. and sulfamic acid, as well as organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, etc., from which the hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate are obtained , the lictate, the tartrate, the methanesulfonate, the ethanesulfonate, the benzenesulfonate, the p-toluenesulfonate, the cyclohexyl sulfamate and the quinate, respectively.
Syreaddisjonssaltene av de nevnte basiske forbindelser, fremstilles enten ved å oppløse den frie base i en vandig eller vandig-alkoholisk oppløsning eller et annet egnet oppløsningsmiddel som inneholder den passende syre, hvoretter man isolerer saltet ved å fordampe oppløsningen, eller ved å reagere den frie basen og syren i et organisk oppløsningsmiddel, og i sistnevnte tilfelle vil saltet skille seg ut direkte eller kan fremstilles ved å konsen-trere oppløsningen. The acid addition salts of the aforementioned basic compounds are prepared either by dissolving the free base in an aqueous or aqueous-alcoholic solution or another suitable solvent containing the appropriate acid, after which the salt is isolated by evaporating the solution, or by reacting the free base and the acid in an organic solvent, and in the latter case the salt will separate out directly or can be prepared by concentrating the solution.
Skjønt farmasøytisk akseptable salter av nevnte basiske forbindelse er foretrukket, så inngår alle syreaddis jonssaltene i oppfinnelsen. Alle slike syreaddisjonssalter kan brukes som utgangspunkt for fremstilling av den frie basen, selv om et spesielt salt som sådan bare er ønskelig som et mellomprodukt, f. eks. når saltet fremstilles bare for å rense eller å identifisere basen, eller når det brukes som et mellomprodukt for fremstilling av farmasøytisk akseptable salter ved ioneutbytningsmetoder. Although pharmaceutically acceptable salts of said basic compound are preferred, all acid addition salts are included in the invention. All such acid addition salts can be used as a starting point for the preparation of the free base, although a particular salt as such is only desirable as an intermediate, e.g. when the salt is prepared only to purify or identify the base, or when it is used as an intermediate for the preparation of pharmaceutically acceptable salts by ion exchange methods.
Molekylstrukturen på de foreliggende forbindelser ble fastslått på basis av infrarøde, kjernemagnetiske resonans og masse spektra, og ved en overensstemmelse mellom beregnete og funnede verdier ved elementæranalyser. The molecular structure of the present compounds was established on the basis of infrared, nuclear magnetic resonance and mass spectra, and by an agreement between calculated and found values by elemental analyses.
Fremgangsmåten for fremstilling av foreliggende forbindelse vil nå bli mer detaljert beskrevet, slik at man lettere kan følge fremgangsmåten når denne skal brukes i den farmasøytiske industri. The method for producing the present compound will now be described in more detail, so that it is easier to follow the method when it is to be used in the pharmaceutical industry.
Reaksjonen mellom et acetylpyridin med formel PY-COCH^(IV) og di (lavere-alkyl)oxomalonat for å frem- The reaction between an acetylpyridine of formula PY-COCH^(IV) and di(lower alkyl)oxomalonate to produce
stille di(lavere-alkyl) hydroksy(2-oxo-2-PY-etyl)propandioat (II) hvor PY er som definert i formel I ovenfor, gjennom-føres ved å oppvarme reaktanten_e til 80 til 120°C, fortrinnsvis meil om 90 og 110UC. Reaksj onen kan hensiktsmessig utføres på et dampbad. Reaksjonen gjennomføres ved å bruke dietyl eller dimetyloksomalonat. Denne fremgangsmåten er illustrert i eksempel A-1 til A-9-i det etterfølgende. still di(lower-alkyl) hydroxy(2-oxo-2-PY-ethyl)propanedioate (II) where PY is as defined in formula I above, is carried out by heating the reactant to 80 to 120°C, preferably over 90 and 110UC. The reaction can conveniently be carried out in a steam bath. The reaction is carried out using diethyl or dimethyl oxomalonate. This method is illustrated in Examples A-1 to A-9 below.
Fremstillingen av lavere-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4--pyridazinkarboksylater ved å reaktere de-(lavere-alkyl) hydr oksy (2-oxo-2-PY-etyl )pr opandioat (II) med et hydrazintall med formel RNHNH9. nH An (III), hvor PY The preparation of lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazine carboxylates by reacting de-(lower-alkyl) hydroxy (2-oxo-2-PY-ethyl) per opanedioate (II) with a hydrazine number of formula RNHNH9. nH An (III), where PY
og R er som definert i formel I ovenfor, og n, x og An er som definert i formel III ovenfor, gjennomføres ved å oppvarme reaktantene til temperaturer mellom 60 og 100°C, fortrinnsvis mellom 75 og 85°C, og fortrinnsvis i nærvær av et egnet oppløsningsmiddel såsom lavere-alkanol, f. eks. metanol, etanol eller isopropylalkohol. Andre egnede oppløsnings-midler er dioksan, tetrahydr of uran, pyridin, etylenglykol o.l. Foretrukne R-hydrazin salter er dihydrokloridene eller sulfatene. Denne fremgangsmåte år illustrert i det etter-følgende eksempel C-2 til C-17. Man skal også nevne eksempel and R is as defined in formula I above, and n, x and An are as defined in formula III above, is carried out by heating the reactants to temperatures between 60 and 100°C, preferably between 75 and 85°C, and preferably in the presence of a suitable solvent such as lower alkanol, e.g. methanol, ethanol or isopropyl alcohol. Other suitable solvents are dioxane, tetrahydrofuran, pyridine, ethylene glycol and the like. Preferred R-hydrazine salts are the dihydrochlorides or sulfates. This method is illustrated in the following example C-2 to C-17. An example must also be mentioned
B-1 hvor dietylhydroksy (2-oxo-2 - (4--pyr idinyl )etyl )pr opan - dioat ble kokt under tilbakeløp med hydrazin-monohydroklorid i metanol i relativt kort tidsrom (mindre enn 2 timer), hvor man fikk fremstilt etyl 2, 3, 4> 5-tetrahydr o-4--hydr oksy-3-oxo - 6-(4--pyridinyl )-4--pyridazinkarboksylat, som deretter, som vist i eksempel C-1, lett ble dehydrert ved å behandle en opp-løsning av forbindelsen i et egnet oppløsningsmiddel så som acetonitril, etanol, tetrahydrofuran eller dioksan, med hydrogenklorid, hvorved man fikk fremstilt etyl 2,3-dihydro-3-oxo - 6 - (4-pyr idinyl ) -4--py r ida z in karboksyl at. B-1 where diethylhydroxy (2-oxo-2 - (4--pyridinyl)ethyl)propan-dioate was boiled under reflux with hydrazine monohydrochloride in methanol for a relatively short time (less than 2 hours), during which one obtained ethyl 2,3,4>5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate, which then, as shown in Example C-1, was easily dehydrated by treating a solution of the compound in a suitable solvent such as acetonitrile, ethanol, tetrahydrofuran or dioxane, with hydrogen chloride, whereby ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)- was produced 4--pyr ida z in carboxyl at.
Omdannelsen av et lavere-alkyl 2,3-dihydro-2-R-3-oxo-6-PI-4-pyridazinkarboksylat (Ia) til det tilsvarende 4- -pyr idaz inkarboks amid (Ic ) kan hensiktsmessig gjennomføres ved ,at man kobler ammoniakk inn i en oppløsning av Ia i et passende inert oppløsningsmiddel, så som en lavere-alkanol, fortrinnsvis etanol eller metanol. Andre egnede oppiøsningsmidler innbefatter isopropylalkohol, acetonitril, tetrahydrofuran, dioksan o.l. Reaksjonen lar seg lett gjennomføre ved romtemperatur. Denne fremgangsmåte er illu-srert i det etterfølgende i eksemplene D-1 til D-16. The conversion of a lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PI-4-pyridazine carboxylate (Ia) to the corresponding 4-pyridaz incarboxamide (Ic) can conveniently be carried out by couples ammonia into a solution of Ia in a suitable inert solvent, such as a lower alkanol, preferably ethanol or methanol. Other suitable solubilizers include isopropyl alcohol, acetonitrile, tetrahydrofuran, dioxane and the like. The reaction can easily be carried out at room temperature. This method is illustrated in the following in examples D-1 to D-16.
Omdannelsen av et lavere-alkyl 2, 3-dihydro-2-R-3-oxo-6-PY-pyridazinkarboksylat (Ia) til det tilsvarende 2,3-dihydro-2-R-3-oxo-6-PY-pyridaz inkarboksyl syre-hydrazin (Ib) ved en reaksjon med hydrazinhydrat eller vannfritt hydrazin gjennomføres ved at man oppvarmer reaktantené til temperaturer mellom 60 og 100°, fortrinnsvis mellom 75 og 85°C i et egnet oppløsningsmiddel, f. eks. en lavere-alkanol, så som metanol, etanol eller isopropylalkohol. Andre egnede opp-løsningsmidler innbefatter pyridin, tetrahydrofuran, dioksan o.l. Denne fremgangsmåten ér illustrert i eksempel E-1 til E-16. The conversion of a lower-alkyl 2, 3-dihydro-2-R-3-oxo-6-PY-pyridazine carboxylate (Ia) to the corresponding 2,3-dihydro-2-R-3-oxo-6-PY-pyridaz incarboxylic acid hydrazine (Ib) by a reaction with hydrazine hydrate or anhydrous hydrazine is carried out by heating the reactants to temperatures between 60 and 100°, preferably between 75 and 85°C in a suitable solvent, e.g. a lower alkanol, such as methanol, ethanol or isopropyl alcohol. Other suitable solvents include pyridine, tetrahydrofuran, dioxane and the like. This procedure is illustrated in examples E-1 to E-16.
En hydrolyse av et lavere-alkyl 2,3-dihydro-2-R - 3-oxo-6-PY-pyridazinkarboksylat (Ia) til den tilsvarende karboksyl syren (Id) gjennomføres ved å oppvarme esteren i. A hydrolysis of a lower alkyl 2,3-dihydro-2-R-3-oxo-6-PY-pyridazine carboxylate (Ia) to the corresponding carboxylic acid (Id) is carried out by heating the ester i.
(Ia med en vandig al kal imetall-hydroksydoppløsning, f. eks. vandig natriumhydroksydoppløsning, f. eks. ved å oppvarme (Ia with an aqueous alkali metal hydroxide solution, e.g. aqueous sodium hydroxide solution, e.g. by heating
reaktantene på et dampbad. Alternativt kan hydrolysen av nevnte 4--pyridazinkarboksylat (Ia) til 4--pyr idaz inkarboksyl - syre (Id) gjennomføres ved at man oppvarmer esteren Ia med en vandig oppløsning av en sterk uorganisk syre som saltsyre, svovelsyre, o.l. Denne hydrolysen er vist i eksempel F-1 til F-16. the reactants on a steam bath. Alternatively, the hydrolysis of said 4-pyridazine carboxylate (Ia) to 4-pyridaz incarboxylic acid (Id) can be carried out by heating the ester Ia with an aqueous solution of a strong inorganic acid such as hydrochloric acid, sulfuric acid, etc. This hydrolysis is shown in Examples F-1 to F-16.
Omdannelsen av 2, 3-dihydr o-3-oxo-6-PY-4--pyri-dazinkarboksylsyre-hydrazid (Ib) til 4-amino-2-R-6-PY-3 (2H)-pyridazinon (le) gjennomføres ved atiiman reagerer Ib med en reagent som er i stand til å omdanne karboksyl syre-hydrazid til amino. Reaksjonen gjennomføres ved først å reagere Ib med salpetersyre i et vandig medium med lav temperatur, fortrinnsvis udner 5°C, hvorved man får dannet det tilsvarende -4--pyridazinkarboksyl syre-azid in situ hvoretter man oppvarmer reaksjonsblandingen, fortrinnsvis til temperaturer mellom 4.5 og 65°C, inntil utviklingen av nitrogen stopper opp. The conversion of 2,3-dihydr o-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ib) to 4-amino-2-R-6-PY-3 (2H)-pyridazinone (le) carried out by atiiman reacts Ib with a reagent capable of converting carboxylic acid hydrazide to amino. The reaction is carried out by first reacting Ib with nitric acid in an aqueous medium at a low temperature, preferably below 5°C, whereby the corresponding -4-pyridazinecarboxylic acid azide is formed in situ, after which the reaction mixture is heated, preferably to temperatures between 4.5 and 65°C, until the evolution of nitrogen stops.
Denne omdannelsen er vist i eksempel G-1 og fra G-23 tilThis conversion is shown in Example G-1 and from G-23 to
G-41 • G-41 •
Omdannelsen av 2, 3 -dihydro -2 -R-3-oxo-6 -PY pyridazinkarboksamid (Ic) til 4-amino-2-R-6-PY-3(2H)-pyridazinon (le) utføres ved at man reagerer Ic med en reagens som er i stand til å omdanne karbamyl til amino. Reak- The conversion of 2,3-dihydro-2-R-3-oxo-6-PY pyridazinecarboxamide (Ic) to 4-amino-2-R-6-PY-3(2H)-pyridazinone (le) is carried out by reacting Ic with a reagent capable of converting carbamyl to amino. Reac-
sjonen utføres ved at man oppvarmer en vandig blanding inneholdende Ic, og et alkalimetall^hypoalit, fortrinnsvis hypobromit eller hypoklorit, hvoretter man surgjør reaksjonsblandingen, fortrinnsvis med en vandig mineralsyre, så som saltsyre. Reaksjonen kan gjennomføres ved t:emperaturer fra 50 til 120°C, fortrinnsvis mellom 70 og 100°. Denne omdannelse er illustrert i det etterfølgende i eksemplene G-4-2 til G-61. The reaction is carried out by heating an aqueous mixture containing Ic and an alkali metal, hypoalite, preferably hypobromite or hypochlorite, after which the reaction mixture is acidified, preferably with an aqueous mineral acid, such as hydrochloric acid. The reaction can be carried out at temperatures from 50 to 120°C, preferably between 70 and 100°. This conversion is illustrated below in Examples G-4-2 to G-61.
Omdannelsen av 2-R-6-PY-3-(2H ) -pyridazinon til 4.-amino-2-R-6-PY-3 (2H )-pyridazinon (le) ved en reaksjon med hydroazin-hydrat eller vannfri hydrazin utføres ved at man omdanner reaktanten i et fravær eller nærvær av et egnet inert oppløsningsmiddel, til temperaturer mellom 80 og 130°C, fortrinnsvis mellom 90 og 110°C. Skjønt reaksjonen kan gjennom- føres fortrinnsvis ved å bruke et overskudd av hydrazin eller hydrazinhydrat som oppløsningsmiddel, så kan den også gjennomføres ved å bruke et egnet inert oppløsningsmiddel som dioksan, etanol, etylenglykol-dimetyleter, o.l. Alternativt kan reaksjonen utføres i en autoklav med eller uten et oppløsningsmiddel. Denne omdannelsen er vist i eksemplene G-2 til G-22. The conversion of 2-R-6-PY-3-(2H )-pyridazinone to 4.-amino-2-R-6-PY-3 (2H )-pyridazinone (le) by a reaction with hydrazine hydrate or anhydrous hydrazine is carried out by converting the reactant in the absence or presence of a suitable inert solvent, to temperatures between 80 and 130°C, preferably between 90 and 110°C. Although the reaction can preferably be carried out by using an excess of hydrazine or hydrazine hydrate as solvent, it can also be carried out by using a suitable inert solvent such as dioxane, ethanol, ethylene glycol dimethyl ether, etc. Alternatively, the reaction can be carried out in an autoclave with or without a solvent. This conversion is shown in Examples G-2 to G-22.
Fremstillingen av de intermediære 4-» 5 -dihydro - 2-(lavere-alkyl)-6-PY-3(2H)-pyridazinoner ved at man reagerer et 4-oxo-4-PY-butanitril med et N-R-hydrazinsalt av en sterk.uorganisk syre eller organisk sulfonsyre, noe som gir de overnevnte 4-» 5 -dihydro-2- (lavere-alkyl eller lavere-hydroksyalkyl)-6-PY-3(2H)-pyridazinoner og deres anvendelse som kardiotoniske midler, er beskrevet i US-patentsøknad nr. U4-.564., 24-3.4.72 og 24-5.086. The preparation of the intermediate 4-»5-dihydro-2-(lower-alkyl)-6-PY-3(2H)-pyridazinones by reacting a 4-oxo-4-PY-butanitrile with an N-R-hydrazine salt of a strong inorganic acid or organic sulfonic acid, giving the above-mentioned 4-»5-dihydro-2-(lower-alkyl or lower-hydroxyalkyl)-6-PY-3(2H)-pyridazinones and their use as cardiotonic agents, is described in US Patent Application Nos. U4-.564., 24-3.4.72 and 24-5.086.
Fremstillingen av de intermediære 4-» 5-dihydro-6-PY-3(2H )-pyridazinoner eller deres tautomeriske 4»5-dihydro-6-PY-3-pyridazinol.er ved en reaksjon med 4-oxo-4--PY-butanitril, er vist i eksemplene H-1 til H-6. The preparation of the intermediate 4-»5-dihydro-6-PY-3(2H )-pyridazinones or their tautomeric 4»5-dihydro-6-PY-3-pyridazinols by a reaction with 4-oxo-4-- PY-butanitrile, is shown in Examples H-1 to H-6.
De intermediære 4-oxo-4--PY-butanitriler er generelt kjente forbindelser, se f. eks. Stetter et al. Chem. Ber. 107, 210 (1 974-)» og kan fremstilles ved fremgangsmåter som i seg selv er kjente. The intermediate 4-oxo-4-PY-butanitriles are generally known compounds, see e.g. Stetter et al. Chem. Pray. 107, 210 (1 974-)" and can be produced by methods which are known per se.
Oimdannelsen av de intermediære 4-» 5-dihydro-2-R-6-PY-3(2H)-pyridazinoner eller hvor R er H, de tautomeriske 4-, 5-dihydro-6-PY-3-pyr idaz inoler ved en reaksjon med brom til de tilsvarende intermediære 2-R-6-PY-3(2H)-pyridazinoner, samt deres anvendelse som kardiotoniske midler, er beskrevet i den verserende patentsøknad nr. 802507 innsendt 22/8-80. The conversion of the intermediate 4-»5-dihydro-2-R-6-PY-3(2H)-pyridazinones or where R is H, the tautomeric 4-,5-dihydro-6-PY-3-pyridaz inols by a reaction with bromine to the corresponding intermediate 2-R-6-PY-3(2H)-pyridazinones, as well as their use as cardiotonic agents, is described in Pending Patent Application No. 802507 filed 8/22-80.
De følgende eksempler illustrerer oppfinnelsen.The following examples illustrate the invention.
A. Di - ( lavere - alkyl ) hydroksy ( 2- oxo- 2 - ( pyridinyl ) e tyl ) propandioater. A. Di-(lower-alkyl)hydroxy (2-oxo-2-(pyridinyl)ethyl)propanedioates.
A -1 . Die tyl hydr oksy (2-oxo -2 - (4-py r idinyl )e tyl )pro - pandioat. A-1. Diethyl hydroxy (2-oxo-2- (4-pyridinyl)ethyl)propanedioate.
En blanding inneholdende 8,71 g dietyloxomalonat og 6, 06 g 4--acetylpyridin ble oppvarmet på et dampbad i 3 timer, og så avkjølt. En liten prøve av reaksjonsblandingen i et lite prøverør ble størknet delvis ved å gni prøven med en glass-stav mot innersiden av prøverøret. Resten av den avkjølte reaksj on sbl åndingen ble oppløst i 13 ml metanol, oppløsningen ble så avkjølt og tilsatt et par krystaller, A mixture containing 8.71 g of diethyl oxomalonate and 6.06 g of 4-acetylpyridine was heated on a steam bath for 3 hours, then cooled. A small sample of the reaction mixture in a small test tube was partially solidified by rubbing the sample with a glass rod against the inside of the test tube. The rest of the cooled reaction mixture was dissolved in 13 ml of methanol, the solution was then cooled and a few crystals added,
og den resulterende blandingen hensatt for stivning. Det faste stoff ble oppsamlet og vasket med en mindre mengde metanol og lufttørket til 4-» V g dietylhydroksy(2-oxo-2 - and the resulting mixture set aside for solidification. The solid was collected and washed with a small amount of methanol and air-dried to 4-» V g of diethylhydroxy(2-oxo-2 -
(4--pyridinyl )etyl )propandioat, sm.p. 130-131,5°. Mer produkt ble oppnådd fra moderluten på følgende måte: Det overnevnte filtrat ble fordampet til tørrhet i et roterende fordampningsapparat under oppvarming på et dampbad, og residuet ble oppvarmet i ytterligere 1 time på nevnte bad. Etter som residuet ikke var størknet, ble en liten prøve i et prøve-rør så belagt med etanol og tilsatt overnevnte produkt, og dette ga et fast stoff. Sistnevnte ble .oppløst i en mini-mummengde varm etanol, og den resulterende oppløsning ble konsentrert på et dampbad og så avkjølt. Det resulterende faste stoff ble oppsamlet, vasket med en minimum-mengde etanol og lufttørket til ytterligere 4-» 4- g di etyl hydroksy (2 -oxo -2 - (4--pyridinyl )etyl )propandioat, sm.p. 127-130°C. (4--pyridinyl)ethyl)propanedioate, m.p. 130-131.5°. More product was obtained from the mother liquor as follows: The above filtrate was evaporated to dryness in a rotary evaporator while heating on a steam bath, and the residue was heated for a further 1 hour on said bath. As the residue was not solidified, a small sample in a test tube was then coated with ethanol and the above product added, and this gave a solid. The latter was dissolved in a minimal amount of hot ethanol, and the resulting solution was concentrated on a steam bath and then cooled. The resulting solid was collected, washed with a minimum amount of ethanol and air dried to an additional 4-» 4-g of diethyl hydroxy (2-oxo-2-(4-pyridinyl)ethyl)propanedioate, m.p. 127-130°C.
De samlede to utbytter (4-, 7 +4,4 = 9,1 g eller 61,7 % utbytte) ble oppløst i ca. 23 ml varm etanol, og oppløsningen avkjølt. Det utskilte faste stoff ble vasket med litt metanol, kort lufttørket og tørket ved 25°C over P^0^ved 10 mm over week-enden, hvorved man fikk 7,4 dietyl hydroksy(2-o.xo -2 - (4--pyridinyl )etyl )propandioat, sm.p. 131^132°C. The combined two yields (4-, 7 +4.4 = 9.1 g or 61.7% yield) were dissolved in approx. 23 ml of hot ethanol, and the solution cooled. The separated solid was washed with a little methanol, briefly air-dried and dried at 25°C over P^0^at 10 mm above the week end, whereby 7,4 diethyl hydroxy(2-o.xo -2 - (4 --pyridinyl)ethyl)propanedioate, m.p. 131^132°C.
Ved å bruke den fremgangsmåte som er beskrevetBy using the procedure described
i eksempel A-1, men ved å bruke i stedenfor 4--acetylpyridin en tilsvarende molar ekvivalent mengde av et passende 3-eller 4--acetylpyridih,: kan man fremstille de tilsvarende dietyl hydroksy(2-oxo-2 -(pyridinyl)etyl)propandiater som er angitt i eksempel A-2 til A-6 nedenfor. in example A-1, but by using instead of 4--acetylpyridine a corresponding molar equivalent amount of a suitable 3- or 4--acetylpyridinium: one can prepare the corresponding diethyl hydroxy(2-oxo-2 -(pyridinyl) ethyl)propane diates as set forth in Examples A-2 to A-6 below.
A-2. Dietyl hydroksy (2-oxo-2 - (3-pyridinyl)etyl)propandioat ved å bruke 3-acetylpyridin.. A-2. Diethyl hydroxy (2-oxo-2-(3-pyridinyl)ethyl)propanedioate using 3-acetylpyridine..
A-3. Dietyl hydroksy (2-oxo-2-(2-metyl-3-pyridinyl ) etyl)propandioat ved å bruke 3-acetyl-2-metylpyridin. A-3. Diethyl hydroxy (2-oxo-2-(2-methyl-3-pyridinyl ) ethyl)propanedioate using 3-acetyl-2-methylpyridine.
A-4-. Dietyl hydroksy (2 -oxo -2 -(5-metyl-3-pyridinyl ) etyl )propandioat ved å bruke 3-acetyl-5-metylpyridin. A-4-. Diethyl hydroxy (2-oxo-2-(5-methyl-3-pyridinyl)ethyl)propanedioate using 3-acetyl-5-methylpyridine.
A-5. Dietyl hydroksy (2roxo -2-(3-etyl-4--pyridinyl )etyl ) propandiaot ved å bruke 4--acetyl-3-etylpyridin. A-5. Diethyl hydroxy (2-roxo-2-(3-ethyl-4-pyridinyl)ethyl)propanedioate using 4-acetyl-3-ethylpyridine.
A-6. Dietyl hydroksy (2-oxo-2 - (2, 6-dime tyl-4--pyridinyl ) etyl )propandiat ved å bruke 4--acetyk-2, 6-dimetylvpyridin. A-6. Diethyl hydroxy (2-oxo-2-(2,6-dimethyl-4-pyridinyl)ethyl)propanediate using 4-acetic-2,6-dimethylvpyridine.
Ved å bruke den fremgangsmåte som er beskrevetBy using the procedure described
i eksempel A-1, men i steden for dietyl oxomalonat bruke en molar ekvivalent mengde av et passende di -(1avere-al kyl)oxomalonat, kan man fremstille de tilsvarende di-(lavere-alkyl) estere som er angitt i eksempel A-7 til A-9. in Example A-1, but instead of diethyl oxomalonate using a molar equivalent amount of a suitable di-(1-lower-alkyl)oxomalonate, one can prepare the corresponding di-(lower-alkyl) esters indicated in Example A- 7 to A-9.
A-7. Dimetyl hydroksy (2-oxo-2 - (4--pyridinyl )etyl )pro - pandioat. A-7. Dimethyl hydroxy (2-oxo-2 - (4--pyridinyl) ethyl ) propanedioate.
A-8. Di-n-propyl hydroksy (2 -oxo -2-(4. -pyr idinyl ) -etyl ) propandioat. A-8. Di-n-propyl hydroxy (2-oxo-2-(4.-pyridinyl)-ethyl)propanedioate.
A-9. Diisobutyl hydroksy (2 -oxo -2 - (4--pyridinyl ) -etyl) propandioat. A-9. Diisobutyl hydroxy (2-oxo-2-(4--pyridinyl)-ethyl)propanedioate.
B. Lavere- alkyl 2, 3, 4> 5- tetrahydro - 2 - R- 4.- h. ydr oksy - 3- oxo - 6- PY- 4-- pyr idaz in karboksyl at er. B. Lower alkyl 2, 3, 4> 5- tetrahydro - 2 - R- 4.- h. ydr oxy - 3- oxo - 6- PY- 4-- pyridaz in carboxyl at er.
B-1. Etyl 2, 3, 4-, 5-tetrahydro-4--hydroksy-3-oxo-6-(4--pyridinyl )-4.-pyridazinkarboksylater. -<:,>B-1. Ethyl 2,3,4-,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4.-pyridazine carboxylates. -<:,>
En 5, 9 g porsjon av dietyl hydroksy (2-oxo-2-(4--pyridinyl )etyl )propåndioat ble tilsatt en varm oppløsning inneholdende 1, 4- g hydrazin -monohydrokiorid i 150 ml metanol, og den resulterende blanding ble kokt forsiktig under tilbake-løp i 1 time og 4-5 minutter, raskt avkjølt og så destillert til tørrhet på et roterende fordampningsapparat. Det resulterende gummiaktige residium ble oppvarmet med en mindre mengde acetonitril, hvorved man fikk et krystallinsk materiale, og blandingen ble så avkjølt. Krystallene ble oppsamlet og vasket med en mindre mengde acetonitril, og luft- tørket til 2,25 g etyl 2, 3, 4-, 5-tetrahydr o-4-hydroksy-3 - oxo - 6 - (4--pyr idinyl ) -4--py r idaz in karboksyl at -hydr oki or id, sm.p. 160-163°C med dekomponering. Et 1,65 g porsjon av dette monohydroklorid ble oppløst i éå<;.>1 0 ml vann, oppløsningen filtrert og fast natriumbikarbonat ble tilsatt i små porsjoner inntil utviklingen av karbondioksyd stoppet opp. Det utfelte faste stoff ble frafiltrert, vasket med vann og tørket over P^ 0^ ved 10 mm og 25° i 6 timer, hvorved man fikk 1 v. 2 g etyl 2, 3, 4-» 5-tetrahydr o-4- -hydr oksy-3-oxo-6 - (4--pyridinyl )-4-pyridazinkarboksylat, sm.p. 1 93-1 95°C med dekomponering . A 5.9 g portion of diethyl hydroxy (2-oxo-2-(4-pyridinyl)ethyl)propanedioate was added to a hot solution containing 1.4 g of hydrazine monohydrochloride in 150 ml of methanol, and the resulting mixture was boiled gently under reflux for 1 hour 4-5 minutes, quickly cooled and then distilled to dryness on a rotary evaporator. The resulting gummy residue was heated with a small amount of acetonitrile to give a crystalline material, and the mixture was then cooled. The crystals were collected and washed with a small amount of acetonitrile, and air-dried to 2.25 g of ethyl 2,3,4-,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl) -4--pyr idaz in carboxyl at -hydr oki or id, m.p. 160-163°C with decomposition. A 1.65 g portion of this monohydrochloride was dissolved in 10 ml of water, the solution filtered and solid sodium bicarbonate added in small portions until the evolution of carbon dioxide stopped. The precipitated solid was filtered off, washed with water and dried over P^ 0^ at 10 mm and 25° for 6 hours, whereby 1 v. 2 g of ethyl 2, 3, 4-» 5-tetrahydr o-4- -hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate, m.p. 1 93-1 95°C with decomposition .
Som vist i eksmepel C-1 kan overnevnte 4-hydroksy-tetrahydro-produkt lett dehydreres ved at det behandles med en sterk uorganisk syre eller en organisk sulfonsyre, fortrinnsvis hydrogenklorid, hvorved man får fremstilt etyl - 2, 3-dihydro-3-oxo - (4--pyr idinyl ) -4--pyr idaz in karboksyl at. As shown in example C-1, the above-mentioned 4-hydroxy-tetrahydro product can be easily dehydrated by treating it with a strong inorganic acid or an organic sulphonic acid, preferably hydrogen chloride, whereby ethyl - 2, 3-dihydro-3-oxo is produced - (4--pyr idinyl ) -4--pyr idaz in carboxyl at.
Det synes således som omdannelsen slik disse er vist i eksemplene C-2 til C-17 går gjennom de tilsvarende lavere-alkyl 2, 3, 4» 5-tetrahydro-4--hydroksy-3-oxo-6-PY-4--pyridazinkarboksy-later, og ingen av disse ble isolert bortsett fra det produkt som er angitt i eksempel B-1. C. Lavere- alkyl 2, 3- dihydro- 2- R- 3- oxo- 6- PY- pyrida - zinkarboksyl ater. C-1. Etyl 2, 3-dihydro-3-oxo-6-(4-pyridinyl )-4.-pyridaz inkarboksylater. It thus appears that the conversion as shown in examples C-2 to C-17 goes through the corresponding lower-alkyl 2,3,4»5-tetrahydro-4-hydroxy-3-oxo-6-PY-4- -pyridazine carboxylates, none of which were isolated except for the product set forth in Example B-1. C. Lower alkyl 2,3-dihydro-2-R-3-oxo-6-PY-pyrida-zinc carboxyl ether. C-1. Ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4.-pyridaz incarboxylates.
Det er nedenfor angitt omdannelsen av forbindelsen fra eksempel B-1 til overnevnte forbindelse. En liters porsjon av acetonitril ble gjennomboblet med gassformet hydrogenklorid under røring i 5 minutter. Acetonitril-blandingen ble tilsatt 9» 5 g etyl 2, 3, 4-» 5-tetrahydr0-4.-hy dr oksy -3-oxo-6- (4.-pyr idinyl ) -4--pyr idaz inkarboksyl at er og hydrogenklorid ble boblet inn i blandingen i ytterligere ett kvarter. Blandingen ble så rørt i 1 time, og et fast stoff skilte seg ut. Reaksjonsblandingen ble rørt i ytterligere 2 timer og så hensatt i romtemperatur over natten (ca. 15 timer). Det hvite bunnfallet ble frafiltrert, tørket i en vakuum-ovn ved 2 timer og 4.0° over ^ 2^ 5' nvorved man fikk 8, 0 g etyl 2, 3-dihydro-3-oxo-6-(4--pyridinyl )-4--pyridazinkarboksylat-dihydroklorid, sm.p. 212-220°C med dekomponer- The conversion of the compound from Example B-1 to the above-mentioned compound is indicated below. A liter portion of acetonitrile was bubbled through with gaseous hydrogen chloride with stirring for 5 minutes. To the acetonitrile mixture was added 9.5 g of ethyl 2,3,4-5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridase incarboxyl and hydrogen chloride was bubbled into the mixture for another quarter of an hour. The mixture was then stirred for 1 hour and a solid separated out. The reaction mixture was stirred for a further 2 hours and then left at room temperature overnight (about 15 hours). The white precipitate was filtered off, dried in a vacuum oven at 2 hours and 4.0° over ^ 2^ 5' nwhereby 8.0 g of ethyl 2, 3-dihydro-3-oxo-6-(4--pyridinyl ) were obtained -4--pyridazine carboxylate dihydrochloride, m.p. 212-220°C with decomposer
ing. Hydrokloridsaltet ble oppløst i en minimal mengde vann, og oppløsningen ble gjort basisk med fast natriumbikarbonat. Det resulterende bunnfall ble frafiltrert, Eng. The hydrochloride salt was dissolved in a minimal amount of water and the solution made basic with solid sodium bicarbonate. The resulting precipitate was filtered off,
vasket med vann og tørket i en vakuum-ovn over ? 2® 5 ve0^ 25°over natten, hvorved man i.fikk 5, 5 g etyl 2, 3-dihydro-3- oxo-6-(4-pyridinyl)-4--pyridazinkarboksylat, sm.p. 196-1 97°C. C-2. Etyl 2, 3-dihydro-3-oxo-6-(4-pyridinyl )-4.-pyridazinkarboksylat. washed with water and dried in a vacuum oven over ? 2® 5 ve0^ 25° overnight, whereby 5.5 g of ethyl 2, 3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate were obtained, m.p. 196-197°C. C-2. Ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4.-pyridazinecarboxylate.
Den etterfølgende syntesen av overnevnte forbindelse ble utført ved at man direkte brukte forbindelsen fra eksempel A-1. En varm oppløsning inneholdende 16,0 g hydrazindihydroklorid i 1 liter absolutt etanol ble under rør-ing tilsatt 4-4-» 25 g dietylhydroksy (2-oxo-2-(4-pyridinyl ) - etyl)propandioat renset med 250 ml absolutt etanol, og blandingen ble kokt under tilbakeløp i 19 timer. Ca. 300 ml etanol ble avdestillert under redusert trykk, og den gjenværende blandingen ble fordampet til et lysebrunt .'fast stoff. Dette ble utrørt i 100 ml vann, og blandingen overført til The subsequent synthesis of the above-mentioned compound was carried out by directly using the compound from Example A-1. A hot solution containing 16.0 g of hydrazine dihydrochloride in 1 liter of absolute ethanol was added with stirring to 4-4-»25 g of diethylhydroxy (2-oxo-2-(4-pyridinyl)-ethyl)propanedioate purified with 250 ml of absolute ethanol , and the mixture was refluxed for 19 hours. About. 300 ml of ethanol was distilled off under reduced pressure and the remaining mixture was evaporated to a light brown solid. This was stirred in 100 ml of water, and the mixture transferred to
en 500 ml kolbe, hvor produktet ble renset med 25 ml vann.a 500 ml flask, where the product was purified with 25 ml of water.
Den vandige oppløsning ble forsiktig tilsatt fast natriumbikarbonat inntil utviklingen av karbondioksyd stoppet opp. Det faste stoff ble oppsamlet, renset med vann, lufttørket Solid sodium bicarbonate was carefully added to the aqueous solution until the evolution of carbon dioxide stopped. The solid was collected, washed with water, air dried
og tørket i vakuum-ovn over P^0^ved 10 mm i 25°C, hvorved man fikk 2, 3-dihydro-3-oxo-6-(4--pyridinyl )-4,-pyridazinkarboksylat. C-3- Etyl - 2, 3-dihydro-2-metyl - 3-oxo-6- (4--pyridinyl ) - 4- -pyridaz inkarboksyl at. and dried in a vacuum oven over P₂O₂ at 10 mm at 25°C, whereby 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4,-pyridazinecarboxylate was obtained. C-3- Ethyl - 2, 3-dihydro-2-methyl - 3-oxo-6-(4--pyridinyl )-4- -pyridaz incarboxyl at.
En blanding inneholdende 26 g 1-metylhydrazin-dihydroklor id, 148 g dietyl-hydroksy (2-oxo-2 - (4--pyr idinyl ) etyl)propandioat i 1500 ml absolutt etanol ble kokt under til-bakeløp over natten (ca. 15 timer), hvoretter blandingen ble oppvarmet i vakuum for å fjerne oppi øsning sniiddele t, og det gjenværende gummiaktige materialet ble oppløst i 600 ml vann hvoretter den vandige oppløsningen ble gjort basisk med fast kaliumkarbonat inntil den var basisk på litmus-papir. Det utfelte faste-;stoff ble oppsamlet og siden slått sammen med ytterligere produkt oppnådd fra filtratet som enda var surt. Filtratet ble gjort basisk med 10 % vandig kaliumkarbonat, og den alkaliske blandingen ble ekstra-hert med kloroform hvoretter ekstraktet ble oppvarmet i vakuum for å fjerne nevnte kloroform. Det resulterende faste prodiikt ble slått sammen med overnevnte produkt, og det hele ble omkrystallisert fra etylacetat og n-hexan og først tørket ved 4-0°C i 17 timer og så ved 60°C i 17 timer, og dette ga totalt 34- g etyl 2,3-dihydro-2-metyl-3-oxo-6-(4--pyridinyl )-4.-pyridazinkarboks.ylat, sm.p. 128-129°C. A mixture containing 26 g of 1-methylhydrazine dihydrochloride, 148 g of diethyl hydroxy (2-oxo-2-(4-pyridinyl)ethyl)propanedioate in 1500 ml of absolute ethanol was refluxed overnight (approx. 15 hours), after which the mixture was heated in vacuo to remove the ladle cut pieces, and the remaining gummy material was dissolved in 600 ml of water after which the aqueous solution was made basic with solid potassium carbonate until it was basic on litmus paper. The precipitated solid was collected and then combined with additional product obtained from the filtrate which was still acidic. The filtrate was basified with 10% aqueous potassium carbonate and the alkaline mixture was extracted with chloroform after which the extract was heated in vacuo to remove said chloroform. The resulting solid product was combined with the above product, and the whole was recrystallized from ethyl acetate and n-hexane and first dried at 4-0°C for 17 hours and then at 60°C for 17 hours, giving a total of 34- g ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4.-pyridazinecarboxylate, m.p. 128-129°C.
Syreaddis jonssalter..av etyl 2, 3-dihydro-2-metyl-3-oxo-6-(4--pyridinyl )4--pyridazinkarboks,ylat kan hensiktsmessig fremstilles ved at man tilsetter en blanding av 1 g etyl 2, 3-dihydro -2 -metyl - 3-oxo-6 - (4--pyr idinyl ) -4 -pyr idaz in - karbokaylat i 20 ml vandig metanol en passende syre, f. eks. saltsyre, metansulfonsyre, svovelsyre, til en pH på fra 2 Acid addition salts of ethyl 2, 3-dihydro-2-methyl-3-oxo-6-(4--pyridinyl)4--pyridazine carboxylate can conveniently be prepared by adding a mixture of 1 g of ethyl 2, 3 -dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazine-carboxylate in 20 ml of aqueous methanol a suitable acid, e.g. hydrochloric acid, methanesulfonic acid, sulfuric acid, to a pH of from 2
til 3, hvoretter man avkjøler blandingen etter delvis fordampning og frafiltrerer det utfelte salt, d.v.s. hydro-klorider, metansulfonater, eller sulfatet henholdsvis. Alternativt kan lactatet eller hydrokloridsyreaddisjons - saltet av etyl 2, 3-dihydro -2-metyl-3-oxo-6 - (4--pyridinyl )-4--pyridazinkarboksylat hensiktsmessig fremstilles i en vandig oppløsning ved at man tilsetter vannet under røring molare ekvivalente mengder av både etyl 2,3-dihydro-2-metyl-3-oxo -6-(4.-pyridinyl ) -4--pyridazinkarbokSylat og melkesyre eller saltsyre, ahenholdsvis. to 3, after which the mixture is cooled after partial evaporation and the precipitated salt is filtered off, i.e. hydrochlorides, methanesulfonates, or the sulfate respectively. Alternatively, the lactate or hydrochloric acid addition salt of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazine carboxylate can conveniently be prepared in an aqueous solution by adding the water while stirring molar equivalent amounts of both ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4.-pyridinyl)-4-pyridazine carboxylate and lactic acid or hydrochloric acid, respectively.
Ved å bruke den fremgangsmåte som er beskrevetBy using the procedure described
i eksempel C-2, men i steden for dietylhydroksy (2-oxo-2- (4.-pyridinyl )etyl )propandioat bruker en molar ekvivalent mengde av et passende dietylhydroksy(2-oxo -2-(pyridinyl)etyl ) propandioat, kan man fremstille de tilsvarende etyl 2,3- in Example C-2, but instead of diethylhydroxy (2-oxo-2-(4.-pyridinyl)ethyl)propanedioate use a molar equivalent amount of an appropriate diethylhydroxy(2-oxo-2-(pyridinyl)ethyl)propanedioate, can one prepare the corresponding ethyl 2,3-
dihydro-3-oxo-6-(pyridinyl)- A-pyridazinkarboksylater som er angitt i eksemplene C-4- til og med C-8. dihydro-3-oxo-6-(pyridinyl)-A-pyridazine carboxylates set forth in Examples C-4 through C-8.
G- A- Etyl 2, 3-dihydro-3-OXO-6-(3-pyridinyl )-4--pyri-dazinkarbo ksylat. C-5. Etyl 2,3-dihydro-6-(2-metyl-3-pyridinyl)-3-oxo- A-pyridazinkarboksylat. C-6. Etyl 2,3-dihydro-6-(5-metyl-3-pyridinyl)-3-oxo- A-pyridazinkarboksylat. C-7. Etyl 6-(3-etyl-pyridinyl )-2, 3-dihydro-3-oxo-4.-pyridazinkarboksylat. C-8. Etyl 2,3-dihydro-6-(2,6-dimetyl- A-pyridinyl)-3- oxo- A-pyridazinkarboksylat. G-A- Ethyl 2,3-dihydro-3-OXO-6-(3-pyridinyl)-4-pyridazinecarboxylate. C-5. Ethyl 2,3-dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-A-pyridazinecarboxylate. C-6. Ethyl 2,3-dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-A-pyridazinecarboxylate. C-7. Ethyl 6-(3-ethyl-pyridinyl)-2,3-dihydro-3-oxo-4.-pyridazinecarboxylate. C-8. Ethyl 2,3-dihydro-6-(2,6-dimethyl-A-pyridinyl)-3-oxo-A-pyridazinecarboxylate.
Ved å brukde den fremgangsmåte som er beskrevetBy using the procedure described
i eksempel C-3, men i steden for 1-metylhydrazindihydroklorid bruke en molar ekvivalent mengde av et tilsvarende 1-R-hydrazindihydroklorid eller et annet salt av sterk uorganisk syre eller en organisk sulfonsyre, kan man fremstille de tilsvarende etyl 2,3-dihydro-2-R-3-oxo-6- (4-pyridinyl)-4-pyridazinkarboksylater som er angitt i eksemplene C-9 til og med C-1 7. in example C-3, but instead of 1-methylhydrazine dihydrochloride use a molar equivalent amount of a corresponding 1-R-hydrazine dihydrochloride or another salt of a strong inorganic acid or an organic sulfonic acid, one can prepare the corresponding ethyl 2,3-dihydro -2-R-3-oxo-6-(4-pyridinyl)-4-pyridazine carboxylates set forth in Examples C-9 through C-17.
C-9. Etyl 2-etyl-2, 3-dihydro-3-0X0-6-(-4-pyridinyl )-4- pyridazinkarboksylat. C-10. Etyl 2-isopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-A-pyridazinkarboksylat. C-1 1. Etyl 2, 3-dihydro-3~oxo -2 -n -propyl-6 - (4--pyridinyl ) - A-pyridazinkarboksylat. C-12. Etyl 2, 3-dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl )-4--pyridazinkarboksylat. C-13. Etyl 2-n-hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4.-pyridazinkarbok.sylat. C-14-. Etyl 2, 3-dihydro-2-(2-hydroksyetyl )-3-oxo-6-(4--pyridinyl ) -4-py r idaz in kar bo ksylat. C-15. Etyl 2,3-dihydro-2-(2-hydroksypropyl )-3-oxo-6-(4-pyridinyl)-4-pyridazinkarboksylat. C-16. Etyl 2,3-dihydro-2-(3-hydroksypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinkarboksylat. C-17. Etyl 2,3-dihydro-2-(4-hydroksybutyl)-3-oxo-6- (4-pyridinyl ) -4-pyridazinkarboksylat. D. Lavere-alkyl 2,3-dihydro-2-R-oxo-6-PY-4-pyridazin - karboksamider. D-1 . 2,3-dihydro -2 -metyl -3-oxo-6 - (4-pyridinyl ) - 4-pyridazinkarboksamid. C-9. Ethyl 2-ethyl-2,3-dihydro-3-OXO-6-(-4-pyridinyl)-4-pyridazinecarboxylate. C-10. Ethyl 2-isopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-A-pyridazinecarboxylate. C-1 1. Ethyl 2, 3-dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)-A-pyridazinecarboxylate. C-12. Ethyl 2,3-dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. C-13. Ethyl 2-n-hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4.-pyridazine carboxylate. C-14-. Ethyl 2, 3-dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4--pyridinyl)-4-pyridase carboxylate. C-15. Ethyl 2,3-dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. C-16. Ethyl 2,3-dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. C-17. Ethyl 2,3-dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. D. Lower alkyl 2,3-dihydro-2-R-oxo-6-PY-4-pyridazine - carboxamides. D-1. 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.
Ammoniakk ble boblet inn i 800 ml absolutt etanol under røring \ ±-løpet av 20 minutter. Blandingen ble så tilsatt 50 g etyl 2,3-dihydro-2-metyl-3-oxo-6-(4-pyridinyl ) - 4-pyridazinkarboksylat, og blandingen ble så rørt i 40 minutter og så hensatt ved romtemperatur over natten. Bunnfallet ble frafiltrert, vasket med absolutt etanol, og omkrystallisert fra absolutt etanol og tørket i vakuum-ovn over natten, noe som ga 15 g 2,3-dihydro-2-metyl-3-oxo-6-(4-pyridinyl)-4-pyridazinkarboksamid, sm.p. 234-235 C. Ytterligere 17,5 g produkt ble oppnådd ved å avdestillere oppiøsningsmiddelet fra moderluten. Ammonia was bubbled into 800 ml of absolute ethanol with stirring over the course of 20 minutes. To the mixture was then added 50 g of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate, and the mixture was then stirred for 40 minutes and then left at room temperature overnight. The precipitate was filtered off, washed with absolute ethanol, and recrystallized from absolute ethanol and dried in a vacuum oven overnight, yielding 15 g of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)- 4-pyridazinecarboxamide, m.p. 234-235 C. A further 17.5 g of product was obtained by distilling off the solvent from the mother liquor.
Syreaddisjonssaltene av 2,3-dihydro-2-metyl-3-oxo-6-(4-pyridinyl)-4-pyridazinkarboksamid kan hensiktsmessig fremstilles ved å tilsette én blanding av 1 g 2,3-dihydro-2- metyl-3-0X0-6-(4-pyridinyl)-4-pyridazinkarboksamid i 20 ml vandig metanol en passende syre, f. eks. saltsyre, metan- ■ sulfonsyre, svovelsyre, til en pH på fra -. 2 til 3, og deretter avkjøle blandingen etter delvis fordampning, hvor- The acid addition salts of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide can conveniently be prepared by adding one mixture of 1 g of 2,3-dihydro-2-methyl-3- OXO-6-(4-pyridinyl)-4-pyridazinecarboxamide in 20 ml of aqueous methanol a suitable acid, e.g. hydrochloric acid, methane- ■ sulphonic acid, sulfuric acid, to a pH of from -. 2 to 3, and then cool the mixture after partial evaporation, where-
etter man frafiltrerer det utfelte salt så som hydrokloridet, metansulfatet, sulfatet, etc. Alternativt kan lactatet eller hydrokloridet av syreaddisjonssaltet av 2,3-dihydro-2-metyl-3- 0X0-6- (4-pyridinyl ) -4-pyr idaz in kar bok sam id hensiktsmessig"'fresmtilles i en vandig oppløsning ved at man tilsetter vann under røring til molare ekvivalente mengder av både 2,3-dihydro-2-metyl-3-oxo-(4-pyridinyl)-4-pyridazinkarboks- after filtering off the precipitated salt such as the hydrochloride, methane sulfate, sulfate, etc. Alternatively, the lactate or hydrochloride of the acid addition salt of 2,3-dihydro-2-methyl-3-OX0-6-(4-pyridinyl)-4-pyridaz in kar bok sam id expedient"' is prepared in an aqueous solution by adding water while stirring to molar equivalent amounts of both 2,3-dihydro-2-methyl-3-oxo-(4-pyridinyl)-4-pyridazinecarbox-
amid og melkesyre eller saltsyre, henholdsvis.amide and lactic or hydrochloric acid, respectively.
Ved å bruke den fremgangsmåte som er beskrevetBy using the procedure described
i eksempel D-1, men i steden for etyl 2,3-dihydro-2-metyl-3- oxo-6-(4-pyridinyl)4-pyridazinkarboksylat bruke en passende molar ekvivalent mengde av et passende etyl 2,3-dihydro-2-R-3-oxo-6-PI-4--pyridazinkarboksylat, kan man fremstille de tilsvarende 2,3-dihydr0-2-R-3-oxo-PY-4-pyridazinkarboks - amider som er angitt i eksmpel D-2 til D-16. in Example D-1, but instead of ethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)4-pyridazinecarboxylate use an appropriate molar equivalent amount of an appropriate ethyl 2,3-dihydro -2-R-3-oxo-6-PI-4-pyridazinecarboxylate, the corresponding 2,3-dihydr0-2-R-3-oxo-PY-4-pyridazinecarboxylate can be prepared, which are indicated in example D -2 to D-16.
D-2 . 2,3 -dihdyr o - 3 -oxo - 6 - (4- -pyr idinyl ) -4.-pyr idaz in - karboksamid. D-3. 2, 3-dihydro-3-oxo-6- (3-pyridinyl ) - 4.-py r idaz in - karboksamid. D-4-. 2,3-dihdyro-6-(2-metyl - 3-pyridinyl )-3-oxo-4--pyridazinkarboksamid . D-5. 2,3-dihydro-6-(5-metyl-3-pyridinyl)-3-oxo-4-pyridazinkarboksamid. D-6. 6-(3-etyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridaz inkarboksamid. D-7. 2, 3-dihydro - 6- (2, 6-di me tyl -4- -pyr idinyl ) - 3 - oxo -4--pyr idaz inkar boksamid . D-8. 2-etyl -2, 3-dihydro-3-oxo-6- (4--pyridinyl ) -4--pyridazinkarboksamid. D-9. 2-isopropyl-2, 3rdihydro-3-oxo-6- (4--pyridinyl ) - 4- -pyr idaz in kar bok sam id . D-2. 2,3 -dihydyr o - 3 -oxo - 6 - (4- -pyridinyl ) -4.-pyridaz in -carboxamide. D-3. 2, 3-dihydro-3-oxo-6-(3-pyridinyl)-4.-pyridazine-carboxamide. D-4-. 2,3-dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxamide. D-5. 2,3-dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxamide. D-6. 6-(3-ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridaz incarboxamide. D-7. 2,3-dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridaz incar boxamide. D-8. 2-Ethyl -2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide. D-9. 2-isopropyl-2, 3-dihydro-3-oxo-6- (4--pyridinyl)-4-pyridaz in kar bok sam id .
D -1 0. 2, 3-dihydro -3-oxo-2 -n -pr opyl - 6- (4.-pyridinyl ) - 4-pyridazinkarboksamid. D-11 . 2, 3-dihydr 0-2 - isobutyl -3-ox0-6- (4--pyr idinyl ) - 4--py r idaz in kar boks am id . D -10.2,3-dihydro-3-oxo-2-n-propyl-6-(4.-pyridinyl)-4-pyridazinecarboxamide. D-11. 2, 3-dihydr 0-2 - isobutyl -3-ox0-6- (4--pyr idinyl ) - 4--pyr idaz in kar box am id .
D -12 . 2 -n -hexyl -2, 3-dihydro - 3-ox 0-6 - (4--pyr idinyl ) -4--pyridazinkarboksamid. D-1 3. 2, 3-dihydro-2- (2-hy dr oksy etyl )- 3-ox 0-6 - (4--pyr idinyl )-4--pyr idazinkarboksamid. D-1£. 2,3-dihydro-2-(2-hydroksypropyl)-3-oxo-6-(4--pyr idinyl ) -4--py r idaz in kar boks am id. D-1 5. 2, 3-dihydro-2- (3-hydroksypropyl )-3-oxo-6- (4--pyridinyl)-4-pyridazinkarboksamid. D-1 6. 2, 3-dihydro-2- (4--hydr oksybutyl )-3-oxo-6- (4--pyridinyl) - 4--pyr idaz in kar boksamid . D-12. 2-n-hexyl-2,3-dihydro-3-ox 0-6-(4-pyridinyl)-4-pyridazinecarboxamide. D-1 3. 2, 3-dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide. D-1£. 2,3-dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4--pyridinyl )-4--pyridase in carboxamide id. D-1 5. 2,3-dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide. D-1 6. 2, 3-dihydro-2-(4--hydroxybutyl )-3-oxo-6-(4--pyridinyl)-4--pyridaz in kar boxamide .
E.'' 2, 3-dihydro-2-R-3-oxo-6-PY-4--pyridazinkarboksyl-syrehydraz ider. E.'' 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazine carboxylic acid hydrazide.
E-1. 2,3-dihydro-3-ox o-6- (4-pyridinyl)-4-pyri - dazinkarboksylsyrehydrazid. E-1. 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyri-dazinecarboxylic acid hydrazide.
En blanding inneholdende 10 g etyl 2, 3-dihydro - 3- 0X0-6—(4-pyridinyl)-4-pyridazinkarboksylat og 300 ml absolutt etanol ble oppvarmet på et dampbad under røring i 10 minutter. Den resulterende oppløsning ble så tilsatt 4- g vanrifritt hydrazin, hvoretter man fikk utfelt et stoff i løpet av 5 minutter. Reaksjonsblandingen ble oppvarmet i ca. 1 time med røring, og det utfelte faste stoff ble frafiltrert, A mixture containing 10 g of ethyl 2,3-dihydro-3-OXO-6-(4-pyridinyl)-4-pyridazinecarboxylate and 300 ml of absolute ethanol was heated on a steam bath with stirring for 10 minutes. The resulting solution was then added to 4 g of anhydrous hydrazine, after which a substance was precipitated within 5 minutes. The reaction mixture was heated for approx. 1 hour with stirring, and the precipitated solid was filtered off,
og tørket i en vakuum-ovn ved 65°C over ^2^5over natten, hvorved man fikk 9» 4- g 2, 3-dihydro-3-oxo-6 - (4--pyridinyl )-4- -pyridazinkarboksyl syrehydraz id, sm.p. ) 300°C. and dried in a vacuum oven at 65°C over 2^5 overnight, whereby 9» 4-g of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide was obtained id, sm.p. ) 300°C.
E - 2. 2, 3-dihydro - 2- metyl- 3- oxo-6 - (4--pyr idinyl ) -4- - pyridazinkarboksylsyrehydrazid. E - 2. 2, 3-dihydro - 2- methyl- 3- oxo-6 - (4- -pyridinyl ) -4- - pyridazine carboxylic acid hydrazide.
Denne syntesen ble utført ved å bruke fremgangsmåten som er angitt i eksempel 1, og ved å bruke 8,5 g etyl 2, 3-dihydro -2-metyl - 3-ox 0-6 (4--pyr idinyl) -4 -pyr idaz in - karboksylat, 10,8 g vannfritt hydrazin og 150 ml etanol. Reaksjonen ble gjennomført ytterligere en gang ved å bruke samme:o mengder av reaktantene. Produktene oble slått sammen og omkrystallisert fra absolutt etanol, hvorved man fikk 10 g 2, 3-dihydro-2-metyl-3-0X0-6-(4-pyridinyl )-4--pyridazinkarboksylsyrehydrazid, sm.p. 209-210°C. Et nytt utbytte på 3 g sm.p. 212-213°C ble oppnådd fra moderluten. This synthesis was carried out using the procedure set forth in Example 1, and using 8.5 g of ethyl 2,3-dihydro-2-methyl-3-ox 0-6(4-pyridinyl)-4- pyr idazin - carboxylate, 10.8 g of anhydrous hydrazine and 150 ml of ethanol. The reaction was carried out once more using the same amounts of the reactants. The products were combined and recrystallized from absolute ethanol, whereby 10 g of 2,3-dihydro-2-methyl-3-Ox0-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide was obtained, m.p. 209-210°C. A new yield of 3 g sm.p. 212-213°C was obtained from the mother liquor.
Syreaddisjonssaltet av 2,3-dihydro-2-metyl-3-oxo - 6 - (4.-pyr idinyl ) -4--pyr idaz inkarboksyl syrehydrazid kan hensiktsmessig fremstilles ved å tilsette en blanding av 1 g 2,3-dihydro-2-me tyl-3-oxo-6-(4-pyridinyl)-4-pyridazin - karboksylsyrehydrazid i 20 ml vandig metanol en passende syre, så som saltsyre, metansulfonsyre, eller svovelsyre til en pH mellom 2 og 3, hvoretter man avkjøler blandingen etter delvis fordampning og frafiltrerer det utfelte salt, d.v.s. hydrokloridet, metansulfonatet eller sulfatet, henholdsvis. Alternativt kan lactatet eller hydrokloridsyreaddisjonssaltet av 2,3-dihydro-2-metyl-3-oxo-6-(4-pyridinyl)-4--pyr idaz inkarboksyl syrehydrazid hensiktsmessig fremstilles i en vandig oppløsning ved at man tilsetter vann til en rørt blanding av molare ekvivalente mengder av både 2,3-dihydro-2-metyl-3-oxo-6 -(4-pyridinyl)-4-pyridazinkarboksylsyre - hydrazid og melkesyre eller saltsyre, henholdsvis. The acid addition salt of 2,3-dihydro-2-methyl-3-oxo-6-(4.-pyridinyl)-4-pyridaz incarboxylic acid hydrazide can conveniently be prepared by adding a mixture of 1 g of 2,3-dihydro- 2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazine - carboxylic acid hydrazide in 20 ml of aqueous methanol a suitable acid, such as hydrochloric acid, methanesulfonic acid, or sulfuric acid to a pH between 2 and 3, after which cooling the mixture after partial evaporation and filters off the precipitated salt, i.e. the hydrochloride, methanesulfonate or sulfate, respectively. Alternatively, the lactate or hydrochloride acid addition salt of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridaz incarboxylic acid hydrazide can conveniently be prepared in an aqueous solution by adding water to a stirred mixture of molar equivalent amounts of both 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid - hydrazide and lactic or hydrochloric acid, respectively.
Ved å bruke den fremgangsmåten som er beskrevet i eksempel E-1, men i steden for etyl 2,3-dihydro-3-ox0-6-(4-pyridinyl)-4-pyridazinkarboksylat bruke en molar ekvivalent mengde av et passende 2,3-dihydro-2-R-oxo-6-BY-4-pyridazinkarboksylat, så> kan man fremstille de tilsvarende 2,3-dihydro-2 -R - 3-oxo -6-PY-4.-pyr idaz in karboksyl syrehydraz idet som er nevnt-Ki eksemplene E-3 til E-16. Using the procedure described in Example E-1, but instead of ethyl 2,3-dihydro-3-oxO-6-(4-pyridinyl)-4-pyridazine carboxylate, using a molar equivalent amount of an appropriate 2, 3-dihydro-2-R-oxo-6-BY-4-pyridazine carboxylate, then> one can prepare the corresponding 2,3-dihydro-2 -R - 3-oxo -6-PY-4.-pyridaz in carboxyl acid hydraz as mentioned-Ki examples E-3 to E-16.
E-3. 2,3-dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazin - karboksylsyrehydrazid. E-3. 2,3-dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazine - carboxylic acid hydrazide.
E-4. 2,3-dihydro -6-(2-metyl-3-pyridinyl)-3-oxo-4-pyridazinkarboksylsyrehydrazid. E-4. 2,3-dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid hydrazide.
E-5. 2, 3-dihydro-6 -;(5-metyl - 3-pyridinyl ) - 3-oxo-4-pyridazinkarboksylsyrehydrazid. E-5. 2, 3-dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazine carboxylic acid hydrazide.
E-6. 6-(3-etyl-4-pyridinyl)-2,3-dihydro-3-oxo-4~pyridazinkarboksylsyrehydrazid. E-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4~pyridazinecarboxylic acid hydrazide.
E-7. 2, 3-dihydro -6- (2* 6-dimetyl -4--pyridinyl) - 3-oxo-5-pyridazinkarboksylsyrehydrazid. ;E -8. 2 -etyl -2, 3-dihydro - 3-oxo -6- (4.-pyridinyl ) - 4-pyridazinkarboksylsyrehydrazid. ;E-9. 2-is.opropyl -2, 3-dihydro -3-oxo -6- (4-pyridinyl ) - ;4--pyr idaz in kar bok syl syrehydraz id.;E-10. 2,3-dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)-4-pyridaz inkarboksylsyrehydrazid. ;E -1 1. 2, 3-dihydro -2 - i so bu tyl - 3-oxo-6 - (4- -pyr idinyl ) - 4--py r idaz inkarboksyl syrehydrazid . ;E-1 2. 2 -n -hexyl -2, 3-dihydro - 3-oxo-6 - (4--pyridinyl ) - 4--pyr idaz inkarboksyl syrehydrazid. ;E-1 3. 2, 3-dihydro -2 - (2 -hydroksy etyl )-3-oxo-6-(4--pyridinyl)-4-pyridazinkarboksylsyrehydrazid. ;E-1 4-. 2, 3-dihydro -2 - (2-hydroksypropyl ) - 3-oxo -6 - (4-pyridinyl)-4-pyridaz inkarboksylsyrehydraz id. ;E-1 5 • 2, 3-dihydro --2 (3-hydroksypropyl )-3-oxo-6-(4--py r idinyl ) -4--pyr idaz inkarboksyl syrehydrazid. ;E-1 6. 2, 3-dihydro-2-(4.-hydroksybutyl )-3-oxo-6-(4.-pyr idinyl) -4--pyr idaz in karboksyl syrehydraz id. ;F. 2, 3- dihydro - 2 - R - 3 - oxo- 6- PY - 4-- pyr idaz in karboksyl - syre. ;F-1 • 2, 3_-dihydro -3-oxo -6- (4.-pyridinyl ) -4-pyridazinkarboksyl syre. ;En blanding inneholdende 10 g etyl 2,3-dihydro-3- oxo-6-(4.-pyridinyl )-4--pyridazinkarboksylat og 100 ml 5 % vandig natriumhydroksydoppløsning ble oppvarmet på et dampbad i 6 timer, avkjølt til romtemperatur og så langs-somt behandlet med eddiksyre inntil et fast stoff begynte å skille seg ut. Blandingen ble hensatt inntil intet mer fast stoff ble utskilt, og sistnevnte ble så frafiltrert, tørket i vakuum-ovn over P^ 0^ ved 4-5°C, noe som ga 7,7 g 2, 3-dihydro-3-oxo -6- (4--pyridinyl ) -4--pyridazinkarboksylsyre, sm.p. 310°C. ;F-2. 2,3-dihydro-2-metyl-3-oxo-6 - (4-pyridinyl ) - 4- -pyr idaz in kar bok syl syre. ;En blanding inneholdende dietyl hydroksy (2-oxo-2 - (4--pyr idinyl )etyl )propandioat og 4.0 ml absolutt etanol, ble tilsatt |,6 g 1-metylhydrazin som på forhånd var behandlet med 6 ml 6N saltsyre. Blandingen ble kokt under tilbakeløp over natten, hvoretter oppiøsningsmiddelet ble avdestillert i vakuum. Det gjenværende gule residium ble behandlet med 300 ml 20 % vandig natriumhydroksydoppløsning ogiiblandingen ble oppvarmet på et dampbad over natten. Reaksjonsblandingen ble hensatt til avkjøling i romtemperatur, og det utskilte faste stoff ble frafiltrert. ;Det ble så omkrystallisert fra 120 ml eddiksyre ved hjelp;av avfargede trekull, og det varme filtratet ble etter fjerning av nevnte trekull behandlet med 120 ml varmt vann. Den resulterende oppløsning ble avkjølt, og det krystallinske produkt og blandingen ble hensatt over week-enden. Bunnfallet ble så frafiltrert og tørket i en vakuum -ovn ved 80°C over ^ 2® 5 over natten, noe som ga 9, 4- g 2, 3 -dihydro-2 - me tyl-3-oxo -6- (4.-pyr idinyl) - 4-pyr idaz inkarboksyl syre, sm.p. 267-268°C. ;Ved å bruke den fremgangsmåten som er beskrevet;i eksempel F-1, men i steden for etyl 2,3-dihydro-3-oxo-6-(4--pyridinyl )-4--pyridazinkarboksylat bruke en molar ekvivalent mengde av et passende etyl 2,3-dihydro-2-R-3-oxo-6-PY-4--pyridazinkarboksylat, så kan man få fremstilt de tilsvarende 2,3-dihydro-2-R-2,3-dihydro-3-oxo-6-PY-pyri - dazinkarboksyl syre som er angitt i eksempel F-3 til F-16. ;F - 3. 2, 3-dihydro - 3-oxo - 6 - (3-pyridinyl ) -4--pyr idaz in - karboksyl syre. ;F -4-. 2, 3-dihydro - 6 - (2-metyl - 3-pyridinyl )-3-oxo-4--pyridazinkarboksyl syre. ;F -5. 2, 3-dihydro -6 - (5 -metyl - 3-pyridinyl )-3-oxo-4--pyridazinkarboksylsyre. ;F-6. 6-(3-etyl-4-pyridinyl )-2, 3-dihydro-3-oxo-4--pyridazinkarboksylsyre. ;F - 7. 2,3 -dihydro -6 -(2,6 -d ime tyl -4--pyr idinyl) - 3-oxo - 4--pyr idaz in kar boksyl syre . ;F - 8. 2-etyl-2,3 -dihydro - 3-oxo-6 - (4-pyridinyl ) -4- - pyridazinkarboksyl syre. ;F-9. 2 -i so pr opyl -2, 3-dihydro - 3 -oxo - 6- (4--pyr idinyl ) - 4--py r idaz in karboksyl sy re . ;F-1 0. 2, 3-dihydro -3-oxo -2 -n -propyl -6- (4--pyridinyl ) -4 pyridazinkarboksyl syre. ;F-11. 2, 3-dihydro-2-i so bu tyl - 3-oxo-6 - (4--pyridinyl) - 4.-pyr idaz in karboksyl sy re. ;F-12. 2-n-hexyl-2, 3-dihydro-3-oxo-6-(4--pyridinyl)-4--pyridazinkarboksyl syre. ;F-13. 2, 3-dihydro-2-(2-hydroksyetyl )-3-oxo-6-(4--pyridinyl ) -4--pyridazinkarboksyl syre. ;F-1 4-. 2, 3-dihydro-2- (2 -hydroksypropyl )-3-oxo-6-(4--pyridinyl)-4-pyridazinkarboksyl syre. ;F-1 5 . 2, 3-dihydro -2 - (3-hydroksypropyl )-3-oxo-6-(4_-py r idinyl ) -4--pyr idaz in karboksyl syre . ;F-16. 2, 3-dihydro-2- (4--hydroksybutyl )-3-oxo-6- (4.-pyridinyl)-4-pyridazinkarboksyl syre. ;G. 4-- amino - 6 - PY- 2 - R- 3 ( 2H ) - pyridazinoner.;G -1. 4--amino -6 - (4--pyr idinyl) - 3 (2H ) -pyridazinon. ;Følgende fremgangsmåte beskriver fremstillingen av overnevnte forbindelse fra det tilsvarende 2,3-dihydro-3-0X0-6- (4- -pyr idinyl ) -4--pyr idaz inkar bok syl syrehydrazid (eksempel E-1). En blanding inneholdende 28 g 2,3-dihydro-3-0X0-6- (4.-pyr idinyl ) -4--pyr idaz inkarboksyl syrehydrazid og 700 ml konsentrert saltsyre og 4-00 ml vann og hvor nevnte blanding var avkjølt i et is -natrium-kloridbad, ble tilsatt en oppløsning inneholdende 20 g natrium-nitrit i 75 ml vann under kraftig røring i løpet av 1/2 time idet den indre temperatur ble holdt på under 5°C. Den kalde reåksjons-blandingen ble rørt i is-saltbadet i ytterligere 3 kvarter og så over romtemperatur 1/2 time, og så langsomt oppvarmet på et dampbad. Da den indre temperatur hadde nådd 55 til 60° ble utviklingen av nitrogen meget rask. Dampkilden ble fjernet inntil - n reaksjonen.ble mer moderat. Reaksjonsblandingen ble så holdt på dampbadet i 2 timer og avkjølt i et isbad. Det utfelte faste stoff ble frafiltrert og vasket med vann (se nedenfor for identifikasjon av dette produkt). De samlede vandige sure filtrater og vaskeopp-løsninger ble konsentrert til tørrhet i vakuum, og residuet tilsatt vandig ammoniumhydroksydoppløsning inntil blandingen var svakt basisk. Blandingen ble så igjen gjort sur med eddiksyre og avkjølt i et isbad. Det resulterende gule faste stoff ble frafiltrert, vasket med vann og tørket. ;Dette produkt (14-, 2 g) ble suspendert i 50 ml 10 %- ig kalium-bikarbonatoppløsning, behandlet med 100 ml vann og blandingen rørt i 1 time ved romtemperatur. Det gule stoff ble frafiltrert, vasket med vann og tørket i en ovn ved 90°C. Det ble så oppløst i 4-00 ml 6N saltsyre ved oppvarming på et dampbad. ;Den varme oppløsningen ble filtrert, og filtratet hensatt i romtemperatur over natten. Det klart gule krystallinske produkt ble frafiltrert, vasket med mindre mengder destillert vann og tørket i en ovn ved 85°, noe som ga 6,8 4--amino-6-(4--pyr idinyl ) - 3 (2H ) -pyridazinon mono hy dr oki or id -mono hy dr at, sm.p. ) 34-0°C. Det overnevnte svakt brune stoff som var frafiltrert fra eddiksyrereaksjonsblandingen og vasket med vann, ble oppløst i vandig ammoniumhydroksydoppløsning og oppløsningen filtrert. Filtratet ble surgjort med eddik-'syre hvoretter man fikk utfelt et fast krystallinsk stoff. Blandingen ble så avkjølt i et isbad. Det krystallinske bunnfall ble frafiltrert, vasket med vann tørket i en ovn ved 80°C, hvorved man fikk 13,5 g produkt, sm.p. } 320°C, og dette ble ved hjelp av sitt NMR-spek.trum identifisert til å være det samme som produktet fra eksempel F-1, d.v.s. 2, 3-dihydro - 3-oxo -6- (4- -pyridinyl ) -4-pyr idaz inkar bok syl syre . ;Den overnevnte fremgangsmåten går først gjennom syreacidet noe som fremgår av den etterfølgende isolasjon av syreacidet som dets monoklorid: En oppløsning avkjølt i et isbad og inneholdende 3» 0 g 2, 3-dihydro-3-oxo-6-(4-- pyridinyl)-4--pyridazinkarboksyl syrehydrazid og 60 ml 6N saltsyre ble dråpvis tilsatt en oppløsning inneholdende 3,0 g natriumnitrit i 10 ml vann i løpet av 1/2 time. Reaksjonsblandingen ble så rørt i 1 time og oppvarmet til romtemperatur. Bunnfallet ble frafiltrert, vasket med vann og tørket i vakuumovn over ^2^5vec^ ^° ^ ^-8 "timer, noe som ga 3» 0 g 2, 3-dihydro-3-oxo-6-(4--pyridinyl)-4.-pyridazinkarboksyl-syre-azid-monohydroklorid, sm.p. y 300°. ;G-2. 4.-amino -6-(4--pyridinyl ) - 3 (2H ) -pyridazinon. ;Overnevnte forbindelse ble fremstilt ved å reagere hydrazin med 6-(4-pyridinyl)-3(2H)-pyridazinon, den tautomeriske formen av 6-(4--pyridinyl )-3-p'yridazinol. En blanding inneholdende 10 g 6-(4--pyridinyl )-3 (2H) -pyridazinon og 70 ml hydrazinhydrat ble oppvarmet på et dampbad i 3 døgn, ;og overskuddet av hydrazin ble avdestillert i vakuum. Residuet ble oppvarmet med ca. 300 ml. metanol, og bunnfallet frafiltrert. Det ble slått sammen med tilsvarende utbytte fremstilt i et annet forsøk hvor man gikk ut fra 15,7 g 6 - (4--pyridinyl )-3 (2H )-pyridazinon og 21 ml hydrazinhydrat, ;og de samlede utbytter ble oppløst i vannfritt kaliumkarbonat-oppløsning og igjen utfelt ved tilsetning av eddiksyre. Bunnfallet ble tørket i 9 timer ved 4-0° over P~0roe så over ;o 2 5 6 ;natten ved 80 . Etter at NMR-spektrum hadde vist at produktet ennå inneholdt noe eddiksyre, så ble det deretter tørket i en vakuum-ovn ved 80° i 2 døgn, hvorved man fikk 18,2 ;(69 % utbytte) av 4--amino-6 - (4. -pyridinyl )-3 (2H ). pyridazinon, sm.p. > 300°C. ;Syreaddisj onssaltet av 4--amino-6 - (4--pyridinyl ) - 3 (2H>)-pyridazinon kan hensiktsmessig fremstilles ved at en oppløsning av 1 g 4.-amino-6-(4.-pyridinyl )-3 (2H ) -pyri- ;dazinon i ca. 20 ml vandig metanol tilsettes en passende syre, f. eks. saltsyre, metansulfonsyre eller svovelsyre, ;til en pH på mellom 2 og 3-Deretter avkjøler man blandingen og delvis fordamper den og oppsamler det utfelte salt, ;d.v.s. hydrokloridet, metansulfatet eller sulfatet, henholdsvis. Videre kan lactatet eller hydrokloridsyreaddisjons - ;saltet av 4--amino-6-(4--pyridinyl )-3 (2H ) -pyridazinon hensiktsmessig fremstilles i en vandig oppløsning ved at man tilsetter vann til molare ekvivalende mengder av 4-amino-6 - (4--pyridinyl)-3 (2H )-pyr idaz inon og melkesyre eller eddiksyre, henholdsvis. ;G - 3. 4--amino -2 -metyl -6 - (4--pyridinyl) - 3 (2H ) -pyridazinon, sm.p. 229-235°C, 6, 4- g ble fremstilt ved å bruke den fremgangsmåten som er angitt i eksempel G-2, og 12 g 2-metyl-6-(4--pyridinyl )-3 (2H )-pyridazinon og 100 ml hydrazinhydrat, og foreta en omkrystallisering fra acetonitril ved å bruke avfarget trekull. ;Syreaddis jonssalter av 4--a;mino -2 -metyl-6-(4--pyridinyl)-3(2H)-pyridazinon kan hensiktsmessig fremstilles ved at en oppløsning av 1 g 4--amino -2 -metyl -6-(4--pyridinyl ) - 3(2HQ-pyridazinon i ca. 20 ml vandig metanol tilsettes en passende syre, f. eks. saltsyre, metansulfonsyre, eller svovelsyre, til en pH på 2r3, avkjøle blandingen etter delvis fordampning og frafiltrerer det utfelte salt, d.v.s. hydrokloridet, metansulfonatet eller sulfatet, henholdsvis. Videre kan lactatet eller hydrokloridsyreaddisjonssaltet ;av 4--amino-2-metyl-6-(4--pyridinyl )-3 (2H )-pyridazinon hensiktsmessig fremstilles i vandig oppløsning ved at man tilsetter vann til rørte molare ekvivalente mengder av 4--amino-2-metyl-6-(4--pyridinyl )-3 (2H ]-pyridazinon og melkesyre eller saltsyre henholdsvis. ;Ved å bruke den fremgangsmåte som er beskrevet;i eksempel G-2, men i steden for 6-(4.-pyridinyl )-3 (2H )-pyridazinon bruke en molar ekvivalent mengde av et passende 2-R-6-PT-3 (2H)-pyridazinon, så kan man få 'fremstilt de 4--amino-2-R-6-PY-3(2H)-pyridazinon som er angitt i eksempel G-4- til G-22. ;G-4-. 4--amino -6 - (3-pyridinyl ) - 3 (2H ) -pyridazinon.;G-5. 4.-amino-6- (2-metyl -3-pyridinyl ) -3 (2H ) -pyr idazinon . ;G -6. 4.-amino -6- (5 -metyl - 3-pyridinyl ) - 3 (2H ) -pyridazinon . ;G-7. 4- -amino - 6 - (3-etyl -4--pyridinyl ) - 3 (2H) -pyridazinon. ;G -8. 4.-amino -6-(2, 6-dimetyl -4.-pyridinyl ) -3 (2H ) -pyridazinon . ;G-9. 4--amino -2-etyl -6- ('4-pyridinyl) - 3 (2H ) -pyri - daz inon. ;G-10. 4-amino-2-isopropyl-6(4-pyridinyl)-3(2H) - pyridazinon. ;G -11 . 4--amino -2 -n -propyl - 6 - (4--pyridinyl) -3 (2H ) -pyrd-dazinon. ;G-12. 4--amino-2-isobutyl-6-(4-pyridinyl ).-3 (2H )-pyridazinon. ;G-13. 4-amino-2-n-hexyl-6-(4-pyridinyl)-3(2H)-pyri-daz inon. ;G-14- 4-amino-2 -(2-hydroksyetyl)-6 -(4-pyridinyl)-3(2H ) - pyridazinon. ;G-15. 4-amino-2-(2-hydroksypropyl)-6-(4-pyridinyl ) - 3(2H)-pyridazinon. ;G-16. 4-amino-2 -(3-hydroksypropyl)-6-(4-pyridinyl)-3(2H)-pyridazinon. ;G-17. 4-amino-2 -(4-hydroksybutyl)-6 -(4-pyridinyl)-3(2H)-pyridazinon. ;G-18. 4-amino-2-metyl-6 -(3-pyridinyl)-3(2H)-pyridazinon. ;G-1 9- 4-amino-2-metyl-6-(2-metyl-3-pyridinyl )-3(2H)-pyridazinon. ;G-2 01' 4-amino -2-metyl -6 - (5-metyl -3-pyridinyl ) -3 (2H) - pyridazinon. ;G-21 4-amino-6 -(3-etyl .-4-pyridinyl)-2-metyl-3(2H) - pyridazinon. ;G-22. 4-amino-2-metyl-6-(2,6-dimetyl-4-pyridinyl)-3 (2H)-pyridazinon. ;Ved å bruke den fremgangsmåte som er beskrevet i eksempel'G-1, men i steden for 2, 3-dihydro-3-oxo-6-(4- pyridinyl )-4 -pyr idaz in kar boksylsyre -hydrazid, bruke en tilsvarende melar.-, e kv iv el ant mengde av ét passende 2, 3-dihydro-2-R-3-oxo-6-PY-4--pyridazinkarboksylsyre-hydrazid, så kan man som i eksempel G-23 til G-4-1 få fremstilt de til- ;svarende 4--amino-6-PY-2-R-3 (2H )-pyridazinoner fremstilt også i eksempel -4 til G-22, henholdsvis. ;G-4-2. 4--amino -2 -metyl -6 - (4--pyr id in yl ) -3 (2H ) -pyr idazinon. ;En oppløsning inneholdende 9, 0 g natrium-hydroksyd i 130 ml vann ble holdt på 0° og dråpvis under røring tilsatt 2,3 ml brom. Den vandige blandingen ble under røring tilsatt '8,0 g 2, 3-dihydro-2-metyl-3-oxo-6-(4--pyridinyl )-4--pyridazinkarboksamid og den resulterende blandingen holdt på et dampbad i 4- timer. Blandingen ble så avkjølt til romtemperatur, langsomt surgjort med 6W saltsyre,oog den resulterende sure blandningen ble rørt i ytterligere 25 minutter. Den ble så nøytralisert med 10 % vandig kal iumbikarbona toppi øsning og avkjølt. Bunn- ;fallet ble frafiltrert, vasket, tørket, omkrystallisert fra acetonitril, frafiltrert, vasket med vann og tørket ca. 15 timer i en vakuumovn ved 65°C over P2 o05r. hvorved man fikk 4--amino -2 -metyl -6 - (4.-pyridinyl ) -3 (2H ) -pyridazinon . ;Ved å bruke den frmegangsmåten som er beskrevet;i eksempel G-4-2, men i steden for 2, 3-dihydro -2 -me tyl-3-o.xo-6 - (4--pyridinyl )-4.-pyridazinkarboksamid bruke en molar ekvivalent mengde av et passende 2,3-dihydro-3-oxo-6-PY-2-R-4--pyridazinkarboksamid, kan man som i ekssmpel G-43 til ;G-61 få fremstilt de tilsvarende 4--amino-6-PY-2-R-3 (2H )-pyrida - zinoner, også fremstilt som angitt i eksempel G-4. til G-22, henholdsvis. ;H. k , 5- dihydro- 2- R- 6- PY- 3( 2H)- pyridazinoner.;H-1. 4-, 5-dihydro-6-(4.-pyr idinyl ) -3 (2H ) -pyr idaz inon .;En blanding inneholdende 2, 4- -g 4-oxo-4--(4--pyri - dinyl )butanitril (det samme som y-oxo-y-(4-pyridinyl )butyro-nitril), 1,96 g hydrazinsulfat, 100 ml absolutt etanol og 100 ml vann ble kokt under " tilbakeløp over natten (ca. 15 timer). Reaksjonsblandingen ble så oppvarmet i vakuum for å fjerne oppiøsningsmiddelblandingen. Residuet ble oppløst i vann og filtrert. Filtratet ble nøytralisert med 10 % ;vandig natriumbikarbonatoppløsning og man fikk utfelt et gult fast stoff. Dette ble frafiltrert, vasket med vann, tørket i vakuum over i ^ "timer. Dets kj ernemagnetiské: re sonens-spektrum og masse spektrum var overensstemmende med det forønskede produkt, men det var visse spor av urenheter. Produktet ble så omkrystallisert fra absolutt etanol, tørket ;i vakuum over ? ~ 2® 5 over natten hvorved man som gyldne krystaller fikk 0, 9 g 4-, 5 -dihydro-6-(4 -pyridinyl )-3 (2H ) - pyridazinon,-,'sm.p. 1 85-187°C som er tautomerisk med 4-» 5-dihydr 0 - 6 - (4--pyr idinyl ) -3 -pyr idaz in ol. ;Ovennevnte reaksjon kan også utføres ved å;bruke en molar ekvivalent mengde av hydrazin dihydrokloridet eller hydrazin di(metansulfonat) i stedén for hydrazinsulfat. ;Syreaddisj onssalter av 4-> 5 -dihydro-6,-(4--pyridinyl )-(2H)-pyridazinon kan hensiktsmessig fremstilles ved at en oppløsning av 1 g 4-» 5 -dihydro -6 - (4- -pyridinyl)-3 (2H) - pyridazinon i ca. 20 ml vandig metanol kan tilsettes en passende syre, så som salter, metansulf onsyre eller svovelsyre til en pH mellom 2 og 3»avkjøle blandingen etter delvis fordampning og oppsamle bunnfallet, d.v.s. salter så ;som hydroklorid, metansulfonatet eller sulfatet, henholdsvis. Videre kan også lactatet eller hydrokloridsyreaddisjons - saltet hensiktsmessig fremstilles i vandig oppløsning ved at vann tilsettes rørte molare ekvivalente mengder av 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinon og melkesyre eller saltsyre, henholdsvis. ;Ved å bruke den fremgangsmåten som er beskrevet;i eksempel H-1, men i steden for 4--oxo-4--(4--pyridinyl ) butanitril bruke en molar ekvivalent mengde av et tilsvarende 4.-0x0-4--PY-butanitril, kan man få fremstilt de tilsvarende 4-, 5-dihydro-6-PY-3 (2H )-pyridazinoner som er nevnt i eksemplene H-2 til H-6. ;H - 2. 4-» 5 -dihydro -6 - (3-pyridinyl ) - 3 - (2H) -pyridazinon . ;H-3. 4, 5-dihydro-6-(2-metyl-3-pyridinyl)-3(2H)-pyridazinon. ;H-4. 4, 5-dihydro-6-(5-metyl-3-pyridinyl)-3-(2H)-pyridazinon. ;H-5. 6- (3-etyl -4 -pyridinyl ) -4, 5 -dihydro -3 (2H ) -pyri-daz inon. ;H-6. 4, 5-dihydro-6-(2, 6-dimetyl-4-pyridinyl )-3(1H)-pyridazinon. ;Anvendbarheten av forbindelse med formel I hvor;R<1>er R" og R er lavere-alkyl eller lavere-hydroksyalkyl, d. v.s. 2-R-4-R"-6-PY-3(2H)-pyridazinoner, eller deres salter, som kardiotoniske midler ble vist ved deres effektivitet i standard-farmakologiske prøver, f. eks. ved at de frem-bragte en betydeligøkning i den kontraktile kraft i isolert katte-atria og i de papilære muskler. Detaljerte beskrivelser av nevnte prøver er angitt i US-patent nr. 4072746. ;Når de ble undersøkt ved hjelp av overnevnte fremgangsmåter, så ga nevnte 2-R-4-R"-PY-3 (2H)-pyridazinoner eller ders farmasøytisk akseptable syreaddisjonssalter, ;i doser på 30, 1 00 og/eller 300 ug/ml, en betydeligøkning, d.v.s. mer enn 25 % i den papilære muskel kraften og/eller en betydelig økning, d.vs. mer enn 25 %, av den høyere for-kammerkraften, mens den ga en lavere prosentvisøkning av slaghastigheten i høyere forkammer. Når f. eks. de foretrukne forbindelser meddf or mel Ie^.';d.v.s. forbindelsene fra eksempel G-2 og G-3^ble prøvet på nevnte dosenivå i denne fremgangsmåte, så ga de en økning på fra 30 til over 200 % av den papilære muskelkraften eg/eller slagkraften i høyere forkammer. De foretrukne forbindelser med formel Ia, Ic og Ib, d.v.s. forbindelsene fra eksempel C-3, D-r1 ;og E-2 ga ved nevnte dosenivåer i nevnte fremgangsmåtet en økning på fra 28 til 72 % i den papilære muskelkraf ten og/eller slagkraften i høyere forkammer. ;Ved prøver med bedøvede hunder så ga forbindelsen med formel le eller deres farmasøytisk akseptable syre addisj onssalter i doser på 1,0, 3» 0 og/eller 10 mg/kg kropps-vekt ved intravenøs tilførsel, en betydelig økning, d.v.s. ;25 % eller mer, i hjertets kontraktile slagkraft eller dets kontraktilitet med lavere forandring med hensyn til blodtrykket og slaghastighet. En foretrukket forbindelse så ;som fra eksempel G-2 ga ved nevnte dosenivå i denne fremgangsmåten en økning på 4-6 % eller mer i den kontraktile slagkraften med lavere forandringer i blodtrykket og puls. ;I klinisk praksis vil en kar.diotonisk aktivs forbindelse eller et salt av denne ifølge foreliggende oppfinnelsen normalt bli tilført 'oralt eller parenteralt ved hjelp av en rekke forskjellige doseringsformer. ;Faste sammensetninger for oral tilførsel av kardiotoniske aktive forbindelser ifølge foreliggende oppfinnelse innbefatter tabletter, piller, pulvere og granu-later. I slike faste sammensetninger vil minst en aktiv forbindelse være blandet med minst et inert fortynningsmiddel, så som stivelse, kalsiumkarbonat, sucrose eller lactose. Nevnte samme setninger kan også inneholde andre forbindelser enn nevnte inerte fortynningsmiddel, f. eks. smøremidler, så som magnesiumstearat, talkum o.l. ;Flytende sammensetninger for oral tilførsel innbefatter farmasøytisk akseptable emulsjoner, oppløsninger, suspensjoner, siruper etc. som inneholder inerte fortynnings^midler av vanlig farmasøytisk type, så;Lsoin vann og flytende parafin. For uten inerte fortynningsmidler kan slike sammensetninger også inneholde andre tilsetninger, så som fuktemidler og suspenderingsmidler, smaksstoffer, parfymer, søt-ningsmidler og konserveringsmidler. Sammensetninger for oral tilførsel kan også innbefatte kapsler av et absorber-bart materiale så som gelatin, som inneholder nevnte aktive komponent med eller uten tilsetninger av fortynningsmidler. ;Preparater ifølge foreliggende oppfinnelse for parenteral tilførsel innbefatter sterile, vandige, vandige-organiske og organiske oppløsninger, suspensjoner og emulsjoner. Eksempler på organiske oppiøsningsmidler eller suspenderende media er propylenglykol, polyetylenglykol, vegetabilske oljer så som olivenoljer og injiserbare organiske estere, så som etyloleat. Slike sammensetninger kan også inneholde andre tilsetninger så som stabilisatorer, konserveringsmidler, fuktemidler, emulgeringsmidler, og dis-pergering smidler. ;De kan f. eks. steriliseres ved at de filtreres gjennom et bakteriefilter, ved at preparatene tilsettes steriliserende midler eller ved bestråling eller oppvarming. ;De kan også opparbeides i form av sterile faste sammensetninger som kan oppløses i sterilt vann eller et annet sterilt injiserbart medium umiddelbart før bruk. ;Prosenten av den aktive komponenten i nevnte. * ' preparater kan varieres slik at man oppnår en egnet dose. E-7. 2, 3-dihydro -6-(2*6-dimethyl-4--pyridinyl)-3-oxo-5-pyridazinecarboxylic acid hydrazide. ;E -8. 2-ethyl-2,3-dihydro-3-oxo-6-(4.-pyridinyl)-4-pyridazinecarboxylic acid hydrazide. E-9. 2-is.opropyl -2, 3-dihydro -3-oxo -6- (4-pyridinyl ) - ;4--pyr idaz in kar bok syl syrehydraz id. ;E-10. 2,3-dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)-4-pyridaz incarboxylic acid hydrazide. ;E -1 1. 2, 3-dihydro -2 - i so butyl - 3-oxo-6 - (4- -pyr idinyl ) - 4--pyr idaz incarboxylic acid hydrazide . ;E-1 2. 2 -n -hexyl -2, 3-dihydro - 3-oxo-6 - (4--pyridinyl ) - 4--pyridaz incarboxylic acid hydrazide. ;E-1 3. 2,3-dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide. ;E-1 4-. 2, 3-dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridaz incarboxylic acid hydrazide. ;E-1 5 2, 3-dihydro --2 (3-hydroxypropyl )-3-oxo-6-(4--pyr idinyl )-4--pyridaz incarboxylic acid hydrazide. ;E-1 6. 2, 3-dihydro-2-(4.-hydroxybutyl )-3-oxo-6-(4.-pyridinyl)-4--pyridaz in carboxylic acid hydrazide. F. 2, 3- dihydro - 2 - R - 3 - oxo- 6- PY - 4-- pyridaz in carboxylic - acid. ;F-1 2,3_-dihydro-3-oxo-6-(4.-pyridinyl)-4-pyridazinecarboxylic acid. ;A mixture containing 10 g of ethyl 2,3-dihydro-3-oxo-6-(4.-pyridinyl)-4-pyridazine carboxylate and 100 ml of 5% aqueous sodium hydroxide solution was heated on a steam bath for 6 hours, cooled to room temperature and then slowly treated with acetic acid until a solid began to separate. The mixture was allowed to stand until no more solid material separated, and the latter was then filtered off, dried in a vacuum oven over P₂O₂ at 4-5°C, giving 7.7 g of 2,3-dihydro-3-oxo -6-(4-pyridinyl)-4-pyridazinecarboxylic acid, m.p. 310°C. ;F-2. 2,3-dihydro-2-methyl-3-oxo-6 - (4-pyridinyl ) - 4- -pyridaz in kar bok syl syre. A mixture containing diethyl hydroxy (2-oxo-2 - (4--pyridinyl)ethyl)propanedioate and 4.0 ml of absolute ethanol was added to |.6 g of 1-methylhydrazine which had previously been treated with 6 ml of 6N hydrochloric acid. The mixture was refluxed overnight, after which the solvent was distilled off in vacuo. The remaining yellow residue was treated with 300 ml of 20% aqueous sodium hydroxide solution and the mixture was heated on a steam bath overnight. The reaction mixture was allowed to cool to room temperature, and the separated solid was filtered off. It was then recrystallized from 120 ml of acetic acid with the help of decoloured charcoal, and the hot filtrate, after removal of said charcoal, was treated with 120 ml of hot water. The resulting solution was cooled, and the crystalline product and the mixture were set aside over the weekend. The precipitate was then filtered off and dried in a vacuum oven at 80°C over ^ 2® 5 overnight, giving 9,4-g 2,3-dihydro-2-methyl-3-oxo-6-(4 .-pyr idinyl) - 4-pyr idaz incarboxylic acid, m.p. 267-268°C. Using the procedure described in Example F-1, but instead of ethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazine carboxylate, use a molar equivalent amount of a suitable ethyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazine carboxylate, then the corresponding 2,3-dihydro-2-R-2,3-dihydro-3 -oxo-6-PY-pyri-dazinecarboxylic acid as set forth in Examples F-3 to F-16. ;F - 3. 2, 3-dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazine-carboxylic acid. ;F -4-. 2, 3-dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid. ; F -5. 2,3-dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylic acid. ;F-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxylic acid. ;F - 7. 2,3-dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridaz in carboxyl acid. ;F - 8. 2-ethyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid. ;F-9. 2-isopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridase in carboxylic acid. ;F-1 0. 2, 3-dihydro-3-oxo-2-n-propyl-6-(4--pyridinyl)-4-pyridazinecarboxylic acid. ;F-11. 2, 3-dihydro-2-isobutyl - 3-oxo-6 - (4--pyridinyl) - 4-pyridaz in carboxylic acid. ;F-12. 2-n-hexyl-2, 3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid. ;F-13. 2, 3-dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid. ;F-1 4-. 2,3-dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid. ;F-1 5 . 2, 3-dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridase in carboxylic acid. ;F-16. 2, 3-Dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid. G. 4-- amino - 6 - PY- 2 - R- 3 ( 2H ) - pyridazinones. ; G -1. 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone. The following procedure describes the preparation of the above-mentioned compound from the corresponding 2,3-dihydro-3-0X0-6-(4-pyridinyl)-4-pyridaz incar bok syl acid hydrazide (Example E-1). A mixture containing 28 g of 2,3-dihydro-3-0X0-6-(4.-pyridinyl)-4-pyridaz incarboxylic acid hydrazide and 700 ml of concentrated hydrochloric acid and 4-00 ml of water and where said mixture was cooled in an ice-sodium chloride bath, a solution containing 20 g of sodium nitrite in 75 ml of water was added with vigorous stirring during 1/2 hour while the internal temperature was kept below 5°C. The cold reaction mixture was stirred in the ice-salt bath for another 3 quarters and then at room temperature for 1/2 hour, and then slowly heated on a steam bath. When the internal temperature had reached 55 to 60°, the evolution of nitrogen became very rapid. The steam source was removed until the reaction became more moderate. The reaction mixture was then kept on the steam bath for 2 hours and cooled in an ice bath. The precipitated solid was filtered off and washed with water (see below for identification of this product). The combined aqueous acidic filtrates and washing solutions were concentrated to dryness in vacuo, and the residue added with aqueous ammonium hydroxide solution until the mixture was slightly basic. The mixture was then again acidified with acetic acid and cooled in an ice bath. The resulting yellow solid was filtered off, washed with water and dried. This product (14.2 g) was suspended in 50 ml of 10% potassium bicarbonate solution, treated with 100 ml of water and the mixture stirred for 1 hour at room temperature. The yellow substance was filtered off, washed with water and dried in an oven at 90°C. It was then dissolved in 4-00 ml of 6N hydrochloric acid by heating on a steam bath. The hot solution was filtered, and the filtrate left at room temperature overnight. The bright yellow crystalline product was filtered off, washed with small amounts of distilled water and dried in an oven at 85°, giving 6.8 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone mono hy dr oki or id -mono hy dr at, sm.p. ) 34-0°C. The above slightly brown substance which was filtered off from the acetic acid reaction mixture and washed with water was dissolved in aqueous ammonium hydroxide solution and the solution filtered. The filtrate was acidified with acetic acid, after which a solid crystalline substance was precipitated. The mixture was then cooled in an ice bath. The crystalline precipitate was filtered off, washed with water and dried in an oven at 80°C, whereby 13.5 g of product were obtained, m.p. } 320°C, and this was identified by means of its NMR spectrum to be the same as the product from example F-1, i.e. 2, 3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridaz inkar bok syl syre. ;The above-mentioned procedure first goes through the acid acid which is evident from the subsequent isolation of the acid acid as its monochloride: A solution cooled in an ice bath and containing 3»0 g of 2,3-dihydro-3-oxo-6-(4-- pyridinyl )-4-pyridazine carboxylic acid hydrazide and 60 ml of 6N hydrochloric acid were added dropwise to a solution containing 3.0 g of sodium nitrite in 10 ml of water over 1/2 hour. The reaction mixture was then stirred for 1 hour and warmed to room temperature. The precipitate was filtered off, washed with water and dried in a vacuum oven over ^2^5vec^ ^° ^ ^-8 "hours, yielding 3»0 g of 2,3-dihydro-3-oxo-6-(4--pyridinyl )-4.-pyridazine carboxylic acid azide monohydrochloride, m.p. y 300°. ;G-2.4.-amino -6-(4--pyridinyl )-3 (2H )-pyridazinone. ;The above compound was prepared by reacting hydrazine with 6-(4-pyridinyl)-3(2H)-pyridazinone, the tautomeric form of 6-(4-pyridinyl)-3-pyridazinol.A mixture containing 10 g of 6-(4 --pyridinyl )-3 (2H)-pyridazinone and 70 ml of hydrazine hydrate were heated on a steam bath for 3 days, and the excess of hydrazine was distilled off in vacuo. The residue was heated with approx. 300 ml of methanol, and the precipitate was filtered off. was combined with corresponding yields produced in another experiment where one started from 15.7 g of 6 - (4--pyridinyl )-3 (2H )-pyridazinone and 21 ml of hydrazine hydrate, and the combined yields were dissolved in anhydrous potassium carbonate -solution and again precipitated by the addition of acetic acid.The precipitate was dried for 9 hours at 4-0° above P~0roe then over ;o 2 5 6 ;night at 80 . After the NMR spectrum had shown that the product still contained some acetic acid, it was then dried in a vacuum oven at 80° for 2 days, whereby 18.2 ; (69% yield) of 4-amino-6 - (4. -pyridinyl )-3 (2H ). pyridazinone, m.p. > 300°C. The acid addition salt of 4-amino-6-(4-pyridinyl)-3(2H>)-pyridazinone can be suitably prepared by a solution of 1 g of 4-amino-6-(4-pyridinyl)-3 (2H )-pyri-;dazinone in approx. 20 ml of aqueous methanol is added to a suitable acid, e.g. hydrochloric acid, methanesulfonic acid or sulfuric acid, to a pH of between 2 and 3 - The mixture is then cooled and partially evaporated and the precipitated salt is collected, i.e. the hydrochloride, methane sulfate or sulfate, respectively. Furthermore, the lactate or hydrochloric acid addition salt of 4--amino-6-(4--pyridinyl)-3 (2H)-pyridazinone can conveniently be prepared in an aqueous solution by adding water to molar equivalent amounts of 4-amino-6 - (4--pyridinyl)-3 (2H )-pyridaz inone and lactic acid or acetic acid, respectively. ;G - 3. 4--amino-2-methyl-6-(4--pyridinyl)-3(2H)-pyridazinone, m.p. 229-235°C, 6.4-g was prepared using the procedure indicated in Example G-2, and 12 g of 2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone and 100 ml of hydrazine hydrate, and carry out a recrystallization from acetonitrile using decolorized charcoal. Acid addition salts of 4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone can conveniently be prepared by a solution of 1 g of 4-amino-2-methyl-6 -(4--pyridinyl )-3(2HQ-pyridazinone in about 20 ml of aqueous methanol, add a suitable acid, e.g. hydrochloric acid, methanesulfonic acid, or sulfuric acid, to a pH of 2r3, cool the mixture after partial evaporation and filter it precipitated salt, i.e. the hydrochloride, the methanesulfonate or the sulfate, respectively. Furthermore, the lactate or the hydrochloric acid addition salt of 4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone can conveniently be prepared in aqueous solution by water is added to stirred molar equivalent amounts of 4--amino-2-methyl-6-(4--pyridinyl )-3 (2H ]-pyridazinone and lactic acid or hydrochloric acid respectively. ;Using the method described;i example G-2, but instead of 6-(4.-pyridinyl )-3 (2H )-pyridazinone use a molar equivalent amount of a suitable 2-R-6-PT-3 (2H)-pyridazinone, then one canobtain the 4-amino-2-R-6-PY-3(2H)-pyridazinones indicated in Examples G-4- to G-22. ;G-4-. 4-amino-6-(3-pyridinyl)-3(2H)-pyridazinone. G-5. 4.-Amino-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone. ; G -6. 4.-Amino-6-(5-methyl-3-pyridinyl)-3(2H)-pyridazinone. G-7. 4-amino-6-(3-ethyl-4-pyridinyl)-3(2H)-pyridazinone. ; G -8. 4.-Amino-6-(2,6-dimethyl-4.-pyridinyl)-3(2H)-pyridazinone. ;G-9. 4-Amino-2-ethyl-6-('4-pyridinyl)-3(2H)-pyri-dazinone. ;G-10. 4-amino-2-isopropyl-6(4-pyridinyl)-3(2H)-pyridazinone. ; G -11 . 4-amino-2-n-propyl-6-(4-pyridinyl)-3(2H)-pyridazinone. ;G-12. 4-amino-2-isobutyl-6-(4-pyridinyl).-3(2H)-pyridazinone. ;G-13. 4-Amino-2-n-hexyl-6-(4-pyridinyl)-3(2H)-pyridazinone. ;G-14- 4-amino-2-(2-hydroxyethyl)-6-(4-pyridinyl)-3(2H )-pyridazinone. ;G-15. 4-amino-2-(2-hydroxypropyl)-6-(4-pyridinyl)-3(2H)-pyridazinone. ;G-16. 4-amino-2-(3-hydroxypropyl)-6-(4-pyridinyl)-3(2H)-pyridazinone. ;G-17. 4-amino-2-(4-hydroxybutyl)-6-(4-pyridinyl)-3(2H)-pyridazinone. ;G-18. 4-amino-2-methyl-6-(3-pyridinyl)-3(2H)-pyridazinone. ;G-1 9- 4-amino-2-methyl-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone. ;G-2 01' 4-amino-2-methyl-6-(5-methyl-3-pyridinyl)-3(2H)-pyridazinone. ;G-21 4-amino-6-(3-ethyl .-4-pyridinyl)-2-methyl-3(2H)-pyridazinone. ;G-22. 4-Amino-2-methyl-6-(2,6-dimethyl-4-pyridinyl)-3(2H)-pyridazinone. Using the procedure described in Example G-1, but instead of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridaz in carboxylic acid hydrazide, use a corresponding melar.-, an equivalent amount of one suitable 2, 3-dihydro-2-R-3-oxo-6-PY-4--pyridazinecarboxylic acid hydrazide, then one can, as in example G-23 to G -4-1 get prepared the corresponding 4--amino-6-PY-2-R-3 (2H )-pyridazinones also prepared in example -4 to G-22, respectively. G-4-2. 4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone. A solution containing 9.0 g of sodium hydroxide in 130 ml of water was kept at 0° and 2.3 ml of bromine was added dropwise with stirring. To the aqueous mixture was added with stirring 8.0 g of 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide and the resulting mixture was kept on a steam bath for 4- hours. The mixture was then cooled to room temperature, slowly acidified with 6W hydrochloric acid, and the resulting acidic mixture was stirred for an additional 25 minutes. It was then neutralized with 10% aqueous potassium bicarbonate in a ladle and cooled. The precipitate was filtered off, washed, dried, recrystallized from acetonitrile, filtered off, washed with water and dried approx. 15 hours in a vacuum oven at 65°C over P2 o05r. whereby 4-amino-2-methyl-6-(4.-pyridinyl)-3(2H)-pyridazinone was obtained. Using the procedure described in Example G-4-2, but instead of 2,3-dihydro-2-methyl-3-o.xo-6-(4-pyridinyl)-4. -pyridazine carboxamide using a molar equivalent amount of a suitable 2,3-dihydro-3-oxo-6-PY-2-R-4--pyridazine carboxamide, as in examples G-43 to ;G-61, the corresponding 4-amino-6-PY-2-R-3 (2H )-pyrida-zinones, also prepared as indicated in Example G-4. to the G-22, respectively. H. k , 5-dihydro-2-R-6-PY-3(2H)-pyridazinones. ;H-1. 4-,5-dihydro-6-(4.-pyridinyl)-3(2H)-pyridazone. ;A mixture containing 2.4- -g of 4-oxo-4-(4--pyridinyl)butanitrile (the same as y-oxo-y-(4-pyridinyl)butyronitrile), 1.96 g hydrazine sulfate, 100 mL of absolute ethanol, and 100 mL of water were refluxed overnight (about 15 hours). The reaction mixture was then heated in vacuo to remove the solvent mixture. The residue was dissolved in water and filtered. The filtrate was neutralized with 10%; aqueous sodium bicarbonate solution and a yellow solid was precipitated. This was filtered off, washed with water, dried in vacuo over ½ hour. Its nuclear magnetic resonance spectrum and mass spectrum were consistent with the desired product, but there were some traces of impurities. The product was then recrystallized from absolute ethanol, dried in vacuum over ? ~ 2® 5 overnight whereby 0.9 g of 4-, 5-dihydro-6-(4-pyridinyl )-3 (2H )-pyridazinone,-,'m.p., was obtained as golden crystals. 1 85-187°C which is tautomeric with 4-» 5-dihydr 0 - 6 - (4--pyr idinyl ) -3 -pyr idaz in ol. The above reaction can also be carried out by using a molar equivalent amount of hydrazine dihydrochloride or hydrazine di(methanesulfonate) instead of hydrazine sulfate. Acid addition salts of 4-> 5-dihydro-6,-(4--pyridinyl)-(2H)-pyridazinone can conveniently be prepared by a solution of 1 g of 4-»5-dihydro-6-(4--pyridinyl )-3 (2H)-pyridazinone for approx. 20 ml of aqueous methanol may be added to a suitable acid, such as salts, methanesulfonic acid or sulfuric acid to a pH between 2 and 3» cool the mixture after partial evaporation and collect the precipitate, i.e. salts such as the hydrochloride, the methanesulfonate or the sulfate, respectively. Furthermore, the lactate or hydrochloric acid addition salt can also conveniently be prepared in aqueous solution by adding water to stirred molar equivalent amounts of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone and lactic acid or hydrochloric acid, respectively. Using the procedure described in Example H-1, but instead of 4--oxo-4--(4--pyridinyl) butanitrile use a molar equivalent amount of a corresponding 4.-0x0-4- -PY-butanitrile, the corresponding 4-, 5-dihydro-6-PY-3 (2H )-pyridazinones mentioned in examples H-2 to H-6 can be prepared. ;H - 2.4-»5-dihydro-6-(3-pyridinyl)-3-(2H)-pyridazinone. ;H-3. 4,5-dihydro-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone. ;H-4. 4,5-dihydro-6-(5-methyl-3-pyridinyl)-3-(2H)-pyridazinone. ;H-5. 6-(3-ethyl-4-pyridinyl)-4,5-dihydro-3(2H)-pyridazinone. ;H-6. 4,5-dihydro-6-(2,6-dimethyl-4-pyridinyl)-3(1H)-pyridazinone. ;The utility of compound of formula I wherein;R<1>is R" and R is lower-alkyl or lower-hydroxyalkyl, i.e. 2-R-4-R"-6-PY-3(2H)-pyridazinones, or their salts, as cardiotonic agents were shown by their effectiveness in standard pharmacological tests, e.g. in that they produced a significant increase in the contractile force in isolated cat atria and in the papillary muscles. Detailed descriptions of said samples are set forth in US Patent No. 4,072,746. When examined by the above methods, said 2-R-4-R"-PY-3 (2H)-pyridazinones or their pharmaceutically acceptable acid addition salts, ;in doses of 30, 100 and/or 300 ug/ml, a significant increase, i.e. more than 25% in the papillary muscle force and/or a significant increase, i.e. more than 25%, of the higher the pre-chamber force, while it produced a lower percentage increase in stroke velocity in higher pre-chambers. When, for example, the preferred compounds with df or mel Ie^.'; i.e., the compounds from Examples G-2 and G-3^ were tested at said dose level in this method, then they produced an increase of from 30 to over 200% of the papillary muscle force eg/or higher atrial stroke force.The preferred compounds of formula Ia, Ic and Ib, i.e. the compounds of Example C-3, D-r1; and E-2 gave, at said dose levels in said method, an increase of from 28 to 72% in the papillary muscle strength and/or ler the impact force in the higher atrium. In tests with anesthetized dogs, the compound of formula I or their pharmaceutically acceptable acid addition salts in doses of 1.0, 3.0 and/or 10 mg/kg body weight by intravenous administration gave a significant increase, i.e. ;25% or more, in the heart's contractile force or its contractility with less change with respect to blood pressure and stroke rate. A preferred compound such as from example G-2 gave at said dose level in this method an increase of 4-6% or more in the contractile impact force with lower changes in blood pressure and pulse. In clinical practice, a cardiotonic active compound or a salt thereof according to the present invention will normally be administered orally or parenterally using a number of different dosage forms. Solid compositions for oral delivery of cardiotonic active compounds according to the present invention include tablets, pills, powders and granules. In such solid compositions, at least one active compound will be mixed with at least one inert diluent, such as starch, calcium carbonate, sucrose or lactose. Said same sentences may also contain other compounds than said inert diluent, e.g. lubricants, such as magnesium stearate, talc etc. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, etc. containing inert diluents of the usual pharmaceutical type, such as water and liquid paraffin. Because without inert diluents, such compositions can also contain other additives, such as wetting agents and suspending agents, flavourings, perfumes, sweeteners and preservatives. Compositions for oral administration may also include capsules of an absorbable material such as gelatin, containing said active component with or without additions of diluents. Preparations according to the present invention for parenteral administration include sterile, aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solubilizing agents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oils and injectable organic esters such as ethyl oleate. Such compositions can also contain other additives such as stabilisers, preservatives, wetting agents, emulsifying agents and dispersing agents. They can e.g. sterilized by filtering through a bacteria filter, by adding sterilizing agents to the preparations or by irradiation or heating. ;They can also be prepared in the form of sterile solid compositions which can be dissolved in sterile water or another sterile injectable medium immediately before use.;The percentage of the active component in the aforementioned. * ' preparations can be varied so that a suitable dose is obtained.
Den dose som skal tilsføres en spesiell pasient vil være variabel avhengig av legens bedømmelse idet han bruker følgende kriterier: Tilførselsvei, varighet av behandling, størrelse og tilstand på pasienten, den aktive komponents styrke og pasientens reaksjon på behandlingen. En effektiv dose av den aktive komponent kan således bare bedømmes ved at legen tar hensyn til alle kriterier og bruker best mulig bedømmelse på vegne av pasienten. The dose to be administered to a particular patient will be variable depending on the doctor's judgment as he uses the following criteria: route of administration, duration of treatment, size and condition of the patient, the strength of the active component and the patient's reaction to the treatment. An effective dose of the active component can thus only be judged by the doctor taking all criteria into account and using the best possible judgment on behalf of the patient.
Claims (8)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/144,697 US4304776A (en) | 1980-04-28 | 1980-04-28 | 4-Substituted-6-(pyridinyl)-3(2h)-pyridazinones and their use as intermediates and cardiotonics |
| US06/144,563 US4305943A (en) | 1980-04-28 | 1980-04-28 | 4-Amino-6-(pyridinyl)-3(2H)-pyridazinones and their use as cardiotonics |
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| Publication Number | Publication Date |
|---|---|
| NO811420L true NO811420L (en) | 1981-10-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO811420A NO811420L (en) | 1980-04-28 | 1981-04-27 | 6- (PYRIDINYL) -4-SUBSTITUTED-3 (2H) -PYRIDAZINONES SUITABLE AS CARDIOTONIC AGENTS AND PROCEDURES FOR THEIR PREPARATION |
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| Country | Link |
|---|---|
| AR (1) | AR230279A1 (en) |
| AU (1) | AU6972481A (en) |
| DE (1) | DE3116861A1 (en) |
| DK (1) | DK186681A (en) |
| ES (1) | ES8301964A1 (en) |
| FI (1) | FI811304L (en) |
| FR (1) | FR2481284A1 (en) |
| GB (1) | GB2075500B (en) |
| IL (1) | IL62675A0 (en) |
| IT (1) | IT1137568B (en) |
| LU (1) | LU83322A1 (en) |
| NL (1) | NL8102077A (en) |
| NO (1) | NO811420L (en) |
| NZ (1) | NZ196844A (en) |
| PT (1) | PT72935B (en) |
| SE (1) | SE8102660L (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2529891A1 (en) * | 1982-07-12 | 1984-01-13 | Nativelle Sa Ets | PYRIDYL-3 ALCOXY-5 PYRAZOLE DERIVATIVES, PREPARATION METHOD AND THERAPEUTIC APPLICATION |
-
1981
- 1981-04-16 NZ NZ196844A patent/NZ196844A/en unknown
- 1981-04-17 IL IL62675A patent/IL62675A0/en unknown
- 1981-04-22 AU AU69724/81A patent/AU6972481A/en not_active Abandoned
- 1981-04-23 GB GB8112638A patent/GB2075500B/en not_active Expired
- 1981-04-24 FR FR8108251A patent/FR2481284A1/en not_active Withdrawn
- 1981-04-27 SE SE8102660A patent/SE8102660L/en not_active Application Discontinuation
- 1981-04-27 PT PT72935A patent/PT72935B/en unknown
- 1981-04-27 ES ES501665A patent/ES8301964A1/en not_active Expired
- 1981-04-27 FI FI811304A patent/FI811304L/en not_active Application Discontinuation
- 1981-04-27 DK DK186681A patent/DK186681A/en not_active Application Discontinuation
- 1981-04-27 NO NO811420A patent/NO811420L/en unknown
- 1981-04-27 IT IT21385/81A patent/IT1137568B/en active
- 1981-04-28 NL NL8102077A patent/NL8102077A/en not_active Application Discontinuation
- 1981-04-28 DE DE19813116861 patent/DE3116861A1/en not_active Withdrawn
- 1981-04-28 LU LU83322A patent/LU83322A1/en unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| GB2075500B (en) | 1984-06-06 |
| PT72935B (en) | 1982-04-12 |
| DE3116861A1 (en) | 1982-01-14 |
| IL62675A0 (en) | 1981-06-29 |
| AR230279A1 (en) | 1984-03-01 |
| FR2481284A1 (en) | 1981-10-30 |
| NZ196844A (en) | 1984-04-27 |
| AU6972481A (en) | 1981-11-05 |
| NL8102077A (en) | 1981-11-16 |
| ES501665A0 (en) | 1983-01-01 |
| GB2075500A (en) | 1981-11-18 |
| SE8102660L (en) | 1981-10-29 |
| FI811304L (en) | 1981-10-29 |
| DK186681A (en) | 1981-10-29 |
| LU83322A1 (en) | 1981-12-01 |
| PT72935A (en) | 1981-05-01 |
| ES8301964A1 (en) | 1983-01-01 |
| IT8121385A0 (en) | 1981-04-27 |
| IT1137568B (en) | 1986-09-10 |
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