JPH01250383A - Benzothiepino(5,4-c)pyridazine compound - Google Patents
Benzothiepino(5,4-c)pyridazine compoundInfo
- Publication number
- JPH01250383A JPH01250383A JP63048464A JP4846488A JPH01250383A JP H01250383 A JPH01250383 A JP H01250383A JP 63048464 A JP63048464 A JP 63048464A JP 4846488 A JP4846488 A JP 4846488A JP H01250383 A JPH01250383 A JP H01250383A
- Authority
- JP
- Japan
- Prior art keywords
- benzothiepino
- pyridazin
- tetrahydro
- compound
- alkyl
- 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.)
- Granted
Links
- -1 Benzothiepino(5,4-c)pyridazine compound Chemical class 0.000 title claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 abstract description 66
- 239000002249 anxiolytic agent Substances 0.000 abstract description 8
- 239000002253 acid Substances 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 4
- 150000002429 hydrazines Chemical class 0.000 abstract description 3
- SWLXVSYLXDKJDB-UHFFFAOYSA-N 2-phenyl-4,4a,5,6-tetrahydro-[1]benzothiepino[5,4-c]pyridazin-3-one Chemical compound O=C1CC2CCSC3=CC=CC=C3C2=NN1C1=CC=CC=C1 SWLXVSYLXDKJDB-UHFFFAOYSA-N 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 2
- 239000000463 material Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 73
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 61
- 238000002844 melting Methods 0.000 description 48
- 230000008018 melting Effects 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000012360 testing method Methods 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 230000000694 effects Effects 0.000 description 16
- 238000000034 method Methods 0.000 description 15
- 238000000354 decomposition reaction Methods 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 230000000949 anxiolytic effect Effects 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- UPAXNLWDRLUQEA-UHFFFAOYSA-N 2h-[1]benzothiepino[5,4-c]pyridazin-3-one Chemical compound C1=CSC2=CC=CC=C2C2=NNC(=O)C=C21 UPAXNLWDRLUQEA-UHFFFAOYSA-N 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 210000000265 leukocyte Anatomy 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- FQHCPFMTXFJZJS-UHFFFAOYSA-N (4-methoxyphenyl)hydrazine;hydrochloride Chemical compound Cl.COC1=CC=C(NN)C=C1 FQHCPFMTXFJZJS-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 5
- 229960003529 diazepam Drugs 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 230000028527 righting reflex Effects 0.000 description 5
- 208000019901 Anxiety disease Diseases 0.000 description 4
- 102000004300 GABA-A Receptors Human genes 0.000 description 4
- 108090000839 GABA-A Receptors Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229940005530 anxiolytics Drugs 0.000 description 4
- 150000001557 benzodiazepines Chemical class 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 235000013336 milk Nutrition 0.000 description 4
- 239000008267 milk Substances 0.000 description 4
- 210000004080 milk Anatomy 0.000 description 4
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 4
- 229940067157 phenylhydrazine Drugs 0.000 description 4
- 238000003825 pressing Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- KDZUAYUWRKMBPN-UHFFFAOYSA-N 7-oxo-2H-[1]benzothiepino[5,4-c]pyridazin-3-one Chemical compound N=1NC(C=C2C1C1=C(S(C=C2)=O)C=CC=C1)=O KDZUAYUWRKMBPN-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- 206010057249 Phagocytosis Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- KSUYUISXWPQBCX-UHFFFAOYSA-N 2-(5-oxo-3,4-dihydro-2h-1-benzothiepin-4-yl)acetic acid Chemical compound O=C1C(CC(=O)O)CCSC2=CC=CC=C21 KSUYUISXWPQBCX-UHFFFAOYSA-N 0.000 description 2
- XXNOGQJZAOXWAQ-UHFFFAOYSA-N 4-chlorophenylhydrazine Chemical compound NNC1=CC=C(Cl)C=C1 XXNOGQJZAOXWAQ-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 206010021118 Hypotonia Diseases 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
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000036640 muscle relaxation Effects 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
- 230000003287 optical effect Effects 0.000 description 2
- 230000000242 pagocytic 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
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 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
- 230000011514 reflex Effects 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- CRRIAWUJYMLJOE-UHFFFAOYSA-N (3-chlorophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=CC(Cl)=C1 CRRIAWUJYMLJOE-UHFFFAOYSA-N 0.000 description 1
- RGGOWBBBHWTTRE-UHFFFAOYSA-N (4-bromophenyl)hydrazine;hydron;chloride Chemical compound Cl.NNC1=CC=C(Br)C=C1 RGGOWBBBHWTTRE-UHFFFAOYSA-N 0.000 description 1
- HMHWNJGOHUYVMD-UHFFFAOYSA-N (4-methylanilino)azanium;chloride Chemical compound Cl.CC1=CC=C(NN)C=C1 HMHWNJGOHUYVMD-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- UMKLWBFJFMDZAH-UHFFFAOYSA-N 1-chloro-1-phenylhydrazine Chemical compound NN(Cl)C1=CC=CC=C1 UMKLWBFJFMDZAH-UHFFFAOYSA-N 0.000 description 1
- AVTHHTZKFGTIRN-UHFFFAOYSA-N 1-chloro-1-phenylhydrazine;hydrochloride Chemical compound Cl.NN(Cl)C1=CC=CC=C1 AVTHHTZKFGTIRN-UHFFFAOYSA-N 0.000 description 1
- JQZAEUFPPSRDOP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1 JQZAEUFPPSRDOP-UHFFFAOYSA-N 0.000 description 1
- CIJROHANRCXFTJ-UHFFFAOYSA-N 1-methoxy-1-phenylhydrazine;hydrochloride Chemical compound Cl.CON(N)C1=CC=CC=C1 CIJROHANRCXFTJ-UHFFFAOYSA-N 0.000 description 1
- DHHCZBKLLAJQSJ-UHFFFAOYSA-N 10-amino-4,4a,5,6-tetrahydro-2h-[1]benzothiepino[5,4-c]pyridazin-3-one Chemical compound S1CCC2CC(=O)NN=C2C2=CC(N)=CC=C21 DHHCZBKLLAJQSJ-UHFFFAOYSA-N 0.000 description 1
- QGQZIDCRANFBKH-UHFFFAOYSA-N 10-fluoro-2-(4-fluorophenyl)-4,4a,5,6-tetrahydro-[1]benzothiepino[5,4-c]pyridazin-3-one Chemical compound C1=CC(F)=CC=C1N1C(=O)CC(CCSC=2C3=CC(F)=CC=2)C3=N1 QGQZIDCRANFBKH-UHFFFAOYSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- LKZRCQBOKZIXCL-UHFFFAOYSA-N 2-(4-chlorophenyl)-10-methoxy-4,4a,5,6-tetrahydro-[1]benzothiepino[5,4-c]pyridazin-3-one Chemical compound N1=C2C3=CC(OC)=CC=C3SCCC2CC(=O)N1C1=CC=C(Cl)C=C1 LKZRCQBOKZIXCL-UHFFFAOYSA-N 0.000 description 1
- ZJOFLISMLXHSJS-UHFFFAOYSA-N 2-(4-chlorophenyl)-10-methyl-4,4a,5,6-tetrahydro-[1]benzothiepino[5,4-c]pyridazin-3-one Chemical compound N1=C2C3=CC(C)=CC=C3SCCC2CC(=O)N1C1=CC=C(Cl)C=C1 ZJOFLISMLXHSJS-UHFFFAOYSA-N 0.000 description 1
- RQCPOXFVJUSNRL-UHFFFAOYSA-N 2-(4-methoxyphenyl)-4,4a,5,6-tetrahydro-[1]benzothiepino[5,4-c]pyridazin-3-one Chemical compound C1=CC(OC)=CC=C1N1C(=O)CC(CCSC=2C3=CC=CC=2)C3=N1 RQCPOXFVJUSNRL-UHFFFAOYSA-N 0.000 description 1
- WZKWIZCWOMXJFB-UHFFFAOYSA-N 2-(7-fluoro-5-oxo-3,4-dihydro-2h-1-benzothiepin-4-yl)acetic acid Chemical compound O=C1C(CC(=O)O)CCSC2=CC=C(F)C=C21 WZKWIZCWOMXJFB-UHFFFAOYSA-N 0.000 description 1
- ADODRSVGNHNKAT-UHFFFAOYSA-N 2-Chlorophenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1Cl ADODRSVGNHNKAT-UHFFFAOYSA-N 0.000 description 1
- DYEXFJNLMLORSG-UHFFFAOYSA-N 2-butyl-4,4a,5,6-tetrahydro-[1]benzothiepino[5,4-c]pyridazin-3-one Chemical compound C1CSC2=CC=CC=C2C2=NN(CCCC)C(=O)CC21 DYEXFJNLMLORSG-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ZXTHWIZHGLNEPG-UHFFFAOYSA-N 2-phenyl-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC=C1 ZXTHWIZHGLNEPG-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- CXUGAWWYKSOLEL-UHFFFAOYSA-N 2h-cinnolin-3-one Chemical compound C1=CC=C2N=NC(O)=CC2=C1 CXUGAWWYKSOLEL-UHFFFAOYSA-N 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
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Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は抗不安薬などの医薬として有用なベンゾチエピ
ノ（５，４−ｃ）ピリダジン化合物に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to benzothiepino(5,4-c)pyridazine compounds useful as pharmaceuticals such as anxiolytics.
現在、神経症、うつ病や各種疾患における不安、緊張な
どの疾病を改善、治療するための抗不安薬としてジアゼ
パムなどのベンゾジアゼピン系化合物が用いられている
。しかしながら、このベンゾジアゼピン化合物はさらに
、鎮静作用、筋弛緩作用、抗痙彎作用、アルコール増強
作用、麻酔増強作用などの薬理作用を有することから、
眠気、ふらつき、注意力・集中力・反射運動能力などの
低下などが副作用として問題になることが多い。Currently, benzodiazepine compounds such as diazepam are used as anti-anxiety drugs to improve and treat diseases such as neurosis, depression, and anxiety and tension in various diseases. However, benzodiazepine compounds also have pharmacological effects such as sedation, muscle relaxation, anticonvulsant effects, alcohol-enhancing effects, and anesthesia-enhancing effects.
Side effects such as drowsiness, light-headedness, and decreased attention, concentration, and reflex movement ability are often problematic.
このことから近年これら副作用が弱いか、またはない、
より選択的な抗不安薬の開発が進んでいる。For this reason, in recent years these side effects have been weak or non-existent.
More selective anxiolytic drugs are being developed.
このような抗不安薬の研究において、脳内ベンゾジアゼ
ピン受容体に親和性を示す非ベンゾジアゼピン系化合物
（特開昭６１−４０２８５号など）が提供されてきてい
るが、依然として作用の選択性が不十分であるとか、安
全性が低いなどの解決すべき課題がある。In research into such anxiolytics, non-benzodiazepine compounds (such as Japanese Patent Application Laid-open No. 61-40285) that show affinity for benzodiazepine receptors in the brain have been provided, but the selectivity of action is still insufficient. There are issues that need to be resolved, such as safety and low safety.
ところで、縮合ピリダジン化合物が種々の薬理作用を有
していることは公知である。特に国際用ｗＭＷＯ８６１
０１５０６には抗不安作用を有する９−クロロ−２−フ
ェニル−４，４ａ、５．６−テトラヒドロベンゾ（ｈ）
シンノリン−３（２Ｈ）−オンなどの化合物が、ヨーロ
ッパ特許出願公開第１２４３１４号明細書および米国特
許第４，６０２，０１９号明細書には強心作用および抗
高血圧作用を有する２、４．４ａ、５−テトラεドロー
７−（ＩＨ−イミダゾール−１−イル）−３Ｈ−インデ
ノ（１゜２−Ｃ〕ピリダジン−３−オンなどの化合物が
、またヨーロッパ特許出願公開第１６９４４３号明細書
および米国特許第４，６９２．４４７号明細書には降圧
作用、血管拡張作用、抗凝集作用、抗血栓作用および細
胞防御作用を有する２−ｎ−ブチル−２，４，４ａ、５
，６．７−ヘキサヒド０−３Ｈ−（６，７）−シクロブ
テン−［１，２−ｃ）−ピリダジン−３−オン−８−ア
ミノなどの化合物が開示されている。By the way, it is known that fused pyridazine compounds have various pharmacological actions. Especially for international wMWO861
01506 contains 9-chloro-2-phenyl-4,4a,5,6-tetrahydrobenzo(h), which has anxiolytic effects.
Compounds such as cinnolin-3(2H)-one have been described in European Patent Application No. 124314 and US Pat. No. 4,602,019 as having inotropic and antihypertensive effects 2,4.4a, Compounds such as 5-tetraε draw 7-(IH-imidazol-1-yl)-3H-indeno(1<2-C]pyridazin-3-one are also described in European Patent Application No. 169443 and U.S. Pat. No. 4,692.447 describes 2-n-butyl-2,4,4a, 5, which has antihypertensive effect, vasodilatory effect, antiaggregation effect, antithrombotic effect and cell protective effect.
, 6,7-hexahydro-3H-(6,7)-cyclobutene-[1,2-c)-pyridazin-3-one-8-amino.
本発明者らは選択的かつ安全性の高い非ベンゾジアゼピ
ン系抗不安薬を開発することを目的として、鋭意研究を
続けてきた。The present inventors have continued intensive research with the aim of developing selective and highly safe non-benzodiazepine anxiolytics.
〔課題を解決するための手段］
本発明者らの研究により、選択的で、かつすぐれた抗不
安作用を有し、さらに低毒性のベンゾチエピノ（５，４
−ｃ〕ピリダジン化合物を見出すに至った。[Means for Solving the Problems] Through research conducted by the present inventors, benzothiepino (5,4
-c] Pyridazine compound was discovered.
本発明は一般式
Ｃ式中、Ｒ’、Ｒ”は同一または異なって水素、ハロゲ
ン、トリフルオロメチル、ヒドロキシ、アミノ、ニトロ
、シアノ、Ｃｌ−４アルキル、Ｃ４−４アルコキシまた
はＣ２−、アルカノイルアミノを、Ｒ２は水素、Ｃ＋−
＊アルキル、ヒドロキシ−ＣＩ−４アルキル、Ｃ１−、
アルカノイルオキシ−Ｃ＋−４アルキル、アリール、ア
リール−０１−４アルキル、ヘテロアリールまたは芳香
環上にハロゲン、トリフルオロメチル、ヒドロキシ、ア
ミノ、ニトロ、シアノ、Ｃ１−、アルキル、Ｃ１−４ア
ルコキシおよびＣＸ−５アルカノイルアミノから選ばれ
る置換基を１〜３個有するアリール、アリール−Ｃ１−
４アルキルもしくはヘテロアリールを、ｎは０．ｌまた
は２を、４位と４ａ位との間の結合−二は単結合または
二重結合を示す、）
で表わされるベンゾチエピノ（５，４−ｃ）ピリダジン
化合物に関する。In the general formula C, R' and R'' are the same or different and hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, Cl-4 alkyl, C4-4 alkoxy or C2-, alkanoylamino , R2 is hydrogen, C+-
*Alkyl, hydroxy-CI-4 alkyl, C1-,
Alkanoyloxy-C+-4 alkyl, aryl, aryl-01-4 alkyl, heteroaryl or halogen on the aromatic ring, trifluoromethyl, hydroxy, amino, nitro, cyano, C1-, alkyl, C1-4 alkoxy and CX- Aryl having 1 to 3 substituents selected from 5-alkanoylamino, aryl-C1-
4 alkyl or heteroaryl, n is 0. The present invention relates to a benzothiepino(5,4-c)pyridazine compound represented by l or 2, the bond between the 4-position and the 4a-position - 2 represents a single bond or a double bond.
一般式（１）の記号を定義により説明すると、ハロゲン
とはフッ素、塩素、臭素、ヨウ素を、Ｃｌ−４アルキル
とはメチル、エチル、プロピル、イソプロピル、ブチル
、イソブチル、第３級ブチルなどを、Ｃ１，４アルコキ
シとはメトキシ、エトキシ、プロポキシ、イソプロポキ
シ、ブトキシ、イソブトキシ、第３級ブトキシなどを、
Ｃｌ−５アルカノイルアミノとはアセチルアミノ、プロ
ピオニルアミノ、ブチリルアミノ、ピバロイルアミノな
どを、ヒドロキシ−０１−４アルキルとはヒドロキシメ
チル、ヒドロキシエチル、ヒドロキシプロピル、ヒドロ
キシブチルなどを、Ｃｔ−Ｓアルカノイルオキシ−０１
−、アルキルとはアセトキシメチル、アセトキシエチル
、アセトキシプロピル、アセトキシブチル、プロピオニ
ルオキシメチル、プロピオニルオキシエチル、プロピオ
ニルオキシプロビル、プロピオニルオキシブチルなどを
、Ｃｌ−＊アルキルとは直鎖または分枝鎖状で、メチル
、エチル、プロピル、イソプロピル、ブチル、第２級ブ
チル、第３級ブチル、ペンチル、イソペンチル、ネオペ
ンチル、ヘキシル、ヘプチル、オクチル、２−エチルヘ
キシルなどを、アリール−０１−４アルキルとはベンジ
ル、フェニルエチル、フェニルプロピル、フェニルブチ
ル、ナフチルメチル、ナフチルエチル、ナフチルプロピ
ル、ナフチルブチルなどを、アリールとはフェニル、ナ
フチルなどを、ヘテロアリールとは２−ピリジル、３−
ピリジル、４−ピリジル、２−チエニル、３−チエニル
、２−フリル、３−フリルなどを、芳香環上にハロゲン
、トリフルオロメチル、ヒドロキシ、アミノ、ニトロ、
シアノ、Ｃｌ−４アルキル、Ｃｌ−４アルコキシおよび
Ｃ！−、アルカノイルアミノから選ばれる置換基を１〜
３個有するアリール、アリール−Ｃ１−４アルキルもし
くはヘテロアリールとは２−クロロフェニル、３−１０
ロフエニル、４−クロロフェニル、３，４−ジクロロフ
ェニル、４−ブロモフェニル、４−フルオロフェニル、
３−１−ＩＪフルオロメチルフェニル、４−ヒドロキシ
フェニル、４−７ミノフエニル、４〜シアノフエニル、
４−メチルフェニル、４−メトキシフェニル、４−アセ
チルアミノフェニル、４−プロピオニルアミノフェニル
、３，４．５−）リメトキシフェニル、４−クロロベン
ジル、４〜メチルベンジル、２．３−ジクロロベンジル
、４−メトキシベンジル、４−ヒドロキシベンジル、３
，４．５−）リメトキシベンジル、２− （４−クロロ
フェニル）エチル、４−（４−クロロフェニル）ブチル
、５−クロロ−２−ピリジル、４．５−ジクロロ−２−
ピリジル、５−メチル−２−チエニル、５−メチル−３
−チエニル、５−１０ロー２−チエニル、５−クロロ−
２−フリルなどを示す。To explain the symbols in general formula (1) by definition, halogen means fluorine, chlorine, bromine, and iodine, and Cl-4 alkyl means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc. C1,4 alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc.
Cl-5 alkanoylamino refers to acetylamino, propionylamino, butyrylamino, pivaloylamino, etc. Hydroxy-01-4 alkyl refers to hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc., Ct-S alkanoyloxy-01
-, Alkyl refers to acetoxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxymethyl, propionyloxyethyl, propionyloxypropyl, propionyloxybutyl, etc.Cl-*Alkyl refers to linear or branched chain. , methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, 2-ethylhexyl, etc., and aryl-01-4 alkyl refers to benzyl, phenyl, etc. Ethyl, phenylpropyl, phenylbutyl, naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl, etc., aryl refers to phenyl, naphthyl, etc., heteroaryl refers to 2-pyridyl, 3-
Pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, etc. on the aromatic ring, halogen, trifluoromethyl, hydroxy, amino, nitro,
cyano, Cl-4 alkyl, Cl-4 alkoxy and C! -, 1 to 1 substituents selected from alkanoylamino
Aryl, aryl-C1-4 alkyl or heteroaryl having 3 atoms is 2-chlorophenyl, 3-10
lophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 4-fluorophenyl,
3-1-IJ fluoromethylphenyl, 4-hydroxyphenyl, 4-7minophenyl, 4-cyanophenyl,
4-methylphenyl, 4-methoxyphenyl, 4-acetylaminophenyl, 4-propionylaminophenyl, 3,4.5-)rimethoxyphenyl, 4-chlorobenzyl, 4-methylbenzyl, 2,3-dichlorobenzyl, 4-methoxybenzyl, 4-hydroxybenzyl, 3
, 4.5-)rimethoxybenzyl, 2-(4-chlorophenyl)ethyl, 4-(4-chlorophenyl)butyl, 5-chloro-2-pyridyl, 4.5-dichloro-2-
Pyridyl, 5-methyl-2-thienyl, 5-methyl-3
-thienyl, 5-10 rho-2-thienyl, 5-chloro-
2- Indicates frills, etc.
本発明の化合物（１）が不斉炭素原子を有する場合には
うセミ体混合物または光学異性体の形で得ることができ
、さらに化合物（１）が少なくとも２個の不斉原子を有
する場合には、個々のジアステレオマーまたはそれらの
混合物として得られる。本発明はこれらの混合物および
個々の異性体をも包含する。また、本発明は立体異性体
をも包含する。When the compound (1) of the present invention has an asymmetric carbon atom, it can be obtained in the form of a cystic mixture or an optical isomer, and when the compound (1) has at least two asymmetric atoms, are obtained as individual diastereomers or as mixtures thereof. The invention also includes mixtures and individual isomers thereof. The present invention also includes stereoisomers.
本発明の好ましい化合物としては２−（４−クロロフェ
ニル）−５，６−シヒドロー（１）ベンゾチエピノ（５
，４−ｃ）ピリダジン−３（２Ｈ）−オン、１０−クロ
ロ−２−（４−クロロフェニル）−５，６−ジヒドロ＝
（１）ベンゾチエピノ（５，４−ｃ）ピリダジン−３（
２Ｈ）−オン・７−オキシド、２−（４−クロロフェニ
ル）−５゜６−シヒドロー〔１］ベンゾチエピノ （５
，４−Ｃ〕ピリダジン−３（２Ｈ）−オン・７−オキシ
ド、２−（４−クロロフェニル）−４，４ａ、５゜６−
テトラヒドロー〔１〕ベンゾチエピノ〔５゜４−Ｃ〕ピ
リダジン−３（２Ｈ）−オン・７−オキシド、２−（４
−クロロフェニル）−１０−フルオロ−５，６−シヒド
ロー（１）ベンゾチエピノ（５，４−ｃ）ピリダジン−
３（２Ｈ）−オン、２−（４−クロロフェニル）−１０
−フルオロ−５，６−シヒドロー〔１〕ベンゾチエピノ
〔５゜４−〇〕ピリダジンー３ （２Ｈ）−オン・７
−オ −キシド、２−（４−ブロモフェニル）−５，
６−シヒドロー（１〕ベンゾチエピノ（５，４−ｃ）ピ
リダジン−３（２Ｈ）−オン・７−オキシド、２−（４
−ブロモフェニル）−４，４ａ、５．６−テトラヒドロ
ー〔１〕ベンゾチエピノ〔５，４−ｃ）ピリダジン−３
（２Ｈ）−オン・７−オキシド、１０−フルオロ−２−
（４−フルオロフェニル）−５，６−シヒドロー（１）
ベンゾチエピノ（５，４−ｃ）ピリダジン−３（２Ｈ）
−オン、８−クロロ−２−（４−クロロフェニル）−５
゜６−シヒドロー（１）ベンゾチエピノ（５，４−Ｃ〕
ピリダジン−３（２Ｈ）−オン・７−オキシド、１０−
フルオロ−２−（４−フルオロフェニル）−５，６−シ
ヒドロー（１）ベンゾチエピノ（５，４−ｃ）ピリダジ
ン−３（２Ｈ）−オン・７−オキシドなどがあげられる
。Preferred compounds of the present invention include 2-(4-chlorophenyl)-5,6-sihydro(1)benzothiepino(5
, 4-c) Pyridazin-3(2H)-one, 10-chloro-2-(4-chlorophenyl)-5,6-dihydro=
(1) Benzothiepino(5,4-c)pyridazine-3 (
2H)-one 7-oxide, 2-(4-chlorophenyl)-5゜6-sihydro[1]benzothiepino (5
,4-C]pyridazin-3(2H)-one 7-oxide, 2-(4-chlorophenyl)-4,4a, 5゜6-
Tetrahydro[1]benzothiepino[5゜4-C]pyridazin-3(2H)-one 7-oxide, 2-(4
-chlorophenyl)-10-fluoro-5,6-sihydro(1)benzothiepino(5,4-c)pyridazine-
3(2H)-one, 2-(4-chlorophenyl)-10
-Fluoro-5,6-sihydro[1]benzothiepino[5゜4-〇]pyridazine-3 (2H)-one 7
-oxide, 2-(4-bromophenyl)-5,
6-sihydro(1)benzothiepino(5,4-c)pyridazin-3(2H)-one 7-oxide, 2-(4
-bromophenyl)-4,4a,5,6-tetrahydro[1]benzothiepino[5,4-c)pyridazine-3
(2H)-one 7-oxide, 10-fluoro-2-
(4-fluorophenyl)-5,6-sihydro (1)
Benzothiepino(5,4-c)pyridazine-3(2H)
-one, 8-chloro-2-(4-chlorophenyl)-5
゜6-Sihydro (1) Benzothiepino (5,4-C)
Pyridazin-3(2H)-one 7-oxide, 10-
Examples include fluoro-2-(4-fluorophenyl)-5,6-sihydro(1)benzothiepino(5,4-c)pyridazin-3(2H)-one 7-oxide.
本発明において一般式（１）の化合物は、たとえば以下
に示す方法によって合成することができる。In the present invention, the compound of general formula (1) can be synthesized, for example, by the method shown below.
一方迭」１つ−
一般式
（式中、各記号は前記と同義である。）で表わされる化
合物と、−ａ式
Ｒ’ ＮＨＮＨ＊ （Ｉ［［）（式中、Ｒ
３は前記と同義である。）
で表わされるヒドラジン誘導体またはその水和物あるい
は酸付加塩とを反応させて得られる一般式（式中、各記
号は前記と同義である。）で表わされる化合物を閉環反
応に付す方法。On the other hand, one compound represented by the general formula (in the formula, each symbol has the same meaning as above) and -a formula R' NHNH* (I[[) (in the formula, R
3 has the same meaning as above. ) A method of subjecting a compound represented by the general formula (in the formula, each symbol has the same meaning as above) obtained by reacting a hydrazine derivative represented by the above or its hydrate or acid addition salt to a ring-closing reaction.
反応は適当な溶媒、たとえばメタノール、エタノール、
プロパツールなどのアルコール系溶媒中、５〜２０時間
加熱還流することにより進行し、−般弐Ｎ）および一般
式（ＩＶ）の化合物を生ずる。The reaction is carried out in a suitable solvent such as methanol, ethanol,
The reaction proceeds by heating under reflux for 5 to 20 hours in an alcoholic solvent such as propatool, yielding compounds of general formula (IV).
−ａ式（Ｉ［［）のヒドラジン誘導体が酸付加塩の場合
、脱酸剤（酢酸ナトリウム、酢酸カリウム、炭酸水素ナ
トリウム、炭酸ナトリウム、炭酸カリウムなど）の存在
下に反応させる。一般式（ｒＶ）の化合物が得られた場
合には、酢酸中５〜１０時間加熱還流することにより一
般式（１）の化合物を得ることができる。-a When the hydrazine derivative of formula (I[[) is an acid addition salt, it is reacted in the presence of a deoxidizing agent (sodium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, etc.). When the compound of general formula (rV) is obtained, the compound of general formula (1) can be obtained by heating under reflux in acetic acid for 5 to 10 hours.
一方法ユエと
−ａ式（＋）においてｎ−０の化合物を酸化反応に付す
ことにより一般式（１）中、ｎ＝１または２の化合物、
すなわちオキシドまたはジオキシド化合物を合成する方
法。On the other hand, by subjecting n-0 compound to an oxidation reaction in formula (+), a compound of n=1 or 2 in general formula (1),
That is, a method for synthesizing oxide or dioxide compounds.
反応は適当な溶媒中、酸化剤（過酢酸、過安息香酸、ｍ
−クロロ過安息香酸、次亜臭素酸ナトリウムなど）の存
在下１０〜１００℃に１〜１０時間保つことにより進行
するが、酢酸溶媒中、過酸化水素の存在下、室温に１〜
５時間保つとｎ−１の化合物が優先的に得られ、３０〜
１００°Ｃに２〜１０時間保つことによりｎ−２の化合
物が得られる。The reaction is carried out using an oxidizing agent (peracetic acid, perbenzoic acid, m
-chloroperbenzoic acid, sodium hypobromite, etc.) at 10 to 100°C for 1 to 10 hours;
When kept for 5 hours, compound n-1 was preferentially obtained, and 30~
Compound n-2 is obtained by keeping at 100°C for 2 to 10 hours.
一方店」」リ−
一般式（１）においてＲ３が水素である化合物と一般式
％式％（）
〔式中、Ｒ４はＣ＋−ｓアルキル、ヒドロキシ−Ｃ＋−
ａアルキル、Ｃ１−、アルカノイルオキシ−０１−４ア
ルキル、アリール−Ｃ＋−４アルキルまたは芳香環上に
置換基を有するアリール−ＣＩ−４アルキルを、Ｘは反
応活性な原子または基（塩素、臭素などのハロゲンまた
はメタンスルホニルオキシ、トルエンスルホニルオキシ
、ベンゼンスルホニルオキシなど）を示す、〕
で表わされる化合物を反応させ、Ｒ２が０１−、アルキ
ル、ヒドロキシ−Ｃ３−４アルキル、Ｃｆｆ１−＋１ア
ルカノイルオキシ−Ｃ３−４アルキル、アリール−Ｃ０
−４アルキルまたは芳香環上に置換基を有するアリール
−ＣＩ−４アルキルである化合物を製造する方法。On the other hand, compounds in which R3 is hydrogen in the general formula (1) and the general formula % formula % () [wherein R4 is C+-s alkyl, hydroxy-C+-
a Alkyl, C1-, alkanoyloxy-01-4 alkyl, aryl-C+-4 alkyl, or aryl-CI-4 alkyl having a substituent on the aromatic ring, and X is a reactive atom or group (chlorine, bromine, etc.). halogen or methanesulfonyloxy, toluenesulfonyloxy, benzenesulfonyloxy, etc.), and R2 is 01-, alkyl, hydroxy-C3-4 alkyl, Cff1-+1 alkanoyloxy-C3- 4 alkyl, aryl-C0
A method for producing a compound that is -4 alkyl or aryl-CI-4 alkyl having a substituent on an aromatic ring.
反応は適当な溶媒、たとえばベンゼン、トルエン、キシ
レンなどの非掻性溶媒、あるいはＮ、 Ｎ−ジメチルホ
ルムアミド、アセトニトリルなどの極性溶媒中、脱酸剤
（水素化ナトリウム、ナトリウムアミド、ナトリウムメ
トキシド、ナトリウムエトキシド、水酸化カリウム、水
酸化ナトリウムなど）の存在下、０〜５０°Ｃで１〜１
０時間保つことにより進行する。The reaction is carried out in a suitable solvent, such as a non-scratchable solvent such as benzene, toluene, xylene, or a polar solvent such as N,N-dimethylformamide, acetonitrile, and a deoxidizing agent (sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, etc.) at 0-50°C.
Progress is made by keeping it for 0 hours.
一立人工皮と
一般式（１）において４位と４ａ位との間の結合が二重
結合である場合は、その結合部位が単結合である化合物
に酢酸溶媒中、臭素を滴下することにより〔ジャーナル
・オブ・メディシナル・ケミストリー（Ｊ、 Ｍｅｄ、
Ｃｈｅｓ＋、）第１４巻、２６２頁（１９７１年）〕
合成することができる０反応は酢酸溶媒中、１〜１．５
倍モル量の臭素を２０〜６０℃で滴下すると好適に進行
する。When the bond between position 4 and position 4a in Hitori artificial skin and general formula (1) is a double bond, by dropping bromine in an acetic acid solvent to a compound whose bond site is a single bond. [Journal of Medicinal Chemistry (J, Med,
Ches+, Volume 14, Page 262 (1971)]
0 reactions that can be synthesized are 1 to 1.5 in acetic acid solvent.
The reaction proceeds preferably when twice the molar amount of bromine is added dropwise at 20 to 60°C.
また、４位と４ａ位との間の結合が二重結合である一般
式（１）の化合物はその結合部位が単結合である化合物
にナトリウム−ｍ−ニトロベンゼンスルホネート（Ｂａ
ｃｈｍａｎｎ法、英国特許第１１６８２９１号明細書）
を反応させることによっても合成することができる。In addition, the compound of general formula (1) in which the bond between the 4-position and the 4a-position is a double bond has a compound in which the bonding site is a single bond, and sodium-m-nitrobenzenesulfonate (Ba
chmann method, British Patent No. 1168291)
It can also be synthesized by reacting.
一必ＡＬＬ！し
上記方法（１）から（ｉｖ ）により得られた化合物の
基Ｒ’、Ｒ”または基Ｒ３の置換基を、通常の有機化学
的手法によって他の基に交換する方法。Must be ALL! A method in which the substituents of the groups R', R'' or the group R3 of the compounds obtained by the above methods (1) to (iv) are exchanged with other groups by ordinary organic chemical techniques.
そのような方法としては、たとえばニトロ基をアミノ基
に還元する方法、アミノ基を低級アルカノイル化する方
法またはアミノ基をシアン基に変換する方法（ザンドマ
イヤー反応、ガラターマン反応など）があげられる。Such methods include, for example, a method of reducing a nitro group to an amino group, a method of converting an amino group to a lower alkanoyl group, or a method of converting an amino group to a cyan group (Sandmeyer reaction, Galaterman reaction, etc.).
このようにして得られる本発明化合物は再結晶法、カラ
ムクロマト法などの常法により単離精製することができ
る。The compound of the present invention thus obtained can be isolated and purified by conventional methods such as recrystallization and column chromatography.
得られる生成物がラセミ体であるときは、たとえば光学
活性な酸との塩の分別再結晶により、もしくは光学活性
な担体を充填したカラムを通すことにより所望の光学異
性体に分割することができる０個々のジアステレオマー
は分別結晶化、クロマトグラフィーなどの手段によって
分離することができる。これらは光学活性な原料化合物
などを用いることによっても得られる。また、立体異性
体は再結晶法、カラムクロマト法などにより単離するこ
とができる。When the resulting product is a racemate, it can be resolved into the desired optical isomers, for example, by fractional recrystallization of a salt with an optically active acid or by passing it through a column packed with an optically active carrier. 0 Individual diastereomers can be separated by means such as fractional crystallization, chromatography, etc. These can also be obtained by using optically active raw material compounds. Furthermore, stereoisomers can be isolated by recrystallization, column chromatography, and the like.
次に、本発明に包含される実施例記載以外の化合物を以
下に例示する。Next, compounds other than those described in Examples included in the present invention are illustrated below.
０１０−フルオロ−２−（４−メトキシフェニル）−４
，４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピノ
（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
０８−クロロ−２−（４−メチルフェニル）−４，４ａ
、５．６−テトラヒドロー（１）ベンゾチエピノ（５，
４−ｃ）ピリダジン−３（２Ｈ）−オン
◎ ８−クロロ−２−（４−クロロフェニル）−４、４
ａ、 ５．６−テトラヒドロー〔１〕ベンゾチエピノ
（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
０９−クロロ−２−（４−クロロフェニル）−４，４ａ
、５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，
４−ｃ）ピリダジン−３（２Ｈ）−オン
０９−クロロ−２−（４−メチルフェニル）−４，４ａ
、５．６−テトラヒドｔ１７−〔１）ベンゾチエピノ（
５，４−ｃ）ピリダジン−３（２Ｈ）−オン
◎ ２− （４−クロロフェニル）−１０−メトキシ−
４，４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピ
ノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
◎ ｌＯ−メトキシ−２−（４−クロロフェニル）−４
，４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピノ
（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
Ｏ１０−ヒドロキシ−２−（４−メチルフェニル）−４
，４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピノ
（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
◎ １０−＝ドロー４．４ａ、５．６−テトラヒドロー
〔１〕ベンゾチエピノ（５，４−ｃ）ピリダジン−３（
２Ｈ）−オン
◎ １０−ニトロ−２−フェニル−４，４ａ、５゜６−
テトラヒドロー（１）ベンゾチエピノ〔５゜４−〇〕ピ
リダジンー３（２Ｈ）−オン０） １０−アミノ−４
，４ａ、５．６−テトラヒドロー（１）ベンゾチエピノ
（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
◎ ｌＯ−アミノ−２−フェニル−４，４ａ、５゜６−
テトラヒドロー（１）ベンゾチエピノ〔５゜４−Ｃ〕ピ
リダジン−３（２Ｈ）−オン０ １０−シアノ−４，４
ａ、５．６−テトラヒドロー（１）ベンゾチエピノ（５
，４−ｃ）ピリダジン−３（２Ｈ）−オン
０ １０−アセチルアミノ−４，４ａ、５．６−テトラ
ヒドロー〔１〕ベンゾチエピノ（５，４−Ｃ〕ピリダジ
ン−３（２Ｈ）−オン
０ １０−アセチルアミノ−２−フェニル−４゜４ａ、
５．６−テトラヒドロー〔１〕ベンゾチエピノ［５，４
−ｃ）ピリダジン−３（２Ｈ）−オ◎ ２−（２−ヒド
ロキシエチル）−４，４ａ。010-Fluoro-2-(4-methoxyphenyl)-4
,4a,5.6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one08-chloro-2-(4-methylphenyl)-4,4a
, 5.6-tetrahydro(1)benzothiepino(5,
4-c) Pyridazin-3(2H)-one ◎ 8-chloro-2-(4-chlorophenyl)-4,4
a, 5,6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one 09-chloro-2-(4-chlorophenyl)-4,4a
, 5.6-tetrahydro[1]benzothiepino (5,
4-c) Pyridazin-3(2H)-one 09-chloro-2-(4-methylphenyl)-4,4a
, 5.6-tetrahydrot17-[1) benzothiepino (
5,4-c) Pyridazin-3(2H)-one◎ 2-(4-chlorophenyl)-10-methoxy-
4,4a,5.6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one ◎ lO-methoxy-2-(4-chlorophenyl)-4
,4a,5.6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one O10-hydroxy-2-(4-methylphenyl)-4
,4a,5.6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one c) Pyridazine-3 (
2H)-one ◎ 10-nitro-2-phenyl-4,4a, 5゜6-
Tetrahydro(1) Benzothiepino[5゜4-〇]pyridazin-3(2H)-one0) 10-amino-4
,4a,5.6-tetrahydro(1)benzothiepino (5,4-c)pyridazin-3(2H)-one ◎ lO-amino-2-phenyl-4,4a, 5゜6-
Tetrahydro(1) Benzothiepino[5゜4-C]pyridazin-3(2H)-one 0 10-cyano-4,4
a, 5,6-tetrahydro(1)benzothiepino(5
,4-c) Pyridazin-3(2H)-one 0 10-acetylamino-4,4a,5.6-tetrahydro[1]benzothiepino(5,4-C]pyridazin-3(2H)-one 0 10- Acetylamino-2-phenyl-4゜4a,
5.6-tetrahydro[1]benzothiepino[5,4
-c) Pyridazine-3(2H)-o◎ 2-(2-hydroxyethyl)-4,4a.
５，６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−ｃ）ビリダシ７−３（２Ｈ）−オン◎ ２−（３−ア
セトキシプロピル）−４，４ａ。5,6-tetrahydro[1]benzothiepino(5,4
-c) Viridase 7-3(2H)-one ◎ 2-(3-acetoxypropyl)-4,4a.
５．６−テトラヒドロー（１）ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オンＧ ２−（４−
アセトキシブチＪＬ／）−４，４ａ。5.6-tetrahydro(1)benzothiepino(5,4
-c) Pyridazin-3(2H)-one G 2-(4-
Acetoxybuty JL/)-4,4a.
５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オン◎ ２−ブチル−
４，４ａ、５．６−テトラヒドロー（１〕ベンゾチエピ
ノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
◎ ２−へキシル−４，４ａ、５．６−テトラヒドロー
（１）ベンゾチエピノ（５，４−ｃ）ピリダジン−３（
２Ｈ）−オン
＋Ｏｆ ２−（３−）リフルオロメチルフェニル）−
４，４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピ
ノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
＊２−（４−ヒドロキシ７ｓニル）−４，４ａ。5.6-tetrahydro[1]benzothiepino(5,4
-c) Pyridazin-3(2H)-one ◎ 2-butyl-
4,4a,5.6-tetrahydro(1)benzothiepino(5,4-c)pyridazin-3(2H)-one ◎ 2-hexyl-4,4a,5.6-tetrahydro(1)benzothiepino(5, 4-c) Pyridazine-3(
2H)-one+Of 2-(3-)lifluoromethylphenyl)-
4,4a,5.6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one*2-(4-hydroxy7snyl)-4,4a.
５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オン◎ ２−（４−ニ
トロフェニル）−４，４ａ、５゜６−テトラヒドロー〔
１〕ベンゾチエピノ〔５゜４−〇〕ピリダジンー３ （
２Ｈ）−オン◎ ２−（４−アミノフェニル）−４，４
ａ、５゜６−テトラヒドロー（１）ベンゾチエピノ〔５
゜４−〇〕ピリダジンー３ （２Ｈ）−オンＱ２−＜４
−シアノフェニル）−４，４ａ、５゜６−テトラヒドロ
ー〔１〕ベンゾチエピノ〔５゜４−Ｃ〕ピリダジン−３
（２Ｈ）−オン◎ ２−（４−アセチルアミノフェニル
）−４゜４ａ、５．６−テトラヒドロー（１）ベンゾチ
エピノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
０ ２−（４−プロピオニルアミノフェニル）−４，４
ａ、５．６−テトラヒドロー（１）ベンゾチエピノ（５
，４−ｃ）ピリダジン−３（２Ｈ）−オン
◎ ２−ベンジル−４，４ａ、５．６−テトラヒドロー
〔１〕ベンゾチエピノ（５，４−ｃ）ピリダジン−３（
２Ｈ）−オン
０２−（４−クロロベンジル）−４，４ａ、５゜６−テ
トラヒドロー〔１〕ベンゾチエピノ〔５゜４−〇〕ピリ
ダジンー３ （２Ｈ）−オンＱ ２−（４−メチルベ
ンジル）−４，４ａ、５゜６−テトラヒドロー〔１〕ベ
ンゾチエピノ〔５゜４−Ｃ〕ピリダジン−３（２Ｈ）−
オン０２−（２−フェニルエチル）−４，４ａ、５゜６
−テトラヒドロー〔１〕ベンゾチエピノ〔５゜４−ｃ〕
ピリダジン−３（２Ｈ）−オンＱ ２−（４−フェニ
ルブチ／Ｌ／）−４，４ａ、５゜６−テトラヒドロー（
１〕ベンゾチエピノ〔５゜４−ｃ〕ピリダジン−３（２
Ｈ）−オン◎ ８．１０−ジメチル−２−フェニル−４
，４ａ。5.6-tetrahydro[1]benzothiepino(5,4
-c) Pyridazin-3(2H)-one ◎ 2-(4-nitrophenyl)-4,4a, 5゜6-tetrahydro [
1] Benzothiepino [5゜4-〇]pyridazine-3 (
2H)-one ◎ 2-(4-aminophenyl)-4,4
a, 5゜6-tetrahydro (1) benzothiepino [5
゜4-〇〜Pyridazine-3 (2H)-one Q2-<4
-cyanophenyl)-4,4a, 5゜6-tetrahydro[1]benzothiepino[5゜4-C]pyridazine-3
(2H)-one◎ 2-(4-acetylaminophenyl)-4゜4a,5.6-tetrahydro(1)benzothiepino(5,4-c)pyridazin-3(2H)-one0 2-(4- propionylaminophenyl)-4,4
a, 5,6-tetrahydro(1)benzothiepino(5
, 4-c) Pyridazin-3(2H)-one
2H)-one 02-(4-chlorobenzyl)-4,4a, 5゜6-tetrahydro[1]benzothiepino[5゜4-〇]pyridazin-3 (2H)-one Q 2-(4-methylbenzyl)- 4,4a,5゜6-tetrahydro[1]benzothiepino[5゜4-C]pyridazine-3(2H)-
02-(2-phenylethyl)-4,4a, 5゜6
-Tetrahydro [1] Benzothiepino [5゜4-c]
Pyridazin-3(2H)-one Q 2-(4-phenylbuty/L/)-4,4a, 5゜6-tetrahydro(
1] Benzothiepino[5゜4-c]pyridazine-3(2
H)-one ◎ 8.10-dimethyl-2-phenyl-4
, 4a.
５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オン０ ２−（４−ク
ロロフェニル）−８，１０−ジメチ／Ｌ／−４，４ａ、
５．６−チトラヒドロー（１）ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オン
０８．１０−ジメチＪｌ／−４．４ａ、５．６−チトラ
ヒドロー〔１〕ベンゾチエピノ（５，４−ｃ）ピリダジ
ン−３（２Ｈ）−オン
◎ ８，１１−ジメチル−４，４ａ、５．６−テトラヒ
ドロー（１）ベンゾチエピノ（５，４−ｃ）ピリダジン
−３（２Ｈ）−オン
◎ ８，１１−ジメチル−２−フェニル−４＋４ａ。5.6-tetrahydro[1]benzothiepino(5,4
-c) pyridazin-3(2H)-one 0 2-(4-chlorophenyl)-8,10-dimethy/L/-4,4a,
5.6-Titrahydro(1) Benzothiepino(5,4
-c) Pyridazin-3(2H)-one 08.10-dimethyJl/-4.4a, 5.6-titrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one ◎ 8, 11-dimethyl-4,4a,5,6-tetrahydro(1)benzothiepino(5,4-c)pyridazin-3(2H)-one ◎ 8,11-dimethyl-2-phenyl-4+4a.
５．６−テトラヒドロー（１）ベンゾチエピノ（５，４
−ｃ）ビリダシ７−３（２Ｈ）−オンＯ２−（５−メチ
ル−２−チェニ）Ｌｔ） −４，４ａ 。5.6-tetrahydro(1)benzothiepino(5,4
-c) Viridase 7-3(2H)-one O2-(5-methyl-2-cheni)Lt) -4,4a.
５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−Ｃ）ピリダジン−３（２Ｈ）−オン０２−（５−メチ
ル−３−チエニル）−４，４ａ。5.6-tetrahydro[1]benzothiepino(5,4
-C) Pyridazin-3(2H)-one 02-(5-methyl-3-thienyl)-4,4a.
５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−ｃ〕ピリダジン−３（２Ｈ）−オン０２−（５−メチ
ル−２−チエニル）−５，６−シヒドロー〔１〕ベンゾ
チエピノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
◎ ２−（５−メチル−３−チエニル）−５，６−シヒ
ドロー（１）ベンゾチエピノ （５，４−ｃａｌピリダ
ジン−３（２）１）−オン
◎ ２−（５−メチル−２−チエニル）−５，６−シヒ
ドロー（１）ベンゾチエピノ［５，４−ｃ）ピリダジン
−３（２Ｈ）−オン・７−オキシド◎ ２−（５−メチ
ル−３−チエニル）−５，６−シヒドロー（１）ベンゾ
チエピノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オン
・７−オキシド◎ ２−（５−メチル−２−チエニル）
−４，４ａ。5.6-tetrahydro[1]benzothiepino(5,4
-c]Pyridazin-3(2H)-one 02-(5-methyl-2-thienyl)-5,6-sihydro[1]Benzothiepino(5,4-c)pyridazin-3(2H)-one◎ 2- (5-Methyl-3-thienyl)-5,6-sihydro(1)benzothiepino (5,4-calpyridazin-3(2)1)-one ◎ 2-(5-methyl-2-thienyl)-5, 6-Sihydro(1) Benzothiepino[5,4-c)pyridazin-3(2H)-one 7-oxide◎ 2-(5-methyl-3-thienyl)-5,6-Sihydro(1) Benzothiepino(5 , 4-c) Pyridazin-3(2H)-one 7-oxide◎ 2-(5-methyl-2-thienyl)
-4,4a.
５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オン・７．７−ジオキ
シド
◎ ２−（５−メチル−３−チエニル） ’Ｌ４ａ。5.6-tetrahydro[1]benzothiepino(5,4
-c) Pyridazin-3(2H)-one 7,7-dioxide◎ 2-(5-methyl-3-thienyl)'L4a.
５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オン・７．７−ジオキ
シド
◎ ２−（５−メチル−２−チエニル）−５，６−シヒ
ドロー〔１〕ベンゾチエピノ（５，４−ｃｌピリダジン
−３（２Ｈ）−オン・７．７−ジオキシド
０ ２−（５−メチル−３−チエニル）−５，６−シヒ
ドロー〔１〕ベンゾチエピノｒ、５． ４−ｃ）ピリダ
ジン−３（２Ｈ）−オン・７．７−ジオキシド
本発明における一般式（ｎ）の化合物は文献未載の新規
化合物であり、たとえば一般式（式中、各記号は前記と
同義である。）で表わされる化合物に、アセトン中、ヨ
ウ化メチルを加え、室温で２〜５時間保持することによ
って第４級アンモニウム化合物とする。これをメタノー
ルあるいはジメチルホルムアミド中、シアン化カリウム
またはシアン化ナトリウムを加えて、４０〜５０℃で４
〜８時間反応させて一般式％式％）
（式中、各記号は前記と同義である。）で表わされるシ
アノ体とし、さらに酢酸および濃塩酸を加え、８０〜１
００℃で８〜１０時間保つことによって、一般式
（式中、各記号は前記と同義である。）の化合物が得ら
れる。5.6-tetrahydro[1]benzothiepino(5,4
-c) Pyridazin-3(2H)-one 7,7-dioxide )-one 7.7-dioxide 0 2-(5-methyl-3-thienyl)-5,6-sihydro[1]benzothiepinol, 5. 4-c) pyridazin-3(2H)-one 7. 7-Dioxide The compound of the general formula (n) in the present invention is a new compound that has not been described in any literature. A quaternary ammonium compound is obtained by adding methyl chloride and holding at room temperature for 2 to 5 hours. This was mixed with potassium cyanide or sodium cyanide in methanol or dimethylformamide and heated to 40°C to 50°C.
A cyano compound represented by the general formula % (%) (in the formula, each symbol has the same meaning as above) was obtained by reacting for ~8 hours, and acetic acid and concentrated hydrochloric acid were further added to give 80 to 1
By keeping the temperature at 00°C for 8 to 10 hours, a compound of the general formula (in the formula, each symbol has the same meaning as above) is obtained.
参考までに化合物（■“）の代表例を物理恒数とともに
示す。For reference, representative examples of compounds (■“) are shown along with their physical constants.
◎ ５−オキソ−２，３，４，５−テトラヒドロ−〔１
〕ベンゾチエピン−４−酢酸、融点１６４〜１６７℃
◎ ７−クロロ−５−オキソ−２，３，４，５−テトラ
ヒドロ−（１）ベンゾチエピン−４＝酢酸、融点２０３
〜２０５°Ｃ
◎ ７−フルオロ−５−オキソ−２，３，４，５−テト
ラヒドロ−（１）ベンゾチエピン−４−酢酸、融点１９
１〜１９３°Ｃ
Ｏ７−メチル−５−オキソ−２，３，４，５−テトラヒ
ドロ−（１）ベンゾチエピン−４−酢酸、融点２００〜
２０２°Ｃ
〔作用および発明の効果〕
以下に本発明化合物の有用性を説明するために、薬理作
用を実験方法とともに示す。◎ 5-oxo-2,3,4,5-tetrahydro-[1
] Benzothiepine-4-acetic acid, melting point 164-167°C ◎ 7-chloro-5-oxo-2,3,4,5-tetrahydro-(1) Benzothiepine-4=acetic acid, melting point 203
~205°C ◎ 7-fluoro-5-oxo-2,3,4,5-tetrahydro-(1) benzothiepine-4-acetic acid, melting point 19
1-193°C O7-Methyl-5-oxo-2,3,4,5-tetrahydro-(1) Benzothiepine-4-acetic acid, melting point 200-
202°C [Actions and Effects of the Invention] In order to explain the usefulness of the compounds of the present invention, pharmacological actions will be shown below along with experimental methods.
試験に用いた化合物は次の通りである。The compounds used in the test are as follows.
化合物Ａ：２−（４−クロロフェニル）−５゜６−シヒ
ドロー（１）ベンゾチエピノ［５，４−Ｃ］ピリダジン
−３（２Ｈ）−オン
化合物Ｂ：１０−クロロ−２−（４−クロロフェニル）
−５，６−シヒドロー（１）ベンゾチエピノ（５，４−
ｃ）ピリダジン−３（２Ｈ）−オン・７−オキシド
化合物Ｃ：２−＜４−クロロフェニル）−５゜６−シヒ
ドロー（１）ベンゾチエピノ（５，４−Ｃ〕ピリダジン
−３（２Ｈ）−オン・７−オキシド
化合物Ｄ：２−（４−クロロフェニル）−４゜４ａ、５
．６−テトラヒドロー（１）ベンゾチエピノ（５，４−
ｃ）ピリダジン−３（２Ｈ）−オン・７−オキシド
化合物Ｅｌ−（４−クロロフェニル）−１０−フルオロ
−５，６−シヒドロー（１）ベンゾチエピノ（５，４−
ｃ）ピリダジン−３（２Ｈ）−オン
化合物Ｆ：２−（４−クロロフェニル）−１０−フルオ
ロ−５，６−ジヒ、ドロー（１）ベンゾチエピノ（５，
４−ｃ）ピリダジン−３（２Ｈ）−オン・７−オキシド
化合物Ｇ：２−（４−ブロモフェニル）−５゜６−シヒ
ドロー（１）ベンゾチエピノ（５，４〜Ｃ〕ピリダジン
−３（２１（）−オン・７−オキシド
化合物Ｈ１−（４−ブロモフェニル）−４゜４ａ、５．
６〜テトラヒドロ−〔１〕ベンゾチエピノ（５，４−ｃ
）ピリダシ７−３（２Ｈ）−オン・７−オキシド
化合物Ｉ：１０−フルオロ−２−（４−フルオロフェニ
ル）−５，５−ジヒドロ−（１）ベンゾチエピノ（５，
４−ｃ）ピリダジン−３（２Ｈ）−オン
化合物Ｊ：８−クロロ−２−（４１０ロフエニル）−５
，６−ジヒドロ＝（１）ベンゾチエピノ（５，４−ｃ）
ピリダジン−３（２Ｈ）−オン・７−オキシド
実験例１：ベンゾジアゼピンに対する置換能特異的ベン
ゾジアゼピン受容体結合力試験をライフ・サイエンス（
Ｌｉｆｅ ５ｃｉｅｎｃｅ）第２ＯＳ、 ２１０１頁（
１９７７年）の方法に準じて行なった。Compound A: 2-(4-chlorophenyl)-5°6-sihydro(1)benzothiepino[5,4-C]pyridazin-3(2H)-one Compound B: 10-chloro-2-(4-chlorophenyl)
-5,6-sihydro(1)benzothiepino(5,4-
c) Pyridazin-3(2H)-one 7-oxide compound C: 2-<4-chlorophenyl)-5゜6-sihydro(1) benzothiepino(5,4-C]pyridazin-3(2H)-one . 7-oxide compound D: 2-(4-chlorophenyl)-4°4a,5
．． 6-tetrahydro(1)benzothiepino(5,4-
c) Pyridazin-3(2H)-one 7-oxide compound El-(4-chlorophenyl)-10-fluoro-5,6-sihydro(1)benzothiepino(5,4-
c) Pyridazin-3(2H)-one compound F: 2-(4-chlorophenyl)-10-fluoro-5,6-dihy, draw(1) benzothiepino(5,
4-c) Pyridazin-3(2H)-one 7-oxide compound G: 2-(4-bromophenyl)-5゜6-sihydro(1) benzothiepino(5,4-C]pyridazine-3(21( )-one 7-oxide compound H1-(4-bromophenyl)-4°4a,5.
6-tetrahydro-[1]benzothiepino(5,4-c
) Pyridacy7-3(2H)-one 7-oxide Compound I: 10-fluoro-2-(4-fluorophenyl)-5,5-dihydro-(1) benzothiepino(5,
4-c) Pyridazin-3(2H)-one Compound J: 8-chloro-2-(410lophenyl)-5
,6-dihydro=(1)benzothiepino(5,4-c)
Pyridazin-3(2H)-one 7-oxide Experimental Example 1: Substitution ability specific benzodiazepine receptor binding ability test for benzodiazepines
Life 5science) 2nd OS, page 2101 (
(1977).
９〜１０週令のウィスター系雄性ラットの大脳皮質より
粗シナブトソーム画分を分離し、１２０ｍＭ塩化ナトリ
ウムおよび５ｍＭ塩化カリウムを含む５０ｍＭ）リス−
塩酸緩衝液（ｐＨ７，４）に懸濁して実験に用いた０次
に、シナプトソーム懸濁液に数種類の濃度の試験化合物
とトリチウム化ジアゼパム（最終濃度２ｎＭ）を加え、
０℃で２０分間反応させた。その後、この懸濁液をホワ
ットマン（賀ｈａｔｍａｎ） Ｇ Ｆ ／ Ｂグラスフ
ァイバーフィルターで濾過し、上記緩衝液でフィルター
を洗った後、フィルター上に残った放射能活性を液体シ
ンチレーションカウンターで測定した。A crude synabutosome fraction was isolated from the cerebral cortex of a 9- to 10-week-old Wistar male rat, and was mixed with 50mM lysate containing 120mM sodium chloride and 5mM potassium chloride.
Next, several concentrations of the test compound and tritiated diazepam (final concentration 2 nM) were added to the synaptosome suspension, which was suspended in hydrochloric acid buffer (pH 7,4) and used in the experiment.
The reaction was carried out at 0°C for 20 minutes. Thereafter, this suspension was filtered through a Whatman GF/B glass fiber filter, and after washing the filter with the above buffer, the radioactivity remaining on the filter was measured using a liquid scintillation counter.
特異的結合量は、総語合量から１０−＆Ｍの非放射性ジ
アゼパムの存在下で得られた結合量を差し引いた値とし
た。試験化合物のベンゾジアゼピン受容体に対する親和
力は、トリチウム化ジアゼパムをその結合部位から置換
する能力によって評価されるものであり、Ｋｉ値で表わ
される。The amount of specific binding was determined by subtracting the amount of binding obtained in the presence of 10-&M non-radioactive diazepam from the total amount. The affinity of a test compound for the benzodiazepine receptor is assessed by its ability to displace tritiated diazepam from its binding site and is expressed as a Ki value.
第１表に試験結果を示す。Table 1 shows the test results.
実験例２：抗ビククリン作用
ライフ・サイエンス（Ｌｉｆｅ ５ｃｉｅｎｃｅ）第２
１１−１１７７９頁（１９７７年）の方法に準じて抗ビ
ククリン作用試験を行った。Experimental Example 2: Anti-bicuculline effect Life Science (Life 5science) No. 2
An anti-bicuculline effect test was conducted according to the method described on page 11-11779 (1977).
体重２０〜２８ｇの雄性ｄｄＹマウスを１群７〜１４匹
として使用した。試験化合物を経口投与して１時間後に
、（＋）ピリダジン０．６■／ｋｇを静脈内投与し５分
以内の強直性伸展痙彎の発現の有無を調べ、５０％有効
濃度（Ｅ Ｄ ｓ。値）を求めた。Male ddY mice weighing 20 to 28 g were used in groups of 7 to 14 mice. One hour after oral administration of the test compound, 0.6 μ/kg of (+)pyridazine was administered intravenously, and the occurrence of tonic extensor convulsion within 5 minutes was examined. .value) was calculated.
第１表に試験結果を示す。Table 1 shows the test results.
第１表
実験例３：抗不安作用
食餌制限によって自由摂取時の約８０％の体重に維持し
た一群８匹の雄性ラットをスキナー箱（Ｓｋｔｎｎｅｒ
−ｂｏｘ）内（側面にレバー、床にグリッドが備えられ
ている。）に入れ、レバー押しによるミルク取りの訓練
を行い、十分な訓練によって最終的にレバーを２０回押
すことにより、１回だけ０、１−のミルクを獲得できる
（定率強化スケジュール、ＦＲ２０）まで訓練した０次
に、１０分間のＦＲ２０によるミルク取りを行わせた（
安全期）後、コンフリクトスケジュールでは５分間高周
波の警告音を与え（警告期）、この警告期に動物がレバ
ーを１回押すとその度にミルクを得られるが、その報酬
と同時にグリッドを介して０．３秒間のｆｏｏｔｓｈｏ
ｃｋ （ＡＣｌｏｏＶ、 ０．４〜０．８ｍＡ）を与え
た。安全期と警告期の反復訓練によって安全期にのみ安
定した連続レバー押し反応を示し、警告期にはほとんど
レバー押し反応を示さず被ショック数が１０以下の動物
を試験に供した。Table 1 Experimental Example 3: Anxiolytic effect A group of 8 male rats, whose body weight was maintained at about 80% of their free intake by dietary restriction, were placed in a Skinner box (Sktnner box).
- box) (with a lever on the side and a grid on the floor), and trained to remove milk by pressing the lever, and with enough training, finally by pressing the lever 20 times, only once. The animals were trained until they were able to obtain 0 and 1- milk (constant rate reinforcement schedule, FR20), and then the animals were given milk for 10 minutes at FR20 (
In the conflict schedule, a high-frequency warning sound is given for 5 minutes (warning period), and each time the animal presses the lever once during this warning period, it receives milk, but at the same time as the reward, it is given a high-frequency warning sound (warning period). 0.3 second footshot
ck (AClooV, 0.4-0.8 mA) was given. Through repeated training in the safety period and the warning period, animals that showed a stable continuous lever-pressing response only during the safety period, showed almost no lever-pressing reaction during the warning period, and received 10 or fewer shocks were subjected to the test.
試験化合物の経口投与３０分後から安全期（１０分間）
と警告期（５分間）を交互に４回くり返し、安全期しバ
ー押し数（計４０分間）および警告翔破ショック数（計
２０分間）を測定し、対照群に比較して警告翔破ショッ
ク数の有意な増加が認められる投与量を最小を動量（Ｍ
ＥＤ、■／ｋｇ）として求めた。結果を第２表に示す。Safety period (10 minutes) starts 30 minutes after oral administration of test compound
The safety period and warning period (5 minutes) were repeated 4 times, and the number of bar presses during the safety period (40 minutes in total) and the number of warning shocks (20 minutes in total) were measured, and the number of warning shocks was compared to the control group. The dose at which a significant increase in kinetics (M
ED, (■/kg). The results are shown in Table 2.
実験例４：筋弛緩作用
一群１０匹の雄性マウスに試験化合物を経口投与し、１
時間後に毎分１１回の速さで回転する直径２．８Ｃ１１
の回転棒にのせ、１分以内に落下する動物の四散を数え
た。５０％の動物を落下させる試験化合物の投与量を５
０％有効投与量（ＥＤｓ。、 ｍｇ／ｋｇ）としてプロ
ビット法により求めた。結果は第２表に示す。Experimental Example 4: Muscle Relaxation Effect A test compound was orally administered to a group of 10 male mice.
Diameter 2.8C11 rotating at a speed of 11 times per minute after hours
The animals were placed on a rotating rod and the number of fallen animals within 1 minute was counted. 5 doses of test compound that cause 50% of animals to drop
The 0% effective dose (EDs., mg/kg) was determined by the probit method. The results are shown in Table 2.
実験例５：麻酔増強作用
２６°Ｃの恒温室内に入れておいた一群１４匹の雄性マ
ウスに試験化合物を経口投与し、１時間後にヘキソバル
ビクール４０■／ｋｇを腹腔内投与した。ヘキソバルビ
タール投与１５分および３０分後に正向反射（ｒｉｇｈ
ｔｉｎｇ ｒｅｆｌｅｘ）の消失を試験した。５０％の
動物において３秒以上にわたる正向反射を消失させる試
験化合物の投与量を５０％有効投与量（ＥＤｓ。、 ｍ
ｇ／ｋｇ）としてプロビット法により求めた。結果は第
２表に示す。Experimental Example 5: Anesthesia Enhancement Effect A test compound was orally administered to a group of 14 male mice kept in a thermostatic chamber at 26°C, and 1 hour later, 40 μ/kg of hexobarbicur was administered intraperitoneally. Righting reflex (righting reflex) 15 and 30 minutes after hexobarbital administration
ting reflex) was tested. The dose of test compound that abolishes the righting reflex for more than 3 seconds in 50% of the animals is defined as the 50% effective dose (EDs., m
g/kg) using the probit method. The results are shown in Table 2.
実験例６：アルコール増強作用
２６℃の恒温室内に入れておいた一群１４匹の雄性マウ
スに試験化合物を経口投与し、１時間後に３０％エタノ
ール０．１ｍ／１０ｇを腹腔内投与した。エタノール投
与１５分および３０分後に正向反射の消失を試験した。Experimental Example 6: Alcohol Enhancement Effect A test compound was orally administered to a group of 14 male mice kept in a constant temperature room at 26°C, and 1 hour later, 0.1 m/10 g of 30% ethanol was administered intraperitoneally. Loss of righting reflex was tested 15 and 30 minutes after ethanol administration.
５０％の動物において３秒以上にわたり正向反射を消失
させる試験化合物の投与量を５０％有効投与量（ＥＤｓ
。、 ｓｇ／ｋｇ）としてプロビット法により求めた。The dose of a test compound that abolishes the righting reflex for more than 3 seconds in 50% of animals is defined as the 50% effective dose (EDs).
. , sg/kg) using the probit method.
結果は第２表に示す。The results are shown in Table 2.
（以下余白）
本発明化合物をラットに投与したところ、３００■／ｋ
ｇ腹腔内投与および１０００■／ｋｇ経口投与において
も死亡例はみられなかった。(Left below) When the compound of the present invention was administered to rats, 300 μ/k
No deaths were observed in intraperitoneal administration at 1000 g/kg or oral administration at 1000 g/kg.
上記した実験を含む種々の薬理実験から、本発明の一般
式（＋）の化合物はベンゾジアゼピン受容体に対して高
い親和性を示し、ビククリン、ペンチレンチトラゾール
などの化学的痙彎誘発剤に対する拮抗作用を有し、また
、ラットにおける抗コンフリクト試験において強い抗不
安作用を示す一方、筋弛緩作用、麻酔増強作用、アルコ
ール増強作用が弱く、かつ毒性も低いことから、本発明
化合物は安全性が高く、しかも選択的な抗不安薬として
有用であることが明、らかになった０本発明化合物の有
用な対象疾病病名としては、たとえば自律神経失調症、
神経性嘔吐症、神経性皮膚炎、神経性狭心症、神経性呼
吸困難症などあるいは各種疾患により誘発される不安・
緊張などの心身症、不安神経症が挙げられ、これらの疾
病の予防・改善または治療に用いることができる。また
、ジアゼパムなどの既存抗不安薬の過量投与あるいは中
毒に対する中和剤としても有用である。Various pharmacological experiments, including those described above, have shown that the compound of general formula (+) of the present invention has high affinity for benzodiazepine receptors and is an antagonist to chemical proconvulsants such as bicuculline and pentylentitrazole. In addition, the compound of the present invention is highly safe because it shows strong anxiolytic effects in anti-conflict tests in rats, while having weak muscle relaxing, anesthesia-enhancing, and alcohol-enhancing effects, and low toxicity. Moreover, it has become clear that the compound of the present invention is useful as a selective anxiolytic drug. Examples of diseases for which the compound of the present invention is useful include, for example, autonomic nervous system ataxia,
Anxiety and anxiety induced by vomiting nervosa, dermatitis nervosa, angina nervosa, dyspnea nervosa, and various other diseases.
These include psychosomatic disorders such as nervousness and anxiety neurosis, and can be used to prevent, improve, or treat these diseases. It is also useful as a neutralizer for overdosing or poisoning of existing anxiolytics such as diazepam.
さらに、本発明のある種の群の化合物は白血球宜食能几
進作用、マクロファージの宜食能九進作用および感染防
御作用などの薬理作用を有し、生体防御能九進剤として
有用である。これらの作用は次の方法によって確認する
ことができる。Furthermore, certain groups of compounds of the present invention have pharmacological effects such as leukocyte phagocytosis-enhancing action, macrophage phagocytosis-enhancing action, and infection prevention action, and are useful as agents for biological defense function. . These effects can be confirmed by the following method.
実験例７：白血球の實食能に対する作用シュトラセル（
Ｓｔｏｓｓｅｌ） らの方法〔ジャーナル・オブ・クリ
ニカル・インベステイゲーション（Ｊｏｕｒｎａｌ ｏ
ｆ Ｃｌ１ｎｉｃａｌ Ｉｎｖｅｓｔｉｇａｔｉｏｎ）
第５１ｊａ。Experimental Example 7: Effect of Strassel on the actual phagocytic ability of leukocytes (
Stossel et al. [Journal of Clinical Investigation (Journal of Clinical Investigation)
fClnical Investigation)
51st ja.
６１５頁、１９７２年〕に準じて行なった。615, 1972].
ＩＣＲマウス（体重３０〜３５ｇ）にグリコーゲンを腹
腔内投与し、３時間後に腹水白血球を採取し、５Ｘ１０
’個／−の白血球懸濁液を調製した。この懸濁液２００
μｌに試験化合物を加え、さらに１００Ｉ／ｆのマウス
血清および１００μ２のイースト死菌（ＩＸＩＯ”個／
−）を加え、３７°Ｃで２０分間反応させた。ついで反
応液中の約２００個の白血球を顕微鏡（倍率４００倍）
下で観察し、１個以上のイースト死菌を貧食した白血球
数を計数した。対照の白血球の貧食率に対し、化合物０
．１μＭ添加時の相対的割合を求めた。Glycogen was intraperitoneally administered to ICR mice (body weight 30-35 g), and ascitic fluid leukocytes were collected 3 hours later and 5x10
A suspension of '/- leukocytes was prepared. This suspension 200
Add test compound to μl, add 100 I/f of mouse serum and 100 μ2 of killed yeast bacteria (IXIO” cells/μl)
-) was added and reacted at 37°C for 20 minutes. Approximately 200 white blood cells in the reaction solution were then examined under a microscope (400x magnification).
The number of white blood cells that had phagocytosed one or more dead yeast cells was counted. Compared to the leukocyte phagocytosis rate of the control, compound 0
．． The relative proportion when 1 μM was added was determined.
実験例８：マクロファージの宜食能に対する作用カゼイ
ン・ナトリウムをラット腹腔内に投与し、３〜４日後に
腹腔内からマクロファージを採取した。を食能を実験例
７と同様に０．ＩＩＩＭ添加時の相対的割合を求めた。Experimental Example 8: Effect on the phagocytic ability of macrophages Sodium caseinate was intraperitoneally administered to rats, and macrophages were collected intraperitoneally 3 to 4 days later. The eating ability was set to 0.0 as in Experimental Example 7. The relative proportion when IIIM was added was determined.
実験例９：感染防御作用
５週令の雄性ＩＣＲマウス（体重２３〜２７ｇ）にシク
ロホスファマイト２００Ｉ１ｇ／ｌＣｇを腹腔内投与し
、４日後にニジエリシア・コリ（Ｅ、ｃｏｌｉ） ０
−１１１株ＩＸ１０−＠ＣＦＵをマウスの皮下に接種し
た（コントロール群）、同様に薬物投与群はシクロホス
ファマイト投与翌日より３日間、３１１ｇ／ｋｇを経口
投与した。 Ｒ０ｃｏｌｉ接種７日後のコントロール群
に対する薬物投与群の生存率を比較した。Experimental Example 9: Infection protection effect Cyclophosphamite 200I1g/lCg was intraperitoneally administered to 5-week-old male ICR mice (body weight 23-27g), and 4 days later, E. coli 0
-111 strain IX10-@CFU was subcutaneously inoculated into mice (control group). Similarly, in the drug administration group, 311 g/kg was orally administered for 3 days from the day after cyclophosphamite administration. Seven days after R0 coli inoculation, the survival rate of the drug-administered group was compared with that of the control group.
本発明化合物を医薬として用いる場合には、製薬上許容
される適宜の賦形剤、担体、希釈剤などの添加剤と混合
し、錠剤、カプセル剤、顆粒、シロップ剤、注射剤、坐
剤または散剤などの形態で投与できる。投与量は、たと
えば経口投与の場合、通常成人１日当り５〜５００■程
度であり、これを１回または数回に分けて投与すること
ができる。When the compound of the present invention is used as a medicine, it is mixed with appropriate pharmaceutically acceptable excipients, carriers, diluents, and other additives, and prepared into tablets, capsules, granules, syrups, injections, suppositories, or It can be administered in a form such as a powder. For example, in the case of oral administration, the dosage is usually about 5 to 500 ml per day for adults, and this can be administered once or in divided doses.
製剤処方例
本発明の化合物（１）１０■を含有する錠剤は次の処方
により調製することができる。Preparation Example Tablets containing 10 kg of the compound (1) of the present invention can be prepared according to the following formulation.
化合物（［） １０．０ ■乳
糖 ５８．５ ■トウモロコ
シデンプン ２５．０ ■結晶セルロース
２０．０ ■ポリビニルピロリドンに−
３０２，０■タルク ４．
０ ■ステアリン酸マグネシウム ０．５１２
０．０■
化合物（１）をアトマイザ−により粉砕し、平均粒子径
１０μ以下の微粉とする。化合物（１）、乳糖、トウモ
ロコシデンプンおよび結晶セルロースを練合機中で十分
に混合したのち、ポリビニルピロリドン糊液を加えて練
合する。練合物を２００メツシユの篩を通して造粒し、
５０℃の熱風乾燥機中で水分３〜４％となるまで乾燥し
、２４メツシユの篩を通したのち、タルクおよびステア
リン酸マグネシウムを混合し、ロータリー弐打錠機によ
り、直径８ｍｍの平面柱を用いて打錠する。Compound ([) 10.0 ■Lactose 58.5 ■Corn starch 25.0 ■Crystalline cellulose
20.0 ■Polyvinylpyrrolidone-
302,0 ■ Talc 4.
0 ■Magnesium stearate 0.512
0.0■ Compound (1) is pulverized using an atomizer to form a fine powder with an average particle size of 10 μm or less. Compound (1), lactose, corn starch and crystalline cellulose are thoroughly mixed in a kneader, and then a polyvinylpyrrolidone paste is added and kneaded. The mixture was granulated through a 200-mesh sieve,
After drying in a hot air dryer at 50°C to a moisture content of 3 to 4% and passing through a 24-mesh sieve, talc and magnesium stearate were mixed, and flat pillars with a diameter of 8 mm were formed using a rotary two-tablet machine. Compress tablets using
以下、本発明を実施例により具体的に説明するが、本発
明はこれらにより何ら限定されるものではない。EXAMPLES Hereinafter, the present invention will be specifically explained with reference to examples, but the present invention is not limited by these in any way.
実施例１
５−オキソ−２，３，４，５−テトラヒドロ−〔ｌ〕ベ
ンゾチエピン−４−酢酸４ｇをエタノール５０−に溶解
し、フェニルヒドラジン２．０１１７を加え、１２時間
加熱還流後、溶媒を留去し、酢酸２０ｍ７を加え２時間
加熱還流する。溶媒を留去し、水を加えた後、酢酸エチ
ルで抽出する。水洗後、無水硫酸マグネシウムにて乾燥
し、溶媒を留去する。粗生成物をカラムクロマトグラフ
ィーにて精製後、得られた結晶をエタノールから再結晶
すると、融点１３８〜１４０°Ｃの、２−フェニル−４
゜４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピノ
（５，４−Ｃ）ピリダジン−３（２Ｈ）−オン２．３ｇ
が得られる。Example 1 4 g of 5-oxo-2,3,4,5-tetrahydro-[l]benzothiepine-4-acetic acid was dissolved in 50% of ethanol, 2.0117 g of phenylhydrazine was added, and after heating under reflux for 12 hours, the solvent was evaporated. After evaporation, 20 m7 of acetic acid was added and the mixture was heated under reflux for 2 hours. The solvent is distilled off, water is added, and the mixture is extracted with ethyl acetate. After washing with water, it is dried over anhydrous magnesium sulfate and the solvent is distilled off. After the crude product was purified by column chromatography, the obtained crystals were recrystallized from ethanol to produce 2-phenyl-4 with a melting point of 138-140°C.
゜4a,5.6-tetrahydro[1]benzothiepino(5,4-C)pyridazin-3(2H)-one 2.3g
is obtained.
実施例２
実施例１で用いたフェニルヒドラジンの代ワリに、ヒド
ラジンを用いて同様の方法により反応および処理を行な
うと、融点１９８〜２００°Ｃの４゜４ａ、５．６−テ
トラヒドロー〔１〕ベンゾチエピノ （５，４−Ｃ）ピ
リダジン−３（２Ｈ）−オンが得られる。Example 2 When hydrazine was used in place of the phenylhydrazine used in Example 1 and the reaction and treatment were carried out in the same manner, 4°4a,5.6-tetrahydro [1] with a melting point of 198-200°C was obtained. Benzothiepino (5,4-C)pyridazin-3(2H)-one is obtained.
実施例３
実施例１で用いたフェニルヒドラジンの代わりに、４−
クロロフェニルヒドラジンを用いて同様の方法により反
応および処理を行なうと、融点１４０〜１４２°Ｃの２
−（４−クロロフェニル）−４゜４ａ、５．６−テトラ
ヒドロー〔１〕ベンゾチエピノＣ５，４−Ｃ）ピリダジ
ン−３（２Ｈ）−オンが得られる。Example 3 Instead of phenylhydrazine used in Example 1, 4-
A similar reaction and treatment using chlorophenylhydrazine yields 2
-(4-chlorophenyl)-4°4a,5,6-tetrahydro[1]benzothiepinoC5,4-C)pyridazin-3(2H)-one is obtained.
実施例４
５−オキソ−２，３，４，５−テトラヒドロ−〔１〕ベ
ンゾチエピン−４−酢酸４ｇをエタノール１００＠Ｚに
溶解し、４−メトキシフェニルヒドラジン・塩酸塩３．
５ｇおよび酢酸ナトリウム１．８ｇを加え、１２時間加
熱還流後、溶媒を留去し、さらに酢酸２０−を加え、２
時間加熱還流する。Example 4 4 g of 5-oxo-2,3,4,5-tetrahydro-[1]benzothiepine-4-acetic acid was dissolved in ethanol 100@Z, and 4-methoxyphenylhydrazine hydrochloride 3.
5 g and 1.8 g of sodium acetate were added, and after heating under reflux for 12 hours, the solvent was distilled off.
Heat to reflux for an hour.
ついで、溶媒を留去し、水を加え酢酸エチルで抽出後、
水洗し、無水硫酸マグネシウムにて乾燥後、溶媒を留去
する。得られた粗生成物をカラムクロマトグラフィーに
て精製し、さらにエタノールから再結晶すると、融点１
４３〜１４５°Ｃの２−（４−メトキシフェニル）
４．４ａ、５．５−テトラヒドロ−〔１〕ベンゾチエピ
ノ［５，４−Ｃ］ピリダジン−３（２Ｈ）−オン１．９
ｇが得られる。Then, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate.
After washing with water and drying over anhydrous magnesium sulfate, the solvent is distilled off. The obtained crude product was purified by column chromatography and further recrystallized from ethanol, resulting in a melting point of 1.
2-(4-methoxyphenyl) at 43-145°C
4.4a,5.5-tetrahydro-[1]benzothiepino[5,4-C]pyridazin-3(2H)-one 1.9
g is obtained.
実施例５
実施例４で用いた４−メトキシフェニルヒドラジン・塩
酸塩の代わりに、４−メチルフェニルヒドラジン・塩酸
塩を用いて同様の方法により反応および処理を行なうと
、融点１２８〜１３０“Ｃの２−（４−メチルフェニル
）−４，４ａ、５．６−テトラヒドローＮ）ベンゾチエ
ピノ〔５，４−Ｃ）ピリダジン−３（２Ｈ）−オンが得
られる。Example 5 When the reaction and treatment were carried out in the same manner using 4-methylphenylhydrazine hydrochloride instead of the 4-methoxyphenylhydrazine hydrochloride used in Example 4, a reaction product with a melting point of 128 to 130"C was obtained. 2-(4-methylphenyl)-4,4a,5,6-tetrahydroN)benzothiepino[5,4-C)pyridazin-3(2H)-one is obtained.
実施例６
実施例４で用いた４−メトキシフェニルヒドラジン・塩
酸塩の代わりに、３−クロロフェニルヒドラジン・塩酸
塩を用いて同様の方法により反応および処理を行なうと
、融点１２２〜１２３℃の２−（３−クロロフェニル）
−４，４ａ、５．６−テトラヒドロー〔１］ベンゾチ
エピノ〔５，４−Ｃ）ピリダジン−３（２Ｈ）−オンが
得られる。Example 6 When the reaction and treatment were carried out in the same manner using 3-chlorophenylhydrazine hydrochloride instead of 4-methoxyphenylhydrazine hydrochloride used in Example 4, 2- (3-chlorophenyl)
-4,4a,5.6-tetrahydro[1]benzothiepino[5,4-C)pyridazin-3(2H)-one is obtained.
実施例７
実施例４で用いた４−メトキシフェニルヒドラジン・塩
酸塩の代わりに、４−ブロモフェニルヒドラジン・塩酸
塩を用いて同様の方法により反応および処理を行なうと
、融点１３５〜１３７℃の２−（４−ブロモフェニル）
−４，４ａ、５．６−テトラヒドロー〔１〕ベンゾチエ
ピノ〔５，４−Ｃ）ピリダジン−３（２Ｈ）−オンが得
られる。Example 7 When 4-bromophenylhydrazine hydrochloride was used in place of the 4-methoxyphenylhydrazine hydrochloride used in Example 4 and the reaction and treatment were carried out in the same manner, 2. -(4-bromophenyl)
-4,4a,5.6-tetrahydro[1]benzothiepino[5,4-C)pyridazin-3(2H)-one is obtained.
実施例８
実施例４で用いた４−メトキシフェニルヒドラジン・塩
酸塩の代わりに、２−クロロフェニルヒドラジン・塩酸
塩を用いて同様の方法により反応および処理を行なうと
、融点１４８〜１５０ ”Ｃの２−（２−クロロフェニ
ル）−４，４ａ、５．６−テトラヒドロー〔１〕ベンゾ
チエピノ（５，４−Ｃ）ピリダジン−３（２Ｈ）−オン
が得られる。Example 8 When 2-chlorophenylhydrazine hydrochloride was used in place of 4-methoxyphenylhydrazine hydrochloride used in Example 4 and the reaction and treatment were carried out in the same manner, -(2-chlorophenyl)-4,4a,5,6-tetrahydro[1]benzothiepino(5,4-C)pyridazin-3(2H)-one is obtained.
実施例９
実施例４で用いた５−オキソ−２，３，４，５−テトラ
ヒドロ−〔１〕ベンゾチエビン−４−酢酸の代わりに、
７−クロロ−５−オキソ−２，３゜４．５−テトラヒド
ロ−（１）ベンゾチエビン−４〜酢酸を用いて同様の方
法により反応および処理を行なうと、融点１５９〜１６
１ ’ＣのｌＯ−クロロ−２−（４−メトキシフェニル
）−４，４ａ。Example 9 Instead of 5-oxo-2,3,4,5-tetrahydro-[1]benzothiebine-4-acetic acid used in Example 4,
7-chloro-5-oxo-2,3゜4.5-tetrahydro-(1) When the reaction and treatment were carried out in the same manner using benzothiebin-4~acetic acid, the melting point was 159-16.
1'C lO-chloro-2-(4-methoxyphenyl)-4,4a.
５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オンが得られる。5.6-tetrahydro[1]benzothiepino(5,4
-c) Pyridazin-3(2H)-one is obtained.
実施例１０
実施例４で用いた５−オキソ−２，３，４，５＝テトラ
ヒドロ−（１）ベンゾチエピン−４−酢酸の代わりに、
７−クロロ−５−オキソ−２，３゜４．５−テトラヒド
ロ−〔１〕ベンゾチエビン−４−酢酸を用い、さらに４
−メトキシフェニルヒドラジン・塩酸塩の代わりに、４
−クロロフェニルヒドラジン・塩酸塩を用いて同様の方
法により反応および処理を行なうと、融点１４１〜１４
３°Ｃの１０−クロロ−２−（４−クロロフェニル）−
４，４ａ、５．６−テトラヒド０−（１）ベンゾチエビ
ン（５，４−ｃ）ピリダジン−３（２Ｈ）−オンが得ら
れる。Example 10 Instead of 5-oxo-2,3,4,5=tetrahydro-(1)benzothiepine-4-acetic acid used in Example 4,
Using 7-chloro-5-oxo-2,3゜4.5-tetrahydro-[1]benzothiebin-4-acetic acid, further 4
-4 instead of methoxyphenylhydrazine hydrochloride
- When the reaction and treatment are carried out in the same manner using chlorophenylhydrazine hydrochloride, the melting point is 141-14
10-chloro-2-(4-chlorophenyl)- at 3°C
4,4a,5,6-tetrahydro-(1)benzothievin(5,4-c)pyridazin-3(2H)-one is obtained.
実施例１１
実施例１０で合成した１０−クロロ−２−（４−クロロ
フェニル）−４，４ａ、５．６−テトラヒドロー（１）
ベンゾチエピノ（５，４−ｃ）ピリダジン−３（２Ｈ）
−オン３．０ｇを酢酸９〇−に溶解し、内温４０〜５０
°Ｃにて臭素０． Ａ ｌ１７を加え、さらに同温にて
３０分撹拌後、減圧下に濃縮し水を加える。析出した結
晶を濾取し、クロロホルムに溶解し、水洗後無水硫酸マ
グネシウムにて乾燥し、溶媒を留去する。得られた粗生
成物をカラムクロマトグラフィーにて精製後、さらにク
ロロホルム−メタノールから再結晶すると、融点２１５
〜２１７°Ｃの１０−クロロ−２−（４−クロロフェニ
ル）−５，６−シヒドロー（１）ベンゾチエピノ（５，
４−ｃ）ピリダジン−３（２Ｈ）−オン２．４ｇが得ら
れる。Example 11 10-chloro-2-(4-chlorophenyl)-4,4a,5.6-tetrahydro (1) synthesized in Example 10
Benzothiepino(5,4-c)pyridazine-3(2H)
- Dissolve 3.0 g of -one in 90 - of acetic acid, internal temperature 40-50
0.0% bromine at °C. After adding Al17 and further stirring for 30 minutes at the same temperature, the mixture was concentrated under reduced pressure and water was added. The precipitated crystals are collected by filtration, dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The resulting crude product was purified by column chromatography and then recrystallized from chloroform-methanol, resulting in a melting point of 215.
10-chloro-2-(4-chlorophenyl)-5,6-sihydro(1)benzothiepino(5,
4-c) 2.4 g of pyridazin-3(2H)-one are obtained.
実施例１２
実施例１１で用いたｌＯ−クロロ−２−（４−クロロフ
ェニル）−４，４ａ、５．６−テトラヒドロー〔１〕ベ
ンゾチエピノ（５，４−Ｃ）ピリダジン−３（２Ｈ）−
オンの代わりに、２−（４−クロロフェニル）−４，４
ａ、５．６−テトラヒドロー〔１〕ベンゾチエピノ（５
，４−Ｃ）ピリダジン−３（２Ｈ）−オンを用いて同様
の方法により反応および処理を行なうと、融点１８５〜
１８６°Ｃの２−（４−クロロフェニル）−５，６＝ジ
ヒドロ−〔１〕ベンゾチエピノ（５，４−ｃ）ピリダジ
ン−３（２Ｈ）−オンが得られる。Example 12 lO-chloro-2-(4-chlorophenyl)-4,4a,5.6-tetrahydro[1]benzothiepino(5,4-C)pyridazine-3(2H)- used in Example 11
2-(4-chlorophenyl)-4,4 instead of
a, 5,6-tetrahydro[1]benzothiepino(5
, 4-C) Pyridazin-3(2H)-one was reacted and treated in a similar manner to give a melting point of 185~
2-(4-chlorophenyl)-5,6=dihydro-[1]benzothiepino(5,4-c)pyridazin-3(2H)-one is obtained at 186°C.
実施例１３
実施例１１で合成した１０−クロロ−２−（４−クロロ
フェニル）−５，６−シヒドロー［１）ベンゾチエピノ
（５，４−ｃ）ピリダジン−３（２Ｈ）−オン２．４ｇ
にアセトン３００−および水２５−を加え、撹拌下、次
亜臭素酸ナトリウム・３水和物２．８ｇを加える。室温
にて１８時間撹拌後、減圧下に濃縮し、水を加え、析出
した結晶を濾取し、ジメチルホルムアミド−水から再結
晶すると、融点２３９〜２４１℃（分解）の１０−クロ
ロ−２−（４−クロロフェニル）−５，６−シヒドロー
（１）ベンゾチエピノ （５，４−ｃ）ピリダジン−３
（２Ｈ）−オン・７−オキシド１．０ｇが得られる。Example 13 2.4 g of 10-chloro-2-(4-chlorophenyl)-5,6-sihydro[1)benzothiepino(5,4-c)pyridazin-3(2H)-one synthesized in Example 11
Add 300 g of acetone and 25 g of water, and add 2.8 g of sodium hypobromite trihydrate while stirring. After stirring at room temperature for 18 hours, it was concentrated under reduced pressure, water was added, and the precipitated crystals were collected by filtration and recrystallized from dimethylformamide-water to give 10-chloro-2- with a melting point of 239-241°C (decomposition). (4-chlorophenyl)-5,6-sihydro(1)benzothiepino (5,4-c)pyridazine-3
1.0 g of (2H)-one.7-oxide is obtained.
実施例１４
実施例１３で用いた１０−クロロ−２−（４−クロロフ
ェニル） −５，６−’；ヒドロー（１）ベンゾチエピ
ノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オンの代わ
りに、実施例１２で合成した２−（４−クロロフェニル
）−５，６−’、；ヒドロ−（１）ベンゾチエピノ（５
，４−ｃ）ピリダジン−３（２Ｈ）−オンを用いて同様
の方法により反応および処理を行なうと、融点２３３〜
２３４°Ｃ（分解）の２−（４−クロロフェニル）−５
，６−シヒドロー〔１〕ベンゾチエピノ （５，４−ｃ
）ピリダジン−３（２Ｈ）−オン・７−オキシドが得ら
れる。Example 14 10-chloro-2-(4-chlorophenyl)-5,6-' used in Example 13; instead of hydro(1) benzothiepino(5,4-c)pyridazin-3(2H)-one , 2-(4-chlorophenyl)-5,6-' synthesized in Example 12; Hydro-(1) benzothiepino(5
, 4-c) Pyridazin-3(2H)-one was reacted and treated in a similar manner to give a melting point of 233~
2-(4-chlorophenyl)-5 at 234°C (decomposition)
,6-sihydro[1]benzothiepino (5,4-c
) Pyridazin-3(2H)-one 7-oxide is obtained.
実施例１５
実施例１３で用いた１０−クロロ−２−（４−クロロフ
ェニル）−５，６−シヒドロー（１）ベンゾチエピノ（
５，４−ｃ）ピリダジン−３（２Ｈ）−オンの代わりに
、実施例４で合成した２−（４−メトキシフェニル）−
４，４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピ
ノ（５，４−ｃ）ピリダジン−３（２ｆ（）−オンを用
いて同様の方法により反応および処理を行なうと、融点
２０３〜２０５’Ｃ（分解）の２−（４−メトキシフェ
ニル）−４，４ａ、５．６−テトラヒドロー（１）ベン
ゾチエピノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オ
ン・７−オキシドが得られる。Example 15 10-chloro-2-(4-chlorophenyl)-5,6-sihydro(1)benzothiepino(
5,4-c) 2-(4-methoxyphenyl)- synthesized in Example 4 instead of pyridazin-3(2H)-one
A similar reaction and treatment using 4,4a,5,6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2f()-one) resulted in a reaction with a melting point of 203-205'C ( 2-(4-methoxyphenyl)-4,4a,5,6-tetrahydro(1)benzothiepino(5,4-c)pyridazin-3(2H)-one·7-oxide is obtained.
実施例１６
実施例１３で用いた１０−クロロ−２−（４−クロロフ
ェニル）−５，６−シヒドロー（１）ベンゾチエピノ（
５，４−ｃ）ピリダジン−３（２Ｈ）−オンの代わりに
、実施例１で合成した２−フェニル−４，４ａ、５．６
−テトラヒドロー〔１〕ベンゾチエピノ（５，４−ｃ）
ピリダジン−３（２Ｈ）−オンを用いて同様の方法によ
り反応および処理を行なうと、融点１８７〜１９０°Ｃ
（分解）の２−フェニル−４，４ａ、５．６−テトラヒ
ドロー〔１〕ベンゾチエピノ（５，４−ｃ）ピリダジン
−３（２Ｈ）−オン・７−オキシドが得られる。Example 16 10-chloro-2-(4-chlorophenyl)-5,6-sihydro (1) benzothiepino (
5,4-c) 2-phenyl-4,4a, 5.6 synthesized in Example 1 instead of pyridazin-3(2H)-one
-tetrahydro[1]benzothiepino(5,4-c)
A similar reaction and treatment using pyridazin-3(2H)-one resulted in a melting point of 187-190°C.
(Decomposition) of 2-phenyl-4,4a,5,6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one.7-oxide is obtained.
実施例１７
実施例１３で用いた１０−クロロ−２−（４−クロロフ
ェニル）−５，６−シヒドロー（１）ベンゾチエピノ（
５，４−ｃ）ピリダジン−３（２Ｈ）−オンの代わりに
、実施例３で合成した２−（４−クロロフェニル）−４
，４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピノ
（５，４−ｃ）ピリダジン−３（２Ｈ）−オンを用いて
同様の方法により反応および処理を行なうと、融点２１
７〜２２０℃（分解）の２−（４−クロロフェニル）−
４，４ａ、５．６−テトラヒドロー（１）ベンゾチエピ
ノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オン・７−
オキシドが得られる。Example 17 10-chloro-2-(4-chlorophenyl)-5,6-sihydro (1) benzothiepino (
5,4-c) 2-(4-chlorophenyl)-4 synthesized in Example 3 instead of pyridazin-3(2H)-one
, 4a, 5.6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one, reacted and treated in a similar manner yields a melting point of 21
2-(4-chlorophenyl)- at 7-220°C (decomposition)
4,4a,5.6-tetrahydro(1)benzothiepino(5,4-c)pyridazin-3(2H)-one 7-
Oxide is obtained.
実施例１８
実施例１７で得られた２−（４−クロロフェニル）−４
，４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピノ
（５，４−ｃ）ピリダジン−３（２Ｈ）−オン・７−オ
キシドをヘキサン−酢酸エチル（３１）の混合溶媒を溶
出液としてシリカゲルカラムクロマトグラフィーにより
分離、精製し、第１溶出部から得られる結晶をイソプロ
ピルアルコールから再結晶すると、融点２４７〜２４８
’Ｃ（分解）の（４ａＲ” 、７Ｓ”）−２−（４−ク
ロロフェニル）−４，４ａ、５．６−テトラヒドロー〔
１〕ヘンゾチエピノ（５，４−’ｃ）ピリダジン−３（
２Ｈ）−オン・７−オキシドが得られる。また、第２溶
出部から得られる結晶をイソプロピルアルコールから再
結晶すると、融点１９０〜１９１°Ｃ（分解）の（４ａ
Ｒ”、７Ｒ”）−２−（４−クロロフェニル）−４，４
ａ、５．６−テトラヒドロー〔１〕ベンゾチエピノ（５
，４−Ｃ〕ピリダジン−３（２Ｈ）−オン・７−オキシ
ドが得られる。Example 18 2-(4-chlorophenyl)-4 obtained in Example 17
, 4a, 5.6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one 7-oxide was subjected to silica gel column chromatography using a mixed solvent of hexane-ethyl acetate (31) as the eluent. When the crystals obtained from the first elution part are recrystallized from isopropyl alcohol, the melting point is 247-248.
'C (decomposition) of (4aR'', 7S'')-2-(4-chlorophenyl)-4,4a,5.6-tetrahydro [
1] Henzothiepino(5,4-'c)pyridazine-3(
2H)-one 7-oxide is obtained. In addition, when the crystals obtained from the second elution part are recrystallized from isopropyl alcohol, (4a
R", 7R")-2-(4-chlorophenyl)-4,4
a, 5,6-tetrahydro[1]benzothiepino(5
,4-C]pyridazin-3(2H)-one 7-oxide is obtained.
実施例１９
実施例１３で用いた１０−クロロ−２−（４−クロロフ
ェニル）−５，６−シヒドロー（１）ベンゾチエピノ（
５，４−ｃ）ピリダジン−３（２Ｈ）−オンの代わりに
、実施例１０７合成した１０−クロロ−２−（４−クロ
ロフェニル）−４，４ａ。Example 19 10-chloro-2-(4-chlorophenyl)-5,6-sihydro (1) benzothiepino (
5,4-c) 10-chloro-2-(4-chlorophenyl)-4,4a synthesized in Example 107 in place of pyridazin-3(2H)-one.
５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−ｃ）ピリダジン−３＜２Ｈ）−オンを用いて同様の方
法により反応および処理を行なうと、融点１９８〜２０
２°Ｃ（分解）の１０−クロロ−２−（４〜クロロフエ
ニル）−４，４ａ、５゜６−テトラヒドロー（１）ベン
ゾチエピノ〔５゜４−〇〕ピリダジンー３ （２Ｈ）−
オン・７−オキシドが得られる。5.6-tetrahydro[1]benzothiepino(5,4
-c) Pyridazin-3<2H)-one, when reacted and treated in a similar manner, has a melting point of 198-20
10-chloro-2-(4-chlorophenyl)-4,4a, 5°6-tetrahydro(1)benzothiepino[5°4-〇]pyridazine-3(2H)- at 2°C (decomposed)
7-oxide is obtained.
実施例２０
実施例１４で合成した２−（４−クロロフェニル）−５
，６−シヒドロー（１）ペンゾチェビノ［５，４−ｃ）
ピリダジン−３（２Ｈ）−オン・７−オキシド１４ｇを
酢酸２００−に溶解し、撹拌下、室温にて過酸化水素１
５１１を加える。さらに５０〜５５°Ｃにて２時間撹拌
後、反応液を水ｌｌにあけ、析出した結晶を濾取する。Example 20 2-(4-chlorophenyl)-5 synthesized in Example 14
,6-sihydro(1)penzochevino[5,4-c)
14 g of pyridazin-3(2H)-one 7-oxide was dissolved in 200 g of acetic acid, and 1 g of hydrogen peroxide was dissolved at room temperature under stirring.
Add 511. After further stirring at 50 to 55°C for 2 hours, the reaction solution was poured into 1 liter of water, and the precipitated crystals were collected by filtration.
得られた粗生成物をシリカゲルカラムクロマトグラフィ
ーにて精製し、クロロホルム−メタノールから再結晶す
ると、融点３１０”Ｃ以上の２−（４−クロロフェニル
）−５，６−シヒドロー（１）ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オン・７．７−ジオキ
シド９．８ｇが得られる。The obtained crude product was purified by silica gel column chromatography and recrystallized from chloroform-methanol to give 2-(4-chlorophenyl)-5,6-sihydro(1)benzothiepino(5, 4
-c) 9.8 g of pyridazin-3(2H)-one 7,7-dioxide are obtained.
実施例２１
実施例１で用いた５−オキソ−２，３，４，５−テトラ
ヒドロ−〔１〕ベンゾチエビン−４−酢酸の代わりに、
７−フルオロ−５−オキソ−２゜３．４．５−テトラヒ
ドロ＝〔ｌ）ベンゾチエピン−４−酢酸を用い、さらに
フェニルヒドラジンの代わりに、４−クロロフェニルヒ
ドラジンを用いて同様の方法により反応および処理を行
なうと、融点１４１〜１４２°Ｃの２−（４−クロロフ
ェニル）−１０−フルオロ−４，４ａ、５．６−テトラ
ヒドロー〔１〕ベンゾチエピノ（５，４−ｃ）ピリダジ
ン−３（２Ｈ）−オンが得られる。Example 21 Instead of 5-oxo-2,3,4,5-tetrahydro-[1]benzothiebine-4-acetic acid used in Example 1,
Reaction and treatment in the same manner using 7-fluoro-5-oxo-2゜3.4.5-tetrahydro=[l)benzothiepine-4-acetic acid and using 4-chlorophenylhydrazine instead of phenylhydrazine. When carried out, 2-(4-chlorophenyl)-10-fluoro-4,4a,5,6-tetrahydro[1]benzothiepino(5,4-c)pyridazine-3(2H)- with a melting point of 141-142°C On is obtained.
実施例２２
実施例１１で用いた１０−クロロ−２−（４−クロロフ
ェニル）−４，４ａ、５．６−テトラヒドロー〔１〕ベ
ンゾチエピノ（５，４−ｃ）ピリダジン−３（２Ｈ）−
オンの代わりに、２−（４−クロロフェニル）−１０−
フルオロ−４，４ａ。Example 22 10-chloro-2-(4-chlorophenyl)-4,4a,5.6-tetrahydro[1]benzothiepino(5,4-c)pyridazine-3(2H)- used in Example 11
2-(4-chlorophenyl)-10- instead of
Fluoro-4,4a.
５．６−テトラヒドロー〔１］ヘンゾチエビノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オンを用いて同様の方
法により反応および処理を行なうと、融点１６０〜１６
２°Ｃの２−（４−クロロフェニル）−１Ｏ−フルオロ
−５，６−シヒドロー〔１〕ベンゾチエピノ（５，４−
ｃ）ピリダジン−３（２Ｈ）−オンが得られる。5.6-tetrahydro[1]henzothievino (5,4
-c) Reaction and treatment in a similar manner with pyridazin-3(2H)-one, melting point 160-16
2-(4-chlorophenyl)-1O-fluoro-5,6-sihydro[1]benzothiepino(5,4-
c) Pyridazin-3(2H)-one is obtained.
実施例２３
実施例２２で合成した２−（４−クロロフェニル）−１
０−フルオロ−５，６−シヒドロー〔１〕ベンゾチエピ
ノ（５，４’−ｃ）ピリダジン−３（２Ｈ）−オン１．
８ ｇを酢酸２０ａ７に熔解し、室温撹拌下、３５％過
酸化水素水１．３−を加える。Example 23 2-(4-chlorophenyl)-1 synthesized in Example 22
0-Fluoro-5,6-sihydro[1]benzothiepino(5,4'-c)pyridazin-3(2H)-one 1.
8 g was dissolved in 20a7 of acetic acid, and 1.3 - 35% hydrogen peroxide solution was added while stirring at room temperature.
さらに同温にて５時間撹拌後、水を加え、析出した結晶
を濾取し、ジメチルホルムアミド−水から再結晶すると
、融点２３３〜２３５°Ｃ（分解）の２−（４−クロロ
フェニル）−１０−フルオロ−５，６−シヒドロー〔１
〕ベンゾチエピノ〔５゜４−ｃ］ピリダジン−３（２Ｈ
）−オン・７−オキシド１．３ｇが得られる。After further stirring for 5 hours at the same temperature, water was added, and the precipitated crystals were collected by filtration and recrystallized from dimethylformamide-water. -Fluoro-5,6-sihydro[1
]Benzothiepino[5゜4-c]pyridazine-3(2H
1.3 g of )-one 7-oxide are obtained.
実施例２４
９−クロロ−５−オキソ−２，３，４，５−テトラヒド
ロ＝（１）ベンゾチエビン−４−酢酸８ｇをブタノール
１００−に溶解し、４−クロロフェニルヒドラジン５ｇ
を加え、１６時間加熱還流する。溶媒を留去し、残金に
酢酸２０−を加え、５時間加熱還流する。溶媒を留去後
、残金に水を加え、酢酸エチルで抽出する。炭酸水素ナ
トリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥
し、溶媒を留去する。残金をシリカゲルカラムクロマト
グラフィーにより精製すると淡褐色油状物質３ｇを得る
。Example 24 9-chloro-5-oxo-2,3,4,5-tetrahydro (1) Dissolve 8 g of benzothiebin-4-acetic acid in 100-butanol, and dissolve 5 g of 4-chlorophenylhydrazine.
and heated under reflux for 16 hours. The solvent was distilled off, and 20% of acetic acid was added to the residue, followed by heating under reflux for 5 hours. After evaporating the solvent, water is added to the residue and extracted with ethyl acetate. After washing with an aqueous sodium hydrogen carbonate solution, drying over anhydrous magnesium sulfate, and distilling off the solvent. The residue was purified by silica gel column chromatography to obtain 3 g of a pale brown oil.
このものを酢酸３０ａＺに溶解し、室温上臭素０．４１
−を加え、さらに内温４０〜５０℃で１時間撹拌する０
反応終了後、溶媒を減圧にて留去し、残金をシリカゲル
カラムクロマトグラフィーにて精製後、エタノールから
再結晶すると、融点１６６〜１６８°Ｃの８−クロロ−
２−（４−クロロホルム／Ｌ／）−５，６−シヒドロー
（１）ベンゾチエビン（５，４−ｃ）ピリダジン−３（
２Ｈ）−オンが得られる。Dissolve this in 30aZ of acetic acid and add 0.41% of bromine at room temperature.
- and stir for 1 hour at an internal temperature of 40-50℃.
After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from ethanol to give 8-chloro-
2-(4-chloroform/L/)-5,6-sihydro(1)benzothiebine(5,4-c)pyridazine-3(
2H)-one is obtained.
実施例２５
実施例２４で合成した８−クロロ−２−（４−クロロフ
ェニル）−５，６−シヒドロー（１）ベンゾチエピノ（
５，４−ｃ）ピリダジン−３（２Ｈ）−オン０．９ｇを
酢酸２０ｍに溶解し、室温にて撹拌下、３５％過酸化水
素水０．６１１７を加え、さらに同温にて１８時間撹拌
する。水を加え、析出する結晶を濾取し、さらにエタノ
ールで洗浄をくり返すと、融点２１７〜２１９°Ｃ（分
解）の８−クロロ−２−（４−クロロフェニル）−５，
６−ジヒドロー〔１〕ベンゾチエピノ（５，４−ｃ）ピ
リダジン−３（２Ｈ）−オン・７−オキシド０．７ｇが
得られる。Example 25 8-chloro-2-(4-chlorophenyl)-5,6-sihydro(1) benzothiepino (
5,4-c) Dissolve 0.9 g of pyridazin-3(2H)-one in 20 m of acetic acid, add 0.6117 g of 35% hydrogen peroxide while stirring at room temperature, and stir at the same temperature for 18 hours. do. By adding water, filtering the precipitated crystals, and repeating the washing with ethanol, 8-chloro-2-(4-chlorophenyl)-5, with a melting point of 217-219°C (decomposition),
0.7 g of 6-dihydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one.7-oxide is obtained.
実施例２６
４．４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピ
ノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オン９２ｇ
を酢酸９２０ｓ７に加え、５０〜６０°Ｃで臭素６４ｇ
を滴下し、同温に１時間保つ、大量の水に注ぎ込み、生
じた結晶を濾取する。塩水、次いでエタノールで洗浄後
乾燥すると、５．６−シヒドロー〔１〕ベンゾチエピノ
［５，４−ｃ）ピリダジン−３（２８）−オン８５ｇを
得る。融点３１１〜３１３’Ｃ（分解）。Example 26 92 g of 4.4a,5.6-tetrahydro[1]benzothiepino(5,4-c)pyridazin-3(2H)-one
was added to 920s7 of acetic acid, and 64g of bromine was added at 50-60°C.
was added dropwise, kept at the same temperature for 1 hour, poured into a large amount of water, and the crystals formed were collected by filtration. After washing with brine and then with ethanol and drying, 85 g of 5,6-sihydro[1]benzothiepino[5,4-c)pyridazin-3(28)-one are obtained. Melting point 311-313'C (decomposed).
実施例２７
実施例２６で得た化合物５ｇをジメチルホルムアミド５
０−に熔解し、６０％水素化ナトリウム１．０ｇを添加
後、３０分間撹拌する。３５〜４０°Ｃでヨウ化メチル
５ｇを滴下し、同温に１時間保つ０反応液を水に注ぎ、
酢酸エチルにて抽出後、水洗し、硫酸マグネシウムで乾
燥する。濃縮して得た結晶を濾取し、エタノールから再
結晶すると、２−メチル−５，６−シヒドロー〔１〕ベ
ンゾチエピノＣ５，４−ｃ）ピリダジン−３（２Ｈ）−
オン２．８ｇを得る。融点１３９〜１４０°Ｃ０実施例
２８
実施例２７のヨウ化メチルの代わりにベンジルクロライ
ドを用いると、２−ベンジル−５，６−シヒドロー〔１
〕ベンゾチエピノ（５，４−ｃ）ピリダジン−３（２Ｈ
）−オンが得られる。融点１９０〜１９２℃。Example 27 5 g of the compound obtained in Example 26 was mixed with 5 g of dimethylformamide.
After adding 1.0 g of 60% sodium hydride, the mixture is stirred for 30 minutes. Add 5 g of methyl iodide dropwise at 35-40°C and keep at the same temperature for 1 hour. Pour the reaction solution into water.
After extraction with ethyl acetate, it is washed with water and dried over magnesium sulfate. The crystals obtained by concentration were collected by filtration and recrystallized from ethanol to give 2-methyl-5,6-cyhydro[1]benzothiepinoC5,4-c)pyridazine-3(2H)-
Obtain 2.8 g of on. Melting point 139-140°C0 Example 28 When benzyl chloride is used in place of methyl iodide in Example 27, 2-benzyl-5,6-cyhydro[1
]Benzothiepino(5,4-c)pyridazine-3(2H
)-on is obtained. Melting point: 190-192°C.
実施例２９
実施例２７のヨウ化メチルの代わりに４−クロロベンジ
ルクロライドを用いると、２−（４−クロロベンジル）
−５，６−シヒドロー（’１）ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オンが得られる。融点
２２４〜２２５°Ｃ０実施例３０
実施例２７のヨウ化メチルの代わりに臭化ブチルを用い
ると、２−ブチル−５，６−シヒドロー〔１〕ベンゾチ
エピノ（５，４−ｃ）ピリダジン−３（２Ｈ）−オンが
得られる。融点１０８〜１１０゛Ｃゆ
実施例３１
実施例２日で得た化合物５．８ｇを酢酸２００ａｆに溶
かし、３５％過酸化水素５ｇを添加し、室温に５時間保
つ、氷水に注ぎ込み、生じた結晶を濾取し、６０％酢酸
水溶液から再結晶すると、２−（４−クロロベンジル）
−５，６−シヒドロー〔１〕ベンゾチエピノ（５，４−
ｃ）ピリダジン−３（２Ｈ）−オン・７−オキシド４．
２ｇが得られる。融点２０７〜２０９°Ｃ（分解）。Example 29 When 4-chlorobenzyl chloride is used in place of methyl iodide in Example 27, 2-(4-chlorobenzyl)
-5,6-sihydro('1)benzothiepino(5,4
-c) Pyridazin-3(2H)-one is obtained. Melting point 224-225°C0 Example 30 When butyl bromide is used in place of methyl iodide in Example 27, 2-butyl-5,6-sihydro[1]benzothiepino(5,4-c)pyridazine-3( 2H)-one is obtained. Melting point: 108-110°C Example 31 5.8 g of the compound obtained in Example 2 was dissolved in 200 af of acetic acid, 5 g of 35% hydrogen peroxide was added, kept at room temperature for 5 hours, poured into ice water, and the crystals formed. was collected by filtration and recrystallized from 60% acetic acid aqueous solution to obtain 2-(4-chlorobenzyl).
-5,6-sihydro[1]benzothiepino(5,4-
c) Pyridazin-3(2H)-one 7-oxide4.
2g is obtained. Melting point 207-209°C (decomposed).
実施例３２
実施例３１で得た化合物３．４ｇを酢酸２０〇−に加え
、４５〜５０°Ｃにて加熱溶解する。３５％過酸化水素
水２０ｇを添加し、同温に３時間保つ。Example 32 3.4 g of the compound obtained in Example 31 was added to 200% of acetic acid and dissolved by heating at 45 to 50°C. Add 20 g of 35% hydrogen peroxide solution and keep at the same temperature for 3 hours.
大量の水に注ぎ込み、生じた結晶を濾取し、水洗後、６
０％酢酸水溶液から再結晶すると、２−（４１０ロベン
ジル） ５．６−’）ヒ）ロー〔１〕ベンゾチエピノ
（５，４−ｃ）ピリダジン−３（２Ｈ）−オン・７，７
−ジオキシド２．６ｇを得る。融点２３８〜２３９°Ｃ
（分解）。Pour into a large amount of water, collect the formed crystals by filtration, wash with water,
Recrystallization from 0% acetic acid aqueous solution yields 2-(410 lobenzyl) 5.6-')hi)low[1]benzothiepino(5,4-c)pyridazin-3(2H)-one 7,7
-2.6 g of dioxide are obtained. Melting point 238-239°C
(Disassembly).
上記実施例と同様にして以下の化合物が得られる。The following compounds are obtained in the same manner as in the above examples.
実施例３３
２−（４−ブロモフェニル）−５，６−シヒドロー〔１
〕ベンゾチエピノ（５，４−ｃ）ピリダジン−３（２Ｈ
）−オン・７−オキシド、融点２２７°Ｃ（分解）
実施例３４
ＩＯ−メチル−４，４ａ、５．６−テトラヒドロー〔１
〕ベンゾチエピノ（５，４−ｃ）ピリダジン−３（２Ｈ
）−オン、融点１８５〜１８７°Ｃ実施例３５
２−（４−クロロフェニル）−１０−メチル−４，４ａ
、５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，
４−ｃ）ピリダジン−３（２Ｈ）−オン、融点１５１〜
１５３°Ｃ
実施例３６
１０−メチル−２−（４−メチルフェニル）−４，４ａ
、５．６−テトラヒドロー〔１〕ペンゾチエピノ（５，
４−ｃ）ピリダジン−３（２Ｈ）−オン、融点１６４〜
１６６℃
実施例３７
２−（４−ブロモフェニル）−４，４ａ、５゜６−テト
ラヒドロー〔１〕ベンゾチエピノ〔５゜４−Ｃ〕ピリダ
ジン−３（２Ｈ）−オン・７−オ牛シト、融点２２７〜
２２９℃（分解）実施例３８
２−（４−ブロモフェニル）−５，６−シヒドロー（１
）ベンゾチエピノＣ５，４−ｃ）ピリダジン−３（２Ｈ
）−オン、融点１９９〜２０１℃実施例３９
２−（４−クロロフェニル）−１０−メチル＝５．６−
シヒドロー（１〕ベンゾチエピノ 〔５゜４−ｃ〕ピリ
ダジン−３（２Ｈ）−オン、融点１８２〜１８４℃
実施例４０
２−（４−クロロフェニル）−ＩＯ−メチル−５，６−
シヒドロー〔１〕ベンゾチエピノ〔５゜４−Ｃ〕ピリダ
ジン−３（２Ｈ）−オン・７−オキシド、融点２３７〜
２３９°Ｃ（分解）実施例４１
１０−フルオロ−２−（４−フルオロフェニル）−４，
４ａ、５．６−テトラヒドロー〔１〕ベンゾチエピノ（
５，４−ｃ）ピリダジン−３（２Ｈ）−オン、融点１７
５〜１７７°Ｃ
実施例４２
１０−フルオロ−２−（４−フルオロフェニル）−５，
６−シヒドロー〔１〕ベンゾチエピノ〔５゜４−Ｃ〕ピ
リダジン−３（２Ｈ）−オン、融点１６９〜１７１°Ｃ
実施例４３
１０−フルオロ−２−（４−フルオロフェニル）−５，
６−シヒドロー〔１〕ベンゾチエピノ〔５゜４−Ｃ〕ピ
リダジン−３（２Ｈ）−オン・７−オキシド、融点２２
７〜２２９°Ｃ（分解）実施例４４
２−（４−フルオロフェニル）−４，４ａ、５゜６−テ
トラヒドロー〔１〕ベンゾチエピノ〔５゜４−Ｃ〕ピリ
ダジン−３（２Ｈ）−オン、融点１４６〜１４７°Ｃ
実施例４５
２−（４−フルオロフェニル）−５，６−シヒドロー〔
１〕ベンゾチエピノ（５，４−ｃ）ピリダジン−３（２
Ｈ）−オン、融点１６３〜１６５℃
実施例４６
２−（４−フルオロフェニル）−５，６−シヒドロー〔
１〕ベンゾチエピノ（５，４−ｃ）ピリダジン−３（２
Ｈ）−オン・７−オキシド、融点２２５〜２２６°Ｃ（
分解）
実施例４７
２−（３，４−ジクロロフェニル）−４，４ａ。Example 33 2-(4-bromophenyl)-5,6-sihydro[1
]Benzothiepino(5,4-c)pyridazine-3(2H
)-one 7-oxide, melting point 227°C (decomposition) Example 34 IO-methyl-4,4a,5,6-tetrahydro[1
]Benzothiepino(5,4-c)pyridazine-3(2H
)-one, melting point 185-187°C Example 35 2-(4-chlorophenyl)-10-methyl-4,4a
, 5.6-tetrahydro[1]benzothiepino (5,
4-c) Pyridazin-3(2H)-one, melting point 151~
153°C Example 36 10-methyl-2-(4-methylphenyl)-4,4a
, 5.6-tetrahydro[1]penzothiepino (5,
4-c) Pyridazin-3(2H)-one, melting point 164~
166°C Example 37 2-(4-bromophenyl)-4,4a, 5゜6-tetrahydro[1]benzothiepino[5゜4-C]pyridazin-3(2H)-one 7-oxito, melting point 227～
229°C (decomposition) Example 38 2-(4-bromophenyl)-5,6-sihydro(1
) BenzothiepinoC5,4-c) Pyridazine-3(2H
)-one, melting point 199-201°C Example 39 2-(4-chlorophenyl)-10-methyl = 5.6-
Sihydro(1)benzothiepino[5°4-c]pyridazin-3(2H)-one, melting point 182-184°C Example 40 2-(4-chlorophenyl)-IO-methyl-5,6-
Sihydro[1]benzothiepino[5゜4-C]pyridazin-3(2H)-one 7-oxide, melting point 237~
239°C (decomposition) Example 41 10-fluoro-2-(4-fluorophenyl)-4,
4a,5.6-tetrahydro[1]benzothiepino(
5,4-c) Pyridazin-3(2H)-one, melting point 17
5-177°C Example 42 10-fluoro-2-(4-fluorophenyl)-5,
6-Sihydro[1]benzothiepino[5°4-C]pyridazin-3(2H)-one, melting point 169-171°C Example 43 10-fluoro-2-(4-fluorophenyl)-5,
6-Sihydro[1]benzothiepino[5゜4-C]pyridazin-3(2H)-one 7-oxide, melting point 22
7-229°C (decomposition) Example 44 2-(4-fluorophenyl)-4,4a, 5°6-tetrahydro[1]benzothiepino[5°4-C]pyridazin-3(2H)-one, melting point 146-147°C Example 45 2-(4-fluorophenyl)-5,6-sihydro [
1] Benzothiepino(5,4-c)pyridazine-3(2
H)-one, melting point 163-165°C Example 46 2-(4-fluorophenyl)-5,6-sihydro[
1] Benzothiepino(5,4-c)pyridazine-3(2
H)-one 7-oxide, melting point 225-226°C (
Decomposition) Example 47 2-(3,4-dichlorophenyl)-4,4a.
５．６−テトラヒドロー〔１〕ベンゾチエピノ（５，４
−Ｃ）ピリダジン−３（２Ｈ）−オン、融点１３４〜１
３６°Ｃ
実施例４８
１０−フルオロ−２−（３，４−ジクロロフェニル）−
５，６−シヒドロー（１）ベンゾチエピノ（５，４−Ｃ
）ピリダジン−３（２Ｈ）−オン、融点１５６〜１５７
°Ｃ
実施例４９
１０−フルオロ−２−（３４リフルオロメチルフエニル
）−５，６−シヒドロー（１）ベンゾチエピノ（５，４
−ｃ）ピリダジン−３（２Ｈ）−オン・７−オキシド、
融点２０３〜２０４ ”Ｃ（分解）
実施例５０
１０−フルオロ−２−（３，４−ジクロロフェニル）−
５，６−シヒドロー（１）ベンゾチエピノ（５，４−ｃ
）ピリダジン−３（２Ｈ）−オン・７，７−ジオキシド
、融点２５３〜２５５°Ｃ（分解）
実施例５１
８−クロロ−２−（４−クロロフェニル）−５゜６−シ
ヒドロー〔１〕ベンゾチエピノ（５，４−Ｃ〕ピリダジ
ン−３（２Ｈ）−オン・７．７−ジオキシド、融点２１
９〜２２０’Ｃ（分解）本発明を上述の明細書およびそ
れに包含される実施例で十分に説明したが、これらは本
発明の精神と範囲に反することなく種々に変更、修飾す
ることができる。5.6-tetrahydro[1]benzothiepino(5,4
-C) Pyridazin-3(2H)-one, melting point 134-1
36°C Example 48 10-Fluoro-2-(3,4-dichlorophenyl)-
5,6-sihydro(1)benzothiepino(5,4-C
) Pyridazin-3(2H)-one, melting point 156-157
°C Example 49 10-fluoro-2-(34lifluoromethylphenyl)-5,6-sihydro(1)benzothiepino(5,4
-c) pyridazin-3(2H)-one 7-oxide,
Melting point 203-204"C (decomposition) Example 50 10-Fluoro-2-(3,4-dichlorophenyl)-
5,6-sihydro(1)benzothiepino(5,4-c
) Pyridazin-3(2H)-one 7,7-dioxide, melting point 253-255°C (decomposition) Example 51 8-chloro-2-(4-chlorophenyl)-5°6-sihydro[1]benzothiepino( 5,4-C]pyridazin-3(2H)-one 7,7-dioxide, melting point 21
9-220'C (Decomposition) The present invention has been fully explained in the above specification and the examples included therein, but these can be variously changed and modified without departing from the spirit and scope of the present invention. .
Claims (1)
ロゲン、トリフルオロメチル、ヒドロキシ、アミノ、ニ
トロ、シアノ、Ｃ＿１＿−＿４アルキル、Ｃ＿１＿−＿
４アルコキシまたはＣ＿２＿−＿５アルカノイルアミノ
を、Ｒ＾３は水素、Ｃ＿１＿−＿８アルキル、ヒドロキ
シ−Ｃ＿１＿−＿４アルキル、Ｃ＿２＿−＿５アルカノ
イルオキシ−Ｃ＿１＿−＿４アルキル、アリール、アリ
ール−Ｃ＿１＿−＿４アルキル、ヘテロアリールまたは
芳香環上にハロゲン、トリフルオロメチル、ヒドロキシ
、アミノ、ニトロ、シアノ、Ｃ＿１＿−＿４アルキル、
Ｃ＿１＿−＿４アルコキシおよびＣ＿２＿−＿５アルカ
ノイルアミノから選ばれる置換基を１〜３個有するアリ
ール、アリール−Ｃ＿１＿−＿４アルキルもしくはヘテ
ロアリールを、ｎは０、１または２を、４位と４ａ位と
の間の結合■は単結合または二重結合を示す。） で表わされるベンゾチエピノ〔５，４−ｃ〕ピリダジン
化合物。[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 and R^2 are the same or different and represent hydrogen, halogen, trifluoromethyl, hydroxy, amino, nitro, Cyano, C_1_-_4 alkyl, C_1_-_
4 alkoxy or C_2_-_5 alkanoylamino, R^3 is hydrogen, C_1_-_8 alkyl, hydroxy-C_1_-_4 alkyl, C_2_-_5 alkanoyloxy-C_1_-_4 alkyl, aryl, aryl-C_1_-_4 alkyl, heteroaryl or halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C_1_-_4 alkyl on the aromatic ring,
Aryl, aryl-C_1_-_4 alkyl or heteroaryl having 1 to 3 substituents selected from C_1_-_4 alkoxy and C_2_-_5 alkanoylamino, where n is 0, 1 or 2, and between the 4-position and the 4a-position The bond between ■ indicates a single bond or a double bond. ) A benzothiepino[5,4-c]pyridazine compound represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63048464A JPH01250383A (en) | 1987-03-02 | 1988-03-01 | Benzothiepino(5,4-c)pyridazine compound |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62-48497 | 1987-03-02 | ||
| JP4849787 | 1987-03-02 | ||
| JP62-172469 | 1987-07-09 | ||
| JP62-306227 | 1987-12-02 | ||
| JP63048464A JPH01250383A (en) | 1987-03-02 | 1988-03-01 | Benzothiepino(5,4-c)pyridazine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01250383A true JPH01250383A (en) | 1989-10-05 |
| JPH0555509B2 JPH0555509B2 (en) | 1993-08-17 |
Family
ID=26388741
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63048464A Granted JPH01250383A (en) | 1987-03-02 | 1988-03-01 | Benzothiepino(5,4-c)pyridazine compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01250383A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993004069A1 (en) * | 1991-08-27 | 1993-03-04 | Yoshitomi Pharmaceutical Industries, Ltd. | Fused pyridazine compound and pharmaceutical use thereof |
| US5597918A (en) * | 1991-08-27 | 1997-01-28 | Yoshitomi Pharmaceutical Industries, Ltd. | Fused pyridazine compound |
-
1988
- 1988-03-01 JP JP63048464A patent/JPH01250383A/en active Granted
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993004069A1 (en) * | 1991-08-27 | 1993-03-04 | Yoshitomi Pharmaceutical Industries, Ltd. | Fused pyridazine compound and pharmaceutical use thereof |
| US5597918A (en) * | 1991-08-27 | 1997-01-28 | Yoshitomi Pharmaceutical Industries, Ltd. | Fused pyridazine compound |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0555509B2 (en) | 1993-08-17 |
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