NO811421L - 4,5-DIHYDRO-6 (PYRIDINYL) -3 (2H) -PYRIDAZINONES SUITABLE AS CARDIOTONIC AGENTS AND PROCEDURES FOR THEIR PREPARATION - Google Patents
4,5-DIHYDRO-6 (PYRIDINYL) -3 (2H) -PYRIDAZINONES SUITABLE AS CARDIOTONIC AGENTS AND PROCEDURES FOR THEIR PREPARATIONInfo
- Publication number
- NO811421L NO811421L NO811421A NO811421A NO811421L NO 811421 L NO811421 L NO 811421L NO 811421 A NO811421 A NO 811421A NO 811421 A NO811421 A NO 811421A NO 811421 L NO811421 L NO 811421L
- Authority
- NO
- Norway
- Prior art keywords
- pyridinyl
- methyl
- dihydro
- pyridazinone
- acid
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims description 32
- 239000000496 cardiotonic agent Substances 0.000 title description 7
- FIULGFJIHJJXMT-UHFFFAOYSA-N [C]1[N]C=CC=C1 Chemical class [C]1[N]C=CC=C1 FIULGFJIHJJXMT-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- -1 N-R hydrazine salt Chemical class 0.000 claims abstract description 35
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 15
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims abstract description 12
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims abstract description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 32
- 239000012458 free base Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 5
- WBQLBWAOILVKJU-UHFFFAOYSA-N 2-methyl-4-oxo-4-pyridin-4-ylbutanenitrile Chemical compound N#CC(C)CC(=O)C1=CC=NC=C1 WBQLBWAOILVKJU-UHFFFAOYSA-N 0.000 claims description 2
- 150000002429 hydrazines Chemical class 0.000 claims 1
- 230000003177 cardiotonic effect Effects 0.000 abstract description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000007792 addition Methods 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 210000003540 papillary muscle Anatomy 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- 150000007513 acids Chemical class 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- WEZLANLGAPCPHL-UHFFFAOYSA-N methyl 4-cyano-2-methyl-4-morpholin-4-yl-4-pyridin-4-ylbutanoate Chemical compound C=1C=NC=CC=1C(C#N)(CC(C)C(=O)OC)N1CCOCC1 WEZLANLGAPCPHL-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- YWJGORHFDXGFTF-UHFFFAOYSA-N 2-methyl-6-pyridin-4-ylpyridazin-3-one Chemical compound C1=CC(=O)N(C)N=C1C1=CC=NC=C1 YWJGORHFDXGFTF-UHFFFAOYSA-N 0.000 description 5
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 230000001746 atrial effect Effects 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000004310 lactic acid Substances 0.000 description 5
- 235000014655 lactic acid Nutrition 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- IRWZLWUYVNDDIX-UHFFFAOYSA-N 2-methyl-6-pyridin-4-yl-4,5-dihydropyridazin-3-one Chemical compound C1CC(=O)N(C)N=C1C1=CC=NC=C1 IRWZLWUYVNDDIX-UHFFFAOYSA-N 0.000 description 4
- WNDHJGIIUPAEBD-UHFFFAOYSA-N 5-methyl-3-pyridin-4-yl-4,5-dihydro-1h-pyridazin-6-one Chemical compound N1C(=O)C(C)CC(C=2C=CN=CC=2)=N1 WNDHJGIIUPAEBD-UHFFFAOYSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 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 description 3
- FPZQRPTXDIFAJN-UHFFFAOYSA-N 2,4-dimethyl-6-pyridin-4-yl-4,5-dihydropyridazin-3-one Chemical compound CN1C(=O)C(C)CC(C=2C=CN=CC=2)=N1 FPZQRPTXDIFAJN-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 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
- 230000000694 effects Effects 0.000 description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 3
- 210000002837 heart atrium Anatomy 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- FVBUUYWJAGGTIR-UHFFFAOYSA-N 2-morpholin-4-yl-2-pyridin-4-ylacetonitrile Chemical compound C=1C=NC=CC=1C(C#N)N1CCOCC1 FVBUUYWJAGGTIR-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
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
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- 239000003513 alkali Substances 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
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- 239000002585 base Substances 0.000 description 2
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- 150000002431 hydrogen Chemical group 0.000 description 2
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- 238000002156 mixing Methods 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
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- QHBYZGQLPMSIFR-UHFFFAOYSA-N 4-oxo-4-pyridin-4-ylbutanoic acid Chemical compound OC(=O)CCC(=O)C1=CC=NC=C1 QHBYZGQLPMSIFR-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical class CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
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- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
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- ZFDIRQKJPRINOQ-HWKANZROSA-N Ethyl crotonate Chemical compound CCOC(=O)\C=C\C ZFDIRQKJPRINOQ-HWKANZROSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
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- 239000002202 Polyethylene glycol Substances 0.000 description 1
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 210000002159 anterior chamber Anatomy 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
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- UKPBEPCQTDRZSE-UHFFFAOYSA-N cyclizine hydrochloride Chemical compound Cl.C1CN(C)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 UKPBEPCQTDRZSE-UHFFFAOYSA-N 0.000 description 1
- ZHGASCUQXLPSDT-UHFFFAOYSA-N cyclohexanesulfonic acid Chemical compound OS(=O)(=O)C1CCCCC1 ZHGASCUQXLPSDT-UHFFFAOYSA-N 0.000 description 1
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- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- ZFCIFDCCTCGJLX-UHFFFAOYSA-N ethyl 4-cyano-2-methyl-4-morpholin-4-yl-4-pyridin-4-ylbutanoate Chemical compound C=1C=NC=CC=1C(C#N)(CC(C)C(=O)OCC)N1CCOCC1 ZFCIFDCCTCGJLX-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
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- 238000013100 final test Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- ZGCHATBSUIJLRL-UHFFFAOYSA-N hydrazine sulfate Chemical compound NN.OS(O)(=O)=O ZGCHATBSUIJLRL-UHFFFAOYSA-N 0.000 description 1
- 239000012493 hydrazine sulfate Substances 0.000 description 1
- 229910000377 hydrazine sulfate Inorganic materials 0.000 description 1
- LIAWOTKNAVAKCX-UHFFFAOYSA-N hydrazine;dihydrochloride Chemical compound Cl.Cl.NN LIAWOTKNAVAKCX-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000000936 membranestabilizing effect Effects 0.000 description 1
- SCAVNZFEUOEBQA-UHFFFAOYSA-N methyl 2-methyl-4-oxo-4-pyridin-4-ylbutanoate Chemical compound COC(=O)C(C)CC(=O)C1=CC=NC=C1 SCAVNZFEUOEBQA-UHFFFAOYSA-N 0.000 description 1
- PMOWLRUZAQQLBL-UHFFFAOYSA-N methyl 4-cyano-2-methyl-4-morpholin-4-yl-4-pyridin-3-ylbutanoate Chemical compound C=1C=CN=CC=1C(C#N)(CC(C)C(=O)OC)N1CCOCC1 PMOWLRUZAQQLBL-UHFFFAOYSA-N 0.000 description 1
- VPBUYQNVZRDUGV-UHFFFAOYSA-N methyl 4-cyano-2-methyl-4-pyridin-4-yl-4-pyrrolidin-1-ylbutanoate Chemical compound C=1C=NC=CC=1C(C#N)(CC(C)C(=O)OC)N1CCCC1 VPBUYQNVZRDUGV-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- WFHJFIQWCRVFAZ-UHFFFAOYSA-N propyl 4-cyano-4-(3-ethylpyridin-4-yl)-2-methyl-4-morpholin-4-ylbutanoate Chemical compound C=1C=NC=C(CC)C=1C(C#N)(CC(C)C(=O)OCCC)N1CCOCC1 WFHJFIQWCRVFAZ-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 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
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 238000012360 testing method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent 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
- C07D213/57—Nitriles
Abstract
Fremstilling av 2-R-4,5-dihydro-4-R'-6-PY-3(2H)-pyridazinoner (I) eller salter derav med kardiotonisk virkning og med den generelle formel:. hvor PY er 4- eller 3-pyridinyl eller 4- eller 3-pyridinyl med en eller to lavere alkylsubstituenter,. R er lavere-alkyl eller lavere-hydroksyalkyl, R' er hydrogen eller metyl og hvor R også kan være hydrogen når R' er metyl. Forbindelsene fremstilt ved at man omsetter 4-okso-4-PY-2-R'-butanitril med et N-R-hydrazinsalt av en sterk uorganisk syre eller oganisk sulfonsyre, eller ved at man omsetter et lavere-alkyl 4-okso-4-PY-2-R'-butanoat eller et lavere-alkyl 4-(BN)-4-cyano-4-PY-2-R'-butanoat med N-R-hydrazin, hvor BN. er 4-morfolinyl, 1-piperidinyl eller 1-pyrrolidinyl.Preparation of 2-R-4,5-dihydro-4-R'-6-PY-3 (2H) -pyridazinones (I) or salts thereof having a cardiotonic effect and having the general formula: wherein PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower alkyl substituents. R is lower alkyl or lower hydroxyalkyl, R 'is hydrogen or methyl and wherein R may also be hydrogen when R' is methyl. The compounds prepared by reacting 4-oxo-4-PY-2-R'-butanitrile with an N-R hydrazine salt of a strong inorganic acid or inorganic sulfonic acid, or by reacting a lower alkyl 4-oxo-4-PY -2-R '-butanoate or a lower alkyl 4- (BN) -4-cyano-4-PY-2-R'-butanoate with N-R-hydrazine, where BN. is 4-morpholinyl, 1-piperidinyl or 1-pyrrolidinyl.
Description
Foreliggende oppfinnelse angår 2-substituerte-4., 5-dihydro-6 (pyridinyl)-3 (2H )-pyridazinoner, hvor nevnte forbindelser kan brukes som kardiotoniske midler, fremgangsmåter for deres fremstilling samt deres anvendelse som kardiotoniske midler. The present invention relates to 2-substituted-4.,5-dihydro-6(pyridinyl)-3(2H )-pyridazinones, where said compounds can be used as cardiotonic agents, methods for their production and their use as cardiotonic agents.
Haginiwa et al. (Yakugaku Zasshi 98 (1), 67-71 (1 978), Chem. Abstrs. 88, 170, 096v (1 978) omsatt 3(2H)-pyridazinon med pyridin 1-oksyd og platinisert Pd-C kata-lysator og fikk fremstilt 6-(2-pyridinyl)-3(2H)-pyridazinon. Haginiwa et al. (Yakugaku Zasshi 98 (1), 67-71 (1978), Chem. Abstrs. 88, 170, 096v (1978) reacted 3(2H)-pyridazinone with pyridine 1-oxide and platinized Pd-C catalyst and obtained 6-(2-pyridinyl)-3(2H)-pyridazinone.
Yoshitomi Pharmaceutical Ind. Ltd. Japansk patent-søknad nr. 19, 987/79, publisert 15 februar 1979 og basert på søknad nr. 85, 1 92/77 innsendt 15 juli 1 977 beskriver blant j. annet fremstillingen av 4-» 5 -dihydro-6-(4.-pyridinyl)-3 (2H ) - pyridazinon ved at man i 2 timer under tilbakeløp kokte en etanolisk oppløsning av 3-(isonicotinoyl)propanoinsyre (det samme som y- okso-y-(4--pyridinyl )-smørsyre ) og hydrazinhydrat. 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 j. another, the preparation of 4-»5-dihydro-6-(4.-pyridinyl)-3 (2H )-pyridazinone by refluxing an ethanolic solution of 3-(isonicotinoyl)propanoic acid (the same as y- oxo-γ-(4-pyridinyl)-butyric acid) and hydrazine hydrate.
4., 5-dihydro-6-(4--pyridinyl) -3- (2H )-pyridazinon og nærstående 4-, 5-dihydro-6-(4-- eller 3- eller 2-pyridinyl)-5-R-3(2H)-pyri - dazinoner hvor R er H eller lavere alkyl, er sagt på side 2 4., 5-dihydro-6-(4--pyridinyl)-3-(2H )-pyridazinone and related 4-, 5-dihydro-6-(4-- or 3- or 2-pyridinyl)-5-R -3(2H)-pyri - dazinones where R is H or lower alkyl, is said on page 2
i den engelske oversettelsen og kunne brukes " ikke bare som medisiner mot for høyt blodtrykk eller mot tromber fordi de har farmakologiskovirkning ved at de motvirker for høyt blodtrykk og at de hemmer blodplatekoagulering for uten at de har membranstabiliserende virkninger, men de kan også brukes som mellomprodukter for syntese av slike medisiner". in the English translation and could be used " not only as medicines against high blood pressure or against thrombi because they have pharmacological side effects in that they counteract high blood pressure and that they inhibit platelet coagulation without having membrane stabilizing effects, but they can also be used as intermediates for the synthesis of such drugs".
Mc Evoy og Allen (J. Org. Chem. 38 4-04-4--4.8 (1973)Mc Evoy and Allen (J. Org. Chem. 38 4-04-4--4.8 (1973)
J. Med. Chem. 17, 281 -286 (1 974-) har beskrevet en fremgangsmåte for fremstilling av 3-(substituerte -benzoyl)-3-substituerte-alkanoinsyre og deres reaksjon med hydrazin for fremstilling av 6-(substituerte -f enyl) - 5 - substituerte - 4-, 5 -dihydr o-3 (2H ) - pyridazinoner som kan brukes mot for høyt blodtrykk. J. Med. Chem. 17, 281 -286 (1974-) have described a process for the preparation of 3-(substituted -benzoyl)-3-substituted-alkanoic acids and their reaction with hydrazine to prepare 6-(substituted -phenyl)-5-substituted - 4-, 5-dihydr o-3 (2H ) - pyridazinones that can be used against high blood pressure.
Curran og Ross (J. Med. Chem. 17, 273-281 (1 974-)) har beskrevet fremstillingen av 6 -f enyl-4-, 5-dihydro-3 (2H ) - pyridazinoner som er virksomme mot for høyt blodtrykk, ved at man under> tilbakeløp koker 3-benzoylpropionsyre med hydrazinhydrat"i etanol. Curran and Ross (J. Med. Chem. 17, 273-281 (1974-)) have described the preparation of 6-phenyl-4-, 5-dihydro-3 (2H )-pyridazinones which are effective against excessive blood pressure , by refluxing 3-benzoylpropionic acid with hydrazine hydrate in ethanol.
Albright, Mc Evoy og Moran (J. Heterocyclic Chem. 15, 881 -892 (1 978) beskriver anvendelsen av a-(substituerte - f enyl)-4--morf olinacetonitr iler i 1, 4--addisjoner til etylacrylat, etylcrotonat, metyl a-metylacrylat, acrylonitril, metylacrylo-nitril, crotononitril og cinnamonitril for å fremstille J+-cyano -4--(4--morfolinyl)-4--(substituert -f enyl ) -but an it r il er og butanoinsyreestere, samt deres omdannelse ved en reaksjon med hydrazin til 6-(substituerte-fenyl)-4-, 5-dihydro-3(2H)-pyri - dazinoner som igjen kan dehydrogeneres ved en reaksj.on med brom til 6-(substituerte-fenyl)-3-(2H)-pyridazinoner som even-tuelt har en metylgruppe i 4-- eller 5-stillingen på pyridazinon-r.ingen. Albright, McEvoy and Moran (J. Heterocyclic Chem. 15, 881-892 (1978) describe the use of α-(substituted-phenyl)-4-morpholineacetonitrile in 1,4-additions to ethyl acrylate, ethyl crotonate , methyl α-methylacrylate, acrylonitrile, methylacrylonitrile, crotononitrile and cinnamonitrile to prepare J+-cyano -4-(4-morpholinyl)-4-(substituted -phenyl)-butanitriles and butanoic acid esters , as well as their conversion by a reaction with hydrazine to 6-(substituted-phenyl)-4-, 5-dihydro-3(2H)-pyridazinones which in turn can be dehydrogenated by a reaction with bromine to 6-(substituted- phenyl)-3-(2H)-pyridazinones which optionally have a methyl group in the 4- or 5-position of the pyridazinone ring.
McEvoy og Albright (J. Org. Chem. 4-4-, 4-597-4603 (1 979) viser blant annet en reaksjon med 2-cyano-2 - (4- eller 3-pyridinyl )-2 - (4--morf ol inyl) etanitril og acrylonitril eller etylacrylat for henholdsvis å få fremstilt etyl 4--cyano-4-- McEvoy and Albright (J. Org. Chem. 4-4-, 4-597-4603 (1979) show, among other things, a reaction with 2-cyano-2 - (4- or 3-pyridinyl )-2 - (4- -morphol inyl) ethanenitrile and acrylonitrile or ethyl acrylate to obtain ethyl 4--cyano-4-- respectively
(4-- eller 3-pyridinyl)-4--(4--morf olinyl ) butanoat eller 4--cyano-4--(4-- eller 3-pyridinyl)-4-(4--morf olinyl )butanenitril. (4-- or 3-pyridinyl)-4--(4--morpholinyl) butanoate or 4--cyano-4--(4-- or 3-pyridinyl)-4-(4--morpholinyl)butanenitrile .
Leete et al. (J. Org. Chem. 37, 4-4-65-6 (1 972 )Leete et al. (J. Org. Chem. 37, 4-4-65-6 (1 972 )
har beskrevet reaksjonen mellom 2-(3-pyridinyl)-2 - (^morfolinyl)-etanenitril med acrylonitril for å få fremstilt 4--cyano-4--(3-pyridinyl )-4--(4--morfolinyl )butanitril og dens omdannelse ved at forbindelsen oppvarmes med eddiksyre, vann og tetrahydrofuran, hvorved man får fremstilt 4-- okso-4--(3-pyridinyl) butanitril. have described the reaction between 2-(3-pyridinyl)-2-(^morpholinyl)-ethanenitrile with acrylonitrile to obtain 4-cyano-4-(3-pyridinyl)-4-(4--morpholinyl)butanitrile and its conversion by heating the compound with acetic acid, water and tetrahydrofuran, whereby 4-- oxo-4--(3-pyridinyl) butanitrile is produced.
Foreliggende oppfinnelse angår 2 -R-4-, 5 -dihydro - 4.-R1 -6-PY-3(2H )-pyridåzinon med formel I The present invention relates to 2-R-4-, 5-dihydro-4.-R1-6-PY-3(2H )-pyridozinone of formula I
eller deres syreaddisj onssalter, hvor PY er 4-- eller 3-pyridinyl eller 4-- eller 3-pyridinyl med en eller to lavere-alkyl substituenter, R er laverealkyl eller lavere alkoksyalkyl og R' er hydrogen eller metyl, og hvor R også kan være hydro - 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 lower alkyl or lower alkoxyalkyl and R' is hydrogen or methyl, and wherein R is also can be hydro -
gen når R' er metyl. Slike forbindelser hvor R er laverealkyl eller hydrogen kan brukse som kardiotoniske midler slik dette ble bestemt ved standard kardiotoniske bedømmelsesmetoder. Foretrukne forbindelser er de hvor PY er 4 -pyridinyl eller 3-pyridinyl, R er metyl eller etyl, og R' er hydrogen. De overnevnte forbindelser med formel I hvor R' er hydrogen er også beskrevet som mellomprodukter for fremstilling av 2-R-6-PY-3(2H)-pyridazinoner som også er kardiotoniske midler, gene when R' is methyl. Such compounds where R is lower alkyl or hydrogen can be used as cardiotonic agents as determined by standard cardiotonic evaluation methods. Preferred compounds are those where PY is 4-pyridinyl or 3-pyridinyl, R is methyl or ethyl, and R' is hydrogen. The above-mentioned compounds of formula I where R' is hydrogen are also described as intermediates for the production of 2-R-6-PY-3(2H)-pyridazinones which are also cardiotonic agents,
i patentsøknad nr. 802507 innsendt 22/8-80. De forbindelser ved formel I hvor R' er metyl kan også brukes for å fremstille de tilsvarende nye 2-R-4.-metyl-6-PY-3 (2H)-pyridazinoner. in Patent Application No. 802507 filed 8/22-80. The compounds of formula I where R' is methyl can also be used to prepare the corresponding new 2-R-4.-methyl-6-PY-3 (2H)-pyridazinones.
4-, 5-dihydro -4--metyl -6-,(4--pyridinyl)3 - (2H ) -pyridazinon (I:PY er 4-pyridinyl, R', er metyl, R er hydrogen) kan eksistere er tautomeriske former, d.v.s. som 4-, 5-dihydro-4--metyl-6-(4--pyridinyl)-3 (2H )-pyridazinon med formel IA og/eller som 4-j. 5-dihydro-4--metyl-6 - (4--pyr idinyl) 3-pyridazinol med formel IB slik dette er vist i det etterfølgende (PY er 4- -pyridinyl): 4-, 5-dihydro -4--methyl -6-,(4--pyridinyl)3-(2H )-pyridazinone (I:PY is 4-pyridinyl, R', is methyl, R is hydrogen) can exist is tautomeric forms, i.e. as 4-, 5-dihydro-4-methyl-6-(4-pyridinyl)-3 (2H )-pyridazinone of formula IA and/or as 4-j. 5-dihydro-4-methyl-6-(4-pyridinyl)3-pyridazinol of formula IB as shown below (PY is 4-pyridinyl):
De to tautomeriske forbindelsene IA og IB er i virkeligheten så nærstående slik at de i alt vesentlig kan betraktés som en og samme forbindelse og at de under et gitt sett av omstendigheter kan enten eksistere i en av de to nevnte former eller i begge former. Skjønt man har foretrukket å bruke nevnte basert på struktur IA, så er det under-forstått at begge strukturer inngår i oppfinnelsen. The two tautomeric compounds IA and IB are in reality so closely related that they can essentially be regarded as one and the same compound and that under a given set of circumstances they can either exist in one of the two mentioned forms or in both forms. Although it has been preferred to use the aforementioned based on structure IA, it is understood that both structures are part of the invention.
Man kan fremstille et 2 -R-4, 5-5 -dihydro-4. -R ' -6 - PY-3(2H)-pyridazinon med formel I ved at man reagerer 2-R' - 4.-okso-4--PY-butanitril, lavere-alkyl 2-R '-4.-okso-4--PY-butanoat eller et laverealkyl 2-R' -4--(BN)-4.-cyano-4--PY-butanoat med N-R-hydrazin eller dets salt av en sterk uorganisk syre eller en organisk sulfonsyre, hvorved man får fremstilt 2-R-4-, 5- dihydro-4--R '-6-PY-3 (2H )-pyridazinon hvor PY, ~ >R] og R er som definert i formel I. I foretrukkede utførelser ble foreliggende fremgangsmåte gjennomført ved å bruke 2 -R ' -4.-okso-4--PY-butan - nitril og N-R-hydrazin saltet av en sterk uorganisk eller organisk sulfonsyre, f. eks. N-R-hydrazinsulfat eller dihydro-klorid, eller ved å bruke metyl 2 -R1 -4--okso-4--PY-butanoat eller metyl 2-R'-4--(4- morf olinyl)-4--cyano-4--(PY )-butanoat med N-R-hydrazin. One can prepare a 2-R-4, 5-5-dihydro-4. -R ' -6 - PY-3(2H)-pyridazinone of formula I by reacting 2-R' - 4.-oxo-4--PY-butanitrile, lower-alkyl 2-R '-4.-oxo -4--PY-butanoate or a lower alkyl 2-R' -4-(BN)-4.-cyano-4--PY-butanoate with N-R-hydrazine or its salt of a strong inorganic acid or an organic sulfonic acid, whereby 2-R-4-, 5-dihydro-4--R '-6-PY-3 (2H )-pyridazinone is produced where PY, ~ >R] and R are as defined in formula I. In preferred embodiments the present method was carried out by using 2-R'-4.-oxo-4--PY-butane-nitrile and N-R-hydrazine salt of a strong inorganic or organic sulphonic acid, e.g. N-R-hydrazine sulfate or dihydro-chloride, or by using methyl 2 -R1 -4--oxo-4--PY-butanoate or methyl 2-R'-4--(4- morpholinyl)-4--cyano- 4-(PY )-butanoate with N-R-hydrazine.
En kardiotonisk sammensetning for å øke hjertets kontraktivitet består i følgende foreliggende oppfinnelse av et farmasøytisk akseptabelt inert fortynningsmiddel eller bærestoff, og som aktiv komponent en kardiotonisk effektiv mengde av et 2 -R-4-, 5 -dihydro-4.-R 1 -PY-3/2H ) -pyr idaz inon (formel I) eller et farmasøytisk akseptabelt syreaddisjonssalt av en slik forbindelse, hvor R er laverealkyl og PY og R' er som definert ovenfor, eller R' er.metyl, R er hydrogen og PY er 4.-pyridinyl. A cardiotonic composition for increasing the contractility of the heart consists in the following present invention of a pharmaceutically acceptable inert diluent or carrier, and as active component a cardiotonically effective amount of a 2-R-4-, 5-dihydro-4.-R 1 -PY -3/2H )-pyridaz inone (formula I) or a pharmaceutically acceptable acid addition salt of such a compound, wherein R is lower alkyl and PY and R' is as defined above, or R' is methyl, R is hydrogen and PY is 4.-pyridinyl.
For å øke hjertets kontraktivitet hos en pasient som krever en slik behandling kan man oralt eller parenteralt'.: gi en fast eller flytende doseringsform til en slik pasient tilføre en sammensetning som innbefatter et faramsøytisk akseptabelt inert bærestoff og som den aktive komponent, en kardiotonisk effektiv mengde av 2 -R-4-, 5 -dihydro-4- -R ' -6 -PY-3 (2H)-pyridazinon eller et farmasøytisk akseptabelt syreaddisjonssalt av en slik forbindelse, hvor R er laverealkyl, og PY og R' er som definert i formel I, eller R' er metyl, R In order to increase the contractility of the heart in a patient who requires such treatment, one can orally or parenterally': give a solid or liquid dosage form to such a patient add a composition which includes a pharmaceutically acceptable inert carrier and as the active component, a cardiotonically effective amount of 2-R-4-, 5-dihydro-4--R' -6-PY-3 (2H)-pyridazinone or a pharmaceutically acceptable acid addition salt of such a compound, wherein R is lower alkyl, and PY and R' are as defined in formula I, or R' is methyl, R
er hydrogen og PY er 4--pyridinyl.is hydrogen and PY is 4--pyridinyl.
Med begrepet "laverealkyl" slik det brukes her,With the term "lower alkyl" as used herein,
f. eks. i forbindelse med betydningen av R i formel I eller som en substituent for PY i formel I, forståes alkylradikaler med fra 1 til 6 karbonatomer som kan være plassert i rette eller grenete kjeder, f. eks. metyl, etyl, n-propyl, iso-propyl, n-butyl, 2.butyl, isobutyl, n-hexyl. e.g. in connection with the meaning of R in formula I or as a substituent for PY in formula I, are understood alkyl radicals with from 1 to 6 carbon atoms which can be located in straight or branched chains, e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2.butyl, isobutyl, n-hexyl.
Symbolet PY slik det brukes her, f. eks. som 6-substituenten i forbindelser med formel I, er 4-- eller 3-pyridinyl eller 4-- eller 3-pyridinyl med en eller to "lavere- alkyl" substituenter, og som eksemplér kan man nevne 2-metyl-4- pyridinyl, 2,6-dimetyl-4-pyridinyl, 3-metyl-4-pyridinyl, 2-metyl-3-pyridinyl, 6-metyl-3-pyridinyl (alternativt 2-metyl-5- pyr idinyl), 2, 3-dime tyl-4 -pyridinyl, 2, 6-dime tyl-^-pyridinyl, 2-etyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl, 2,6-dietyl-4-pyridinyl, 2,6-dietyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl o.l. The symbol PY as used here, e.g. as the 6-substituent in compounds of formula I is 4- or 3-pyridinyl or 4- or 3-pyridinyl with one or two "lower alkyl" substituents, and as examples one can mention 2-methyl-4-pyridinyl , 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively 2-methyl-5-pyridinyl), 2, 3- dimethyl-4-pyridinyl, 2, 6-dimethyl-^-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl- 4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diethyl-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 formel I, forståes hydroksyalkyl-radikaler med fra to til seks karbon - atomer og som har sin hydroksygr uppe og sin frie valence - binding (eller tilknyttende binding) på forskjellige karbon - atomer, og hvor sistnevnte kan være plassert i rette eller grenede kjeder, og som eksempler kan man nevne 2-hydroksy- With the term "lower hydroxyalkyl" as used herein, e.g. in connection with the meaning of R in formula I, is understood hydroxyalkyl radicals with from two to six carbon atoms and which have their hydroxy group and their free valence bond (or associated bond) on different carbon atoms, and where the latter can be placed in straight or branched chains, and as examples one can mention 2-hydroxy-
etyl, 2-hydroksypropyl, 3-hydroksypropyl, 2-hydroksy-2-metyl-propyl, 2-hydroksy-1,1-dimetyletyl, 4-hydroksybutyl, 5-hydroksy-amyl, 6-hydroksyhexyl, o.l. ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methyl-propyl, 2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl, 5-hydroxy-amyl, 6-hydroxyhexyl, etc.
Forbindelser ifølge foreliggende oppfinnelse med formel I kan brukes både i form av den frie basen og i form av syreaddisjonssalter, og begge former inngår i oppfinnelsen. Syreaddisjonssaltene er vanligvis mer enkle og mer praktiske Compounds according to the present invention with formula I can be used both in the form of the free base and in the form of acid addition salts, and both forms are included in the invention. The acid addition salts are usually simpler and more convenient
å bruke, men bruken av saltet gir samme virkning som baseformen. De syrer som kan brukes for å fremstille syre-addis jonssalter innbefatter de som når de blir kombinert med den frie basen, gir farmasøytisk akseptable salter, d.v.s. salter hvis anioner er relativt ufarlige i dyreorganismen i farmasøytiske doser av saltet, slik at de fordelaktige kardiotoniske egenskaper som forefinnes i den frie basen i de kardiotoniske aktive forbindelser ifølge foreliggende oppfinnelse, ikke blir tilsidesatt av sideeffekter som kan til-skrives anionene. Ved gjennomføring av foreliggende oppfinnelse er det hensiktsmessig å bruke den frie baseformen, to use, but the use of the salt gives the same effect as the base form. The acids which can be used to prepare acid addition salts 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 in pharmaceutical doses of the salt, so that the beneficial cardiotonic properties found in the free base in the cardiotonic active compounds according to the present invention are not overridden by side effects attributable to the anions. When carrying out the present invention, it is appropriate to use the free base form,
men farmasøytiske akseptable salter ligger også innenfor foreliggende oppfinnelse, f. eks;'; de som er avledet av mineral - syrer så som salter, svovelsyre, fosforsyre og sulfaminsyre, but pharmaceutically acceptable salts are also within the scope of the present invention, e.g.; those derived from mineral acids such as salts, sulfuric acid, phosphoric acid and sulfamic acid,
foruten organiske syrer som eddiksyre, sitronsyre, melkesyre, tartarsyre, metansulfon syre, etansulfonsyre, benzensulfonsyre, p-toluensulfonsyre, cyklohexylsulfaminsyre, kininsyre, o.l., hvorved man får fremstilt hydrokloridet, sulfatet, fosfatet, sulfonatet, acetatet, citratet, lactatet, tartratet, metan-sulf onatet, etansulfonatet, benzensulfonatet, p-toluensul-fonatet, cyklohexylsufonatet og kinatet, henholdsvis. in addition to 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., whereby the hydrochloride, sulfate, phosphate, sulfonate, acetate, citrate, lactate, tartrate, methane are produced -sulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfonate and quinate, respectively.
Syreaddisj onssalter av nevnte basiske forbindelser kan fremstilles enten at man oppløser den frie basen i en vandig eller vandig-alkoholisk oppløsning eller i andre egnede oppløsninger eller hvor syren er tilført, hvoretter man iso-lerer saltet ved å fordampe oppløsningen eller ved at man reagerer den frie basen og syrene i et organisk .oppiøsnings-middel, og i sistnevnte tilfelle vil saltet skille seg ut direkte eller kan oppnås ved at man konsentrerer oppløsningen. Acid addition salts of said basic compounds can be prepared either by dissolving the free base in an aqueous or aqueous-alcoholic solution or in other suitable solutions or where the acid has been added, after which the salt is isolated by evaporating the solution or by reacting it the free base and the acids in an organic solvent, and in the latter case the salt will separate out directly or can be obtained by concentrating the solution.
Skjønt farmasøytisk akseptable salter av nevnte basiske forbindelse er foretrukket, så ligger alle syreaddisjonssalter innenfor oppfinnelsen- Alle typer syreaddisjonssalter kan brukes som utgangspunkt for den frie baseformen selv om saltet som sådan bare erønskelig som et mellomprodukt, f. eks. når saltet dannes for å rense eller å identifisere basen, eller når saltet brukes som et mellomprodukt for fremstilling av farmasøytisk akseptabelt salt ved ioneutbytningsr metode. Although pharmaceutically acceptable salts of said basic compound are preferred, all acid addition salts are within the scope of the invention - All types of acid addition salts can be used as a starting point for the free base form, even if the salt as such is only desirable as an intermediate product, e.g. when the salt is formed to purify or identify the base, or when the salt is used as an intermediate for the preparation of a pharmaceutically acceptable salt by the ion exchange method.
Molekylstrukturen på forbindelser med-formel I ble fastslått på basis av infrarøde, kjernemagnetiske resonans og massespektra og ved en overensstemmelse mellom beregnedef\Qg funnede verdier i elementæranalyser. The molecular structure of compounds of formula I was established on the basis of infrared, nuclear magnetic resonance and mass spectra and by an agreement between calculated values and values found in elementary analyses.
Fremgangsmåten for fremstilling og bruk av foreliggende forebindelser vil nå bli mer generelt beskrevet. The procedure for the production and use of the present compounds will now be described more generally.
Reaksjonen mellom et 2-R 1-4-okso-4-PY-butanitrilThe reaction between a 2-R 1-4-oxo-4-PY-butanitrile
og et N-R-hydrazinsalt at en sterk uorganisk eller organisk sulfonsyre for fremstilling av 2-R-4,5-dihydro-4-R 1-6-PY-3 (2H)-pyridazinon utføres ved at man oppvarmer raaktantene til temperaturer mellom 65 og 120°C i et egnet oppiøsningmiddél, fortrinnsvis mellom 80 og 100 i en blanding av vann og en lavere- and an N-R-hydrazine salt that a strong inorganic or organic sulfonic acid for the preparation of 2-R-4,5-dihydro-4-R 1-6-PY-3 (2H)-pyridazinone is carried out by heating the reactants to temperatures between 65 and 120°C in a suitable solvent, preferably between 80 and 100 in a mixture of water and a lower
alkanol. Reaksjonen utføres fortrinnsvis ved at man under tilbakeløp koker 2-R'-4-okso-4-PY-butanitril og hydrazinsulfat i vandig etanol. Andre N-R-hydrazin salter som kan brukes er N-R-hydrazin dihydroklor.id, N-R-hydrazin-dimetan-sulfonat og lignende salter avledet fra fosforsyre, etan-sulf onsyre, benzensulfonsyre og lignende syrer. Andre lavere-alkanoler som kan brukes som oppløsningmiddel er metanol, n-propanol, 2-propanol, n-butanol, 2-butanol og 2-metyl-n-propanol. Denne type reaksjon er illustrert i det etter-følgende i eksempel A-1 til A-.1>5. alkanol. The reaction is preferably carried out by refluxing 2-R'-4-oxo-4-PY-butanitrile and hydrazine sulphate in aqueous ethanol. Other N-R-hydrazine salts that can be used are N-R-hydrazine dihydrochlorid, N-R-hydrazine dimethane sulfonate and similar salts derived from phosphoric acid, ethane sulfonic acid, benzene sulfonic acid and similar acids. Other lower alkanols that can be used as solvents are methanol, n-propanol, 2-propanol, n-butanol, 2-butanol and 2-methyl-n-propanol. This type of reaction is illustrated below in examples A-1 to A-.1>5.
Det intermediære 2-R 1-4-okso-4-PY-butanitriler er generelt kjente forbindelser, se f. eks. Stetter et al. Chem. Ber. 107, 210 (1974). Leete et al. J. Org. Chem. 37, 4466 (1 972) og Stetter et al. U.S. Patent 4-014-889 (Mar. 29, The intermediate 2-R 1-4-oxo-4-PY-butanitriles are generally known compounds, see e.g. Stetter et al. Chem. Pray. 107, 210 (1974). Leete et al. J. Org. Chem. 37, 4466 (1972) and Stetter et al. U.S. Patent 4-014-889 (Mar. 29,
1977), og fremstilles ved generelt kjente fremgangsmåter. Fremstillingen av disse forbindelser er vist i eksemplene C-1 til C-6. 1977), and is produced by generally known methods. The preparation of these compounds is shown in Examples C-1 to C-6.
Reaksjonen mellom et lavere-alkyl 2-R '-4-okso-4-PY-butanoat eller ét lavere-alkyl-2-R 1-4-(BN)-4-cyano-4-PY-butanoat og N-R-hydrazin for fremstilling av 2-R-4,5-dihydro - 4-R1 -6-PY-3(2H)-pyridazinon utføres ved at man oppvarmer reaktantene til temperaturer mellom 65 og 120°C i et egnet opp-løsning smiddel, fortrinnsvis mellom 80 og 100° i en lavere-alkanol. Reaksjonen utføres ved at man koker reaktantene under tilbakeløp i etanol. Andre lavere alkanoler som kan brukes er metanol, n-butanol, 2-butanol og 2-metyl-n-propanol. Denne reaksjonen er illustrert i eksemplene. A-16 til A-24- The reaction between a lower-alkyl 2-R'-4-oxo-4-PY-butanoate or a lower-alkyl-2-R 1-4-(BN)-4-cyano-4-PY-butanoate and N-R-hydrazine for the production of 2-R-4,5-dihydro - 4-R1 -6-PY-3(2H)-pyridazinone is carried out by heating the reactants to temperatures between 65 and 120°C in a suitable solvent, preferably between 80 and 100° in a lower alkanol. The reaction is carried out by boiling the reactants under reflux in ethanol. Other lower alkanols that can be used are methanol, n-butanol, 2-butanol and 2-methyl-n-propanol. This reaction is illustrated in the examples. A-16 to A-24-
Det intermediære lavere-alkyl 2-R<1->4-okso-4-PY-butanoatet og/eller tilsvarende syrer er generelt kjente forbindelser (Wada et al. J. Am. Chem. Soc. 76, 155 (1 954), som lett fremstilles ved å hydrolysere generelt kjente 2-R'-4-okso-4-PY-butannitriler og deretter forestre de resulterende 2-R'-4- okso-4-PY-butanoinsyrer. The intermediate lower alkyl 2-R<1->4-oxo-4-PY-butanoate and/or corresponding acids are generally known compounds (Wada et al. J. Am. Chem. Soc. 76, 155 (1954) , which is easily prepared by hydrolyzing generally known 2-R'-4-oxo-4-PY-butanenitriles and then esterifying the resulting 2-R'-4-oxo-4-PY-butanoic acids.
Reaksjonen mellom 2 - (BN )-2-PY-etan.itril (III)The reaction between 2 - (BN )-2-PY-ethane.itrile (III)
og et lavere-alkyl 2-R'-2-propenoat (IV) for å få fremstilt et lavere-alkyl 2-R' -4-(BN)-4-cyano-4-PY-butanat (II) ut- and a lower-alkyl 2-R'-2-propenoate (IV) to produce a lower-alkyl 2-R'-4-(BN)-4-cyano-4-PY-butanate (II) from
føres under vannfri betingelser ved at man blander reaktanten mellom 25 og 60°C, fortrinnsvis mellom 30 og 50°C, i et egnet oppløsningsmiddel i nærvær av et basisk kondensasjonsmiddel. is carried out under anhydrous conditions by mixing the reactant between 25 and 60°C, preferably between 30 and 50°C, in a suitable solvent in the presence of a basic condensing agent.
Reaksjonen kan hensiktsmessig utføres ved at man blander reaktantene mellom 30 og 50° i tørr tetrahydrofuran i nærvær av et alkalihydroksyd i metanol. Andre egnede opp-løsningsmidler er lavere-alkanoler så som etanol og isopropylalkohol, dimetylformamid, acetonitril, tetrahydrofuran, benzen o.l. Egnede basiske kondensasjonsmidler innbefatter alkalihydroksyder, så som kalium eller natriumhydroksyd, alkali-lavere-alkoksyder så som natriummetoksyd eller kaliumetoksyd, natriumhydrid, o.l. The reaction can conveniently be carried out by mixing the reactants between 30 and 50° in dry tetrahydrofuran in the presence of an alkali hydroxide in methanol. Other suitable solvents are lower alkanols such as ethanol and isopropyl alcohol, dimethylformamide, acetonitrile, tetrahydrofuran, benzene and the like. Suitable basic condensing agents include alkali hydroxides such as potassium or sodium hydroxide, alkali lower alkoxides such as sodium methoxide or potassium ethoxide, sodium hydride, and the like.
De intermediære 2-(BN)-2-PY-etanitriler (III) er generelt kjente forbindelser, se f. eks. Janssen et al., J. The intermediate 2-(BN)-2-PY-ethanenitriles (III) are generally known compounds, see e.g. Janssen et al., J.
Am. Pharm. Assoc, Sei. Ed., 4-4-, 465-7 (1 955), og kan fremstilles ved kjente fremgangsmåter. Fremstillingen av disse forbindelser er vist i eksemplene E-1 til E-5. Am. Pharm. Assoc, Sei. Ed., 4-4-, 465-7 (1955), and can be produced by known methods. The preparation of these compounds is shown in Examples E-1 to E-5.
Omdannelsen av de indermediære 4»5-dihydro-2-R - 4-R'-6-PY-3(2H)-pyridazinoner ved en reaksjon med brom til de tilsvarende 2-R-4-R'-PY-3(2H)-pyridazinoner, og hvor man får ved denne omdannelsen fremstilt 2-R-4-R'-6-PY-3(2H)-pyridazinoner og deres anvendelse når R' er hydrogen, som kardiotoniske midler, ér beskrevet i overnevnte patentsøknad. The conversion of the intermediate 4»5-dihydro-2-R - 4-R'-6-PY-3(2H)-pyridazinones by a reaction with bromine to the corresponding 2-R-4-R'-PY-3( 2H)-pyridazinones, and how 2-R-4-R'-6-PY-3(2H)-pyridazinones are produced by this conversion and their use when R' is hydrogen, as cardiotonic agents, is described in the above-mentioned patent application .
Denne omdannelse og de produkter som dermed blir fremstilt,This transformation and the products that are thus produced,
er vist i eksempel B-1 for en forbindelse hvor R' er hydrogen, og i eksemplene m.B-2 til B-9 for forbindelser hvor R' er metyl. is shown in example B-1 for a compound where R' is hydrogen, and in examples m.B-2 to B-9 for compounds where R' is methyl.
De følgende eksempler illustrerer " oppl.innel sen.The following examples illustrate "opl.innel sen.
A. 4, 5- dihydro- 2- R- 4- R' - 6- PY- 3 ( 2H )- pyridazinonerA. 4, 5- dihydro- 2- R- 4- R' - 6- PY- 3 ( 2H )- pyridazinones
A-1. 4, 5- dihydro- 2- metyl- 6-( 4- pyridinyl)- 3( 2H)- pyridazinon. A-1. 4, 5-Dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
En rørt varm oppløsning inneholdende 25,6 g N-metylhydrazin-dihydroklorid, 400 ml absolutt etanol og 70 ml vann ble tilsatt 32 g 4-okso-4-(4-pyridinyl)butanitril, og den resulterende blanding ble kokt under tilbakeløp i 15 timer. Oppløsningsmiddelet ble avdestillert i vakuum, og det gjen værende faste stoff ble omkrystallisert fra etanol og tørket i en vakuum-ovn ved 65° over natten, hvorved man fikk 10,5 4,5-dihydro-2-metyl-6-(4-pyridinyl)-3(2H )pyridazinon som dets monohydroklor.id, sm.p. 21 9-225°C med dekomponering. To a stirred hot solution containing 25.6 g of N-methylhydrazine dihydrochloride, 400 ml of absolute ethanol and 70 ml of water was added 32 g of 4-oxo-4-(4-pyridinyl)butanitrile, and the resulting mixture was refluxed for 15 hours. The solvent was distilled off in vacuo, and the remaining solid was recrystallized from ethanol and dried in a vacuum oven at 65° overnight, yielding 10.5 4,5-dihydro-2-methyl-6-(4- pyridinyl)-3(2H )pyridazinone as its monohydrochloride, m.p. 21 9-225°C with decomposition.
Syreaddisjonssalter av 4,5 -dihydro-2-metyl-6-(4 - pyridinyl)-3(2H)-pyridazinon kan hensiktsmessig fremstilles ved at man tilsetter en oppløsning av 1 g 4»5 -dihydro-2-metyl - 6-(4-pyridinyl )-3(2H)-pyridazinon i 20 ml vandig metanol en passende syre, f. eks. salter, metansulfonsyre eller svovelsyre, til en pH mellom 2 og 3, avkjøler blandingen etter delvis fordampning og oppsamler det utfelte Salt, d.v.s. hydrokloridet, metansulfonatet eller sulfatet henholdsvis. Videre kan lactatet eller hydroki oridsyreaddisjonssaltet av 4,5-dihydro-2-metyl-6 - (4-pyridinyl) -3(2H) -pyridaz inon hensikt s-messig fremstilles i vandi<g->''oppløsning ved at vann under . røring tilsettes molare ekvivalente mengder av 4»5-dihydro-2-metyl-6(4-pyridinyl)-3(2H)-pyridazinon samt melkesyre eller saltsyre henholdsvis. Acid addition salts of 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone can conveniently be prepared by adding a solution of 1 g of 4»5-dihydro-2-methyl-6- (4-pyridinyl)-3(2H)-pyridazinone in 20 ml of aqueous methanol a suitable acid, e.g. salts, methanesulphonic acid or sulfuric acid, to a pH between 2 and 3, cools the mixture after partial evaporation and collects the precipitated Salt, i.e. the hydrochloride, methanesulfonate or sulfate respectively. Furthermore, the lactate or the hydrochloric acid addition salt of 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazone can conveniently be prepared in aqueous solution by adding water under . stirring, molar equivalent amounts of 4'5-dihydro-2-methyl-6(4-pyridinyl)-3(2H)-pyridazinone and lactic acid or hydrochloric acid respectively are added.
Ved å bruke den fremgangsmåten som er beskrevetBy using the procedure described
i eksempel A-1 men istedenfor N-metylhydrazindihydroklorid bruke en molar ekvivalent mengde av et passende N-R-hydrazin - dihydroklorid eller et annet salt av den sterkt uorganiske syre eller organiske sulfonsyre, så kan man få fremstilt de til svarende 4,5-dihydro-2-R-6 -(4-pyridinyl)-3 (2H)-pyridaz inon (eller deres salter) som er angitt i eksemplene A-2 til A-10. in example A-1, but instead of N-methylhydrazine dihydrochloride use a molar equivalent amount of a suitable N-R-hydrazine dihydrochloride or another salt of the strong inorganic acid or organic sulphonic acid, then you can get those corresponding to 4,5-dihydro- 2-R-6-(4-pyridinyl)-3(2H)-pyridaz inone (or their salts) as set forth in Examples A-2 to A-10.
A-2. 2-etyl-4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinon . A-2. 2-Ethyl-4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.
A- 3- 4» 5-dihydro-2-isopropyl-6-(4-pyridinyl)-3 (2H) - pyridazinon. A-3-4»5-dihydro-2-isopropyl-6-(4-pyridinyl)-3 (2H)-pyridazinone.
A-4- 4» 5-dihydro-2-n-propyl-6- (4-pyridinyl ) -3 (2H ) - pyridazinon. A-4-4'5-dihydro-2-n-propyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
A-5. 4,5-dihydro-2-isobutyl-6-(4-pyridinyl)-3(2H)-pyridaz inon. A-5. 4,5-dihydro-2-isobutyl-6-(4-pyridinyl)-3(2H)-pyridaz inone.
A-6. 2-n-hexyl-4, 5 -dihydro-6- (4-pyr idinyl )-3 (2H ) - pyridazinon. A-6. 2-n-hexyl-4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.
A-7. 2- (2-hydroksyetyl ) -4» 5-dihydro-6- (4.-pyridinyl ) - 3 (2H) -pyr idaz inon, sm.p. 14-2 -1 44°C . A-7. 2-(2-Hydroxyethyl)-4'5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazone, m.p. 14-2 -1 44°C .
A-8. 2- (2-hydroksypropyl) -4-, 5-dihydro-6- (4--pyridinyl) - 3{<?H) -pyridazinon. A-8. 2-(2-Hydroxypropyl)-4-,5-dihydro-6-(4-pyridinyl)-3{<?H)-pyridazinone.
A - 9. 2 - (3 -hydroksypropyl) -4-, 5 -dihydro - 6- (4--pyridinyl) - 3(2H)-pyridazinon. A - 9. 2-(3-Hydroxypropyl)-4-,5-dihydro-6-(4--pyridinyl)-3(2H)-pyridazinone.
A-1 0. 2- (4--hydroksybutyl) -4» 5-dihydro-6- (4--pyridinyl) - 3(2H)-pyridazinon. A-1 0.2-(4-hydroxybutyl)-4-5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.
Ved å bruke den fremgangsmåten som er beskrevetBy using the procedure described
i eksempel A-1, men i steden for 4-okso-4--(4- -pyridinyl )butan-nitril bruke en molar ekvivalent mengde av et passende 4-okso-4--PY-butanitril, så kan man få. fremstilt de 4-» 5 -dihydr o-6-PY-2-metyl-3(2H)-pyridazinoner som er nevnt i eksemplene A-11 til A-15. in Example A-1, but instead of 4-oxo-4--(4--pyridinyl)butanenitrile use a molar equivalent amount of a suitable 4-oxo-4--PY-butanitrile, then one can obtain. prepared the 4-»5-dihydro-6-PY-2-methyl-3(2H)-pyridazinones mentioned in Examples A-11 to A-15.
A-11. 4, 5-dihydro-2-metyl-6-(3-pyridinyl)-3(2H)-pyridaz inon. A-11. 4, 5-dihydro-2-methyl-6-(3-pyridinyl)-3(2H)-pyridaz inone.
A-12. 4» 5-dihydro-2-metyl-6-(2-metyl-3-pyridinyl) - 3(2H)-pyridazinon. A-12. 4'' 5-dihydro-2-methyl-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone.
A-13. 4,5-dihydro-2-metyl-6 -(5-metyl -3-pyridinyl ) - 3(2H)-pyridaz inon. A-13. 4,5-dihydro-2-methyl-6-(5-methyl-3-pyridinyl)-3(2H)-pyridaz inone.
A-14- 2-etyl-6-(3-etyl-4-pyridinyl)-4,5-dihydro-2-metyl - 3(2H)-pyridazinon. A-14-2-ethyl-6-(3-ethyl-4-pyridinyl)-4,5-dihydro-2-methyl-3(2H)-pyridazinone.
A-15- 4,5-dihydro-2-metyl-6-(2,6-dimetyl-4-pyridinyl ) - 3(2H)-pyridazinon. A-15- 4,5-dihydro-2-methyl-6-(2,6-dimethyl-4-pyridinyl)-3(2H)-pyridazinone.
A-16. 4, 5-dihydro-2>.4-dimetyl-6-(4-pyridinyl )-3(2H)-pyridazinon. A-16. 4,5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
En blanding inneholdende 16 g metyl 4-cyano-2-metyl 4-(4-morfolinyl)-4-(4-pyridinyl)butanoat, 30 ml N-metylhydra-zin og 220 ml absolutt etanol ble kokt under tilbakeløp i ca. 17 timer. Etanolen ble avdestillert i vakuum, og det oljeaktige residuet ble plassert på en kolonne av silisium-dioksydgel (7 cm høy og 15 cm i diameter), i en stor glass-trakt med filter og eluert med en 50-50 blanding (pr. volum) av eter og n-hexan. En fordampning av de elueringsmengder som inneholdt hovedmengden av produktet slik dette kunne påvises ved tyhnsjiktkromatografianalyse (CHCl^: CH^CH: i-C3H7NH2/90 % : 5 % : 5 % pr. volum), ga et fast produkt som I. ble omkrystallisert fra eter-n-hexan og tørket i vakuum ved 50°, og som ga 3» 0 g 4» 5 -dihydro -2, 4 -dimetyl -6 - (4 -pyr idinyl) - 3(2H)-pyridazinon, sm.p. 71-81°C. A mixture containing 16 g of methyl 4-cyano-2-methyl 4-(4-morpholinyl)-4-(4-pyridinyl)butanoate, 30 ml of N-methylhydrazine and 220 ml of absolute ethanol was refluxed for approx. 17 hours. The ethanol was distilled off in vacuo, and the oily residue was placed on a column of silica gel (7 cm high and 15 cm in diameter), in a large glass funnel with a filter and eluted with a 50-50 mixture (per volume ) of ether and n-hexane. Evaporation of the eluting amounts which contained the main amount of the product as this could be detected by thin-layer chromatography analysis (CHCl^: CH^CH: i-C3H7NH2/90% : 5% : 5% by volume), gave a solid product which I. was recrystallized from ether-n-hexane and dried in vacuo at 50°, and which gave 3»0 g of 4»5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone, sm .p. 71-81°C.
Syreaddisj onssalter av 4> 5-dihydro -2, 4-dimetyl-6 - Acid addition salts of 4>5-dihydro-2,4-dimethyl-6-
(4--pyridinyl )-3 (2H)-pyridazinon kan hensiktsmessig fremstilles vedrat en oppløsning av 1 g 4>5-dihydro-2,4-dimetyl-6-(4-pyri - dinyl )-3(2H)-pyridazinon i ca. 20 ml vandig metanol tilsettes en passende syre, f. eks. salter, metansulfonsyre eller svovelsyre, til en pH på fra 2 til 3, avkjøle blandingen etter delvis fordampning og oppsamle det utfelte salt, d.v.s. hydrokloridet, metansulfonatet eller sulfatet henholdsvis. Også lactatet eller hydroklorid.-syreaddis j onssaltet av 4,5-dihydro-2,4-dimetyl-6-(4-pyridinyl)-3(2H)-pyridazinon kan hensiktsmessig fremstilles i vandig oppløsning ved at man til vann under røring tilsetter molare ekvivalende mengder av 4,5-dihydro-2,4-dimetyl-6-(4-pyridinyl)-3(2H)-pyridazinon samt melkesyre eller saltsyre henholdsvis. (4--pyridinyl)-3(2H)-pyridazinone can conveniently be prepared from a solution of 1 g of 4>5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone for about. 20 ml of aqueous methanol is added to a suitable acid, e.g. salts, methanesulfonic acid or sulfuric acid, to a pH of from 2 to 3, cool the mixture after partial evaporation and collect the precipitated salt, i.e. the hydrochloride, methanesulfonate or sulfate respectively. The lactate or hydrochloride acid addition salt of 4,5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone can also be conveniently prepared in aqueous solution by adding water while stirring molar equivalent amounts of 4,5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone and lactic acid or hydrochloric acid respectively.
Ved å bruke den fremgangsmåten som er beskrevet i eksempel A-16, men i steden for metyl 4-cyano-4-(4-morfolinyl )-4-(4-pyridinyl)-2-metylbutanoat og N-metylhydroazin, -bruke tilsvarende molare ekvålente mengder av et passende lavere-alkyl 4--cyano-4--(BN )-4.-PI-2-metylbutanoat og N-R-hydrazin, By using the procedure described in example A-16, but instead of methyl 4-cyano-4-(4-morpholinyl)-4-(4-pyridinyl)-2-methylbutanoate and N-methylhydroazine, -use correspondingly molar equivalent amounts of an appropriate lower alkyl 4-cyano-4-(BN )-4.-PI-2-methylbutanoate and N-R-hydrazine,
kan man få fremstilt de 4, 5 -dihydr o-4,-metyl-6 -PY-2-R-3 (2H ) - pyridazinoner som er nevnt-i eksempel A-17 til A-23- can be produced the 4, 5-dihydro-4,-methyl-6-PY-2-R-3 (2H ) - pyridazinones that are mentioned-in examples A-17 to A-23-
A-17. 4» 5-dihydro-2,4-dimetyl-6-(3-pyridinyl)-3(2H)-pyridazinon. A-17. 4'' 5-dihydro-2,4-dimethyl-6-(3-pyridinyl)-3(2H)-pyridazinone.
A-18. 2-etyl-4,5-dihydro-4-metyl-6-(4-pyridinyl)-3(2H)-pyridazinon. A-18. 2-Ethyl-4,5-dihydro-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
A-1 9. 4» 5-dihydro-4-metyl-2-n-propyl-6- (4-pyridinyl)-3 (2H)-pyridazinon. A-1 9. 4'5-dihydro-4-methyl-2-n-propyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
A-2 0. 4> 5-dihydro -2-isopropyl -4-metyl -6- (4-pyridinyl ) - 3(2H)-pyridazinon. A-2 0. 4> 5-dihydro-2-isopropyl-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
A-21 2-(n-butyl)-4» 5-dihydro-4-metyl-6-(4-pyridinyl)-3(2H)-pyridaz inon. A-21 2-(n-butyl)-4'' 5-dihydro-4-methyl-6-(4-pyridinyl)-3(2H)-pyridaz inone.
A-22. 2-etyl-6-(3-etyl-4-pyridinyl)-4,5-dihydro-4-metyl-3(2H)-pyridazinon. A-22. 2-Ethyl-6-(3-ethyl-4-pyridinyl)-4,5-dihydro-4-methyl-3(2H)-pyridazinone.
A-23. 4,5-dihydro-2-(2-hydroksyetyl)-4-metyl-6-(4-pyridinyl)-3(2H)-pyridazinon. A-23. 4,5-dihydro-2-(2-hydroxyethyl)-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
Ved å bruke den fremgangsmåte som er beskrevetBy using the procedure described
i eksempel A-16, meri i steden for metyl 4-cyano- J+-(4-morfo - linyl)-4-(4-pyridinyl )2-metylbutanoat bruke en molar ekvivalent mengde av metyl 2-metyl-4-okso-4-(4-pyridinyl)butanoat, kan man f å--f r ems tilt 4» 5 -dihydr o-2, 4-dimetyl -6- (4-pyridinyl ) - 3 (2H ) - pyridazinon. Denne forbindelsen kan også fremstilles ved å bruke den fremgangsmåten som er beskrevet i eksempel A-1, men i stedenffor 4-okso-4-(4-pyridinyl)butanitril bruke en molar©kvalent mengde av 2-metyl-4-okso-4(4-pyridinyl)butan-nitril. in Example A-16, instead of methyl 4-cyano-J+-(4-morpho-linyl)-4-(4-pyridinyl)2-methylbutanoate use a molar equivalent amount of methyl 2-methyl-4-oxo- 4-(4-pyridinyl)butanoate, one can obtain 4"5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone. This compound can also be prepared using the method described in Example A-1, but instead of 4-oxo-4-(4-pyridinyl)butanitrile use a molar equivalent amount of 2-methyl-4-oxo-4 (4-pyridinyl)butanenitrile.
A-24. 4, 5-dihydro-4-metyl-6-(4-pyridinyl)-3(2H)-pyridaz inon. A-24. 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3(2H)-pyridaz inone.
En blanding ..inneholdende 15 g metyl 4-cyano-2-c; metyl-4-(4-morfolinyl)-4-(4-pyridinyl)butanoat, 26 ml 85 % hydrazinhydrat og 220 ml absolutt etanol ble kokt under til-bakeløp ca. 17 timer, hvoretter oppi øsning:smiddelet ble avdestillert i vakuum. Det gjenværende krystallinske bunn- A mixture ..containing 15 g of methyl 4-cyano-2-c; methyl 4-(4-morpholinyl)-4-(4-pyridinyl)butanoate, 26 ml of 85% hydrazine hydrate and 220 ml of absolute ethanol were refluxed for approx. 17 hours, after which the agent was distilled off in a vacuum. The remaining crystalline bottom-
fall ble omkrystallisert fra etylacetat, tørket ved 90° G og slått sammen med en annen prøve av samme forbindelse fremstilt ved hjelp av samme fremgangsmåte idet man går ut fra 11 g metyl 4-cyano-2-mety.-4-(4-morfolinyl)-4-(4-pyridinyl ) - butanoat og omkrystalliserer produktet fra acetonitril. De samlede produkter ble omkrystallisert fra isopropylalkohol idet man brukte avfarget trekull og tørket ved 120°C, noe som ga 10 g 4,5-dihydro-4-metyl-6-(4-pyridinyl)-3 (2H)-pyridazinon, sm.p. 184-185°C, som er tautomerisk med 4,5-dihydro-4-me tyl - 6- (4-rpyridinyl ) -3-pyr idaz in ol. precipitate was recrystallized from ethyl acetate, dried at 90° G and combined with another sample of the same compound prepared by the same procedure starting from 11 g of methyl 4-cyano-2-methyl-4-(4-morpholinyl )-4-(4-pyridinyl )-butanoate and recrystallizes the product from acetonitrile. The combined products were recrystallized from isopropyl alcohol using decolorized charcoal and dried at 120°C to give 10 g of 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone, m .p. 184-185°C, which is tautomeric with 4,5-dihydro-4-methyl-6-(4-pyridinyl)-3-pyridaz in ol.
Syreaddisj onssalter av 4, 5-dihydr 0-4.-metyl-6-(4-pyridinyl)-3(2H )-pyridazinon kan hensiktsmessig fremstilles ved å bruke den fremgangsmåte som er beskrevet i eksempel A-1 . Acid addition salts of 4,5-dihydro 0-4.-methyl-6-(4-pyridinyl)-3(2H )-pyridazinone can conveniently be prepared by using the method described in example A-1.
Ved å bruke den fremgangsmåte som er beskrevet overfor, men i steden for metyl 4-cyano-2-metyl-4-(4--morfolinyl )-4--(4-pyridinyl )butanoat, bruke en molar ekvivalent mengde av et passende lavere-alkyl, fortrinnsvis metyl eller etyl, 4-cyano-2-metyl-4-(BN)-4-(4-pyridinyl)butanoat, hvor BN er 1-piperidinyl eller 1-pyrrolidinyl, kan man få fremstilt 4,5-dihydro-4-metyl-6-(4-pyridinyl)-3(2H)-pyridazinon. Using the procedure described above, but instead of methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate, use a molar equivalent amount of an appropriate lower alkyl, preferably methyl or ethyl, 4-cyano-2-methyl-4-(BN)-4-(4-pyridinyl)butanoate, where BN is 1-piperidinyl or 1-pyrrolidinyl, 4,5 -dihydro-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
B-1. 2-metyl-6-(4-pyridinyl)-3 (2H)-pyridazinon.B-1. 2-Methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
En varm oppiøsning inneholdende 28 g 4,5-dihydro-2-metyl-6-(4-pyridinyl)-3(2H)-pyridazinon monohydroklorid og 140 ml eddiksyre ble under røring tilsatt 100 ml brom, og blandingen ble kokt under tilbakeløp over natten og så av-kjølt ved romtemperatur. Det utskilte stoff ble frafUtrert, rørt ut i 150 ml vann, og blandingen ble tilsatt natriumbi-sulfit inntil boblingen stoppet. Man fikk en blekt gul opp-løsning som ble tilsatt tilstrekkelig fast natriumbikarbonat til at det ble gjort svakt basisk, og den resulterende blanding ble ekstrahert med kloroform. Klororformekstrakten ble oppvarmet i vakuum for å fjerne oppløsningsmiddelet, og det resulterende faste stoff ble omkrystallisert fra metanol og eter og deretter i vakuum-ovn ved 60° over natten, noe som ga 15 g 2-metyl-6-(4-pyridinyl)-3(2H)-pyridazinon, sm.p. 175-1 85°C. A hot solution containing 28 g of 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone monohydrochloride and 140 ml of acetic acid was added with stirring to 100 ml of bromine, and the mixture was refluxed over overnight and then cooled at room temperature. The precipitated substance was filtered off, stirred into 150 ml of water, and sodium bisulphite was added to the mixture until bubbling stopped. A pale yellow solution was obtained to which was added sufficient solid sodium bicarbonate to render it weakly basic, and the resulting mixture was extracted with chloroform. The chloroform extract was heated in vacuo to remove the solvent and the resulting solid was recrystallized from methanol and ether and then in a vacuum oven at 60° overnight to give 15 g of 2-methyl-6-(4-pyridinyl)- 3(2H)-pyridazinone, m.p. 175-185°C.
Syreaddisjonssalter av 2-metyl-6-(4-pyridinyl)-3(2H)-pyridazinon kan hensiktsmessig fremstilles ved at en oppløsning av 1 g 2-metyl6-(4-pyridinyl)-3 (2H)-pyridazinon 1 ca. 20 ml vandig metanol tilsettes en passende syre, f. eks. saltsyre, metansulfonsyre eller svovelsyre, til en pH mellom Acid addition salts of 2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone can conveniently be prepared by adding a solution of 1 g of 2-methyl6-(4-pyridinyl)-3 (2H)-pyridazinone 1 approx. 20 ml of aqueous methanol is added to a suitable acid, e.g. hydrochloric acid, methanesulfonic acid or sulfuric acid, to a pH between
2 og 3, avkjøler blandingen etter delvis fordampning og oppsamler det utfelte øalt, d.v.s. hydrokloridet, metansulfonatet eller sulfatet henholdsvis. Også lactatet eller hydroklorid-syreaddisjonssaltet av 2-metyl-6-(4-pyridinyl)-3(2H)-pyridazinon kan hensiktsmessig fremstilles i en vandig oppløsning ved at vann under røring tilsettes molare ekvalente mengder av 2-metyl6-(4-pyridinyl )-3 (2H) -pyridazinon samt melkesyre eller saltsyre henholdsvis. 2 and 3, cools the mixture after partial evaporation and collects the precipitated oil, i.e. the hydrochloride, methanesulfonate or sulfate respectively. The lactate or hydrochloride acid addition salt of 2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone can also be conveniently prepared in an aqueous solution by adding water while stirring to molar equivalent amounts of 2-methyl6-(4-pyridinyl) )-3 (2H)-pyridazinone as well as lactic acid or hydrochloric acid respectively.
Ved å bruke den fremgangsmåten som er beskrevet i eksmpel i.B-1, men i steden for 4» 5-dihydr o-2-metyl-6-(4-pyridinyl)-3 (2H)-pyridazinon eller dets monohydroklor.id, bruke en tilsvarende molar ekv.alent mengde av et passende 4,5-dihydro-2-R-4-R<1->PY-pyridazinon ellér dets monohydroklorid-salt, kan man får fremstilt 2-R-4-R'-PY-3(2H)-pyridazinon som er nevnte i eksemplene B-2 til B-9« Using the procedure described in Example i.B-1, but instead of 4'5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone or its monohydrochloride, use a corresponding molar equivalent amount of a suitable 4,5-dihydro-2-R-4-R<1->PY-pyridazinone or its monohydrochloride salt, 2-R-4-R'-PY can be prepared -3(2H)-pyridazinone mentioned in Examples B-2 to B-9"
B-2. 2, 4-dimetyl-6-(4-pyridinyl)-3(2H)-pyridazinon.B-2. 2,4-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
B-3. 2,4-dimetyl-6-(3-pyridinyl)-4(2H)-pyridazinon.B-3. 2,4-Dimethyl-6-(3-pyridinyl)-4(2H)-pyridazinone.
B-4- 2 -etyl-4-metyl-6-(4-pyridinyl)-3(2H)-pyridazinon. B-4-2-ethyl-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
B-5. 4-metyl-2-n-propyl-6(4-pyridinyl)3(2H)-pyridaz inon. B-5. 4-Methyl-2-n-propyl-6(4-pyridinyl)3(2H)-pyridaz inone.
B-6. 2-isopropyl-4-metyl-6-(4-pyridinyl)-3(2H)-pyridazinon. B-6. 2-isopropyl-4-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.
B-7?2- (n-butyl) -4-metyl -6-(4-pyr idinyl) -3(-2H ) -pyridaz inon. B-7?2-(n-butyl)-4-methyl-6-(4-pyridinyl)-3(-2H )-pyridaz inone.
B-8. 2-etyl-6-(3-etyl-4-pyridinyl)-4-metyl-3(2H)-pyridaz inon. B-8. 2-Ethyl-6-(3-ethyl-4-pyridinyl)-4-methyl-3(2H)-pyridaz inone.
B-9. 2-(2-hydroksyetyl)-4-metyl-6-(4-pyridinyl)2(2H)-pyridazinon. B-9. 2-(2-Hydroxyethyl)-4-methyl-6-(4-pyridinyl)2(2H)-pyridazinone.
C. 4-okso-5-PY-butanitriler.C. 4-oxo-5-PY-butanitriles.
C-1. 4- okso- 4-( 4- pyridinyl) butanitril.C-1. 4-oxo-4-(4-pyridinyl)butanitrile.
En rørt blanding inneholdende 29,4 g natriumcyanid og'500 ml acetonitril ble etter røring i 10 minutter dråp- A stirred mixture containing 29.4 g of sodium cyanide and 500 ml of acetonitrile was, after stirring for 10 minutes, dropwise
vis i løpet av 3 timer tilsatt en oppløsning inneholdende 64,2 g 4-pyridinkarboxaldehyd i 500 ml acetonitril, og blandingen ble rørt ved romtemperatur i 1 time. Det ble så lang-som i løpet av 1 time tilsatt en oppløsning av 24,5 g acrylonitril i 200 ml acetonitril, og blandingen ble således rørt over natten ved romtemperatur. Blandingen ble renset i vakuum for oppiøsningsmiddel ved en temperatur som ikke over- vis in the course of 3 hours was added a solution containing 64.2 g of 4-pyridinecarboxaldehyde in 500 ml of acetonitrile, and the mixture was stirred at room temperature for 1 hour. A solution of 24.5 g of acrylonitrile in 200 ml of acetonitrile was added over the course of 1 hour, and the mixture was thus stirred overnight at room temperature. The mixture was cleaned in vacuo of solvent at a temperature not exceeding
steg 54°C. Det semi-faste residuet ble avkjølt, blandet med 4.00 ml kloroform og filtrert. Klororformen ble avdestillert i vakuum ved en temperatur som var maksimalt 50°, rose 54°C. The semi-solid residue was cooled, mixed with 4.00 ml of chloroform and filtered. The chlorine form was distilled off in vacuum at a temperature which was a maximum of 50°,
og det oljeaktige residuet ble ekstrahert med tre 200 ml porsjoner av toluen. Toluenoppløsningen ble filtrert gjennom diatomerjord hvorpå filtratet ble destillert i vakuum under 50° for å fjerne nevnte toluen. Residuet utkrystalliserte seg ved avkjøling. En liten prøve ble bevart, mens resten ble oppløst i 50 ml varm isopropylalkohol. Oppløsningen ble avkjølt og så langsomt fortynnet med 125 ml eter, avkjølt og tilsatt et par krystaller fra overnevnte prøve. Det utskilte krystallinske produkt ble f raf iltrert|. vasket med 25 ml 1:3 (v:v) blanding av isopropylalkohol og eter, og så luftr tørket til 52,1 g 4-okso-4--(4-pyridinyl )butanitril, sm.p. 53- 55°G. and the oily residue was extracted with three 200 ml portions of toluene. The toluene solution was filtered through diatomaceous earth whereupon the filtrate was distilled in vacuum below 50° to remove said toluene. The residue crystallized on cooling. A small sample was preserved, while the rest was dissolved in 50 ml of hot isopropyl alcohol. The solution was cooled and then slowly diluted with 125 ml of ether, cooled and a couple of crystals from the above sample were added. The precipitated crystalline product was filtered. washed with 25 ml of 1:3 (v:v) mixture of isopropyl alcohol and ether, and then air dried to 52.1 g of 4-oxo-4-(4-pyridinyl)butanitrile, m.p. 53-55°G.
Ved å bruke den fremgangsmåte som er beskrevet i eksempel C-1, men i steden for 4-pyridinkarboksaldehyd, bruke en molar ekvalent mengde av et passende 4- eller 3-PY-karbo.ks-aldehyd, kan man få fremstilt de tilsvarende 4-okso-4--PY-butan-nitriler som er nevnt i eksemplene C-2 til C-6. By using the procedure described in example C-1, but instead of 4-pyridinecarboxaldehyde, using a molar equivalent amount of a suitable 4- or 3-PY-carboxaldehyde, the corresponding 4 -oxo-4--PY-butane nitriles mentioned in Examples C-2 to C-6.
C-2. 4-okso-4-(3-pyridinyl )butanitril.C-2. 4-oxo-4-(3-pyridinyl)butanitrile.
C-3. 4-(2-metyl-3-pyridinyl)-4-oksobutanitril.C-3. 4-(2-Methyl-3-pyridinyl)-4-oxobutanitrile.
C-4- 4-(5-metyl-3-pyridinyl) -4-oksobutanitril.C-4-4-(5-methyl-3-pyridinyl)-4-oxobutanitrile.
C - 5 • 4~(3-etyl-4-pyridinyl)-4-oksobutanitril.C - 5 • 4~(3-ethyl-4-pyridinyl)-4-oxobutanitrile.
C-6. 4-(2, 6-dimetyl-4-pyridinyl)-4-bksobutanitril.C-6. 4-(2,6-Dimethyl-4-pyridinyl)-4-bisobutanitrile.
Ved å bruke den fremgangsmåte som er beskrevetBy using the procedure described
i eksempel C-1, men i steden for acrylinitril, bruke en molar ekvivalent mengde av metacrylonitril, kan man få?fremstilt den forbindelse som er nevnt i eksempel C-7. in example C-1, but instead of acrylonitrile, using a molar equivalent amount of methacrylonitrile, can the compound mentioned in example C-7 be prepared?
C-7. 2-metyl4-okso-4 - (4-pyridinyl )butanitril.C-7. 2-methyl4-oxo-4-(4-pyridinyl)butanitrile.
D. Lavere- alkyl 4-( BN)- 4- cyano- 4- PY- 2- R 1- butanoater D-1. Metyl 4-cyano-2-metyl-4-(4-morfolinyl)-4- (4-pyr - dinyl)butanoat. D. Lower alkyl 4-( BN)- 4- cyano- 4- PY- 2- R 1- butanoates D-1. Methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyr-dinyl)butanoate.
En blanding inneholdende 16 g 2 -(4-morfolinyl )-2- A mixture containing 16 g of 2 -(4-morpholinyl )-2-
(4 -pyridinyl )etanitril og 150 ml tetrahydrof uran i en kolbe utstyrt med en rører og et tørkerør, ble. under røring tilsatt 6 ml 30 % kaliumhydroksyd i metanol fulgt av 8,5 g metylmetacrylat. I løpet av 4-0 minutter fikk man en eksotermisk reaksjon, og et hvitt fast stoff begynte å skille seg ut. Blandingen ble rørt i 1 time og så hensatt ved romtemperatur over natten. Blandingen ble så konsentrert ved oppvarming i vakuum, og residuet ble behandlet med absolutt eter (ca. (4-pyridinyl)ethanenitrile and 150 ml of tetrahydrofuran in a flask equipped with a stirrer and a drying tube were. with stirring added 6 ml of 30% potassium hydroxide in methanol followed by 8.5 g of methyl methacrylate. Within 4-0 minutes an exothermic reaction occurred and a white solid began to separate. The mixture was stirred for 1 hour and then left at room temperature overnight. The mixture was then concentrated by heating in vacuo, and the residue was treated with absolute ether (ca.
600 ml) og filtrert. Filtratet ble konsentrert til et volum på ca. 50 ml, avkjølt, behandlet med 50 ml n-hexan og igjen avkjølt. Det utfelte produkt ble frafiltrert og tørket ved 70°, noe som ga 11 g metyl-4-cyano-2-metyl-4-(4-morfolinyl)-4--(4--pyridinyl )butanoat, sm.p. 93-94-°C. 600 ml) and filtered. The filtrate was concentrated to a volume of approx. 50 ml, cooled, treated with 50 ml n-hexane and cooled again. The precipitated product was filtered off and dried at 70°, which gave 11 g of methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate, m.p. 93-94-°C.
Syreaddisjonssalter av me tyl .;.4-cyano-2-metyl-4 - Acid addition salts of methyl .;.4-cyano-2-methyl-4 -
(4--morf olinyl )-4-(4--pyridinyl )butanoat kan hensiktsmessig fremstilles ved at en oppløsning av 1 g metyl-4-cyano-2-metyl-4-(4-morfolinyl)-4-(4-pyridinyl)butanoat i ca. 20 ml vandig metanol, ble tilsatt en passende syre, f. eks. saltsyre, metan-sulf onsyre eller svovelsyre, til en pH mellom 2 og 3, avkjøle blandingen etter delvis fordampning og deretter oppsamle det utfelte salt, d.v.s. hydrokloridet, metansulfonatet eller sulfatet henholdsvis. Også laetatet eller hydrokloridsyre-addisjonssaltet av metyl 4-cyano-2-metyl 4-(4-morfolinyl)-4-(4-pyridihyl)-butonat kan hensiktsmessig fremstilles i en vandig oppløsning ved at vann under røring tilsettes molare ekvivalente mengder av metyl 4-cyano-2-metyl-4-(4-morfolinyl ) - 4-(4-pyridinyl)butanoat samt melkesyre eller saltsyre henholdsvis . (4-morpholinyl)-4-(4-pyridinyl)butanoate can conveniently be prepared by adding a solution of 1 g of methyl-4-cyano-2-methyl-4-(4-morpholinyl)-4-(4- pyridinyl)butanoate for approx. 20 ml of aqueous methanol, was added a suitable acid, e.g. hydrochloric acid, methanesulfonic acid or sulfuric acid, to a pH between 2 and 3, cool the mixture after partial evaporation and then collect the precipitated salt, i.e. the hydrochloride, methanesulfonate or sulfate respectively. Also the laetate or hydrochloric acid addition salt of methyl 4-cyano-2-methyl 4-(4-morpholinyl)-4-(4-pyridihyl)-butonate can conveniently be prepared in an aqueous solution by adding molar equivalent amounts of methyl to water while stirring 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate and lactic acid or hydrochloric acid respectively.
Ved å bruke den fremgangsmåte som er beskrevet i eksempel D-1, men i steden for 2-(4-morfolinyl)-2-(4-pyridinyl ) -etanitril og metylmetacrylat, bruke ekvalente mengder henholdsvis av et passende 2-(BN)-2-PY-etanitril og et lavere-alkylmetacrylat, kan man få fremstilt to tilsvarende lavere-alkyl 4-cyano-2-metyl-4-(BN)-4-PY-butanoat som er nevnt i eksemplene D-2 til D-6. Using the procedure described in Example D-1, but instead of 2-(4-morpholinyl)-2-(4-pyridinyl)-ethanenitrile and methyl methacrylate, using equivalent amounts, respectively, of an appropriate 2-(BN) -2-PY-ethanenitrile and a lower-alkyl methacrylate, two corresponding lower-alkyl 4-cyano-2-methyl-4-(BN)-4-PY-butanoate mentioned in examples D-2 to D can be prepared -6.
D-2. Metyl 4-cyano -2 -metyl-4- (1 -piperddinyl)-4-(4--pyridinyl)butanoat. D-3. Metyl 4 cyano-2-metyl-4--(4--pyridinyl )-4-(1-pyrrolidinyl)butanoat. D-4. Metyl 4-cyano-2-metyl-4-(4-morfolinyl)-4-(3-pyridinyl )butanoat. D-5. Etyl 4-cyano-2-metyl-4-(4-morfolinyl)-4-(4-pyridinyl)butanoat. D-6. n-propyl 4-cyano-4-(3-etyl-4-pyridinyl )-2-metyl-4~(4-morfolinyl)butanoat. D-2. Methyl 4-cyano-2-methyl-4-(1-piperdinyl)-4-(4-pyridinyl)butanoate. D-3. Methyl 4-cyano-2-methyl-4-(4-pyridinyl)-4-(1-pyrrolidinyl)butanoate. D-4. Methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(3-pyridinyl)butanoate. D-5. Ethyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate. D-6. n-propyl 4-cyano-4-(3-ethyl-4-pyridinyl)-2-methyl-4-(4-morpholinyl)butanoate.
E. 2-(BN)-2-PY-etanitriler.E. 2-(BN)-2-PY-ethanenitriles.
Disse generelt kjente mellomprodukter kan fremstilles ved at man reagerer et cyklisk amin med formel BN-H These generally known intermediates can be prepared by reacting a cyclic amine with the formula BN-H
og et alkalicyanid med et PY-aldehyd -bisulf it -kompieks slik det er beskrevet av Janssen et al (J. Am. Pharm. Assoc, Sei. Ed. 44»465-7 (1 955) eller ved den følgende alternative fremgangsmåte som er beskrevet i eksempel E-1. and an alkali cyanide with a PY-aldehyde bisulfite complex as described by Janssen et al (J. Am. Pharm. Assoc, Sci. Ed. 44»465-7 (1955) or by the following alternative method which is described in Example E-1.
E-1. 2 -(4-morfolinyl)-2 -(4-pyridinyl)etanitril.E-1. 2-(4-morpholinyl)-2-(4-pyridinyl)ethanenitrile.
En blanding : inneholdende 72 g 4-pyridinkarboksaldehyd, 14-0 g morfolin, 152 g p-toluensulfonsyre og 800 ml tetrahydrofuran ble kokt under tilbakeløp og røring i 2 timer og så avkjølt til romtemperatur. Blandingen ble så tilsatt 64 g kaliumcyanid i 20 ml vann, hvorpå blandingen ble kokt under tilbakéløp i 2 timer og så hensatt over natten ved romtemperatur. Blandingen ble filtrert, og filtratet oppvarmet i vakuum for å fjerne oppiøsningsmiddelet. Det resulterende gummiaktige residåum ble tilsatt ca. 800 ml kloroform og 300 ml av mettet ::natriumkloridoppl øsning. Blandingen ble rørt i 2 timer og filtrert, og det heterogene filtrat ble overført til en skilletrakt, ristet, hvoretter kloroform-laget ble tatt ut av og oppvarmet i vakuum for å fjerne kloro-formen. Residuet ble kokt med ca. 300 ml vann, avkjølt og tilsatt et par krystaller, hvorpå man fikk utfelt blekt gule krystaller. Filtratet ble konsentrert i vakuum til ca. A mixture: containing 72 g of 4-pyridinecarboxaldehyde, 14-0 g of morpholine, 152 g of p-toluenesulfonic acid and 800 ml of tetrahydrofuran was refluxed and stirred for 2 hours and then cooled to room temperature. The mixture was then added with 64 g of potassium cyanide in 20 ml of water, after which the mixture was refluxed for 2 hours and then left overnight at room temperature. The mixture was filtered and the filtrate heated in vacuo to remove the solvent. The resulting gummy residue was added approx. 800 ml of chloroform and 300 ml of saturated ::sodium chloride solution. The mixture was stirred for 2 hours and filtered, and the heterogeneous filtrate was transferred to a separatory funnel, shaken, after which the chloroform layer was taken off and heated in vacuo to remove the chloroform. The residue was boiled with approx. 300 ml of water, cooled and a couple of crystals added, whereupon pale yellow crystals were precipitated. The filtrate was concentrated in vacuo to approx.
60 ml, og man fikk:et nytt utbytte av blekt gule krystaller.60 ml, and a new yield of pale yellow crystals was obtained.
Det samlede utbytte av gule krystaller ble først tørket iThe total yield of yellow crystals was first dried in
en vakuum-ovn ved 100 mm og 25°, så i 100 timer over P^ y noe som ga 4-0 g 2 - (4-morf ol inyl ) -2 - (4-pyridinyl )etanitril, sm. p. 64-65°C. a vacuum oven at 100 mm and 25°, then for 100 hours over P^ y which gave 4-0 g of 2 - (4-morphol inyl ) -2 - (4-pyridinyl ) ethanenitrile, sm. at 64-65°C.
Ved å bruke den fremgangsmåte som er beskrevetBy using the procedure described
i eksempel E-1, men ved å bruke molare ekvivalente mengder av et passende pyridinkarboksyaldehyd og et amin (BN-H) i stedenfor 4-pyridinkarboksyaldehyd og morfolin, kan man få. fremstilt de tilsvarende 2-(BM)-2-PY-etantriler som er nevnt i eksempel E-2 til E-5. in Example E-1, but by using molar equivalent amounts of an appropriate pyridine carboxyaldehyde and an amine (BN-H) in place of 4-pyridine carboxyaldehyde and morpholine, one can obtain. prepared the corresponding 2-(BM)-2-PY ethanetriles mentioned in Examples E-2 to E-5.
E-2. 2 -(4-pyridinyl)-2 -(1-pyrrolidinyl)etanitril.E-2. 2-(4-pyridinyl)-2-(1-pyrrolidinyl)ethanenitrile.
E-3. 2 - (1 -piper idinyl) -2 - (4-pyridinyl ) etanitr il .v.' K E-3. 2-(1-piperidinyl)-2-(4-pyridinyl)ethanitrile.v.' K
E-4. 2 -(3-etyl-4-pyridinyl)-2 -(4-morfolinyl)-étanitril. E-4. 2-(3-Ethyl-4-pyridinyl)-2-(4-morpholinyl)-ethanenitrile.
E - 5 • 2 - (5 - metyl -3-pyr id inyl) -2 - (4 -morf ol inyl ) etan it ril. E - 5 • 2 - (5 - methyl -3-pyr id inyl) -2 - (4 - morphol inyl ) ethan it ril.
Anvendbarheten av forbindelser med formel I eller deres salter som kardiotoniske midler ble vist ved deres effekt-ivitet i standard-farmakologiske prøver, f. eks. ved at de ga en betydeligøkning i den kontriaktive slagkraft i isolerte katte-atria og i de papilære muskler, og de ga en betydeligøkning av den kontraktileslagkraft hos en bedøvet hund med lave eller minimale forandringer med hensyn til puls og blodtrykk. Detaljerte beskrivelser av disse prøver er angitt i US-patent 4-072.746, utstedt 7 februar 1980. The utility of compounds of formula I or their salts as cardiotonic agents was demonstrated by their efficacy 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, and they produced a significant increase in the contractile force in an anesthetized dog with low or minimal changes in heart rate and blood pressure. Detailed descriptions of these samples are given in US patent 4-072,746, issued 7 February 1980.
Når de ble undersøkt ved hjelp av nevnte prøver hvor man anvendte isolerte katte-atria og papilære muskler, When examined using said samples using isolated cat atria and papillary muscles,
så ga forbindelser med formel I eller deres farmasøytiske akseptablé syreaddisjonssalter i doser på 10, 30, 100 og/eller 300 ug/ml, en betydelig økning, d.v.s. med en 25 % i den papilære muskelkraften og en betydelig økning, d.v.s. mer enn 25 % i den høyere hjerteforkammerslagkraften, samtidig som man fikk::en lav prosentvis økning (ca. 1/3 eller mindre enn den prosentviseøkningen i den høyere forkammers slagkraft eller den papilære muskelkraf ten) av pulsen i høyere.' forkammer. Når f. eks. den ble undersøkt i en dose på 10, 30 then compounds of formula I or their pharmaceutically acceptable acid addition salts at doses of 10, 30, 100 and/or 300 µg/ml gave a significant increase, i.e. with a 25% in the papillary muscle power and a significant increase, i.e. more than 25% in the higher cardiac atrial stroke force, while obtaining::a low percentage increase (about 1/3 or less than the percentage increase in the higher atrial stroke force or the papillary muscle force) of the heart rate in the higher.' anterior chamber. When e.g. it was examined in a dose of 10.30
og 100 ug/ml i denne fremgangsmåten, så ga forbindelsen fra eksempel A-1, d.v.s. i, 5 -dihydro-2 -metyl-6-(4--pyridinyl)-3 (2H ) - pyridazinon som sitt monohydroklorid, en økning på fra 35 and 100 ug/ml in this procedure, then the compound from Example A-1 gave, i.e. i, 5-dihydro-2-methyl-6-(4--pyridinyl)-3 (2H )-pyridazinone as its monohydrochloride, an increase of from 35
til 77 % av den papilære muskel kraften og/eller høyere forkammers slagkraft, og i en dose på 100 ug/ml i en sammenlign-bar sluttprøve hvor man brukte isloerte marssvinsatria og papilære muskler, så ga forbindelsen fra eksempel A-16, to 77% of the papillary muscle force and/or higher atrial stroke force, and at a dose of 100 ug/ml in a comparable final test using isolated guinea pig atria and papillary muscles, the compound of Example A-16 gave,
d.v.s. 4-, 5 -dihydro-2, 4--dimetyl -6 - (4--pyr id inyl) - 3 (2H ) -pyridazinon en henholdsvis økning på 75 og 63 % av den papilære m muskelkraf ten og høyere forkammers slagkraft. 4-, 5-dihydr o - 4.-metyl-6-(4--pyridinyl)-3 (2H) -pyridazinon (eksempel A-24-) i.e. 4-, 5-dihydro-2, 4--dimethyl-6 - (4--pyr id inyl)-3 (2H )-pyridazinone a respective increase of 75 and 63% of the papillary muscle force and higher atrial stroke force. 4-, 5-dihydro - 4.-methyl-6-(4--pyridinyl)-3(2H)-pyridazinone (Example A-24-)
ga henholdsvisøkninger på 139 % og 86 % av den papilære muskelkraf ten og høyere forkammers slagkraft ved en dose på 100 ug/ ml, mens den papilære muskelkraf ten økte med 4-5 % ved en dose på 30 ug/ml. produced increases of 139% and 86% respectively in papillary muscle force and higher atrial stroke at a dose of 100 ug/ml, while papillary muscle force increased by 4-5% at a dose of 30 ug/ml.
I klinisk praksis blir forbindelser eller salter med formel I hvor R er lavere-alkyl, normalt blir tilført oralt eller parenteralt i en rekke forskjellige doserings-former. Faste sammensetninger for oral tilførsel innbefatter tabletter, piller, pulvere og granulater. I slike faste sammensetninger vil minst en aktiv forbindelse være blandet med minst et inert fortynningsmiddel så som stivelse, kalsium-karbonat, suctrose ellér lactose. Slike sammensetninger kan dessuten inneholde andre forbindelser enn nevnte inerte for-tynnihgsmidler, f. eks. smøremidler så som magnesiumstearat, talkum o.l. In clinical practice, compounds or salts of formula I where R is lower alkyl are normally administered orally or parenterally in a number of different dosage forms. Solid compositions for oral administration 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. Such compositions may also contain compounds other than the aforementioned inert diluents, e.g. lubricants such as magnesium stearate, talc etc.
Preparater ifølge foreliggende oppfinnelse for parenteral tilførsel innbefatter sterile vandige, vandige-organiske samt organiske oppløsninger, suspensjoner og emul-sjoner. Eksempler på organiske oppiøsningsmidler eller sus-penderende media er propylenglykol, polyetylenglykol, vege-tabilske olje så som olivenolje samt injiserbare organiske estere,så som etyloleat. Slike sammensetninger kan også inneholde tilsetninger som stabilisatorer, konserveringsmidler, fuktemidler, emulgeringsmidler og dispergeringsmidler. Preparations according to the present invention for parenteral administration include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solubilizers or suspending media are propylene glycol, polyethylene glycol, vegetable oil such as olive oil and injectable organic esters such as ethyl oleate. Such compositions may also contain additives such as stabilizers, preservatives, wetting agents, emulsifying agents and dispersing agents.
De kan steriliseres, f. eks. ved at de filtreres gjennom et bakteriefilter, ved at man tilsetter steriliserings-middelet i sammensetning med bestråling eller omforming. De kan også fremstilles i form av sterile faste sammensetninger som kan oppløses i sterilt vann eller et annet sterilt inji-serbart middel umiddelbart før bruk. They can be sterilized, e.g. by filtering them through a bacterial filter, by adding the sterilizing agent in combination with irradiation or transformation. They can also be produced in the form of sterile solid compositions that can be dissolved in sterile water or another sterile injectable agent immediately before use.
Prosenten av den aktive komponent i nevnte sammensetning samt fremgangsmåten for å øke hjertets kontraktivi- The percentage of the active component in said composition as well as the method for increasing the contractility of the heart
tet kan varieres slik at man oppnår en egnet dose. Den dose som tilføres en spesiell pasient vil være variabel og vil være avhengig av legens bedømmelse idet han bruker følgende kriterier: Tilførselsvei, varighet av behandling, størrelse og tilstand på pasienten, styrke på den aktive komponent, tet can be varied so that a suitable dose is achieved. The dose administered to a particular patient will be variable and will depend on the physician's judgment using the following criteria: route of administration, duration of treatment, size and condition of the patient, strength of the active component,
samt pasientens reaksjon på behandlingen. En effektiv doserings-mengde av-den aktive komponent kan således bare bedømmes ved at lågen tar hensyn til alle kriterier og bruker beste skjønn på vegne av pasienten. as well as the patient's reaction to the treatment. An effective dosage amount of the active component can thus only be judged by the hospital taking into account all criteria and using best judgment on behalf of the patient.
Claims (9)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14456480A | 1980-04-28 | 1980-04-28 | |
| US06/243,472 US4337253A (en) | 1980-04-28 | 1981-03-13 | 4,5-Dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone and its use as a cardiotonic |
| US06/245,086 US4486431A (en) | 1981-01-14 | 1981-03-18 | Cardiotonic use of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinones |
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| Publication Number | Publication Date |
|---|---|
| NO811421L true NO811421L (en) | 1981-10-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO811421A NO811421L (en) | 1980-04-28 | 1981-04-27 | 4,5-DIHYDRO-6 (PYRIDINYL) -3 (2H) -PYRIDAZINONES SUITABLE AS CARDIOTONIC AGENTS AND PROCEDURES FOR THEIR PREPARATION |
Country Status (15)
| Country | Link |
|---|---|
| AT (1) | ATA190481A (en) |
| DE (1) | DE3116791A1 (en) |
| DK (1) | DK186781A (en) |
| ES (1) | ES8203880A1 (en) |
| FR (1) | FR2481282A1 (en) |
| GB (1) | GB2076807B (en) |
| IL (1) | IL62679A0 (en) |
| IT (1) | IT1137465B (en) |
| LU (1) | LU83320A1 (en) |
| NL (1) | NL8102078A (en) |
| NO (1) | NO811421L (en) |
| NZ (1) | NZ196889A (en) |
| PH (1) | PH16845A (en) |
| PT (1) | PT72936B (en) |
| SE (1) | SE8102661L (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4304777A (en) * | 1979-08-30 | 1981-12-08 | Sterling Drug Inc. | 6-(Pyridinyl)-3(2H)-pyridazinones and their use as cardiotonics |
-
1981
- 1981-04-17 IL IL62679A patent/IL62679A0/en unknown
- 1981-04-22 NZ NZ196889A patent/NZ196889A/en unknown
- 1981-04-23 GB GB8112639A patent/GB2076807B/en not_active Expired
- 1981-04-24 FR FR8108252A patent/FR2481282A1/en not_active Withdrawn
- 1981-04-27 DK DK186781A patent/DK186781A/en not_active Application Discontinuation
- 1981-04-27 SE SE8102661A patent/SE8102661L/en not_active Application Discontinuation
- 1981-04-27 NO NO811421A patent/NO811421L/en unknown
- 1981-04-27 IT IT21384/81A patent/IT1137465B/en active
- 1981-04-27 PT PT72936A patent/PT72936B/en unknown
- 1981-04-27 ES ES501666A patent/ES8203880A1/en not_active Expired
- 1981-04-27 PH PH25564A patent/PH16845A/en unknown
- 1981-04-28 DE DE19813116791 patent/DE3116791A1/en not_active Withdrawn
- 1981-04-28 NL NL8102078A patent/NL8102078A/en not_active Application Discontinuation
- 1981-04-28 AT AT811904A patent/ATA190481A/en not_active IP Right Cessation
- 1981-04-28 LU LU83320A patent/LU83320A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES501666A0 (en) | 1982-04-01 |
| NZ196889A (en) | 1984-04-27 |
| IL62679A0 (en) | 1981-06-29 |
| IT8121384A0 (en) | 1981-04-27 |
| SE8102661L (en) | 1981-10-29 |
| PT72936A (en) | 1981-05-01 |
| PT72936B (en) | 1982-04-12 |
| IT1137465B (en) | 1986-09-10 |
| NL8102078A (en) | 1981-11-16 |
| GB2076807B (en) | 1984-03-14 |
| FR2481282A1 (en) | 1981-10-30 |
| ATA190481A (en) | 1983-12-15 |
| GB2076807A (en) | 1981-12-09 |
| ES8203880A1 (en) | 1982-04-01 |
| DK186781A (en) | 1981-10-29 |
| PH16845A (en) | 1984-03-19 |
| DE3116791A1 (en) | 1982-04-15 |
| LU83320A1 (en) | 1981-12-01 |
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