JPH0222274A - Pyridazinone derivative - Google Patents
Pyridazinone derivativeInfo
- Publication number
- JPH0222274A JPH0222274A JP705589A JP705589A JPH0222274A JP H0222274 A JPH0222274 A JP H0222274A JP 705589 A JP705589 A JP 705589A JP 705589 A JP705589 A JP 705589A JP H0222274 A JPH0222274 A JP H0222274A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- substituted
- lower alkyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 title description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 7
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 5
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 7
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 154
- 239000000496 cardiotonic agent Substances 0.000 abstract description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 2
- 125000006295 amino methylene group Chemical group [H]N(*)C([H])([H])* 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- 238000004519 manufacturing process Methods 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000013078 crystal Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- -1 5ec-butyl Chemical group 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 238000009835 boiling Methods 0.000 description 8
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 8
- 239000007810 chemical reaction solvent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 235000008504 concentrate Nutrition 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 230000003177 cardiotonic effect Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 125000006848 alicyclic heterocyclic group Chemical group 0.000 description 3
- 230000037005 anaesthesia Effects 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
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 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
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 3
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 230000002107 myocardial effect Effects 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 2
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 2
- YFAJEGYHRPNULY-UHFFFAOYSA-N 4-(4-bromophenyl)-3-methyl-4-oxobutanoic acid Chemical compound OC(=O)CC(C)C(=O)C1=CC=C(Br)C=C1 YFAJEGYHRPNULY-UHFFFAOYSA-N 0.000 description 2
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 2
- JQUCWIWWWKZNCS-LESHARBVSA-N C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F Chemical compound C(C1=CC=CC=C1)(=O)NC=1SC[C@H]2[C@@](N1)(CO[C@H](C2)C)C=2SC=C(N2)NC(=O)C2=NC=C(C=C2)OC(F)F JQUCWIWWWKZNCS-LESHARBVSA-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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 210000003194 forelimb Anatomy 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000000297 inotrophic effect Effects 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 150000002905 orthoesters Chemical class 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 230000002861 ventricular Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 description 1
- DJMOXMNDXFFONV-UHFFFAOYSA-N 1,3-dimethyl-7-[2-(n-methylanilino)ethyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCN(C)C1=CC=CC=C1 DJMOXMNDXFFONV-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- WGFNXGPBPIJYLI-UHFFFAOYSA-N 2,6-difluoro-3-[(3-fluorophenyl)sulfonylamino]-n-(3-methoxy-1h-pyrazolo[3,4-b]pyridin-5-yl)benzamide Chemical compound C1=C2C(OC)=NNC2=NC=C1NC(=O)C(C=1F)=C(F)C=CC=1NS(=O)(=O)C1=CC=CC(F)=C1 WGFNXGPBPIJYLI-UHFFFAOYSA-N 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000004041 inotropic agent Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 description 1
- 229960003574 milrinone Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 235000013842 nitrous oxide Nutrition 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- NPIJXCQZLFKBMV-YTGGZNJNSA-L pancuronium bromide Chemical compound [Br-].[Br-].C[N+]1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 NPIJXCQZLFKBMV-YTGGZNJNSA-L 0.000 description 1
- 229960003379 pancuronium bromide Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 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
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 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 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229920002050 silicone resin Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 238000005987 sulfurization reaction Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、強心作用を有する新規なピリダジノン誘導体
またはその薬理的に許容される酸付加塩に関する。DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a novel pyridazinone derivative having cardiotonic action or a pharmacologically acceptable acid addition salt thereof.
従来の技術
強心作用を示すピリダジノン環を有する化合物としては
、次式
で表されるビモベンダン（特開昭５５−３３４７９号公
報）。Prior Art As a compound having a pyridazinone ring that exhibits cardiotonic action, bimobendan is represented by the following formula (Japanese Unexamined Patent Publication No. 55-33479).
で表されるＬＹ１９５１１５（特開昭６１−２２０８０
号公報）。LY195115 (JP-A-61-22080
Publication No.).
で表されるＣｌ−９３０（特開昭５８−７４６７９号公
報）等が、またピリドン環を有する化合物として次式
で表されるミルリノン（特開昭５７−７０８６８号公報
）等がそれぞれ開示されている。Cl-930 (Japanese Unexamined Patent Publication No. 58-74679), which is represented by the following formula, and milrinone (Japanese Unexamined Patent Publication No. 57-70868), which is represented by the following formula as a compound having a pyridone ring, have been disclosed. There is.
発明が解決しようとする課題
慢性心不全に対する治療として強心剤が用いられている
が、その効果の強度や持続性においていまだ満足できる
ものはない。Problems to be Solved by the Invention Cardiotropic agents have been used as a treatment for chronic heart failure, but none of them has yet been satisfactory in terms of intensity and durability of their effects.
本発明により、強心作用を有する新規なピリダジノン誘
導体が提供される。The present invention provides novel pyridazinone derivatives having cardiotonic effects.
課題を解決するための手段
本発明は式（Ｉ）
に４
Ｒ２
（式中、Ｘ−Ｙは、−Ｃ１，−ＮＨ−； −Ｃ＝Ｎ〔式
中、Ｒ１は水素、低級アルキル、−ＮＲ１Ｒａ〔式中、
Ｒ１およびＲ３は同一または異なって、水素、置換もし
くは非置換の低級アルキノペ脂環式アルキル、低級アル
ケニノへ置換もしくは非置換のアラルキル、置換もしく
は非置換のアリール、アミン、低級アルコキシカルボニ
ルアミノ、る複素環基を表わす〕、ヒドロキシル、低級
アルコキシル、メルカプト、低級アルキルチオまた原子
、硫黄原子、Ｃ（ＣＯＯＲｓ） ２ （式中、Ｒ３は
前記と同義である）またはＮｉ！、、を表わし、Ｒｌａ
およびＲ。Means for Solving the Problems The present invention provides formula (I) with 4 R2 (wherein X-Y is -C1, -NH-; -C=N [wherein R1 is hydrogen, lower alkyl, -NR1Ra [During the ceremony,
R1 and R3 are the same or different and are hydrogen, substituted or unsubstituted lower alkinope alicyclic alkyl, lower alkenino substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, amine, lower alkoxycarbonylamino, heterocycle ], hydroxyl, lower alkoxyl, mercapto, lower alkylthio or atom, sulfur atom, C(COORs) 2 (wherein R3 is as defined above) or Ni! , , and Rla
and R.
は同一または異なって、水素、置換もしくは非置換の低
級アルキノ吠脂環式アルキル、低級アルケニル、置換も
しくは非置換のアラルキル、置換もしくは非置換のアリ
ール、アミノ、低級アルコキシカルボニルアミノまたは
またはＲ，とＲ２が一緒になってＮを含んで形成されま
たは低級アルキルを表わす）を表わし、Ｒ８は、水素ま
たは低級アルキルを表わし、Ｒ１は、水素、置換もしく
は非置換の低級アルキル、ヒドロキシル、低級アルキル
チルルカプト、低級アルキルチオまたは−ＮＲＩＲ２（
式中、Ｒ１およびＲ２は前記と同義である）を表わす）
で表わされるビリダジノン誘導体〔以下、化合物（１）
という。他の式番号の化合物についても同様である〕ふ
よびその薬理的に許容される酸付加塩に関する。are the same or different and are hydrogen, substituted or unsubstituted lower alkinoalicyclic alkyl, lower alkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, amino, lower alkoxycarbonylamino or or R, and R2 together represent N or represent lower alkyl), R8 represents hydrogen or lower alkyl, R1 represents hydrogen, substituted or unsubstituted lower alkyl, hydroxyl, lower alkyl tylcapto, lower alkylthio or -NRIR2(
(wherein R1 and R2 have the same meanings as above)
A pyridazinone derivative represented by [hereinafter referred to as compound (1)]
That's what it means. The same applies to compounds of other formula numbers] and its pharmacologically acceptable acid addition salts.
式（１）の各層の定義において、低級アルキル、低級ア
ルコキシカルボニルアミノ、低級アルコキシルおよび低
級アルキルチオにおけるアルキル部分は、炭素数１〜８
の直鎖または分岐状の例えばメチル、エチル、プロピル
、イソプロピル、ブチル、イソブチル、５ｅｃ−ブチル
、ｔｅｒｔ−ブチル、ペンチノペイソベンチル、ネオペ
ンチル、ｓｅｃペンチル、ｔｅｒｔ−ペンチル、ヘキシ
ル、イソヘキシル、ヘプチル、オクチルおよびインオク
チル等が包含される。置換アルキルにおける置換基とは
、同一または異なって置換数１〜３のヒドロキシル、低
級アルコキシル、カルボキシノペ低級アルコキシカルボ
ニル、アミン、モノアルキル置換アミノ、ジアルキル置
換アミノ、含窒素脂環式複素環基、ニトロおよびハロゲ
ン等が包含される。ここで、低級アルコキシル、低級ア
ルコキシ力ルポニノペモノアルキル置換アミンおよびジ
アルキル置換アミノにおけるアルキル部分は炭素数１〜
４の直鎖または分岐状の、例えばメチノペエチル、プロ
ピ／Ｌ／、イソプロピル、ブチル、イソブチノペｓｅｃ
−ブチルおよびｔｅｒｔ−ブチル等が、含窒素脂環式
複素環基としては、ピロリジニル、ピペリジノ、ビペラ
ジニＪｌ／、 Ｎ−メチルピペラジニル、モルホリノ、
チオモルホリノ、ホモピペラジニルおよびＮ−メチルホ
モピペラジニル等が、またハロゲンとしてはフッ素、塩
素、臭素およびヨウ素の各原子がそれぞれあげられる。In the definition of each layer of formula (1), the alkyl moiety in lower alkyl, lower alkoxycarbonylamino, lower alkoxyl, and lower alkylthio has 1 to 8 carbon atoms.
Straight chain or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, tert-butyl, pentynopeisobentyl, neopentyl, sec-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, Included are octyl, inoctyl, and the like. The substituents in substituted alkyl include hydroxyl, lower alkoxyl, carboxynope lower alkoxycarbonyl, amine, monoalkyl-substituted amino, dialkyl-substituted amino, nitrogen-containing alicyclic heterocyclic group, nitro and Includes halogen and the like. Here, the alkyl moiety in lower alkoxyl, lower alkoxyl monoalkyl-substituted amine, and dialkyl-substituted amino has 1 to 1 carbon atoms.
4 linear or branched, e.g. methinopethyl, propy/L/, isopropyl, butyl, isobutinope sec
-butyl and tert-butyl, nitrogen-containing alicyclic heterocyclic groups include pyrrolidinyl, piperidino, biperazini Jl/, N-methylpiperazinyl, morpholino,
Examples of the halogen include thiomorpholino, homopiperazinyl and N-methylhomopiperazinyl, and fluorine, chlorine, bromine and iodine atoms, respectively.
脂環式アルキルとは炭素数３〜８の、例えばシクロプロ
ピル、シクロペンチル、シクロヘキシルおよびシクロオ
クチル等が包含される。Alicyclic alkyl includes those having 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, and cyclooctyl.
低級アルケニルとは炭素数２〜６のビニル、アリル、プ
ロペニノペブテニルおよびヘキセニル等が包含される。Lower alkenyl includes C2-C6 vinyl, allyl, propeninopebutenyl, hexenyl, and the like.
アラルキルとは炭素数７〜１５のベンジル、フェネチル
およびベンズヒドリル等が、アリールとは炭素数６〜１
０のフェニルおよびナフチル等がそれぞれ包含される。Aralkyl includes benzyl, phenethyl, benzhydryl, etc. having 7 to 15 carbon atoms, and aryl includes 6 to 1 carbon atoms.
0 phenyl and naphthyl, respectively.
アラルキルの芳香環部分およびアリールにおける置換基
としては、同一または異なって置換数１〜２のヒドロキ
シル、低級アルコキシル、アミノ、モノアルキル置換ア
ミノ、ジアルキル置換アミノ、ニトロおよびハロゲン等
が包含される。ここで、低級アルコキシル、モノアルキ
ル置換アミノ、ジアルキル置換アミノおよびハロゲンの
各層は、前記した置換アルキルにおける置換基と同様の
ものがあげられる。Substituents on the aromatic ring moiety and aryl of aralkyl include hydroxyl, lower alkoxyl, amino, monoalkyl-substituted amino, dialkyl-substituted amino, nitro, halogen, etc., which are the same or different and have 1 to 2 substitutions. Here, the lower alkoxyl, monoalkyl-substituted amino, dialkyl-substituted amino and halogen layers include the same substituents as the above-mentioned substituted alkyl.
また、Ｒ８とＲ２が一緒になってＮを含んで形成される
複素環基としては、前記した含窒素脂環式複素環基と同
様のものがあげられる。Further, examples of the heterocyclic group formed by combining R8 and R2 and containing N include those similar to the nitrogen-containing alicyclic heterocyclic group described above.
また、化合物（Ｉ）の中には互変異性体が存在し得るも
のがあり、例えばＲ２ａが水素原子である化合物は、下
記に示すようないくつかの互変異性体として表わされる
。本発明はこれらに限らず全ての互変異性体を包含する
。Further, some compounds (I) may have tautomers; for example, a compound in which R2a is a hydrogen atom is expressed as several tautomers as shown below. The present invention is not limited to these, but includes all tautomers.
化合物（Ｉ）の薬理的に許容される酸付加塩としては種
々の無機酸との塩、例えば塩酸塩、臭化水素酸塩、ヨウ
化水素酸塩、硝酸塩、硫酸塩、リン酸塩など、また種々
の有機酸との塩、例えばギ酸塩、酢酸塩、安息香酸塩、
マレイン酸塩、フマル酸塩、コハク酸塩、酒石酸塩、ク
エン酸塩、シュウ酸塩、グリオキシル酸塩、アスパラギ
ン酸塩。Pharmaceutically acceptable acid addition salts of compound (I) include salts with various inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, phosphate, etc. Also, salts with various organic acids, such as formates, acetates, benzoates,
Maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxylate, aspartate.
メタンスルホン酸塩、ベンゼンスルホン酸塩などがあげ
られる。Examples include methanesulfonate and benzenesulfonate.
次に化合物（Ｉ）の製造法について説明する。Next, a method for producing compound (I) will be explained.
化合物（Ｉ）は、次の反応工程に従って得られる化合物
（ＩＩ ａ−ｃ）等を原料として製造することができる
。Compound (I) can be produced using compounds (II a-c) and the like obtained according to the following reaction steps as raw materials.
（ｎｂ） Ｒ。(nb) R.
（ｎｃ）
（式中、Ｒ１およびＲ４は前記と同義であり、Ｒ１はア
ルキルまたはアリールを、Ｈａｌはハロゲンを表わす）
ここで、Ｒ１の定義におけるアルキルとは炭素数１〜３
の例えばメチル、エチル、プロピル、イソプロピル等で
あり、アリールとはフェニル等を表わし、１ｌａｌで表
わされるハロゲンとは塩素、臭素、ヨウ素等を意味する
。(nc) (In the formula, R1 and R4 have the same meanings as above, R1 represents alkyl or aryl, and Hal represents halogen)
Here, alkyl in the definition of R1 has 1 to 3 carbon atoms.
For example, methyl, ethyl, propyl, isopropyl, etc., aryl represents phenyl, etc., and halogen represented by 1lal means chlorine, bromine, iodine, etc.
反応はまず化合物（Ｉｌｌ［） （Ｊ、Ｏｒｇ、Ｃｈ
ｅｍ、、 ３８゜４０４４ （１９７３）等に記載〕と
発煙硝酸とを反応し、ニトロ体（ｒＶ）を得る。化合物
（１’Ｖ）にヒドラジンを作用させ、環化したビリダジ
ノン体（Ｖ）を得る。次いで、化合物（Ｖ）とシアン化
銅を反応することにより、シアノ体（ＶＩ）を得る。化
合物（Ｖｌ）を還元し、化合物（ｆｆａ）を得ることが
できる。The reaction begins with the compound (Ill[) (J, Org, Ch
Em., 38° 4044 (1973) etc.] is reacted with fuming nitric acid to obtain the nitro compound (rV). Compound (1'V) is reacted with hydrazine to obtain a cyclized pyridazinone (V). Next, compound (V) and copper cyanide are reacted to obtain cyano compound (VI). Compound (Vl) can be reduced to obtain compound (ffa).
次いで化合物（Ｉ［ａ）にオルトエステル体を反応する
ことにより化合物（ＩＩｂ）を、またハロギ酸エステル
を反応することにより化合物（Ｉｌｃ）をそれぞれ得る
ことができる。Next, Compound (IIb) can be obtained by reacting Compound (I[a) with an orthoester, and Compound (Ilc) can be obtained by reacting Compound (I[a) with a haloformic acid ester.
製法Ａ
（式中、Ｌａ 、Ｒ３およびＲ１は前記と同義である）
化合物（Ｉ ａ）は、化合物（Ｉｆ ｂ）と次式％式％
（）
（式中、Ｒ□は前記と同義である〉
で示される化合物（Ｌａ）とを反応させることにより製
造することができる。Manufacturing method A (wherein La, R3 and R1 have the same meanings as above)
Compound (I a) and compound (If b) have the following formula% formula%
() (In the formula, R□ has the same meaning as above.) It can be produced by reacting with a compound (La) represented by the following formula.
化合物（Ｌａ）は化合物（Ｉｌｂ）に対して少なくとも
１当量以上用いるのが望ましく、溶媒を兼ねて大過剰量
用いても良い。Compound (La) is preferably used in an amount of at least 1 equivalent or more relative to compound (Ilb), and may also be used in large excess to serve as a solvent.
また、化合物（Ｌａ）は酸付加塩として使用することも
可能であり、反応に際しては化合物（Ｌａ）に対して１
当量以上の塩基の存在下に行うことが好ましい。酸付加
塩としては、前述した化合物（Ｉ）の酸付加塩と同様の
ものがあげられ、使用する塩基としてはアルカリ金属の
水酸化物（水酸化ナトリウム、水酸化カリウム等）、ア
ルコキシド類（ソジウムメトキシド、ポタシウムエトキ
シド等）およびアミン類（トリエチルアミン、ピリジン
等）などがあげられる。Moreover, compound (La) can also be used as an acid addition salt, and in the reaction, 1
It is preferable to carry out the reaction in the presence of an equivalent or more amount of base. Examples of acid addition salts include those similar to the acid addition salt of compound (I) mentioned above, and bases used include alkali metal hydroxides (sodium hydroxide, potassium hydroxide, etc.), alkoxides (sodium hydroxide, potassium hydroxide, etc.), (dium methoxide, potassium ethoxide, etc.) and amines (triethylamine, pyridine, etc.).
反応は、無溶媒あるいは反応に不活性な溶媒申付われる
。使用される溶媒としては水、アルコール類（メタノー
ル、エタノール等）、非プロトン性極性溶媒（ジメチル
ホルムアミド、ジメチルスルホキシド等）およびハロゲ
ン化炭化水素（ジクロロメタン、クロロホルム等）など
があげられる。The reaction is carried out without a solvent or with a solvent inert to the reaction. Examples of solvents used include water, alcohols (methanol, ethanol, etc.), aprotic polar solvents (dimethylformamide, dimethyl sulfoxide, etc.), and halogenated hydrocarbons (dichloromethane, chloroform, etc.).
反応温度は０℃ないし使用される溶媒の沸点の間で行わ
れ１０分〜１２時間で反応は終了する。The reaction temperature is between 0° C. and the boiling point of the solvent used, and the reaction is completed in 10 minutes to 12 hours.
製法Ｂ
（式中、ＲｏふよびＲ２は前記と同義である）化合物（
Ｉａａ）は、製法Ａと同様の方法より化合物（ｎｂ）に
代えて化合物（Ｉｌｃ）と化合物（Ｌａ）とより得るこ
とができる。Production method B (wherein Ro and R2 have the same meanings as above) Compound (
Iaa) can be obtained by a method similar to Production Method A using compound (Ilc) and compound (La) instead of compound (nb).
製法Ｃ
Ｈ
（式中、Ｒ１、Ｒ２、Ｒ３およびＲ４は前記と同義であ
る）化合物Ｎ ｂ）は、次式
（式中、Ｒ３およびＲ４は前記と同義であり、Ｌは脱離
基を表す）
で示される化合物（■）と次式
％式％（）
（式中、Ｒ１およびＲ２は前記と同義である）で示され
る化合物（■ｂ）とを反応させることにより得ることが
できる。Production method C H (wherein R1, R2, R3 and R4 are as defined above) Compound Nb) is produced by the following formula (wherein R3 and R4 are as defined above and L represents a leaving group) ) It can be obtained by reacting a compound (■) represented by the following formula with a compound (■b) represented by the following formula % (in which R1 and R2 have the same meanings as above).
ここで、して示される脱離基とは、メルカプト基、塩素
、臭素等のハロゲン原子、メトキシ、エトキシ等のアル
コキシル基、メチルチオ、エチルチオ等のアルキルチオ
基、フェニルチオ等のアリールチオ基、メチルスルフィ
ニル、エチルスルフィニル等のアルキルスルフィニル基
、フェニルスルフィニル等のアリールスルフィニル基、
メチルスルホニル、トリフルオロメチルスルホニル、エ
チルスルホニル等の低級アルキルスルホニル基おヨヒフ
ェニルスルホニル、ｐ−）ルエンスルホニル等のアリー
ルスルホニル基等を意味する。Here, the leaving groups represented by are mercapto groups, halogen atoms such as chlorine and bromine, alkoxyl groups such as methoxy and ethoxy, alkylthio groups such as methylthio and ethylthio, arylthio groups such as phenylthio, methylsulfinyl, and ethyl. Alkylsulfinyl groups such as sulfinyl, arylsulfinyl groups such as phenylsulfinyl,
It means lower alkylsulfonyl groups such as methylsulfonyl, trifluoromethylsulfonyl, and ethylsulfonyl, and arylsulfonyl groups such as hyophenylsulfonyl and p-)luenesulfonyl.
化合物（■ｂ）は化合物（■）に対し１当最以上大過剰
量使用される。また、反応を促進するためにトリエチル
アミン等の第三級アミン類を添加することも可能である
。Compound (■b) is used in a large excess of at least 1 mole relative to compound (■). It is also possible to add tertiary amines such as triethylamine to accelerate the reaction.
反応溶媒としては、無溶媒あるいは水、アルコール類（
メタノール、エタノールなど）および非プロトン性極性
溶媒（ジメチルホルムアミド、ジメチルスルホキシド等
）などが好ましく用いられる。Reaction solvents include no solvent, water, alcohols (
(methanol, ethanol, etc.) and aprotic polar solvents (dimethylformamide, dimethyl sulfoxide, etc.) are preferably used.
反応は室温ないし溶媒の沸点の間で行い、１０分〜２４
時間で終了する。The reaction is carried out between room temperature and the boiling point of the solvent for 10 minutes to 24 minutes.
Finish in time.
原料化合物（■）としては、後述する製法ＨおよびＪ等
で得られる化合物、あるいは該化合物をさらに通常知ら
れている方法、例えば酸化、ハロゲン化などの方法で得
られる化合物が使用される。As the raw material compound (■), used are compounds obtained by the below-mentioned production methods H and J, or compounds obtained by further known methods such as oxidation and halogenation.
製法Ｄ ■ 等）などが好ましく用いられる。Manufacturing method D ■ etc.) are preferably used.
使用する塩基としては製法Ａで述べたものが同様に使用
される。As the base to be used, those described in Production Method A are used in the same manner.
反応温度は室温ないし溶媒の沸点の間で行われ、１０分
〜２４時間で反応は終了する。The reaction temperature is between room temperature and the boiling point of the solvent, and the reaction is completed in 10 minutes to 24 hours.
製法Ｅ
（式中、Ｒ７いＲ３およびＲ４は前記と同義である）化
合物（Ｉｂａ）は、製法Ａで得られる化合物（Ｉ ａ）
を塩基存在下に処理することによって得ることができる
。Production method E Compound (Iba) (wherein R7, R3 and R4 have the same meanings as above) is the compound (Ia) obtained by production method A.
can be obtained by treating in the presence of a base.
反応溶媒としては水、アルコール類（メタノール、エタ
ノール等）および非プロトン性極性溶媒（ジメチルホル
ムアミド、ジメチルスルホキシド（式中、Ｒ１およびＲ
９は前記と同義であり、Ｒ８は低級アルキルを表す）
ここで、Ｒ１で示される低級アルキルとは前記した式（
１）の低級アルキルの定義と同義である。Reaction solvents include water, alcohols (methanol, ethanol, etc.) and aprotic polar solvents (dimethylformamide, dimethyl sulfoxide (in the formula, R1 and R
9 has the same meaning as above, R8 represents lower alkyl) Here, the lower alkyl represented by R1 is represented by the above formula (
It has the same meaning as the definition of lower alkyl in 1).
Ｈａ Ｉ ＣＯＯＲｅ
（ＩＸ）
（式中、Ｒ６右よびＨａｌは前記と同義である）で示さ
れる化合物（ＩＸ）とより塩基の存在下に得ることがで
きる。It can be obtained from the compound (IX) represented by Ha I COORe (IX) (wherein R6 and Hal have the same meanings as above) in the presence of a base.
塩基としては、製法Ａに述べたものが同様に使用される
。反応溶媒は、ジメチルホルムアミド、ハロゲン化炭化
水素（ジクロロメタン、クロロホルム等）など、あるい
はピリジン、トリエチルアミン等の塩基を溶媒を兼ね使
用することができる。As the base, those mentioned in Production Method A are used in the same manner. The reaction solvent may be dimethylformamide, a halogenated hydrocarbon (dichloromethane, chloroform, etc.), or a base such as pyridine or triethylamine may also be used as a solvent.
反応は、０〜１００℃で１０分〜１２時間で終了する。The reaction is completed in 10 minutes to 12 hours at 0 to 100°C.
製法Ｆ
（式中、Ｒ５およびＲ４は前記と同義である）化合物（
Ｉ Ｃ’）は、化合物（Ｕ ｂ）をピリジン、トリエチ
ルアミン等の塩基性溶媒単独または混合溶媒中、硫化水
素と反応することにより得ることができる。反応は、
水素ガスを１０分から
了する。Production method F (wherein R5 and R4 have the same meanings as above) Compound (
I C') can be obtained by reacting compound (U b) with hydrogen sulfide in a basic solvent such as pyridine or triethylamine alone or in a mixed solvent. The reaction was completed after 10 minutes of hydrogen gas.
製法Ｇ
０℃ないし溶媒の沸点で硫化
３時間通気することにより終
（式中、Ｒ５は前記と同義である）
化合物（Ｉｅ、）は、製法Ｆと同様の方法により化合物
（Ｉｌｂ）に代えて化合物（Ｉｌａ）を、硫化水素に代
え二硫化炭素を用いることにより得ることができる。Production method G The sulfurization is completed by aeration for 3 hours at 0°C or the boiling point of the solvent (in the formula, R5 has the same meaning as above). Compound (Ila) can be obtained by using carbon disulfide in place of hydrogen sulfide.
製法Ｈ
■
製法Ｉ
（式中、Ｒ３、Ｒ４右よびＲ１は前記と同義である）化
合物（Ｉ ｄ）は製法Ｆ等で得られる化合物（Ｉ ｃ）
を塩基の存在下、ハロゲン化アルキルあるいはジアゾア
ルカンなどのアルキル化剤と反応することによって得ら
れる。Production method H ■ Production method I (In the formula, R3, R4 and R1 have the same meanings as above) Compound (I d) is a compound (I c) obtained by Production method F etc.
is obtained by reacting with an alkylating agent such as an alkyl halide or a diazoalkane in the presence of a base.
使用される塩基としては、水酸化ナトリウム、炭酸カリ
ウム、ジアザビシクロウンデセン（口８０）、トリエチ
ルアミン、ピリジン、ジメチルアミノピリジン、水素化
ナトリウムなどがあげられる。Bases used include sodium hydroxide, potassium carbonate, diazabicycloundecene (80%), triethylamine, pyridine, dimethylaminopyridine, sodium hydride, and the like.
反応は、反応に不活性な溶媒申付われる。使用される溶
媒としては水、アルコール類（メタノール、エタノール
等）、非プロトン性極性溶媒（ジメチルホルムアミド、
ジメチルスルホキシド等）およびハロゲン化炭化水素（
ジクロロメタン、クロロホルム等）などがあげられる。The reaction is carried out using a solvent that is inert to the reaction. Solvents used include water, alcohols (methanol, ethanol, etc.), aprotic polar solvents (dimethylformamide,
dimethyl sulfoxide) and halogenated hydrocarbons (such as dimethyl sulfoxide) and halogenated hydrocarbons (
dichloromethane, chloroform, etc.).
反応温度は０℃ないし使用される溶媒の沸点の間で行わ
れ１０分〜１２時間で反応は終了する。The reaction temperature is between 0° C. and the boiling point of the solvent used, and the reaction is completed in 10 minutes to 12 hours.
（式中、Ｒ３、Ｒ４およびＲ６は前記と同義である）化
合物（Ｉ ｅ）は、アルキル化剤として次式８式％（）
（式中、Ｒ３右よび）Ｉａｌは前記と同義である）で示
される化合物（Ｘ）を用い、製法Ｈと同様の方法で得る
ことができる。(In the formula, R3, R4 and R6 have the same meanings as above) Compound (Ie) is used as an alkylating agent by the following formula 8% () (In the formula, R3 right and Ial have the same meanings as above) It can be obtained in the same manner as Production Method H using the compound (X) shown below.
製法Ｊ ■ に４ａ （式中、Ｒ８およびＲ８は前記と同義であり、ｌｔ。Manufacturing method J ■ to 4a (In the formula, R8 and R8 have the same meanings as above, and lt.
は前記Ｒ１の定義中の低級アルキルを意味する）反応は
まず、化合物（ＩＩａ）を適当なアシル化剤と反応し化
合物（ＩＩｄ）とする。(means lower alkyl in the definition of R1 above) In the reaction, first, compound (IIa) is reacted with a suitable acylating agent to form compound (IId).
（式中、Ｒ１およびＲ４Ｍは前記と同義である）アシル
化剤としては対応するカルボン酸の酸無水物あるいは酸
ハロゲン化物等があげられる。(In the formula, R1 and R4M have the same meanings as above.) Examples of the acylating agent include acid anhydrides or acid halides of the corresponding carboxylic acids.
次いで、化合物（Ｉ［ｄ）と次式
％式％（）
（式中、Ｒ８は前記と同義である）
で示されるアルコール類（ＸＩ）とを塩基の存在下反応
することにより化合物（Ｉ ｆ）を得ることができる。Next, the compound (I[d) and the alcohol (XI) represented by the following formula % formula % () (in the formula, R8 has the same meaning as above) are reacted in the presence of a base to obtain the compound (I f ) can be obtained.
使用される塩基、反応溶媒等の反応条件は製法Ｈに記載
したものが適用される。The reaction conditions such as the base and reaction solvent used are those described in Production Method H.
製法に
■
（式中、Ｒ３、Ｒ４およびＲ，は前期と同義である）化
合物（Ｉ ｇ）は、製法■で得られる化合物（Ｉ ｅ）
を塩基の存在下にトリフェニルホスフィンで処理するこ
とにより得ることができる。The compound (I g) (wherein R3, R4 and R are the same as those in the previous term) is the compound (I e) obtained by the production method ■
can be obtained by treating with triphenylphosphine in the presence of a base.
使用される塩基、反応溶媒等の反応条件は製法Ｈに記載
したものが適用される。The reaction conditions such as the base and reaction solvent used are those described in Production Method H.
製法Ｌ
■
（式中、Ｒ３およびＲ１は前記と同義である）化合物（
Ｉ ｈ）は、製法にで得られる化合物（Ｉｇ）をアルカ
リ条件下にケン化することにより得られる。Production method L ■ Compound (wherein R3 and R1 are the same as defined above) (
Ih) can be obtained by saponifying the compound (Ig) obtained in the production method under alkaline conditions.
反応は、水酸化す）ＩＪウム、水酸化カリウム等のアル
カリ水溶液あるいはアルコール類（メタノール、エタノ
ール等）との混合溶媒中、室温ないし溶媒の沸点の間で
行なわれ、１０分〜１２時間で終了する。The reaction is carried out in an aqueous alkaline solution of IJ hydroxide, potassium hydroxide, etc. or a mixed solvent with an alcohol (methanol, ethanol, etc.) at room temperature or the boiling point of the solvent, and is completed in 10 minutes to 12 hours. do.
製法Ｍ
化合物（１１）は、製法Ｈで得られる化合物（Ｉｄ＞を
還元（脱硫）することによって得られる。Production Method M Compound (11) is obtained by reducing (desulfurizing) the compound (Id> obtained by Production Method H).
還元剤としては、ラネーニッケルが好適に用いられ、水
、アルコール類（メタノール、エタノール等）およびジ
メチルホルムアミド等の溶媒中、室温ないし溶媒の沸点
で３０分〜１２時間で反応は終了する。As the reducing agent, Raney nickel is suitably used, and the reaction is completed in 30 minutes to 12 hours at room temperature to the boiling point of the solvent in a solvent such as water, alcohols (methanol, ethanol, etc.) and dimethylformamide.
製法Ｎ
（式中、Ｒ８およびＲ４は前記と同義である）（式中、
Ｒ１およびＲ１は前記と同義である）化合物（Ｉ ｊ）
は、製法Ｍで得られる化合物（Ｉ ｉ）を酸化すること
により得られる。Manufacturing method N (in the formula, R8 and R4 have the same meanings as above) (in the formula,
R1 and R1 are as defined above) Compound (I j)
is obtained by oxidizing compound (I i) obtained by Production Method M.
適当な酸化剤としては、二酸化マンガン、クロム酸、過
酸化水素などがあげられ、反応は０〜５０℃で１０分〜
１２時間で終了する。Suitable oxidizing agents include manganese dioxide, chromic acid, hydrogen peroxide, etc., and the reaction is carried out at 0 to 50°C for 10 minutes or more.
It will end in 12 hours.
製法Ｏ
製法Ｐ
（式中、Ｒ８、Ｒ１およびｎは前記と同義である）化合
物（Ｉ ｋ）は、化合物（ＩＩ ｂ）と次式％式％（）
（式中、ｎは前記と同義である）
で示される化合物（■Ｃ）あるいはその酸付加塩とより
、製法へと同様の方法で得ることができる。Production method O Production method P (wherein R8, R1 and n have the same meanings as above) Compound (I k) is combined with compound (II b) by the following formula % formula % () (wherein n has the same meaning as above) It can be obtained using the same method as the compound (■C) or its acid addition salt.
また、化合物（■ｂ）に代え化合物（ＩＩｃ）を用いる
ことにより、化合物（Ｉ ｋ）においてＲ１がヒドロキ
シルである化合物を得ることができる。Furthermore, by using compound (IIc) in place of compound (■b), a compound in which R1 is hydroxyl in compound (Ik) can be obtained.
（式中、Ｒ５、Ｒ６およびＲ６は前記と同義である）Ｒ
ｍＣＯＯＨ（Ｘ ＩＩ）
で示されるカルボン酸（ＸＩ）あるいはその反応性誘導
体（例えば、エステル、オルトエステル、酸ハライドな
ど）とを反応させることにより得られる。(In the formula, R5, R6 and R6 have the same meanings as above) R
It can be obtained by reacting carboxylic acid (XI) represented by mCOOH(X II) or its reactive derivative (eg, ester, orthoester, acid halide, etc.).
反応は、化合物（ＸＩＩ）を溶媒を兼ねて大過剰用い、
室温ないし溶媒の沸点で３０分〜１２時間で終了する。The reaction was carried out using compound (XII) in large excess, which also served as a solvent.
The process is completed in 30 minutes to 12 hours at room temperature to the boiling point of the solvent.
製法Ｑ
〔化合物（Ｉ）において、Ｒ４がアルキルチオである化
合物（Ｉｍ））
（式中、Ｘ−Ｙ、Ｒ，およびＲ８は前記と同義である）
化合物（１ｍ）は、製法Ｇ等で得られるＲ１がメルカプ
トである化合物（■。）より、製法Ｈと同様の方法によ
り得られる。Production method Q [Compound (Im) in which R4 is alkylthio in compound (I)) (wherein, X-Y, R, and R8 have the same meanings as above)
Compound (1m) is obtained by the same method as Production Method H from the compound (■.) in which R1 is mercapto obtained by Production Method G and the like.
製法Ｒ
■
化合物（Ｉ ｎ）は、製法Ｑで得られる化合物（１ｍ）
のアルキルチオ基を適当な酸化剤で酸化したのち、アミ
ン（■ｂ）と反応させることにより得られる。Manufacturing method R ■ Compound (I n) is the compound (1m) obtained by manufacturing method Q
It can be obtained by oxidizing the alkylthio group of with a suitable oxidizing agent and then reacting it with an amine (■b).
酸化剤としては、過マンガン酸カリウム、過酸化水素、
ｍ−クロロ過安息香酸等があげられ、化合物（■ｂ）と
の反応は製法Ｃと同様の方法で行うことができる。Oxidizing agents include potassium permanganate, hydrogen peroxide,
Examples include m-chloroperbenzoic acid, and the reaction with compound (■b) can be carried out in the same manner as in Production Method C.
なお、化合物（１）の製造法は、原料化合物（Ｉｌ、〜
ｅ）を含めここに例示した方法だけに限定されるもので
はない。Note that the method for producing compound (1) is based on the starting material compounds (Il, -
It is not limited to the methods exemplified here including e).
例えば、ヒドラジンでの閉環工程は各製法の工程の最後
に回しても良く、例えば化合物（■）より前記した製法
に準じて先に前駆体（ＸＩＩ［、〜。）を得る。For example, the ring-closing step with hydrazine may be carried out at the end of each production process, and, for example, the precursor (XII[, ~.) is obtained first from compound (■) according to the above-mentioned production method.
（式中、Ｘ−Ｙ、Ｒ，、Ｒ２およびＲ５は前記と同義で
ある）
〔式中、Ｒ，１ｔ−Ｎｌ２（ＸＩＩ［ａ）、−Ｎ ＝Ｃ
Ｈ，−ＯＲ，（Ｘ ｍ ｂ）または−ＮＨＣ口０Ｒｔ（
Ｘｌｎｃ）を表わし、Ｒ５、Ｒ４およびＲ７は前記と同
義である〕
得られた化合物（Ｘｌ、〜Ｃ）は、前述した製法Ａ〜Ｒ
等の反応と同様の方法により先にキナゾリン環を得、そ
の後ヒドラジンとの反応でビリダジノン環とすることに
よって化合物（１）を得ることもできる。(In the formula, X-Y, R,, R2 and R5 have the same meanings as above)
H, -OR, (X m b) or -NHC port 0Rt (
Xlnc), and R5, R4 and R7 have the same meanings as above] The obtained compound (Xl, -C) can be prepared by the above-mentioned production methods A to R.
Compound (1) can also be obtained by first obtaining a quinazoline ring by a method similar to the above reaction, and then reacting with hydrazine to form a pyridazinone ring.
上述した製法における中間体および目的化合物は、有機
合成化学で常用される精製法、例えばｐ過、抽出、洗浄
、乾燥、濃縮、再結晶、各種クロマトグラフィー等に付
して単離精製することができる。また中間体においては
、特に精製することなく次の反応に供することも可能で
ある。The intermediates and target compounds in the above-mentioned production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as p-filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can. Further, the intermediate can also be subjected to the next reaction without being particularly purified.
化合物（Ｉ）の塩を取得したいとき、化合物（１）が塩
の形で得られる場合には、そのまま精製すればよく、ま
た、遊離の形で得られる場合には、通常の方法により塩
を形成させればよい。When you want to obtain a salt of compound (I), if compound (1) is obtained in the form of a salt, you can simply purify it as it is, or if it is obtained in a free form, you can obtain the salt by a conventional method. Just let it form.
また、化合物（Ｉ）およびその薬理上許容される塩は、
水あるいは各種溶媒の付加物の形で存在することもある
が、これら付加物も本発明に包含される。In addition, compound (I) and its pharmacologically acceptable salts are:
It may exist in the form of adducts of water or various solvents, and these adducts are also included in the present invention.
なお本発明は、化合物（Ｉ）において、前述の互変異性
体に限らず、すべての可能な立体異性体およびそれらの
混合物も包含される。In addition, the present invention includes not only the above-mentioned tautomers but also all possible stereoisomers and mixtures thereof in compound (I).
各製法によって得られる化合物（Ｉ）の具体例および物
性値を第１−１表〜第１−６表に示す。Specific examples and physical property values of compound (I) obtained by each production method are shown in Tables 1-1 to 1-6.
第 １
１表
第１
Ｈ
表
第１−３表
■
第 １−４ 表
第 １−５ 表
Ｈ
第１−６表
次に、代表的な化合物（１）の強心作用および急性毒性
について、試験例で説明する。Table 1 1 1 H Table 1-3 ■ 1-4 Table 1-5 Table H Table 1-6 Next, test examples are shown for the cardiac inotropic effect and acute toxicity of representative compound (1). I will explain.
試験例１゜
化合物（１）の強心作用
体重８〜１５ｋｉの雌雄雑種成犬にペンドパルビクール
のナトリウム塩を３０１１ｇ／ｋｇの割合で静脈内投与
し、麻酔をかけた。人工呼吸下で、左縁頚動脈よりカテ
ーテル型圧トランスデユーサ−を逆行性に左心室内に挿
入し、左心室内圧を測定した。また、大腿動脈に挿入し
たカテーテルを介して圧トランスデユーサーにより末梢
血圧を測定した。心筋収縮力は左心室内圧の１機微分の
最大値（ｄｐ／ｄｔ ｍａｘ）を措標にし、心拍数はＥ
ＣＧ波型（第■誘導）をタコメーターに導入し計測した
。測定中の麻酔の維持は、ハロタンと笑気を用いた吸入
麻酔により行った。Test Example 1 Inotropic effect of compound (1) An adult male and female mixed breed dog weighing 8 to 15 kilograms was anesthetized by intravenously administering the sodium salt of pendoparvicur at a rate of 3011 g/kg. Under artificial respiration, a catheter-type pressure transducer was retrogradely inserted into the left ventricle from the left marginal carotid artery, and the left ventricular pressure was measured. In addition, peripheral blood pressure was measured using a pressure transducer via a catheter inserted into the femoral artery. Myocardial contractile force is measured by the maximum value of the single-component differential of left ventricular pressure (dp/dt max), and heart rate is measured by E.
The CG waveform (lead Ⅰ) was introduced into a tachometer and measured. Anesthesia was maintained during the measurements by inhalation anesthesia using halothane and laughing gas.
同時に筋弛緩薬（臭化パンクロニウム）を０．１■／ｋ
ｇ／時の割合で左前肢静脈より持続注入した。この方法
により、長時間安定した麻酔状態を得ることができた。Simultaneously administer muscle relaxant (pancuronium bromide) at 0.1■/k.
Continuous infusion was carried out through the left forelimb vein at a rate of g/hour. Using this method, we were able to obtain a stable state of anesthesia for a long period of time.
試験化合物はＰＥＧ−４００に溶解して、右前肢静脈（
ｉｖ）より第２表に示した用量を投与した。投与後６０
分までの心筋収縮力、心拍数、末梢平均血圧の投与前値
に対する最大変化率および心筋収縮力変化の持続時間を
求めた。Test compounds were dissolved in PEG-400 and administered into the right forelimb vein (
iv) The doses shown in Table 2 were administered. 60 days after administration
The maximum rate of change in myocardial contractile force, heart rate, and peripheral mean blood pressure from the pre-administration values to minutes and the duration of the change in myocardial contractile force were determined.
結果を第２表に示す。The results are shown in Table 2.
第
表
試験例２゜
化合物（Ｉ）の急性毒性
体重２０±１ｇのｄｄ系雌雄マウス１群３匹用い試験化
合物を経口投与した。投与後７日後の死亡状況を観察し
、最小死亡量値を求めた。Table 1 Test Example 2: Acute Toxicity of Compound (I) The test compound was orally administered to a group of 3 male and female DD mice weighing 20±1 g. Mortality was observed 7 days after administration, and the minimum mortality value was determined.
結果を第３表に示す。The results are shown in Table 3.
第 ３ 表
化合物（Ｉ）もしくはその薬理的に許容される酸付加塩
を含有する強心剤は、たとえば錠剤。Table 3 The cardiotonic agent containing Compound (I) or a pharmacologically acceptable acid addition salt thereof is, for example, a tablet.
カプセル剤、シロップ剤、注射剤１点滴剤、坐剤等の通
常適用される剤形に調製して経口的にあるいは筋肉内注
射、静脈内注射、動脈内注射。Prepared into commonly used dosage forms such as capsules, syrups, injections, and suppositories for oral, intramuscular, intravenous, and intraarterial injection.
点滴、坐剤による直腸内投与のような非経口的投与で投
与することができる。それらの経口的または非経口的に
投与する剤形の製剤化には通常知られた方法が適用され
、例えば、各種の賦形剤、滑沢剤、結合剤、崩壊剤、懸
濁化剤、等張化剤、乳化剤等を含有していてもよい。It can be administered parenterally, such as intrarectally by infusion or suppository. Generally known methods are applied to formulate dosage forms for oral or parenteral administration, such as various excipients, lubricants, binders, disintegrants, suspending agents, It may contain an isotonic agent, an emulsifier, etc.
使用する製剤用担体としては、例えば、水、注射用蒸留
水、生理食塩水、グルコース、フラクトース、白糖、マ
ンニット、ラクトース、でん粉、セルロース、メチルセ
ルロース、カルボキシメチルセルロース、ヒドロキシプ
ロピルセルロース、アルギン酸、タルク、クエン酸ナト
リウム、炭酸カルシウム、リン酸水素カルシウム、ステ
アリン酸マグネシウム、尿素、シリコーン樹脂、ソルビ
タン脂肪酸エステノペグリセリン脂肪酸エステル等があ
げられる。Pharmaceutical carriers used include, for example, water, distilled water for injection, physiological saline, glucose, fructose, white sugar, mannitol, lactose, starch, cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, alginic acid, talc, and citric acid. Examples include sodium acid, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid esteropeglycerin fatty acid ester, and the like.
投与量は、投与形態、患者の年齢、体重、症状等により
異なるが、例えば通常経口で０．０５〜２００■／６０
ｋｇ／日が適当であり、点滴の場合は、０．０１〜５■
／ｋｇ／分で１日あたり経口投与量の限度をこえない範
囲とするのが好ましい。The dosage varies depending on the dosage form, patient's age, weight, symptoms, etc., but for example, it is usually 0.05 to 200 μ/60 orally.
kg/day is appropriate, and in the case of intravenous drip, 0.01 to 5 ■
/kg/min, preferably within a range that does not exceed the daily oral dosage limit.
以下に実施例と参考例をもって本発明の詳細な説明する
。The present invention will be explained in detail below using Examples and Reference Examples.
実施例１゜
参考例５で得られる化合物ｅ １．５ ｇを４０％メチ
ルアミン−メタノール溶液３Ｑｍｌに溶解し５０℃で３
０分間攪拌した。析出してきた結晶をＰ取、乾燥し４，
５−ジヒドロ−５−メチル−６−（３−メチル−４（３
Ｈ）−キナゾリンイミン−７−イル）−３（２Ｈ）−ピ
リダジノン（化合物１）０．９ｇ（６３％）を得た。Example 1 1.5 g of the compound e obtained in Reference Example 5 was dissolved in 3 Q ml of 40% methylamine-methanol solution and heated at 50°C.
Stirred for 0 minutes. The precipitated crystals are removed by P and dried 4.
5-dihydro-5-methyl-6-(3-methyl-4(3
0.9 g (63%) of H)-quinazolinimin-7-yl)-3(2H)-pyridazinone (compound 1) was obtained.
実施例２．〜１０゜
実施例１と同様な方法で第４−１表に示すような条件で
目的化合物を得た。なあ、必要な場合には粗生成物を前
述したクロマトグラフィー、再結晶等の操作で精製した
。Example 2. ~10° The target compound was obtained in the same manner as in Example 1 under the conditions shown in Table 4-1. If necessary, the crude product was purified by the aforementioned chromatography, recrystallization, etc. operations.
第 ４ １表 ＊反応溶媒は、いずれもメタノールを使用した。Part 4 1 table *Methanol was used as the reaction solvent in all cases.
実施例１１゜
実施例１０４０％メチルアミン−メタノール溶液を濃ア
ンモニア水２０ｍ１−メタノール２０１１に変更した以
外は実施例１と同様に行い、６−（４アミノキナゾリン
−７−イル）−４，５−ジヒドロ−５−メチル−３（２
Ｈ）−ピリダジノン（化合物１１） ０．８ｇ （５９
％）を得た。Example 11゜Example 10 The procedure of Example 1 was repeated except that the 40% methylamine-methanol solution was changed to 20ml of concentrated ammonia water-methanol 2011, and 6-(4aminoquinazolin-7-yl)-4,5- dihydro-5-methyl-3(2
H)-pyridazinone (compound 11) 0.8g (59
%) was obtained.
実施例１２゜
実施例１１で得られる化合物１１０．３４ｇを１規定塩
酸１０ｍ１に加熱下溶解した。冷却し、析出してきた結
晶をｐ取、乾燥し、６−（４−アミノキナゾリン−７−
イル）−４，５−ジヒドロ−５−メチル−３（２Ｈ）−
ピリダジノン・１塩酸塩・ｌ水和物（化合物１１’）
０．２１ｇ （５４％）を得た。Example 12 110.34 g of the compound obtained in Example 11 was dissolved in 10 ml of 1N hydrochloric acid under heating. After cooling, the precipitated crystals were collected and dried to give 6-(4-aminoquinazoline-7-
yl)-4,5-dihydro-5-methyl-3(2H)-
Pyridazinone monohydrochloride monohydrate (compound 11')
0.21 g (54%) was obtained.
実施例１３゜
実施例１で得られた化合物１０．２９ｇを２規定水酸化
ナトリウム１０ｍ１中１００℃で５時間攪拌した。ｌ規
定塩酸で中和し、析出してきた結晶をｐ取、乾燥し、４
．５−ジヒドロ−５−メチル−６−（４−メチルアミノ
キナゾリン−７−イル）−３（２Ｈ）−１：’！Ｊダシ
ノン（化合物１２）０．２２ｇ（７６％）を得た。Example 13 10.29 g of the compound obtained in Example 1 was stirred in 10 ml of 2N sodium hydroxide at 100° C. for 5 hours. Neutralize with 1 normal hydrochloric acid, remove the precipitated crystals, dry,
．． 5-dihydro-5-methyl-6-(4-methylaminoquinazolin-7-yl)-3(2H)-1:'! 0.22 g (76%) of J dacinone (compound 12) was obtained.
実施例１４〜１７゜
実施例１３と同様な方法で第４−２表に示すような条件
で目的化合物を得た。なお、必要な場合には粗生成物を
前述したクロマトグラフィー、再結晶等の操作で精製し
た。Examples 14 to 17 The target compound was obtained in the same manner as in Example 13 under the conditions shown in Table 4-2. In addition, if necessary, the crude product was purified by the above-mentioned operations such as chromatography and recrystallization.
第４−２表
＊反応溶媒は、いずれもジメチルホルムアミドを使用し
た。Table 4-2 *Dimethylformamide was used as the reaction solvent in all cases.
実施例１８゜
参考例５で得られる化合物ｅＯ，６３ｇをピリジン１０
ｍ１およびトリエチルアミン１ｍｌに溶解し、室温で硫
化水素ガスを通気した。３０分後行出してきた結晶を沖
取し、水洗、乾燥し、４，５−ジヒドロ−６−〈４−メ
ルカプトキナゾリン−７−イル〉−５−メチル−３（２
Ｈ）−ピリダジノン（化合物５６） ０．５１ｇ （８
５％）を得た。Example 18゜63 g of the compound eO obtained in Reference Example 5 was added to pyridine 10
The solution was dissolved in 1 ml of triethylamine and 1 ml of triethylamine, and hydrogen sulfide gas was bubbled through the solution at room temperature. After 30 minutes, the crystals that came out were harvested, washed with water, and dried to give 4,5-dihydro-6-<4-mercaptoquinazolin-7-yl>-5-methyl-3(2
H)-pyridazinone (compound 56) 0.51g (8
5%).
実施例１９゜
実施例１８で得られる化合物５６０．３６ｇにジメチル
ホルムアミドｌＱｍｌ、）リエチルアミン０．２ｍｌお
よびヨウ化メチルＱ、１ｍｌを加え室温で３０分間攪拌
した。濃縮し、水を加え析出した結晶をｐ取、乾燥し、
４．５−ジヒドロ−５−メチル−６−（４−メチルチオ
キナゾリン−７−イル）−３（２Ｈ）−ピリダジノン（
化合物５７）０．３ｇ（７９％）を得た。Example 19 To 560.36 g of the compound obtained in Example 18 were added 1 Q ml of dimethylformamide, 0.2 ml of ethylamine and 1 ml of methyl iodide Q, and the mixture was stirred at room temperature for 30 minutes. Concentrate, add water, collect the precipitated crystals, and dry.
4.5-dihydro-5-methyl-6-(4-methylthioquinazolin-7-yl)-3(2H)-pyridazinone (
Compound 57) 0.3 g (79%) was obtained.
実施例２０゜
実施例１９で得られる化合物５７０．６ｇをジメチルホ
ルムアミド１０ｍ１．）リエチルアミン１ｍｌおよび５
０％ジメチルアミン水溶液５ｍｌに溶解し、６０℃で４
時間攪拌した。ａ縮後、水を加え析出してきた結晶を戸
数、乾燥し、４．５−ジヒドロ−５−メチル−６−（４
−ジメチルアミノキナゾリン−７−イル）−３（２Ｈ）
−ピリダジノン（化合物１３） ０．３ｇ （５１％）
を得た。Example 20 570.6 g of the compound obtained in Example 19 was added to 10 ml of dimethylformamide. ) 1 ml of ethylamine and 5
Dissolve in 5 ml of 0% dimethylamine aqueous solution and incubate at 60°C for 4 hours.
Stir for hours. After condensation, water was added and the precipitated crystals were dried several times to form 4,5-dihydro-5-methyl-6-(4
-dimethylaminoquinazolin-7-yl)-3(2H)
-Pyridazinone (Compound 13) 0.3g (51%)
I got it.
実施例２１．〜５５゜
実施例２０と同様な方法で第４−３表に示すような条件
で目的化合物を得た。なお、必要な場合には粗生成物を
前述したクロマトグラフィー、再結晶等の操作で精製し
た。Example 21. ~55° The target compound was obtained in the same manner as in Example 20 under the conditions shown in Table 4-3. In addition, if necessary, the crude product was purified by the above-mentioned operations such as chromatography and recrystallization.
第４
３表
＊は無溶媒で、その他はジメチルスルホキシド中で反応
した。Table 4 3* was used without solvent, and the others were reacted in dimethyl sulfoxide.
実施例５６゜
実施例１１で得られる化合物１１０．２０ｇをピリジン
５ｍｌに溶解し、クロロギ酸エチル０．１ｍｌヲ加え室
温で３時間攪拌した。濃縮し、残渣に水を加え析出した
結晶をＰ取、乾燥し、６− （４−４）キシカルボニル
アミノキナゾリン−７−イル）−４，５−ジヒドロ−５
−メチル−３（２Ｈ）−ピリダジノン（化合物５３）
０．２１ ｇ （８２％）を得た。Example 56 110.20 g of the compound obtained in Example 11 was dissolved in 5 ml of pyridine, 0.1 ml of ethyl chloroformate was added, and the mixture was stirred at room temperature for 3 hours. It was concentrated, water was added to the residue, and the precipitated crystals were collected and dried to give 6-(4-4)oxycarbonylaminoquinazolin-7-yl)-4,5-dihydro-5.
-Methyl-3(2H)-pyridazinone (compound 53)
0.21 g (82%) was obtained.
実施例５７゜
実施例１８で得られる化合物５６ ３．７ｇ、 ）リ
エチルアミン１３．１１ｍ１およびジメチルホルムアミ
ド１（１０１１１１の混合物にブロモマロン酸ジエチル
２．４１１１１を加え室温で２時間攪拌した。濃縮し、
残渣を水クロロホルムで分配し、有機層を乾燥した後濃
縮した。残渣を１５０ｇのシリカゲルカラムで精製し、
ジエチルエーテルから結晶化し、３．４３ ｇ（５９％
）のジエチル［７−（２，３，４，５−テトラヒドロ−
５−メチル−３−オキソ−２Ｈ−ピリダジン−６−イル
）キナゾリン−４−イルチオ〕マロネート（化合物５８
）を得た。Example 57 To a mixture of 3.7 g of compound 56 obtained in Example 18, 13.11 ml of ethylamine and 101111 dimethylformamide was added 2.41111 diethyl bromomalonate and stirred at room temperature for 2 hours. Concentrated,
The residue was partitioned between water and chloroform, and the organic layer was dried and concentrated. The residue was purified with a 150 g silica gel column,
Crystallized from diethyl ether, 3.43 g (59%
) of diethyl [7-(2,3,4,5-tetrahydro-
5-Methyl-3-oxo-2H-pyridazin-6-yl)quinazolin-4-ylthio]malonate (compound 58
) was obtained.
実施例５８゜
実施例５７で得られる化合物５８ ２．７ ｇ、 ）
ＩＪフェニルホスフィン１．９ｇ、炭酸カリウム５．７
ｇおよびジメチルホルムアミド２０ｍ１の混合物を１２
０℃で３時間攪拌した。室温まで冷却後、水−酢酸エチ
ルで分配した。水層を１規定塩酸でｐＨ４に調整し、析
出した結晶をｐ取、乾燥して１．４ｇ（５６％）のジエ
チルＣ７−（２，３，４，５−テトラヒドロ−５−メチ
ル−３−オキソ−２Ｈ−ピリダジン−６−イル）キナゾ
リン−４−イル〕マロネート（化合物７０）を得た。Example 58 2.7 g of compound 58 obtained in Example 57)
IJ phenylphosphine 1.9g, potassium carbonate 5.7
12 g of a mixture of 20 ml of dimethylformamide
The mixture was stirred at 0°C for 3 hours. After cooling to room temperature, the mixture was partitioned between water and ethyl acetate. The aqueous layer was adjusted to pH 4 with 1N hydrochloric acid, and the precipitated crystals were collected and dried to give 1.4 g (56%) of diethyl C7-(2,3,4,5-tetrahydro-5-methyl-3- Oxo-2H-pyridazin-6-yl)quinazolin-4-yl]malonate (compound 70) was obtained.
実施例５９゜
実施例５８で得られる化合物７０ ０．７７ｇ、エタノ
ール２０ｍ１および２規定水酸化ナトリウム７、Ｏｍｌ
の混合物を９０℃で２時間攪拌した。濃縮し、■規定塩
酸で中和し、水−クロロホルムで分配した。有機層を乾
燥した後濃縮し、残渣をメタノールから結晶化すること
により、４，５−ジヒドロ−５−メチル−６−（４−メ
チルキナゾリン−７−イル）−３（２Ｈ）−ビリダジノ
ン（化合物５５）０．３４ｇ（７０％）を得た。Example 59゜ Compound 70 obtained in Example 58 0.77 g, ethanol 20 ml and 2N sodium hydroxide 7, Oml
The mixture was stirred at 90°C for 2 hours. It was concentrated, neutralized with normal hydrochloric acid, and partitioned between water and chloroform. The organic layer was dried and then concentrated, and the residue was crystallized from methanol to obtain 4,5-dihydro-5-methyl-6-(4-methylquinazolin-7-yl)-3(2H)-pyridazinone (compound 55) Obtained 0.34 g (70%).
実施例６０゜
参考例４で得られる化合物ｄ４．５ｇ、ピリジン４Ｑｍ
ｌおよび二硫化炭素５ｍｌの混合物を１００℃で４時間
攪拌した。水を加え析出した結晶をν取、乾燥し、４．
５−ジヒドロ−５−メチル−６−（２，４−ジメルカプ
トキナゾリン−７−イル）−３（２Ｈ）−ピリダジノン
（化合物６９） ５．５ｇ （８９％）を得た。Example 60゜ Compound d obtained in Reference Example 4 4.5 g, pyridine 4Qm
1 and 5 ml of carbon disulfide was stirred at 100° C. for 4 hours. 4. Add water, collect the precipitated crystals, and dry.
5.5 g (89%) of 5-dihydro-5-methyl-6-(2,4-dimercaptoquinazolin-7-yl)-3(2H)-pyridazinone (compound 69) was obtained.
実施例６１゜
実施例６０で得られる化合物６９０．９ｇをメタノール
３Ｑｍｌおよび２規定水酸化ナトリウム２１１１１に溶
解し、ヨウ化メチルＱ、４３ｍ１を加え室温で１時間攪
拌した。水を加え析出した結晶をｐ取、乾燥し、４．５
−ジヒドロ−５−メチル−６−Ｃ２，４−ビスメチルチ
オキナゾリン−７−イル）−３（２Ｈ）−ビリダジノン
（化合物５９） ０．８７ ｇ （８９％）を得た。Example 61° 690.9 g of the compound obtained in Example 60 was dissolved in 3 Q ml of methanol and 21,111 ml of 2N sodium hydroxide, 43 ml of methyl iodide Q was added, and the mixture was stirred at room temperature for 1 hour. Add water, collect the precipitated crystals, dry them, 4.5
-dihydro-5-methyl-6-C2,4-bismethylthioquinazolin-7-yl)-3(2H)-pyridazinone (compound 59) 0.87 g (89%) was obtained.
実施例６２゜
実施例６１で得られる化合物５９０．４０ｇを４０％メ
チルアミン−メタノール溶液５０ｍ１に懸濁し、６０℃
で３時間攪拌した。濃縮し、水を加え析出した結晶をｐ
取、乾燥し、４，５−ジヒドロ−５−メチル−６−（４
−メチルアミノ−２−メチルチオキナゾリン−７−イル
）−３（２Ｈ）−ビリダジノン（化合物６０） ０．３
４ ｇ （８９％）を得た。Example 62゜590.40 g of the compound obtained in Example 61 was suspended in 50 ml of 40% methylamine-methanol solution and heated at 60°C.
The mixture was stirred for 3 hours. Concentrate, add water and collect the precipitated crystals.
4,5-dihydro-5-methyl-6-(4
-Methylamino-2-methylthioquinazolin-7-yl)-3(2H)-pyridazinone (compound 60) 0.3
4 g (89%) were obtained.
実施例６３゜
実施例６２の４０％メチルアミン−メタノール溶液を４
０％ｎ−プロピルアミン−メタノール溶液に変更する以
外は同様の操作で４，５−ジヒドロ−５−メチル−６−
（２−メチルチオ−４−ｎ−プロピルアミノキナゾリン
−７−イル）−３（２Ｈ）−ビリダジノン（化合物６１
） ０．１２ ｇ （３９％）を得た。Example 63゜40% methylamine-methanol solution of Example 62
4,5-dihydro-5-methyl-6-
(2-Methylthio-4-n-propylaminoquinazolin-7-yl)-3(2H)-pyridazinone (compound 61
) 0.12 g (39%) was obtained.
実施例６４゜
実施例６３で得られる化合物６１０．４０ｇを５０％酢
酸２０ｍ１に溶解し５〜１０℃で過マンガン酸カリウム
０．５０ ｇを加え、１０分間攪拌した。水１００ｍ１
を加え２０ｍ１のクロロホルムで５回抽出した。Example 64 610.40 g of the compound obtained in Example 63 was dissolved in 20 ml of 50% acetic acid, and 0.50 g of potassium permanganate was added at 5 to 10°C, followed by stirring for 10 minutes. 100ml of water
was added and extracted five times with 20 ml of chloroform.
クロロホルム層を４０％メチルアミン−メタノール溶液
中に加え６０℃で１０時間攪拌した。濃縮し、水−クロ
ロホルムで分配し、有機層を乾燥した後濃縮した。残渣
をジメチルホルムアミド−水から結晶化し、０．２７ｇ
（６９％）の４．５−ジヒドロ−５−メチル−６−（２
−メチルアミノ−４−ｎ−プロピルアミノキナゾリン−
７−イル）−３（２Ｈ）−ビリダジノン（化合物６２）
を得た。The chloroform layer was added to a 40% methylamine-methanol solution and stirred at 60°C for 10 hours. It was concentrated, partitioned between water and chloroform, and the organic layer was dried and concentrated. The residue was crystallized from dimethylformamide-water, 0.27 g
(69%) of 4,5-dihydro-5-methyl-6-(2
-Methylamino-4-n-propylaminoquinazoline-
7-yl)-3(2H)-pyridazinone (compound 62)
I got it.
実施例６５゜
参考例４で得られる化合物ｄ３．Ｏｇをピリジン３Ｑｍ
ｌに溶解しアセチルクロリド３ｍｌを加え８０℃で３時
間攪拌した。濃縮し、水−クロロホルムで分配したのち
有機層を濃縮した。残渣にメタノール５ Ｑｍｌ、水５
０ｍ１および炭酸カリウム２．０ｇを加え８０℃で３時
間攪拌した。濃縮し、析出してきた結晶をｐ取、乾燥し
１．１ｇ（２８％）の４．５−ジヒドロ−６−（４−メ
トキシ−２−メチルキナゾリン−７−イル）−５−メチ
ル−３（２Ｈ）−ビリダジノン（化合物６３）を得た。Example 65 Compound d3 obtained in Reference Example 4. Og to pyridine 3Qm
3 ml of acetyl chloride was added thereto, and the mixture was stirred at 80° C. for 3 hours. After concentration and partitioning between water and chloroform, the organic layer was concentrated. Add 5 Qml of methanol and 5 Qml of water to the residue.
0ml and 2.0g of potassium carbonate were added and stirred at 80°C for 3 hours. The precipitated crystals were collected and dried to give 1.1 g (28%) of 4.5-dihydro-6-(4-methoxy-2-methylquinazolin-7-yl)-5-methyl-3( 2H)-pyridazinone (compound 63) was obtained.
実施例６６゜
実施例６５で得られる化合物６３０．５０ｇを４０％メ
チルアミン−メタノール２０ｍ１に懸濁し、加熱還流下
に４時間攪拌した。濃縮し、残渣に水−クロロホルムを
加え分配し、有機層を乾燥した後濃縮した。残渣をジメ
チルホルムアミド−水から結晶化し、０．３８ｇ（７６
％）の４．５−ジヒドロ−５−メチル−６−（４−メチ
ルアミノ−２−メチルキナゾリン−７−イル）−３（２
Ｈ）−ビリダジノン（化合物６４）を得た。Example 66 630.50 g of the compound obtained in Example 65 was suspended in 20 ml of 40% methylamine-methanol and stirred under heating under reflux for 4 hours. The mixture was concentrated, water and chloroform were added to the residue for partitioning, and the organic layer was dried and concentrated. The residue was crystallized from dimethylformamide-water to yield 0.38 g (76
%) of 4.5-dihydro-5-methyl-6-(4-methylamino-2-methylquinazolin-7-yl)-3(2
H)-pyridazinone (compound 64) was obtained.
実施例６７
実施例６６で得られる化合物６４ ０．７６ｇ、ベンジ
ルアミンｌ ５＋＋＋１およびジメチルスルホキシド１
５ｍ１の混合物を１５０℃で３時間攪拌した。濃縮し、
残渣を水−クロロホルムで分配し有機層を乾燥した後濃
縮した。残渣を１００ｇのシリカゲルカラムで精製し０
．３１ｇ（３２％）の６−（４−ベンジルアミノ−２−
メチルキナゾリン−７−イル）４．５−ジヒドロ−５−
メチル−３（２Ｈ）−ビリダジノン（化合物６５）を得
た。Example 67 0.76 g of compound 64 obtained in Example 66, 5+++1 benzylamine and 1 dimethyl sulfoxide
5ml of the mixture was stirred at 150°C for 3 hours. concentrate,
The residue was partitioned between water and chloroform, and the organic layer was dried and concentrated. The residue was purified with a 100g silica gel column to 0.
．． 31 g (32%) of 6-(4-benzylamino-2-
Methylquinazolin-7-yl)4,5-dihydro-5-
Methyl-3(2H)-pyridazinone (compound 65) was obtained.
実施例６８゜
参考例６で得られる化合物ｒ０．３０ｇをジメチルスル
ホキシド５ｍｌに溶解し１５０℃に加熱した。アンモニ
アガスを通気しながら２時間攪拌した。水を加え析出し
てきた結晶をｐ取、乾燥し０．２ｇ（７４％）の６−（
４−アミノ−１，２−ジヒドロ−２−オキソ−ＩＨ−キ
ナゾリン−７−イル）−４，５−ジヒドロ−５−メチル
−３（２Ｈ）ビリダジノン（化合物６６）を得た。Example 68 0.30 g of the compound r obtained in Reference Example 6 was dissolved in 5 ml of dimethyl sulfoxide and heated to 150°C. The mixture was stirred for 2 hours while bubbling ammonia gas. After adding water, the precipitated crystals were collected and dried, and 0.2 g (74%) of 6-(
4-Amino-1,2-dihydro-2-oxo-IH-quinazolin-7-yl)-4,5-dihydro-5-methyl-3(2H)pyridazinone (Compound 66) was obtained.
実施例６９゜
実施例６８でアンモニアガスの代わりに４０％メチルア
ミン−メタノール溶液１ｍｌを滴下する以外は全く同様
の操作で４．５−ジヒドロ−６−（１，２゜３．４−テ
トラヒドロ−４−イミノ−３−メチル−２−オキソ−Ｉ
Ｈ，３Ｈ−キナゾリン−７−イル）−５−メチル−３（
２Ｈ）−ビリダジノン（化合物６７） ０．２１ｇ （
７４％）を得た。Example 69゜4,5-dihydro-6-(1,2゜3.4-tetrahydro- 4-Imino-3-methyl-2-oxo-I
H,3H-quinazolin-7-yl)-5-methyl-3(
2H)-pyridazinone (compound 67) 0.21g (
74%).
実施例７０゜
実施例６８でアンモニアガスの代りにエチレンジアミン
１ｍｌを加える以外は全く同様の操作で４．５−ジヒド
ロ−６−（２，３−ジヒドロ−５−オキソ６Ｈ−イミダ
ゾ（１，２−ｃ）キナゾリン−８−イル）−５−メチル
−３（２Ｈ）−ピリダジノン（化合物６８） ０．２０
ｇ （６７％）を得た。Example 70° 4,5-dihydro-6-(2,3-dihydro-5-oxo6H-imidazo(1,2- c) Quinazolin-8-yl)-5-methyl-3(2H)-pyridazinone (Compound 68) 0.20
g (67%) was obtained.
実施例７１゜
実施例１９で得られる化合物５７１．０ｇをジメチルホ
ルムアミド１０ｍ１に溶解し、ラネーニッケル５、Ｏｇ
を加え６０℃で１時間攪拌した。触媒を濾過によって除
きＰ液を濃縮した。残渣に水を加え析出した結晶をｐ取
、乾燥し、０．２２ｇ（２６％）の４，５−ジヒドロ−
６−（３，４−ジヒドロキナゾリン−７−イル）−５−
メチル−３（２Ｈ）−ビリダジノン（化合物７１）を得
た。Example 71゜571.0 g of the compound obtained in Example 19 was dissolved in 10 ml of dimethylformamide, and Raney nickel 5, Og
was added and stirred at 60°C for 1 hour. The catalyst was removed by filtration, and the P solution was concentrated. Water was added to the residue, and the precipitated crystals were collected and dried to give 0.22 g (26%) of 4,5-dihydro-
6-(3,4-dihydroquinazolin-7-yl)-5-
Methyl-3(2H)-pyridazinone (compound 71) was obtained.
実施例７２゜
実施例７１で得られる化合物７１０．２５ｇをクロロホ
ルム２Ｑｍｌに溶解し、二酸化マンガン２．０ｇを加え
室温で１時間攪拌した。不溶物を濾過によって除き、ｐ
液を濃縮した。残渣にジエチルエーテルを加え結晶化し
、０．２ｇ（８３％）の４，５−ジヒドロ−５−メチル
−６−（７−キナゾリニル）−３（２Ｈ）−ビリダジノ
ン（化合物５４）を得た。Example 72 710.25 g of the compound obtained in Example 71 was dissolved in 2 Q ml of chloroform, 2.0 g of manganese dioxide was added, and the mixture was stirred at room temperature for 1 hour. Insoluble matter is removed by filtration, p
The liquid was concentrated. Diethyl ether was added to the residue for crystallization to obtain 0.2 g (83%) of 4,5-dihydro-5-methyl-6-(7-quinazolinyl)-3(2H)-pyridazinone (Compound 54).
実施例７３゜
実施例６のシクロプロピルアミンをエチレンジアミン３
ｍｌに変更する以外は同様の操作で０．６ｇ（６１％）
の４．５−ジヒドロ−（２，３−ジヒドロイミダゾＣ１
，２−Ｃ）キナゾリン−８−イル）−５−メチル−３（
２Ｈ）−ビリダジノン（化合物７２）を得た。Example 73゜The cyclopropylamine of Example 6 was converted into ethylenediamine 3
0.6g (61%) using the same procedure except changing to ml
4,5-dihydro-(2,3-dihydroimidazoC1
,2-C)quinazolin-8-yl)-5-methyl-3(
2H)-pyridazinone (compound 72) was obtained.
実施例７４゜
実施例１０で得られる化合物１００．３５ｇおよびオル
トギ酸エチルｌ Ｑｍｌの混合物を１５０℃で３時間攪
拌した。濃縮し、残渣に水を加え析出した結晶をＰ取、
乾燥し、０．２８ｇ（７７％）の４．５ジヒドロ−５−
メチル−５−（ｓ−）リアゾロ（１，５−Ｃ）キナゾリ
ン−９−イル）−３（２Ｈ）−ピリダジノン（化合物７
３）を得た。Example 74 A mixture of 100.35 g of the compound obtained in Example 10 and 1 Qml of ethyl orthoformate was stirred at 150°C for 3 hours. Concentrate, add water to the residue, collect the precipitated crystals,
Dry, 0.28g (77%) of 4.5dihydro-5-
Methyl-5-(s-)riazolo(1,5-C)quinazolin-9-yl)-3(2H)-pyridazinone (compound 7
3) was obtained.
実施例７５゜
参考例１１で得られる化合物ｋ ｏ、３０ｇを４０％メ
チルアミン−メタノール溶液１０１′ｎｌに溶解し、室
温で１時間攪拌した。析出してきた結晶をｐ取、乾燥し
４．５−ジヒドロ−６−〔３−メチル−４（３Ｈ）−キ
ナゾリンイミン−７−イル〕−３（２Ｈ）−ビリダジノ
ン（化合物７４）０．２３ｇ（８２％）を得た。Example 75 30g of the compound ko obtained in Reference Example 11 was dissolved in 101'nl of a 40% methylamine-methanol solution and stirred at room temperature for 1 hour. The precipitated crystals were collected and dried to give 0.23 g of 4.5-dihydro-6-[3-methyl-4(3H)-quinazolinimin-7-yl]-3(2H)-pyridazinone (compound 74). 82%).
実施例７６゜
実施例７５で得られる化合物７４ ０．１６ｇ、４０％
メチルアミン−メタノール溶液１ Ｑｍｌ右よびジメチ
ルホルムアミドｌ Ｑｍｌの混合物を還流下３時間攪拌
した。冷却し析出してきた結晶をｐ取、乾燥して、４．
５−ジヒドロ−６−（４−メチルアミノキナゾリン−７
−イル）−３（２Ｈ）−ビリダジノン（化合物７５）
０．０８ ｇ （４４％〉を得た。Example 76゜ Compound 74 obtained in Example 75 0.16 g, 40%
A mixture of 1 Qml of methylamine-methanol solution and 1 Qml of dimethylformamide was stirred under reflux for 3 hours. After cooling, the precipitated crystals were collected and dried. 4.
5-dihydro-6-(4-methylaminoquinazoline-7
-yl)-3(2H)-pyridazinone (compound 75)
0.08 g (44%) was obtained.
実施例７７゜
実施例１８の化合物ｅを参考例１１で得られる化合物に
０．６７ｇに変更する以外は同様の操作で４゜５−ジヒ
ドロ−６−（４−メルカプトキナゾリン＝７−イル）−
３（２Ｈ）−ビリダジノン（化合物７６） ０．４９
ｇ （７７％）を得た。Example 7 7゜4゜5-dihydro-6-(4-mercaptoquinazolin=7-yl)-
3(2H)-pyridazinone (compound 76) 0.49
g (77%) was obtained.
実施例７８゜
実施例１９の化合物５６を実施例７８で得られる化合物
７６０．１０ｇに変更する以外は同様の操作で４．５−
ジヒドロ−６−（４−メチルチオキナゾリン−７−イル
）−３（２Ｈ）−ビリダジノン（化合物７７） ０．１
０ ｇ （９５％）を得た。Example 78゜4.5-
Dihydro-6-(4-methylthioquinazolin-7-yl)-3(2H)-pyridazinone (compound 77) 0.1
0 g (95%) was obtained.
実施例７９゜
実施例３６の化合物５７を実施例７８で得られる化合物
７７０．２９ｇに変更する以外は同様の操作で、６−（
４−ベンジルアミノキナゾリン−７−イル）−４，５−
ジヒドロ−３（２Ｈ）−ビリダジノン（化合物７８）
０．０６ ｇ （１７％）を得た。Example 79゜6-(
4-Benzylaminoquinazolin-7-yl)-4,5-
Dihydro-3(2H)-pyridazinone (compound 78)
0.06 g (17%) was obtained.
参考例１゜
発煙硝酸３００ｍｌ中で内温１０〜２０℃に保ちながら
３−（４−ブロモベンゾイル）酪酸５１ｇを少しずつ加
え２時間攪拌した。反応液を氷水ｌｌ中に注ぎクロロホ
ルムで抽出した。クロロホルム層は水で洗浄し濃縮した
。残渣を水より結晶化し、３−（４−ブロモ−３−二ト
ロベンゾイル）酪酸〔化合物（ＩＶ） ：Ｒ，＝ＣＨ
，、化合物ａ〕４６ｇ（７７％）を得た。Reference Example 1 51 g of 3-(4-bromobenzoyl)butyric acid was added little by little to 300 ml of fuming nitric acid while keeping the internal temperature at 10 to 20° C. and stirred for 2 hours. The reaction solution was poured into 1 liter of ice water and extracted with chloroform. The chloroform layer was washed with water and concentrated. The residue was crystallized from water to give 3-(4-bromo-3-nitrobenzoyl)butyric acid [Compound (IV): R,=CH
, Compound a] 46 g (77%) was obtained.
融点：１１１〜１１３℃
Ｉ Ｒ（ＫＢｒ） ｃｒ’ ：１７００． １６９０．
１６０ＯＮＭＲ（ＣＤＣ１３） １１Ｉ）ｍ ： ８
．３．７．肌３．８゜３．０．２．５． １．２
参考例２゜
参考例１で得られる化合物ａ ５２ｇを酢酸３００ｍ
１とヒドラジン・１水和物５２ｍ１の混合物に加え１０
０℃で３時間攪拌した。約１７３容最まで濃縮し、水５
０ Ｑｍｌを加え析出した結晶を戸数、乾燥１、．６−
（４−ブロモ−３−二トロフェニル）４．５−ジヒド
ロ−５−メチル−３（２Ｈ）−ビリダジノン〔化合物（
Ｖ） ；Ｌ＝Ｃ＋ｂ 、化合物ｂ〕５４ｇ （１０
０％）を得た。Melting point: 111-113°C IR(KBr) cr': 1700. 1690.
160ONMR (CDC13) 11I)m: 8
．． 3.7. Skin 3.8°3.0.2.5. 1.2 Reference Example 2゜52g of compound a obtained in Reference Example 1 was added to 300ml of acetic acid.
1 and 52 ml of hydrazine monohydrate and add 10
The mixture was stirred at 0°C for 3 hours. Concentrate to approximately 173 volumes, and add 5 liters of water.
0 Qml was added and the precipitated crystals were dried for 1 hour. 6-
(4-Bromo-3-nitrophenyl)4.5-dihydro-5-methyl-3(2H)-pyridazinone [Compound (
V); L=C+b, compound b] 54 g (10
0%) was obtained.
融点＝１９６℃
Ｉ Ｒ（ＫＢｒ） ｃｎ−’ ：１７２０．１６２０．
１５４ＯＮＭＲ（ＣＤＣｌ ３） ｐｐｍ ： １１．
２，８Ｊ、 ８．０゜３．４．２．８．２．３．１．１
参考例３゜
参考例２で得られる化合物ｂ １９ｇをジメチルホル
ムアミド１０ Ｑｍｌに溶解し、シアン化第−銅６．７
ｇを加え、１１０℃で２時間攪拌した。反応液を冷却し
エチレンジアミン３０ｍ１−水２０ Ｑｍｌの混合物中
に注ぎ、不溶物は濾過して除いた。ｐ液を水−クロロホ
ルムで分配し、クロロホルム層を乾燥後濃縮した。残渣
をクロロホルム−ジエチルエーテルより結晶化し、６−
（４−シアノ−３ニトロフエニル）−４，５−ジヒド
ロ−５−メチル−３（２Ｈ）−ピリダジノン〔化合物（
■） ：Ｒ，＝Ｃ）ｌ、 ；化合物ｃ） ６．９ ｇ
（４４％）を得た。Melting point = 196°C IR(KBr) cn-': 1720.1620.
154ONMR (CDCl3) ppm: 11.
2,8J, 8.0° 3.4.2.8.2.3.1.1 Reference Example 3° 19 g of compound b obtained in Reference Example 2 was dissolved in 10 Qml of dimethylformamide, and cupric cyanide was dissolved. 6.7
g was added thereto, and the mixture was stirred at 110°C for 2 hours. The reaction solution was cooled and poured into a mixture of 30 ml of ethylenediamine and 20 Qml of water, and insoluble materials were removed by filtration. The p solution was partitioned between water and chloroform, and the chloroform layer was dried and concentrated. The residue was crystallized from chloroform-diethyl ether to give 6-
(4-cyano-3nitrophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone [Compound (
■) :R,=C)l, ;Compound c) 6.9 g
(44%).
融点：２０８〜２０９℃
ＩＲ（にＢｒ） ａｍ−’ ：２２１０．１６８０．１
６０ＯＮＭＲ（ＣＤＣＩ３） Ｉ）ｌ１ｍ ： １１．
４．８．７．８．３゜３．５．２．８．２．３．１．１
参考例４゜
濃塩酸４ｍｌおよび塩化第１錫・２水和物１．４ｇの混
合物を氷冷し、参考例３で得られる化合物ＣＯ，５２ｇ
を加え１０分間攪拌した。５規定水酸化ナトリウムでｐ
Ｈを１０に調整し、析出した結晶を戸数した。結晶をジ
メチルホルムアミドに溶解し不溶物はと過によって除き
ｐ液を濃縮した。残渣に水を加え結晶化し、６−（３−
アミノ−４−シアノフェニル）−４，５−ジヒドロ−５
−メチル−３（２Ｈ）−ピリダジノン〔化合物（Ｉｌａ
）：Ｒ，＝ＣＨ，；化合物ｄ） ０．４ ｇ （８７％
）を得た。Melting point: 208-209°C IR (Br) am-': 2210.1680.1
60ONMR (CDCI3) I) l1m: 11.
4.8.7.8.3゜3.5.2.8.2.3.1.1 Reference Example 4゜A mixture of 4 ml of concentrated hydrochloric acid and 1.4 g of stannous chloride dihydrate was cooled on ice. Compound CO obtained in Reference Example 3, 52 g
was added and stirred for 10 minutes. p with 5N sodium hydroxide
H was adjusted to 10, and the precipitated crystals were counted. The crystals were dissolved in dimethylformamide, insoluble materials were removed by filtration, and the p solution was concentrated. Water was added to the residue to crystallize it, and 6-(3-
Amino-4-cyanophenyl)-4,5-dihydro-5
-Methyl-3(2H)-pyridazinone [Compound (Ila
):R,=CH,; Compound d) 0.4 g (87%
) was obtained.
融点：２０８〜２０９℃
Ｉ Ｒ（ＫＢｒ） ｃＩＩ＋−’ ：２２００． １
６８０． １６４ＯＮＭＲ（ＤＭＳＯ−ｄｓ） ｐｐ
ｍ ： １１．０． ７．４゜７２、 ７．０． ６
．１． ３．２． ２．７． ２．３． １．１参考例
５゜
参考例４で得られる化合物ｄ Ｉｇにオルトギ酸エチ
ルｌ Ｑｍｌおよびジメチルホルムアミド１ｍｌを加え
還流下５時間攪拌した。濃縮し、残渣をエタノール−ジ
エチルエーテルより結晶化し、６−（４−シアノ−３−
エトキシメチレンアミノフェニル）−４，５−ジヒドロ
−５−メチル−３（２Ｈ）ビリダジノン〔化合物（ＩＩ
ｂ） ：Ｒ３＝ＣＨａ 、Ｒ４＝Ｈ、Ｒ，−Ｃ，Ｈ
，；化合物ｅ） ０．３ ｇ （２４％）を得た。Melting point: 208-209°C IR(KBr) cII+-': 2200. 1
680. 164ONMR (DMSO-ds) pp
m: 11.0. 7.4°72, 7.0. 6
．． 1. 3.2. 2.7. 2.3. 1.1 Reference Example 5 To the compound d Ig obtained in Reference Example 4 were added 1 Qml of ethyl orthoformate and 1 ml of dimethylformamide, and the mixture was stirred under reflux for 5 hours. The residue was crystallized from ethanol-diethyl ether to give 6-(4-cyano-3-
ethoxymethyleneaminophenyl)-4,5-dihydro-5-methyl-3(2H)pyridazinone [Compound (II
b) :R3=CHa, R4=H, R, -C,H
, ; Compound e) 0.3 g (24%) was obtained.
融点＝１５０〜１５２℃
Ｉ Ｒ（ＫＢｒ） ｃｒ’ ：２２１０． １６８０．
１６３ＯＮＭＲ（ＤＭＳＯ−ｄ６） １１１）ｍ ：
１１．２．８．１゜７．８．７，７．７，５．４．３
．３．４．２．７．２．３． １．４゜１．１
参考例６゜
参考例４で得られる化合物ｄ４．５ｇ、クロルギ酸エチ
ル２．３ｍｌおよびピリジン４０ｍ１の混合物を室温で
３０分間攪拌した。濃縮し、水を加え析出した結晶を戸
数、乾燥し、４−（２，３，４，５−テトラヒドロ−５
−メチル−３−オキソ−２Ｈ−ピリダジン−６−イル）
−Ｎ−エトキシ力ルポニルアンスラニロニトリル〔化合
物（ｎｃ） ：Ｒ，＝ＣＨ，、Ｒ７＝ Ｃ２Ｈｓ ；
化合物ｆ）３．０ｇ（５０％）を得た。Melting point = 150-152°C IR(KBr) cr': 2210. 1680.
163ONMR (DMSO-d6) 111)m:
11.2.8.1゜7.8.7, 7.7, 5.4.3
．． 3.4.2.7.2.3. 1.4゜1.1 Reference Example 6゜A mixture of 4.5 g of compound d obtained in Reference Example 4, 2.3 ml of ethyl chloroformate and 40 ml of pyridine was stirred at room temperature for 30 minutes. After concentrating, adding water and drying the precipitated crystals, 4-(2,3,4,5-tetrahydro-5
-methyl-3-oxo-2H-pyridazin-6-yl)
-N-Ethoxyluponyl anthranilonitrile [Compound (nc): R, = CH,, R7 = C2Hs;
3.0 g (50%) of compound f) was obtained.
融点：１９８〜２００℃
Ｉ Ｒ（ＫＢｒ） ｃ＋＋＋−’ ：２２００．１７４
０．１６７ＯＮＭＲ（ＤＭＳＯ−ｄ、） ｐｐｍ ：
１１．１．９．８゜８．９．８．８．８．７．４．２．
２．８．２．３．１．２．１．１参考例７゜
参考例１の３−（４−ブロモベンゾイル）酪酸１− （
４−ブロモベンゾイル）フロピオン酸１０、０ ｇに変
更する以外は同様の操作で３−（４−フロモー３−二ト
ロベンゾイル）プロピオン酸〔化合物（ＩＶ） ：Ｒ
，＝Ｈ；化合物ｇ） ７．１ ｇ （５９％）を得た。Melting point: 198-200°C IR (KBr) c+++-': 2200.174
0.167ONMR (DMSO-d,) ppm:
11.1.9.8゜8.9.8.8.8.7.4.2.
2.8.2.3.1.2.1.1 Reference Example 7゜Reference Example 1 3-(4-bromobenzoyl)butyric acid 1-(
3-(4-bromo-3-nitrobenzoyl)propionic acid [Compound (IV): R
,=H; 7.1 g (59%) of compound g) was obtained.
融点：１４５〜１４７℃
Ｉ Ｒ（ＫＢｒ） Ｃｔａ−’ ： １６９０．１６０
ＯＮＭＲ（ＤＭＳＯｄｓ） ｐｐｍ ： ８．５．８．
１．３Ｊ、 ２．６参考例８゜
参考例２の化合物ａを参考例７で得られる化合物ｇ
１３．８ｇに変更する以外は同様の操作で６−（４−ブ
ロモ−３−ニトロフェニル）−４，５−ジヒドロ−３（
２Ｈ）−ビリダジノン〔化合物（Ｖ）：Ｒ３＝Ｈ；化合
物ｈ） ５．３ ｇ （３７％）を得た。Melting point: 145-147°C IR(KBr) Cta-': 1690.160
ONMR (DMSOds) ppm: 8.5.8.
1.3J, 2.6 Reference Example 8゜Compound a of Reference Example 2 was converted to compound g obtained in Reference Example 7
6-(4-bromo-3-nitrophenyl)-4,5-dihydro-3(
5.3 g (37%) of 2H)-pyridazinone [compound (V): R3=H; compound h) was obtained.
融点：２０１〜２０４℃
Ｉ Ｒ（ＫＢｒ） ｃ＋１−’ ： １７００．１６２
ＯＮＭＲ（ＤＭＳＯ−ｄｉ） Ｉ）Ｉｌｌｆｆｌ ：
１１．１．８．３．７．９゜３．０．２．５
参考例９゜
参考例３の化合物すを参考例８で得られる化合物ｈ５．
１ｇに変更する以外は同様の操作で６−（４−シアノ−
３−二トロフェニル）−４，５−ジヒドロ−３（２Ｈ）
−ビリダジノン〔化合物（Ｖｌ）：Ｒ，＝Ｈ；化合物ｉ
ｌｌ ３．４ ｇ （８１％）を得た。Melting point: 201-204°C IR (KBr) c+1-': 1700.162
ONMR (DMSO-di) Illffl:
11.1.8.3.7.9゜3.0.2.5 Reference Example 9゜Compound h5.
6-(4-cyano-
3-nitrophenyl)-4,5-dihydro-3(2H)
-Viridazinone [Compound (Vl): R, =H; Compound i
3.4 g (81%) was obtained.
融点：２３５〜２４１℃
Ｉ Ｒ（ＫＢｒ） ｃｍ７’ ：２２１０． １６８
０． １６０ＯＮＭＲ（ＤＭＳＯ−ｄＪ ｐｐｍ ：
１１．１． ８．６． ８．２゜３．１，２．５
参考例１０゜
参考例４の化合物Ｃを参考例９で得られる化合物ｉ３．
３ｇに変更する以外は同様の操作で６−（３−アミノ−
４−シアノフェニル）−４，５−ジヒドロ−３（２Ｈ）
−ビリダジノン〔化合物（ＩＩ ａ）：Ｒ３＝Ｈ；化合
物ｊ：１１．１ｇ（３８％）を得た。Melting point: 235-241°C IR (KBr) cm7': 2210. 168
0. 160ONMR (DMSO-dJ ppm:
11.1. 8.6. 8.2° 3.1, 2.5 Reference Example 10° Compound C of Reference Example 4 was mixed with Compound i3. obtained in Reference Example 9.
6-(3-amino-
4-cyanophenyl)-4,5-dihydro-3(2H)
-Biridazinone [Compound (II a): R3=H; Compound j: 11.1 g (38%) was obtained.
融点：２５４〜２５７℃
Ｉ Ｒ（ＫＢｒ） ｃ＋ｓ−’ ：２２１０．１６８０
．１６４ＯＮＭＲ（ＤＭＳＯ−ｄｏ） ｐｐｍ ： １
１．１．７．４゜？、１．６．肌６．１．２．９．２．
４参考例１１゜
参考例５の化合物ｄを参考例１０で得られる化合物ｊ１
．１ｇに変更する以外は同様の操作で６（４−シアノ−
３−エトキシメチレンアミノフェニル）−４，５−ジヒ
ドロ−３（２Ｈ）−ビリダジノン〔化合物（ｎ ｂ）
：Ｒ３＝Ｈ，Ｒ４＝Ｈ，Ｒｔ＝ＣＪｓ：化合物ｋ）
１．０ ｇ （７２％）を得た。Melting point: 254-257°C IR (KBr) c+s-': 2210.1680
．． 164ONMR (DMSO-do) ppm: 1
1.1.7.4°? , 1.6. Skin 6.1.2.9.2.
4 Reference Example 11゜Compound d of Reference Example 5 was converted to compound j1 obtained in Reference Example 10
．． 6 (4-cyano-
3-Ethoxymethyleneaminophenyl)-4,5-dihydro-3(2H)-pyridazinone [Compound (n b)
:R3=H, R4=H, Rt=CJs: compound k)
1.0 g (72%) was obtained.
融点：１７２℃
Ｉ Ｒ（ＫＢｒ） Ｃｓ−’ ：２２１０． １６８
０． １６４ＯＮＭＲ（ＤＭＳＯ−ｄｓ） ｐｐｍ ：
１１．０． ８．１． ７．８゜７．６．７．５．
４．３．３．０． ２．５． １．３参考例１２゜
化合物１２ １０重景部重質酸化マグネ
シウム １０ 〃
乳糖 ８０〃
を均一に混合して粉末または細粒状とし散剤とする。Melting point: 172°C IR(KBr) Cs-': 2210. 168
0. 164ONMR (DMSO-ds) ppm:
11.0. 8.1. 7.8°7.6.7.5.
4.3.3.0. 2.5. 1.3 Reference Example 12 Compound 12 10 heavy magnesium oxide 10 lactose 80 are mixed uniformly into a powder or fine granules to form a powder.
発明の効果
本発明の化合物（１）およびその薬理的に許容される塩
は、優れた強心作用を示し強心剤として有用である。Effects of the Invention The compound (1) of the present invention and its pharmacologically acceptable salts exhibit excellent cardiotonic action and are useful as cardiotonic agents.
Claims (1)
式、表等があります▼〔式中、Ｒ＿ａは水素、低級アル
キル、−ＮＲ＿１Ｒ＿２〔式中、Ｒ＿１およびＲ＿２は
同一または異なって、水素、置換もしくは非置換の低級
アルキル、脂環式アルキル、低級アルケニル、置換もし
くは非置換のアラルキル、置換もしくは非置換のアリー
ル、アミノ、低級アルコキシカルボニルアミノ、 ▲数式、化学式、表等があります▼（式中、ｍは１また
は２である） またはＲ＿１とＲ＿２が一緒になってＮを含んで形成さ
れる複素環基を表わす〕、ヒドロキシル、低級アルルコ
キシル、メルカプト、低級アルキルチオまたは−ＳＣＨ
（ＣＯＯＲ＿５）＿２（式中、Ｒ＿５は低級アルキルを
表わす）を表わす〕；▲数式、化学式、表等があります
▼〔式中、Ｒ＿ｂは酸素原子、硫黄原子、Ｃ（ＣＯＯＲ
＿５）＿２（式中、Ｒ＿５は前記と同義である）または
ＮＲ＿１＿ａを表わし、Ｒ＿１＿ａおよびＲ＿２＿ａは
同一または異なって、水素、置換もしくは非置換の低級
アルキル、脂環式アルキル、低級アルケニル、置換もし
くは非置換のアラルキル、置換もしくは非置換のアリー
ル、アミノ、低級アルコキシカルボニルアミノまたは ▲数式、化学式、表等があります▼（式中、ｍは前記と
同義である） を表わす〕；▲数式、化学式、表等があります▼（式中
、ｎは２または ３である）または▲数式、化学式、表等があります▼（
式中、Ｒ＿６は水素または低級アルキルを表わす）を表
わし、Ｒ＿３は、水素または低級アルキルを表わし、Ｒ
＿４は、水素、置換もしくは非置換の低級アルキル、ヒ
ドロキシル、低級アルコキシル、メルカプト、低級アル
キルチオまたは−ＮＲ＿１Ｒ＿２（式中、Ｒ＿１および
Ｒ＿２は前記と同義である）を表わす｝で表わされるピ
リダジノン誘導体およびその薬理的に許容される酸付加
塩。[Claims] Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ {In the formula, X-Y is -CH_2-NH-; ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_a is hydrogen, lower alkyl, -NR_1R_2 [wherein R_1 and R_2 are the same or different, hydrogen, substituted or unsubstituted lower alkyl, alicyclic alkyl, lower alkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, Amino, lower alkoxycarbonylamino, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, m is 1 or 2) or R_1 and R_2 together represent a heterocyclic group containing N. ], hydroxyl, lower alkoxyl, mercapto, lower alkylthio or -SCH
(COOR_5)_2 (in the formula, R_5 represents lower alkyl); ▲ Numerical formulas, chemical formulas, tables, etc. are available. ▼ [In the formula, R_b is an oxygen atom, a sulfur atom,
_5)_2 (in the formula, R_5 has the same meaning as above) or NR_1_a, and R_1_a and R_2_a are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, alicyclic alkyl, lower alkenyl, substituted or unsubstituted Substituted aralkyl, substituted or unsubstituted aryl, amino, lower alkoxycarbonylamino, or ▲Represents a mathematical formula, chemical formula, table, etc.▼ (in the formula, m has the same meaning as above); ▲Mathematical formula, chemical formula, table, etc. There are ▼ (in the formula, n is 2 or 3) or ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ (
In the formula, R_6 represents hydrogen or lower alkyl), R_3 represents hydrogen or lower alkyl, and R
_4 represents hydrogen, substituted or unsubstituted lower alkyl, hydroxyl, lower alkoxyl, mercapto, lower alkylthio, or -NR_1R_2 (wherein R_1 and R_2 have the same meanings as above); and their pharmacology. Acceptable acid addition salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP705589A JPH0222274A (en) | 1988-01-23 | 1989-01-13 | Pyridazinone derivative |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1330188 | 1988-01-23 | ||
| JP63-13301 | 1988-01-23 | ||
| JP705589A JPH0222274A (en) | 1988-01-23 | 1989-01-13 | Pyridazinone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0222274A true JPH0222274A (en) | 1990-01-25 |
Family
ID=26341299
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP705589A Pending JPH0222274A (en) | 1988-01-23 | 1989-01-13 | Pyridazinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0222274A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002535391A (en) * | 1999-01-27 | 2002-10-22 | ファイザー・プロダクツ・インク | Substituted bicyclic derivatives useful as anticancer agents |
| JP2009079029A (en) * | 2007-09-25 | 2009-04-16 | Medical & Pharmaceutical Industry Technology & Development Center | USE OF 2-[PIPERIDINYL]METHYL-2,3-DIHYDROIMIDAZO[1,2-c]QUINAZOLIN-5(6H)-ONE FOR PROVIDING ANALGESIC EFFECT, ANTI-ALLERGIC EFFECT AND HISTAMINE H1 RECEPTOR ANTAGONISM EFFECT |
-
1989
- 1989-01-13 JP JP705589A patent/JPH0222274A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002535391A (en) * | 1999-01-27 | 2002-10-22 | ファイザー・プロダクツ・インク | Substituted bicyclic derivatives useful as anticancer agents |
| JP2009079029A (en) * | 2007-09-25 | 2009-04-16 | Medical & Pharmaceutical Industry Technology & Development Center | USE OF 2-[PIPERIDINYL]METHYL-2,3-DIHYDROIMIDAZO[1,2-c]QUINAZOLIN-5(6H)-ONE FOR PROVIDING ANALGESIC EFFECT, ANTI-ALLERGIC EFFECT AND HISTAMINE H1 RECEPTOR ANTAGONISM EFFECT |
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