JPH07620B2 - Condensed imidazopyridine derivative - Google Patents
Condensed imidazopyridine derivativeInfo
- Publication number
- JPH07620B2 JPH07620B2 JP24812086A JP24812086A JPH07620B2 JP H07620 B2 JPH07620 B2 JP H07620B2 JP 24812086 A JP24812086 A JP 24812086A JP 24812086 A JP24812086 A JP 24812086A JP H07620 B2 JPH07620 B2 JP H07620B2
- Authority
- JP
- Japan
- Prior art keywords
- crystals
- water
- acid
- yield
- 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.)
- Expired - Fee Related
Links
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 150000002431 hydrogen Chemical group 0.000 claims description 9
- 229940001470 psychoactive drug Drugs 0.000 claims description 7
- 239000004089 psychotropic agent Substances 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims 2
- 239000013078 crystal Substances 0.000 description 95
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 82
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- 239000000243 solution Substances 0.000 description 45
- 238000002844 melting Methods 0.000 description 42
- 230000008018 melting Effects 0.000 description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- 238000000921 elemental analysis Methods 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 31
- 238000003756 stirring Methods 0.000 description 28
- -1 1-methylisobutyl Chemical group 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 25
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 25
- 238000001914 filtration Methods 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
- 238000001953 recrystallisation Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 17
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- 239000005457 ice water Substances 0.000 description 16
- 238000000354 decomposition reaction Methods 0.000 description 14
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 9
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 9
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- UTOMICFLROGMAE-UHFFFAOYSA-N quinoline-3,4-diamine Chemical compound C1=CC=CC2=C(N)C(N)=CN=C21 UTOMICFLROGMAE-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000013076 target substance Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ALBKIWPCLGJBRC-UHFFFAOYSA-N thieno[3,2-b]pyridine-2,3-diamine Chemical compound C1=CN=C2C(N)=C(N)SC2=C1 ALBKIWPCLGJBRC-UHFFFAOYSA-N 0.000 description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000036461 convulsion Effects 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 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
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 230000000704 physical effect Effects 0.000 description 4
- 229920000137 polyphosphoric acid Polymers 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ITIRVXDSMXFTPW-UHFFFAOYSA-N 1H-imidazo[4,5-c]quinoline Chemical compound C1=CC=CC2=C(NC=N3)C3=CN=C21 ITIRVXDSMXFTPW-UHFFFAOYSA-N 0.000 description 3
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 3
- NECFGUMXYZTAKN-UHFFFAOYSA-N 4-n-ethylquinoline-3,4-diamine Chemical compound C1=CC=C2C(NCC)=C(N)C=NC2=C1 NECFGUMXYZTAKN-UHFFFAOYSA-N 0.000 description 3
- OGAYBYZECXWINC-UHFFFAOYSA-N 4-n-methylquinoline-3,4-diamine Chemical compound C1=CC=C2C(NC)=C(N)C=NC2=C1 OGAYBYZECXWINC-UHFFFAOYSA-N 0.000 description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 102000004300 GABA-A Receptors Human genes 0.000 description 3
- 108090000839 GABA-A Receptors Proteins 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960003529 diazepam Drugs 0.000 description 3
- 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 3
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910052722 tritium Inorganic materials 0.000 description 3
- GMONMYANVINCBA-UHFFFAOYSA-N 2-(4-fluorophenyl)-1-methylimidazo[4,5-c]quinoline Chemical compound N=1C2=CN=C3C=CC=CC3=C2N(C)C=1C1=CC=C(F)C=C1 GMONMYANVINCBA-UHFFFAOYSA-N 0.000 description 2
- FJIDYVNPZOVPOX-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]-3h-imidazo[4,5-c]quinoline Chemical compound FC(F)(F)C1=CC=CC(C=2NC3=C4C=CC=CC4=NC=C3N=2)=C1 FJIDYVNPZOVPOX-UHFFFAOYSA-N 0.000 description 2
- BNBXCUUGSQYUKN-UHFFFAOYSA-N 3-methyl-5-(1-methylimidazo[4,5-c]quinolin-2-yl)-1,2-oxazole Chemical compound O1N=C(C)C=C1C1=NC2=CN=C(C=CC=C3)C3=C2N1C BNBXCUUGSQYUKN-UHFFFAOYSA-N 0.000 description 2
- CAXDADCRMDLTTD-UHFFFAOYSA-N 3-nitro-1h-thieno[3,4-b]pyridin-4-one Chemical compound O=C1C([N+](=O)[O-])=CNC2=CSC=C21 CAXDADCRMDLTTD-UHFFFAOYSA-N 0.000 description 2
- HYEJSLRWMHOGQD-UHFFFAOYSA-N 3-nitrothieno[3,4-b]pyridin-4-amine Chemical compound NC1=C([N+]([O-])=O)C=NC2=CSC=C12 HYEJSLRWMHOGQD-UHFFFAOYSA-N 0.000 description 2
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 description 2
- AFEUKCAYJAPNOY-UHFFFAOYSA-N 4-chloro-2-methyl-5-nitrothieno[2,3-b]pyridine Chemical compound [O-][N+](=O)C1=CN=C2SC(C)=CC2=C1Cl AFEUKCAYJAPNOY-UHFFFAOYSA-N 0.000 description 2
- ZRFUZDDJSQVQBY-UHFFFAOYSA-N 4-chloro-3-nitroquinoline Chemical compound C1=CC=CC2=C(Cl)C([N+](=O)[O-])=CN=C21 ZRFUZDDJSQVQBY-UHFFFAOYSA-N 0.000 description 2
- CWERVYXPYRJHTP-UHFFFAOYSA-N 4-chloro-3-nitrothieno[3,4-b]pyridine Chemical compound ClC1=C([N+](=O)[O-])C=NC2=CSC=C21 CWERVYXPYRJHTP-UHFFFAOYSA-N 0.000 description 2
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IFLKEBSJTZGCJG-UHFFFAOYSA-N 5-methyl-2-thiophenecarboxylic acid Natural products CC=1C=CSC=1C(O)=O IFLKEBSJTZGCJG-UHFFFAOYSA-N 0.000 description 2
- VCNGNQLPFHVODE-UHFFFAOYSA-N 5-methylthiophene-2-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)S1 VCNGNQLPFHVODE-UHFFFAOYSA-N 0.000 description 2
- WWRBGVOLARSNJR-UHFFFAOYSA-N 6-nitro-4h-thieno[3,2-b]pyridin-7-one Chemical compound OC1=C([N+]([O-])=O)C=NC2=C1SC=C2 WWRBGVOLARSNJR-UHFFFAOYSA-N 0.000 description 2
- PWQJQRFSIUKIEB-UHFFFAOYSA-N 6-nitrothieno[3,2-b]pyridin-7-amine Chemical compound NC1=C([N+]([O-])=O)C=NC2=C1SC=C2 PWQJQRFSIUKIEB-UHFFFAOYSA-N 0.000 description 2
- RKZKGVJIROTNKJ-UHFFFAOYSA-N 7-chloro-6-nitrothieno[3,2-b]pyridine Chemical compound [O-][N+](=O)C1=CN=C2C=CSC2=C1Cl RKZKGVJIROTNKJ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- BUTPBERGMJVRBM-UHFFFAOYSA-N methanol;methylsulfinylmethane Chemical compound OC.CS(C)=O BUTPBERGMJVRBM-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- HAAYRLITTXBZOP-UHFFFAOYSA-N n-methyl-3-nitroquinolin-4-amine Chemical compound C1=CC=C2C(NC)=C([N+]([O-])=O)C=NC2=C1 HAAYRLITTXBZOP-UHFFFAOYSA-N 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000014347 soups Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000006103 sulfonylation Effects 0.000 description 2
- 238000005694 sulfonylation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
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- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940125425 inverse agonist Drugs 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- UBFPEDQEBZSKIQ-UHFFFAOYSA-N n-(4-aminoquinolin-3-yl)-3-(trifluoromethyl)benzamide Chemical compound C1=NC2=CC=CC=C2C(N)=C1NC(=O)C1=CC=CC(C(F)(F)F)=C1 UBFPEDQEBZSKIQ-UHFFFAOYSA-N 0.000 description 1
- PWTBYBSSPALUHM-UHFFFAOYSA-N n-(4-aminoquinolin-3-yl)-5-methylthiophene-2-carboxamide Chemical compound S1C(C)=CC=C1C(=O)NC1=CN=C(C=CC=C2)C2=C1N PWTBYBSSPALUHM-UHFFFAOYSA-N 0.000 description 1
- OZSYEIOYLBMVPI-UHFFFAOYSA-N n-[4-(3h-imidazo[4,5-c]quinolin-2-yl)phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1C1=NC2=CN=C(C=CC=C3)C3=C2N1 OZSYEIOYLBMVPI-UHFFFAOYSA-N 0.000 description 1
- FHIBMRPAQHEOTH-UHFFFAOYSA-N n-ethyl-3-nitroquinolin-4-amine Chemical compound C1=CC=C2C(NCC)=C([N+]([O-])=O)C=NC2=C1 FHIBMRPAQHEOTH-UHFFFAOYSA-N 0.000 description 1
- BZKSAWDBBGWYNF-UHFFFAOYSA-N n-methylquinolin-4-amine Chemical compound C1=CC=C2C(NC)=CC=NC2=C1 BZKSAWDBBGWYNF-UHFFFAOYSA-N 0.000 description 1
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- RIBFXMJCUYXJDZ-UHFFFAOYSA-N propanoyl bromide Chemical compound CCC(Br)=O RIBFXMJCUYXJDZ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILHBCSHYDFMFRN-UHFFFAOYSA-N thieno[2,3-b]pyridine-4,5-diamine Chemical compound NC1=CN=C2SC=CC2=C1N ILHBCSHYDFMFRN-UHFFFAOYSA-N 0.000 description 1
- AIWIVJNRSOBFST-UHFFFAOYSA-N thieno[2,3-b]quinoline Chemical compound C1=CC=C2N=C(SC=C3)C3=CC2=C1 AIWIVJNRSOBFST-UHFFFAOYSA-N 0.000 description 1
- DDSUOVLOOXEJNS-UHFFFAOYSA-N thieno[3,2-b]pyridine-6,7-diamine Chemical compound NC1=CN=C2C=CSC2=C1N DDSUOVLOOXEJNS-UHFFFAOYSA-N 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 238000012345 traction test Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は縮合イミダゾピリジン誘導体またはこれを含有
する向精神薬に関する。TECHNICAL FIELD The present invention relates to a condensed imidazopyridine derivative or a psychotropic drug containing the same.
従来の技術 ソ連特許第509,588号は1H−２−オキソ−３−フエニル
−７−メチルイミダゾ［4,5−ｃ］キノリンが生理活性
物質の合成中間体として有用であると開示している。ま
たAbbasiら、Monatsh.Chem.,111,963（1980）には３−
ヒドロキシ−２−ヒドロキシメチル−８−メトキシ−９
−ニトロ−４−スチリル−2H−イミダゾ［4,5−ｃ］キ
ノリンとその類似体が生理活性物質の合成中間体である
ことが記載されている。さらに、ヨーロツパ特許出願第
145,340号では２−ヒドロキシアルキル−1H−イミダゾ
［4,5−ｃ］キノリン類は気管支拡張剤または抗ウイル
ス剤として有用であることが報告されているが、向精神
薬としての有用性の記載はない。また本発明の縮合イミ
ダゾキノリン誘導体は２位に芳香環を有しており、上に
挙げた化合物とは全く異なるものである。PRIOR ART Soviet Patent No. 509,588 discloses that 1H-2-oxo-3-phenyl-7-methylimidazo [4,5-c] quinoline is useful as an intermediate for the synthesis of physiologically active substances. In Abbasi et al., Monatsh. Chem., 111 , 963 (1980), 3-
Hydroxy-2-hydroxymethyl-8-methoxy-9
It is described that -nitro-4-styryl-2H-imidazo [4,5-c] quinoline and its analogues are intermediates for the synthesis of physiologically active substances. In addition, European patent application No.
In No. 145,340, 2-hydroxyalkyl-1H-imidazo [4,5-c] quinolines are reported to be useful as bronchodilators or antiviral agents, but there is no description of their usefulness as psychotropic drugs. Absent. Further, the fused imidazoquinoline derivative of the present invention has an aromatic ring at the 2-position, which is completely different from the above-mentioned compounds.
発明の開示 本発明は一般式： （式中、Ｒは置換もしくは非置換のフエニル、置換もし
くは非置換の５員または６員のヘテロ環残基;Qは水素、
アルキル、アシル、アルキルスルホニルまたはアリルス
ルホニル、 R1、R2、R3およびR4はそれぞれ水素、ハロゲン、アルキ
ル、アルコキシまたはハロアルキルを表わし、Ｑは１、
３または５位の窒素原子の上に存在し、点線は環上の３
個の２重結合の組合わせを示しており、（2-3、3a-3b、
4-5）位、（1-3b、2-3、3a-4）位および（1-2、3a-3b、
4-5）位に存在することを意味する。） で示される化合物またはその塩、およびこれを有効成分
として含有する向精神薬に関する。DISCLOSURE OF THE INVENTION The present invention has the general formula: (Wherein R is a substituted or unsubstituted phenyl, a substituted or unsubstituted 5- or 6-membered heterocyclic residue; Q is hydrogen,
Alkyl, acyl, alkylsulfonyl or allylsulfonyl, R 1 , R 2 , R 3 and R 4 each represent hydrogen, halogen, alkyl, alkoxy or haloalkyl, and Q is 1,
It exists on the nitrogen atom at the 3 or 5 position, and the dotted line is 3 on the ring.
Shows the combination of two double bonds, (2-3, 3a-3b,
4-5) position, (1-3b, 2-3, 3a-4) position and (1-2, 3a-3b,
4-5) means to exist in the position. And a salt thereof, and a psychotropic drug containing the same as an active ingredient.
上記定義で用いる用語について説明すると、Ｒで示され
るフエニル上に存在しうる置換基としては、トリフルオ
ロメチル、アルキル、アルコキシ、アルキルチオ、ニト
ロ、ハロゲン、アミノ、アルカノイルアミノおよびアル
コキシカルボニルが例示され、これらの置換基は１また
は２個存在してもよい。５員または６員のヘテロ環残基
上に存在しうる置換基としては、アルキル、アルコキシ
およびハロゲンが例示される。これらの置換基も１また
は２個存在してもよい。アルキルとしては、メチル、エ
チル、プロピル、イソプロピル、ブチル、イソブチル、
ｔ−ブチル、ペンチル、ネオペンチル、１−メチルイソ
ブチルなどが例示される。アルコキシとしては、メトキ
シ、エトキシ、プロポキシ、イソプロポキシ、ブトキ
シ、ペンチルオキシなど、アルキルチオとしては、メチ
ルチオ、エチルチオ、プロピルチオ、ブチルチオ、イソ
ブチルチオ、ネオペンチルチオなどが例示される。アル
カノイルアミノとしては、ホルミルアミノ、アセチルア
ミノ、プロピオニルアミノ、ブチリルアミノ、バレリン
アミノ、イソバレリンアミノが例示される。アルコキシ
カルボニルとしては、メトキシカルボニル、エトキシカ
ルボニル、プロポキシカルボニル、ブトキシカルボニ
ル、ペンチルオキシカルボニルが例示される。アシルと
しては、ホルミル、アセチル、プロピオニル、ブチリ
ル、バレリル、イソバレリル、ベンゾイル、トルオイル
またはプロピルベンゾイルなどが挙げられ、アルキルス
ルホニルとしては、メチルスルホニル、エチルスルホニ
ル、プロピルスルホニル、イソブチルスルホニル、ペン
チルスルホニルなどが挙げられ、アリールスルホニルと
しては、フエニルスルホニル、トリルスルホニル、キシ
リルスルホニル、ナフチルスルホニルなどが挙げられ
る。ハロアルキルとしては、フルオロメチル、クロロエ
チル、ブロモプロピル、ヨードブチル、トリフルオロメ
チルなどが例示され、ハロゲンとしては、フツ素、塩
素、臭素、ヨウ素などが例示される。５員または６員環
のヘテロ環残基としては、イソオキサゾリル、イソチア
ゾリル、ピラゾリル、オキサゾリル、チアゾリル、イミ
ダゾリル、チアジアゾリル、オキサジアゾリル、チエニ
ル、フリル、ピリジルなどか挙げられる。またR1、R2、
R3、R4で示されるハロゲン、アルキル、アルコキシおよ
びハロアルキルの例示も上記と同様である。Explaining the terms used in the above definition, examples of the substituent which may be present on the phenyl represented by R include trifluoromethyl, alkyl, alkoxy, alkylthio, nitro, halogen, amino, alkanoylamino and alkoxycarbonyl. There may be one or two substituents. Substituents that may be present on a 5- or 6-membered heterocyclic residue are exemplified by alkyl, alkoxy and halogen. One or two of these substituents may be present. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples are t-butyl, pentyl, neopentyl, 1-methylisobutyl and the like. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy and the like, and examples of alkylthio include methylthio, ethylthio, propylthio, butylthio, isobutylthio, neopentylthio and the like. Examples of alkanoylamino include formylamino, acetylamino, propionylamino, butyrylamino, valerinamino, isovalerinamino. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and pentyloxycarbonyl. Examples of the acyl include formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl, benzoyl, toluoyl or propylbenzoyl and the like, and examples of the alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isobutylsulfonyl, pentylsulfonyl and the like. Examples of the arylsulfonyl include phenylsulfonyl, tolylsulfonyl, xylylsulfonyl, naphthylsulfonyl and the like. Examples of haloalkyl include fluoromethyl, chloroethyl, bromopropyl, iodobutyl, trifluoromethyl, and the like, and examples of halogen include fluorine, chlorine, bromine, iodine, and the like. Examples of the 5- or 6-membered heterocyclic residue include isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, pyridyl and the like. Also R 1 , R 2 ,
Examples of halogen, alkyl, alkoxy and haloalkyl represented by R 3 and R 4 are the same as above.
本発明の化合物（Ｉ）は一般式 （式中、Ｑ′は水素またはアルキルを表わし、 は前記と同意義を有する。） で示されるジアミンをアシル化し、得られる一般式 （式中、Ｑ′、Ｒ、および は前記と同意義を有する。） で示されるアミドを閉環させたのち、必要なら、Ｑ′が
水素の場合、閉環生成物をアルキル化、アシル化または
スルホニル化に付して得られる。The compound (I) of the present invention has the general formula (In the formula, Q ′ represents hydrogen or alkyl, Has the same meaning as above. ) Is obtained by acylating a diamine represented by (Where Q ′, R, and Has the same meaning as above. ) Is subjected to ring closure, and if necessary, when Q ′ is hydrogen, the ring closure product is subjected to alkylation, acylation or sulfonylation.
すなわち、化合物（Ｉ）の製造法は次式によつて示され
る。That is, the production method of compound (I) is represented by the following formula.
（式中、Ｑ′は水素またはアルキル;Q、Ｒ、および は前記と同意義を有する。） 第１工程 アミド体（III）はジアミン体（II）にアシル化剤を反
応させることにより得られる。本反応は比較的低温（例
えば、−10〜５℃）で行なえばよく、一般には適当な溶
媒中、所望のアシル基に相当するアシル化剤を使用す
る。 (Wherein Q ′ is hydrogen or alkyl; Q, R, and Has the same meaning as above. ) First step The amide compound (III) is obtained by reacting the diamine compound (II) with an acylating agent. This reaction may be carried out at a relatively low temperature (for example, -10 to 5 ° C), and generally, an acylating agent corresponding to the desired acyl group is used in a suitable solvent.
溶媒としては、ジメチルホルムアミド、アセトニトリ
ル、クロロホルム、ヘキサメチルホスホラミド、エーテ
ル、テトラヒドロフラン、およびそれらの混合物などが
挙げられる。Examples of the solvent include dimethylformamide, acetonitrile, chloroform, hexamethylphosphoramide, ether, tetrahydrofuran, and a mixture thereof.
アシル化剤としては、酸クロリド、酸ブロミドなどの酸
ハロゲニド；酸無水物；カルボン酸とクロル炭酸エチル
との混合物；カルボン酸と塩化チオニル、または、DC
C、ポリリン酸など縮合剤との混合物を用いればよい。As the acylating agent, acid halides such as acid chloride and acid bromide; acid anhydrides; a mixture of carboxylic acid and ethyl chlorocarbonate; carboxylic acid and thionyl chloride, or DC
A mixture with C, a polyphosphoric acid, or a condensing agent may be used.
第２工程 上記のアミド体（III）を約50〜250℃の温度で、好まし
くは、100〜250℃で、閉環剤の存在下あるいは不存在下
に適当な溶媒中で閉環させれば、化合物（Ia）が得られ
る。Second Step If the above amide (III) is ring-closed at a temperature of about 50 to 250 ° C., preferably 100 to 250 ° C. in the presence or absence of a ring-closing agent in a suitable solvent, the compound is obtained. (Ia) is obtained.
閉環剤としては、ポリリン酸、ポリリン酸エステル、硫
酸、酢酸、五酸化リンなどが挙げられる。Examples of the ring-closing agent include polyphosphoric acid, polyphosphoric acid ester, sulfuric acid, acetic acid, phosphorus pentoxide and the like.
溶媒としては、ヘキサメチルホスホラミド、ジフエニル
エーテル、グリセリントリエチルエーテル、ブチルエー
テル、イソアミルエーテル、ジエチレングリコール、ト
リエチレングリコール、ダウサームＡ（Dow Chemical C
o.）などが挙げられる。As the solvent, hexamethylphosphoramide, diphenyl ether, glycerin triethyl ether, butyl ether, isoamyl ether, diethylene glycol, triethylene glycol, Dowtherm A (Dow Chemical C
o.) and so on.
第３工程 必要ならば、Ｑ′が水素の場合の化合物（Ia）はアルキ
ル化、アシル化またはスルホニル化に付してもよい。反
応は、水素化アルカリ金属（例えば、水素化ナトリウ
ム、水素化カリウムなど）またはアルカリ金属アルコキ
シド（例えば、ナトリウムメトキシド、カリウムエトキ
シド、ナトリウムイソプロポキシなど）のような塩基の
存在下、適当な溶媒中30〜120℃にてアルキル化剤、ア
シル化剤、またはスルホニル化剤を用いて行なう。Third Step If necessary, the compound (Ia) when Q ′ is hydrogen may be subjected to alkylation, acylation or sulfonylation. The reaction is carried out in the presence of a suitable solvent in the presence of a base such as an alkali metal hydride (eg sodium hydride, potassium hydride etc.) or an alkali metal alkoxide (eg sodium methoxide, potassium ethoxide, sodium isopropoxy etc.). At 30-120 ° C. with an alkylating agent, an acylating agent, or a sulfonylating agent.
アルキル化剤としては、ヨウ化メチル、臭化エチル、塩
化ブロピル、ヨウ化ブチルなどのハロゲン化アルキル；
硫酸ジメチル、硫酸ジエチルなどの硫酸ジアルキルなど
が挙げられる。Alkylating agents include alkyl halides such as methyl iodide, ethyl bromide, bropropyl chloride and butyl iodide;
Examples thereof include dialkyl sulfates such as dimethyl sulfate and diethyl sulfate.
アシル化剤としては、アセチルクロリド、臭化プロピオ
ニル、塩化ブチリル、塩化ベンゾイルなどのハロゲン化
アシル；無水酢酸、無水ブロピオン酸などの酸無水物が
挙げられる。Examples of the acylating agent include acyl halides such as acetyl chloride, propionyl bromide, butyryl chloride and benzoyl chloride; and acid anhydrides such as acetic anhydride and bromopropionic anhydride.
スルホニル化剤としては、塩化メシル、塩化ブチルスル
ホニル、塩化トシルなどが挙げられる。Examples of the sulfonylating agent include mesyl chloride, butylsulfonyl chloride, tosyl chloride and the like.
溶媒としては、テトラヒドロフラン、ジオキサン、ジグ
リム、ジメチルホルムアミド、クロロホルム、エタノー
ルなどが例示される。Examples of the solvent include tetrahydrofuran, dioxane, diglyme, dimethylformamide, chloroform, ethanol and the like.
原料物質として使用されるジアミン（II）は、例えば文
献G.B.Bachmanら、J.Am.Chem.Soc.,69,365（1947）、お
よびA.R.Surreyら、J.Am.Chem.Soc.,73,2413（1951）に
記載の方法に従つて、以下のようにして得られる。Diamine (II) used as a raw material is, for example, GB Bachman et al., J. Am. Chem. Soc., 69 , 365 (1947), and AR Surrey et al., J. Am. Chem. Soc., 73 , 2413 ( It is obtained as follows according to the method described in 1951).
（式中、Acはアセチル、 およびＱ′は前記と同意義を有する。） 化合物（Ｉ）には次に示す３種の化合物が含まれる。 (In the formula, Ac is acetyl, And Q'have the same meaning as above. ) Compound (I) includes the following three types of compounds.
（式中、 Ｑ、およぴＲは前記と同意義を有する。） 化合物（Ｉ）は製剤学的に適当な酸付加塩に変換するこ
とができる。そのような酸としては、塩酸、硫酸、リン
酸、または硝酸のような無機酸；酢酸、マレイン酸、リ
ンゴ酸、クエン酸、乳酸、コハク酸、またはメタンスル
ホン酸などの有機酸が例示される。 (In the formula, Q and R have the same meaning as described above. ) Compound (I) can be converted pharmaceutically into an appropriate acid addition salt. Examples of such acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or nitric acid; organic acids such as acetic acid, maleic acid, malic acid, citric acid, lactic acid, succinic acid, or methanesulfonic acid. .
化合物（Ｉ）または製剤学的に適当な酸付加塩はベンゾ
ジアゼピンレセプターに高い親和性を示し、精神機能賦
活薬または抗不安薬のような向精神薬として有用であ
る。Compound (I) or a pharmaceutically suitable acid addition salt has a high affinity for the benzodiazepine receptor and is useful as a psychoactive drug such as a psychoactive drug or an anxiolytic drug.
化合物（Ｉ）は経口または非経口投与によつてヒトまた
は哺乳類に投与できる。それらは、製剤上の常法によ
り、錠剤、カプセル剤、丸剤、粒剤、注射剤、座剤、シ
ロツプ剤に製剤することができる。製剤上許容される担
体、希釈剤、賦形剤としては、乳糖、シヨ糖、小麦でん
ぷん、じやがいもでんぷん、ステアリン酸マグネシウ
ム、ゼラチン、メチルセルロース、寒天、水などが例示
される。必要に応じて、適宜安定剤、乳化剤、湿展剤、
緩衝剤、その他の製剤助剤を添加してもよい。１日当り
の投与量は、経口投与で0.1〜500mg、注射の場合0.1〜3
00mgが適当である。Compound (I) can be administered to humans or mammals by oral or parenteral administration. They can be formulated into tablets, capsules, pills, granules, injections, suppositories, and syrups by a conventional formulation method. Examples of pharmaceutically acceptable carriers, diluents and excipients include lactose, sucrose, wheat starch, jiyaigaimo starch, magnesium stearate, gelatin, methyl cellulose, agar, water and the like. If necessary, stabilizers, emulsifiers, wetting agents,
Buffers and other formulation aids may be added. The daily dose is 0.1-500 mg by oral administration and 0.1-3 by injection.
00 mg is suitable.
以下に実施例、参考例および製剤例を示して、本発明の
態様を明らかにする。Hereinafter, the embodiments of the present invention will be clarified by showing Examples, Reference Examples and Formulation Examples.
実施例、参考例および表で用いた略字は以下に示す意味
を表わす。Abbreviations used in Examples, Reference Examples and Tables have the following meanings.
HMPA:ヘキサメチルホスホラミド； Me:メチル;Et:エチル;AcOH:酢酸； PPA:ポリリン酸;PPE:ポリリン酸エステル； MeCN:アセトニトリル;MeOH:メタノール； EtOH:エタノール；Et2O：エーテル； AcOEt:酢酸エチル； DMF:ジメチルホルムアミド；（ｄ）：分解 Ｑが水素の場合、化合物（Ia）と（Ib）は相互に互変異
性体であるが、便宜上（Ia）と命名する。例えば、実施
例１の２−（３−トリフルオロメチルフエニル）−1H−
イミダゾ［4,5−ｃ］キノリンC1 は、２−（３−トリフ
ルオロメチルフエニル）−3H−イミダゾ［4,5−ｃ］キ
ノリンとして命名してもよい。HMPA: hexamethylphosphoramide; Me: methyl; Et: ethyl; AcOH: acetic acid; PPA: polyphosphoric acid; PPE: polyphosphate ester; MeCN: acetonitrile; MeOH: methanol; EtOH: ethanol; Et 2 O: ether; AcOEt: Ethyl acetate; DMF: dimethylformamide; (d): Decomposition When Q is hydrogen, compounds (Ia) and (Ib) are tautomers with each other, but for convenience, they are named (Ia). For example, 2- (3-trifluoromethylphenyl) -1H- of Example 1
The imidazo [4,5-c] quinoline C 1 may be designated as 2- (3-trifluoromethylphenyl) -3H-imidazo [4,5-c] quinoline.
実施例１ ２−（３−トリフルオロメチルフエニル）−1H−イミダ
ゾ［4,5−ｃ］キノリンC1 ３−トリフルオロメチル安息香酸500mgの無水HMPA6ml−
無水MeCN0.6ml溶液に窒素気流下で塩化チオニル305mgを
−５〜０℃の温度に保ちながら滴下する。同温度で30分
間攪拌後、3,4−ジアミノキノリンA1 380mgを加え、０〜
５℃で３時間攪拌する。反応液を氷水で希釈し、飽和重
ソウ水で中和する。析出する結晶を濾取し、水洗乾燥す
ると４−アミノ−３−（３−トリフルオロメチルベンゾ
イルアミノ）キノリンB1 の粗結晶780mgを得る。B1 をPPA
15gに懸濁させ、窒素気流下に120℃で４時間攪拌する。
反応液を氷水に加え、1N水酸化ナトリウム水溶液で中和
する。析出する固体を濾取、水洗乾燥する。次いでシリ
カゲルカラムクロマトグラフイーに付し、クロロホルム
−メタノール（10:1 v/v）で溶出する。得られる油状物
をｎ−ヘキサン−酢酸エチルから結晶化するとC1 の結晶
350mg（A1 からの収率47％）を得る。本品を酢酸エチル
から再結晶すると、融点254-256℃の無色結晶となる。Example 1 2- (3-Trifluoromethylphenyl) -1H-imidazo [4,5-c] quinoline C 1 3-Trifluoromethylbenzoic acid 500 mg anhydrous HMPA 6 ml-
Thionyl chloride (305 mg) was added dropwise to a solution of anhydrous MeCN (0.6 ml) under a nitrogen stream while maintaining the temperature at -5 to 0 ° C. After stirring at the same temperature for 30 minutes, 380 mg of 3,4-diaminoquinoline A 1 was added, and 0-
Stir at 5 ° C. for 3 hours. The reaction solution is diluted with ice water and neutralized with saturated sodium bicarbonate water. The precipitated crystals are collected by filtration, washed with water and dried to give 780 mg of crude crystals of 4-amino-3- (3-trifluoromethylbenzoylamino) quinoline B 1 . B 1 to PPA
It is suspended in 15 g and stirred under a nitrogen stream at 120 ° C. for 4 hours.
The reaction solution is added to ice water and neutralized with a 1N aqueous sodium hydroxide solution. The precipitated solid is collected by filtration, washed with water and dried. Then, apply to silica gel column chromatography and elute with chloroform-methanol (10: 1 v / v). The obtained oily substance was crystallized from n-hexane-ethyl acetate to give C 1 crystals.
350 mg (47% yield from A 1 ) are obtained. Recrystallization of this product from ethyl acetate gives colorless crystals with a melting point of 254-256 ° C.
元素分析：C17H10N3F3 計算値（％）:C,65.18;H,3.22;N,13.41;F,18.19 実測値（％）:C,64.74;H,3.54;N,13.20;F,18.30 実施例２〜３ 実施例１と同様にして、表１に示す反応条件により目的
物質を得る。物性は表３に記載する。Elemental analysis: C 17 H 10 N 3 F 3 Calculated (%): C, 65.18; H, 3.22; N, 13.41; F, 18.19 Found (%): C, 64.74; H, 3.54; N, 13.20; F, 18.30 Examples 2 to 3 In the same manner as in Example 1, the target substance was obtained under the reaction conditions shown in Table 1. The physical properties are shown in Table 3.
実施例４ ２−（５−メチルチオフエン−２−イル）−1H−イミダ
ゾ［4,5−ｃ］キノリンC4 ５−メチル−２−チオフエンカルボン酸555mgの無水HMP
A9ml−無水MeCN0.9ml溶液に窒素気流下、塩化チオニル4
55mgを−５〜０℃で滴下する。同温度で30分間攪拌後、
3,4−ジアミノキノリンA1 570mgを加え、０〜５℃で４時
間攪拌する。反応液を実施例１と同様に処理すると900m
gの白色固体として４−アミノ−３−（５−メチルチオ
フエン−２−カルボニルアミノ）キノリンB4 が得られ
る。これを15gのPPEに懸濁し、125℃で３時間攪拌す
る。反応液を氷水で希釈、1N水酸化ナトリウム水溶液で
中和後、酢酸エチルで抽出する。抽出液を水、飽和食塩
水で順次洗浄し、硫酸マグネシウムで乾燥する。酢酸エ
チルを留去し、得られる残留物をシリカゲルカラムクロ
マトグラフイーに付し精製する。クロロホルム−メタノ
ール（10:1 v/v）で溶出する画分を濃縮し、ｎ−ヘキサ
ンで結晶化させると456mg（収率48％）のC4 を得る。本
品をエタノールで再結晶すると融点293-295℃（分解）
の淡黄色結晶となる。 Example 4 2- (5-Methylthiophen-2-yl) -1H-imidazo [4,5-c] quinoline C 4 5-Methyl-2-thiophenecarboxylic acid 555 mg anhydrous HMP
Thionyl chloride 4 in A9ml-MeCN 0.9ml solution under nitrogen stream
55 mg are added dropwise at -5 to 0 ° C. After stirring at the same temperature for 30 minutes,
570 mg of 3,4-diaminoquinoline A 1 is added, and the mixture is stirred at 0 to 5 ° C for 4 hours. When the reaction solution is treated in the same manner as in Example 1, it is 900 m.
4-amino-3- (5-methylthiophene-2-carbonylamino) quinoline B 4 is obtained as g of a white solid. This is suspended in 15 g of PPE and stirred at 125 ° C. for 3 hours. The reaction mixture is diluted with ice water, neutralized with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract is washed successively with water and saturated brine and dried over magnesium sulfate. Ethyl acetate is distilled off, and the resulting residue is purified by silica gel column chromatography. The fraction eluted with chloroform-methanol (10: 1 v / v) was concentrated and crystallized with n-hexane to obtain 456 mg (yield 48%) of C 4 . Recrystallizing this product with ethanol, melting point 293-295 ℃ (decomposition)
Becomes pale yellow crystals.
元素分析：C15H11N3Sとして 計算値（％）:C,67.90;H,4.18;N,15.84;S,12.08 実測値（％）:C,68.16;H,4.25;N,15.76;S,11.63 実施例５ ２−（４−ピリジニル）−1H−イミダゾ［4,5−ｃ］キ
ノリンC5 イソニコチン酸325mgの無水HMPA8ml−無水MeCN0.8ml溶
液に塩化チオニル305mgを窒素気流下に−５〜０℃で滴
下し、45分間攪拌後、3,4−ジアミノキノリンA1 380mgを
加え、０℃で4.5時間攪拌する。実施例１と同様に後処
理を行なうと560mgのB5 の粗結晶を得る。これを酢酸10m
lに溶かし、４時間加熱還流する。反応液を減圧下に濃
縮、残渣に氷水を加え、飽和重ソウ水で中和する。析出
する結晶を濾取、水洗乾燥すると510mg（収率87％）のC
5 を得る。本品を酢酸エチル−メタノールから再結晶す
ると融点270-272℃の無色結晶となる。Elemental analysis: Calculated as C 15 H 11 N 3 S (%): C, 67.90; H, 4.18; N, 15.84; S, 12.08 Measured value (%): C, 68.16; H, 4.25; N, 15.76; S, 11.63 example 5 2- (4-pyridinyl)-1H-imidazo [4,5-c] key <br/> Norin C 5 To a solution of 325 mg isonicotinic acid in 8 ml of anhydrous HMPA and 0.8 ml of anhydrous MeCN, 305 mg of thionyl chloride was added dropwise at -5 to 0 ° C under a nitrogen stream, and after stirring for 45 minutes, 380 mg of 3,4-diaminoquinoline A 1 was added and Stir for 4.5 hours. The post-treatment is carried out in the same manner as in Example 1 to obtain 560 mg of B 5 crude crystals. This is acetic acid 10m
Dissolve in l and heat to reflux for 4 hours. The reaction mixture is concentrated under reduced pressure, ice water is added to the residue, and the mixture is neutralized with saturated sodium bicarbonate water. The precipitated crystals are collected by filtration, washed with water and dried to give 510 mg (87% yield) of C.
Get 5 Recrystallization of this product from ethyl acetate-methanol gives colorless crystals with a melting point of 270-272 ° C.
元素分析：C15H10N4として 計算値（％）:C,73.16;H,4.09;N,22.75 実測値（％）:C,72.79;H,4.20;N,22.37 実施例６ ２−（４−トリフルオロメチルフエニル）−1H−イミダ
ゾ［4,5−ｃ］キノリンC6 ４−トリフルオロメチル安息香酸395mgの無水HMPA5ml−
無水MeCN0.5ml溶液に塩化チオニル240mgを窒素気流下に
−５〜０℃で滴下する。30分間攪拌後、3,4−ジアミノ
キノリンA1 300mgを加え、０〜５℃で４時間攪拌する。
実施例１と同様に処理すると605mgのB6 の粗結晶を得
る。B6 を無水HMPA10ml−酢酸2.5mlに懸濁し、窒素気流
下に155℃で15分間攪拌する。反応液を冷却後、水で希
釈し、飽和重ソウ水で中和する。析出する固体を濾取
し、水洗乾燥後、シリカゲルカラムクロマトグラフイー
にて精製する。クロロホルム−メタノール（10:1 v/v）
で溶出し、ｎ−ヘキサン−酢酸エチルから結晶化すると
440mg（収率75％）のC6 を得る。本品をエタノールから
再結晶すると融点340℃以上の無色結晶となる。Elemental analysis: Calculated as C 15 H 10 N 4 (%): C, 73.16; H, 4.09; N, 22.75 Measured value (%): C, 72.79; H, 4.20; N, 22.37 Example 6 2- ( 4-trifluoromethylphenyl) -1H-imidazo [4,5-c] quinoline C 6 4-Trifluoromethylbenzoic acid 395 mg anhydrous HMPA 5 ml-
To a solution of anhydrous MeCN (0.5 ml), thionyl chloride (240 mg) was added dropwise at -5 to 0 ° C under a nitrogen stream. After stirring for 30 minutes, 300 mg of 3,4-diaminoquinoline A 1 is added, and the mixture is stirred at 0 to 5 ° C for 4 hours.
Treatment as in Example 1 gives 605 mg of crude B 6 crystals. B 6 is suspended in anhydrous HMPA (10 ml) -acetic acid (2.5 ml) and stirred under a nitrogen stream at 155 ° C. for 15 minutes. After cooling the reaction solution, it is diluted with water and neutralized with saturated sodium bicarbonate water. The precipitated solid is collected by filtration, washed with water and dried, and then purified by silica gel column chromatography. Chloroform-methanol (10: 1 v / v)
Elution with and crystallization from n-hexane-ethyl acetate
440 mg (75% yield) of C 6 are obtained. Recrystallization of this product from ethanol gives colorless crystals with a melting point of 340 ° C or higher.
元素分析：C17H10N3F3として 計算値（％）:C,65.18;H,3.22;N,13.41;F,18.19 実測値（％）:C,64.95;H,3.44;N,13.24;F,18.10 実施例7-93 実施例６と同様の方法で、表２に示す反応条件により目
的物質を得る。目的物質の物性を表３に示す。Elemental analysis: Calculated as C 17 H 10 N 3 F 3 (%): C, 65.18; H, 3.22; N, 13.41; F, 18.19 Measured value (%): C, 64.95; H, 3.44; N, 13.24 F, 18.10 Examples 7-93 In the same manner as in Example 6, the target substance is obtained under the reaction conditions shown in Table 2. Table 3 shows the physical properties of the target substance.
実施例94 ２−（４−アミノフエニル）−1H−イミダゾ［4,5−
ｃ］キノリンC94 ２−（４−アセチルアミノフエニル）−1H−イミダゾ
［4,5−ｃ］キノリンC19 320mgを1N水酸化ナトリウム水
溶液10mlに懸濁し、1.5時間還流する。反応液を冷却
し、酢酸で中和する。析出する結晶を濾取し、水、エタ
ノールで順次洗浄し、乾燥すると195mg（収率71％）のC
94 が得られる。本品をエタノールから再結晶すると融点
340℃以上の無色結晶となる。 Example 94 2- (4-aminophenyl) -1H-imidazo [4,5-
c] quinoline C 94 320 mg of 2- (4-acetylaminophenyl) -1H-imidazo [4,5-c] quinoline C 19 is suspended in 10 ml of a 1N aqueous sodium hydroxide solution and refluxed for 1.5 hours. The reaction solution is cooled and neutralized with acetic acid. The precipitated crystals were collected by filtration, washed successively with water and ethanol, and dried to yield 195 mg (71% yield) of C.
94 is obtained. Melting point when recrystallized from ethanol
It becomes colorless crystals above 340 ℃.
元素分析：C16H12N4・1/8C2H5OHとして 計算値（％）:C,73.36;H,4.83;N,21.06 実測値（％）:C,73.44;H,4.93;N,20.95 実施例95 ２−（４−メチルフエニル）−1H−イミダゾ［4,5−
ｃ］キノリンC95 ４−メチル安息香酸326mgと3,4−ジアミノキノリン318m
gをPPA10g中に懸濁し、窒素気流下に180℃で４時間攪拌
する。放冷後、氷水を加え水酸化ナトリウム水溶液で中
和し、生成する固体を濾取し、水洗乾燥する。これをシ
リカゲルクロマトグラフイーに付し、クロロホルム−メ
タノール（25:1 v/v）で溶出して得られた結晶をエタノ
ールから再結晶してC95 の無色結晶430mg（収率83％）を
得る。Elemental analysis: C 16 H 12 N 4 · 1 / 8C 2 H 5 OH Calculated (%): C, 73.36; H, 4.83; N, 21.06 Found (%): C, 73.44; H, 4.93; N , 20.95 Example 95 2- (4-Methylphenyl) -1H-imidazo [4,5-
c] Quinoline C 95 4-methylbenzoic acid 326 mg and 3,4-diaminoquinoline 318 m
g is suspended in 10 g of PPA, and the suspension is stirred under a nitrogen stream at 180 ° C. for 4 hours. After allowing to cool, ice water is added and the mixture is neutralized with an aqueous sodium hydroxide solution, and the resulting solid is collected by filtration, washed with water and dried. This was subjected to silica gel chromatography, chloroform - methanol: obtaining (25 1 v / v) as a colorless crystal of C 95 was recrystallized crystals obtained by elution from ethanol 430 mg (83% yield) of .
融点326-329℃（分解） 元素分析：C17H13N3・1/3H2Oとして 計算値（％）:C,76.96;H,5.19;N,15.84 実測値（％）:C,76.86;H,4.84;N,15.52 実施例96 ２−（４−クロロフエニル）−1H−イミダゾ［4,5−
ｃ］キノリンC96 ４−クロロ安息香酸239mgと3,4−ジアミノキノリン470m
gをPPA9gに懸濁し窒素気流下に185℃で４時間攪拌す
る。実施例95と同様の後処理を行い、得られた粗結晶を
エタノールから再結晶してC96 の無色結晶248mg（収率59
％）を得る。Mp 326-329 ℃ (decomposition) Elemental analysis: C 17 H 13 N 3 · 1 / 3H 2 O Calculated (%): C, 76.96; H, 5.19; N, 15.84 Found (%): C, 76.86 ; H, 4.84; N, 15.52 Example 96 2- (4-chlorophenyl) -1H-imidazo [4,5-
c] Quinoline C 96 4-chlorobenzoic acid 239 mg and 3,4-diaminoquinoline 470 m
g was suspended in 9 g of PPA and the mixture was stirred under a nitrogen stream at 185 ° C. for 4 hours. The same post-treatment as in Example 95 was performed, and the obtained crude crystals were recrystallized from ethanol to give C 96 colorless crystals (248 mg, yield 59).
%).
融点335-337℃（分解） 元素分析：C16H10N3Clとして 計算値（％）:C,68.70;H,3.60;N,15.02;Cl,12.68 実測値（％）:C,68.42;H,3.71;N,14.83;Cl,12.76 実施例97 ２−（４−フルオロフエニル）−１−メチル−1H−イミ
ダゾ［4,5−ｃ］キノリンC97 ４−フルオロ安息香酸390mgの無水HMPA6ml−無水アセト
ニトリル0.6ml溶液に窒素気流下、塩化チオニル320mgを
−５〜０℃の温度を保ちながら滴下する。同温度で30分
間攪拌後、３−アミノ−４−メチルアミノキノリンA15 4
40mgの無水HMPA4ml溶液を加え、０℃で2.5時間攪拌す
る。反応液を実施例１と同様の処理をするとB97 の白色
固体750mgが得られる。次いでこれを酢酸10mlに溶か
し、１時間加熱還流する。反応液を減圧下に濃縮し、残
留物を酢酸エチル−飽和重ソウ水に分配する。酢酸エチ
ル層を分離、水、飽和食塩水で順次洗浄し、硫酸マグネ
シウムで乾燥する。酢酸エチルを留去し、得られる残渣
をｎ−ヘキサンで結晶化させると610mg（87％）のC97 を
得る。本品を酢酸エチルから再結晶すると、融点185-18
7℃の無色結晶となる。Melting point 335-337 ° C (decomposition) Elemental analysis: Calculated as C 16 H 10 N 3 Cl (%): C, 68.70; H, 3.60; N, 15.02; Cl, 12.68 Measured value (%): C, 68.42; H, 3.71; N, 14.83; Cl, 12.76 Example 97 2- (4-Fluorophenyl) -1-methyl-1H-imidazo [4,5-c] quinoline C 97 To a solution of 4-fluorobenzoic acid (390 mg) in anhydrous HMPA (6 ml) -anhydrous acetonitrile (0.6 ml), thionyl chloride (320 mg) was added dropwise under a nitrogen stream while maintaining a temperature of -5 to 0 ° C. After stirring at the same temperature for 30 minutes, 3-amino-4-methylaminoquinoline A 15 4
40 mg of anhydrous HMPA in 4 ml is added, and the mixture is stirred at 0 ° C. for 2.5 hours. When the reaction mixture is treated in the same manner as in Example 1, 750 mg of a white solid B 97 is obtained. Then, this is dissolved in 10 ml of acetic acid and heated under reflux for 1 hour. The reaction mixture is concentrated under reduced pressure, and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate water. The ethyl acetate layer is separated, washed successively with water and saturated brine, and dried over magnesium sulfate. Ethyl acetate was distilled off and crystallized residue obtained in n- hexane obtaining C 97 of 610mg (87%). Recrystallization of this product from ethyl acetate gave a melting point of 185-18.
It becomes colorless crystals at 7 ℃.
元素分析：C17H12N3Fとして 計算値（％）:C,73.63;H,4.36;N,15.15;F,6.85 実測値（％）:C,73.73;H,4.36;N,15.15;F,6.77 実施例98 １−エチル−２−（５−メチルチオフエン−２−イル）
−1H−イミダゾ［4,5−ｃ］キノリンC98 ５−メチル−２−チオフエンカルボン酸270mgの無水HMP
A5ml−無水アセトニトリル0.5ml溶液に窒素気流下、塩
化チオニル215mgを−５〜０℃で滴下する。同温度で30
分間攪拌後、３−アミノ−４−エチルアミノキノリンA
16 320mgの無水HMPA0.5ml溶液を加える。０−５℃で３時
間攪拌後、実施例１と同様の後処理を行ない510mgの白
色固体B98 を得る。B98 を酢酸10mlに懸濁、１時間加熱還
流する。反応液を濃縮後、残留物を酢酸エチル−飽和重
ソウ水に分配し、酢酸エチル層を分離、水、飽和食塩水
で洗浄する。硫酸マグネシウムで乾燥後、酢酸エチルを
留去し得られる残留物をシリカゲルカラムクロマトグラ
フイーに付し精製する。クロロホルム−メタノール（2
0:1 v/v）で溶出する画分を濃縮し、ｎ−ヘキサンで結
晶化させると380mg（収率76％）のC98 を得る。本品を酢
酸エチルで再結晶すると融点205-206℃の無色結晶とな
る。Elemental analysis: Calculated as C 17 H 12 N 3 F (%): C, 73.63; H, 4.36; N, 15.15; F, 6.85 Measured value (%): C, 73.73; H, 4.36; N, 15.15; F, 6.77 Example 98 1-Ethyl-2- (5-methylthiophen-2-yl)
-1H-imidazo [4,5-c] quinoline C 98 5-Methyl-2-thiophenecarboxylic acid 270 mg anhydrous HMP
To a solution of A5 ml-anhydrous acetonitrile 0.5 ml, under a nitrogen stream, 215 mg of thionyl chloride was added dropwise at -5 to 0 ° C. 30 at the same temperature
After stirring for 3 minutes, 3-amino-4-ethylaminoquinoline A
16 320 mg of anhydrous HMPA 0.5 ml solution is added. After stirring at 0-5 ° C for 3 hours, the same post-treatment as in Example 1 was carried out to obtain 510 mg of white solid B 98 . Suspend B98 in 10 ml of acetic acid and heat to reflux for 1 hour. After the reaction solution was concentrated, the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, the ethyl acetate layer was separated, and washed with water and saturated brine. After drying over magnesium sulfate, ethyl acetate is distilled off and the resulting residue is purified by silica gel column chromatography. Chloroform-methanol (2
0: 1 v concentrating the fractions eluted with / v), and crystallized by n- hexane obtaining C 98 of 380 mg (76% yield). Recrystallization of this product from ethyl acetate gives colorless crystals with a melting point of 205-206 ° C.
元素分析：C17H15N3Sとして 計算値（％）:C,69.60;H,5.15;N,14.32;S,10.93 実測値（％）:C,69.66;H,4.96;N,14.30;S,10.88 実施例99 ２−（４−メチルオキサゾール−５−イル）−1H−イミ
ダゾ［4,5−ｃ］キノリンC99 ４−メチルオキサゾール−５−カルボン酸300mgの無水H
MPA4ml−無水MeCN0.4ml溶液に塩化チオニル268mgを−５
〜０℃で加え、同温度で30分間攪拌後、3,4−ジアミノ
キノリンA1 340mgを加え、０〜５℃で３時間攪拌する。
反応液を氷水で希釈し、飽和重ソウ水で中和し、析出し
た結晶を濾取すると４−アミノ−３−（４−メチルオキ
サゾール−５−カルボニルアミノ）キノリンの粗結晶42
5mgを得る。この結晶400mgをダウサームA12mlに懸濁
し、2.5時間還流する。放冷後、ヘキサン50mlで希釈
し、析出した結晶を濾取する。これをシリカゲルカラム
クロマトグラフイーに付し、CH2Cl2‐MeOH（20:1 v/v）
で溶出し、溶出液を濃縮する。得られた結晶を酢酸エチ
ル−メタノールから再結晶してC99 の淡黄色結晶297mgを
得る。Elemental analysis: Calculated as C 17 H 15 N 3 S (%): C, 69.60; H, 5.15; N, 14.32; S, 10.93 Measured value (%): C, 69.66; H, 4.96; N, 14.30; S, 10.88 Example 99 2- (4-Methyloxazol-5-yl) -1H-imidazo [4,5-c] quinoline C 99 4-Methyloxazole-5-carboxylic acid 300 mg anhydrous H
MPA 4ml-5% anhydrous MeCN 0.4ml with thionyl chloride 268mg
Added at ~0 ° C., after stirring for 30 minutes at the same temperature, 3,4-aminoquinoline A 1 340 mg is added and stirred for 3 hours at 0 to 5 ° C..
The reaction solution was diluted with ice water, neutralized with saturated sodium bicarbonate water, and the precipitated crystals were collected by filtration to give 4-amino-3- (4-methyloxazole-5-carbonylamino) quinoline crude crystals.
You get 5 mg. 400 mg of the crystals are suspended in 12 ml of Dowtherm A and refluxed for 2.5 hours. After allowing to cool, it is diluted with 50 ml of hexane, and the precipitated crystals are collected by filtration. This was subjected to silica gel column chromatography, CH 2 Cl 2 -MeOH (20: 1 v / v)
Elute with and concentrate the eluate. The obtained crystals are recrystallized from ethyl acetate-methanol to obtain 297 mg of C 99 pale yellow crystals.
融点289-292℃（分解） 元素分析：C14H10N4O・1/8H2Oとして 計算値（％）:C,66.59;H,4.09;N,22.19 実測値（％）:C,66.86;H,4.18;N,21.98 実施例100 ２−（３−メチルイソオキサゾール−５−イル）−1H−
イミダゾ［4,5−ｃ］キノリン塩酸塩C100 ２−（３−メチルイソオキサゾール−５−イル）−1H−
イミダゾ［4,5−ｃ］キノリンC45 300mgをエタノールに
溶かし、塩化水素−エーテル溶液を加えた後、溶媒を留
去する。残渣をアセトンで洗浄してC100 を得た。Melting point 289-292 ℃ (decomposition) Elemental analysis: Calculated as C 14 H 10 N 4 O ・ 1 / 8H 2 O (%): C, 66.59; H, 4.09; N, 22.19 Measured value (%): C, 66.86; H, 4.18; N, 21.98 Example 100 2- (3-Methylisoxazol-5-yl) -1H-
Imidazo [4,5-c] quinoline hydrochloride C 100 2- (3-methylisoxazol-5-yl) -1H-
300 mg of imidazo [4,5-c] quinoline C 45 is dissolved in ethanol, hydrogen chloride-ether solution is added, and the solvent is distilled off. The residue was washed with acetone to give C 100 .
融点248.5〜252℃（分解） 元素分析：C14H11N4OCl・1/3H2Oとして 計算値（％）:C,57.45;H,4.02;N,19.14;Cl,12.11 実測値（％）:C,57.64;H,4.27;N,18.90;Cl,12.23 実施例101 ３−メタンスルホニル−２−（３−メチルイソオキサゾ
ール−５−イル）−3H−イミダゾ［4,5−ｃ］キノリンC
101 ２−（３−メチルイソオキサゾール−５−イル）−1H−
イミダゾ［4,5−ｃ］キノリンC45 300mgをTHF20mlに溶か
し、60％油性水素化ナトリウム56mgを加え、75℃で２時
間攪拌する。反応液を氷浴で冷やし、塩化メタンスルホ
ニル180mgを滴下し、０〜５℃で２時間攪拌する。溶媒
を留去し、残留物に氷水を加え、析出する結晶を濾取す
る。これをシリカゲルカラムクロマトグラフイーに付
し、CH2Cl2‐MeOH（50:1 v/v）で溶出し、得られる結晶
を酢酸エチルから再結晶してC101 の無色結晶157mg（収
率40％）を得る。Melting point 248.5-252 ℃ (decomposition) Elemental analysis: Calculated as C 14 H 11 N 4 OCl ・ 1 / 3H 2 O (%): C, 57.45; H, 4.02; N, 19.14; Cl, 12.11 Measured value (%) ): C, 57.64; H, 4.27; N, 18.90; Cl, 12.23 Example 101 3-Methanesulfonyl-2- (3-methylisoxazol-5-yl) -3H-imidazo [4,5-c] quinoline. C
101 2- (3-methylisoxazol-5-yl) -1H-
300 mg of imidazo [4,5-c] quinoline C 45 is dissolved in 20 ml of THF, 56 mg of 60% oily sodium hydride is added, and the mixture is stirred at 75 ° C. for 2 hours. The reaction solution is cooled in an ice bath, 180 mg of methanesulfonyl chloride is added dropwise, and the mixture is stirred at 0 to 5 ° C for 2 hours. The solvent is distilled off, ice water is added to the residue, and the precipitated crystals are collected by filtration. This was subjected to silica gel column chromatography, eluted with CH 2 Cl 2 -MeOH (50: 1 v / v), and the obtained crystals were recrystallized from ethyl acetate to give C 101 colorless crystals (157 mg, yield 40%). %).
融点167.5〜169℃（分解） 元素分析：C15H12N4O3Sとして 計算値（％）:C,54.86;H,3.68;N,17.06 実測値（％）:C,54.95;H,3.97;N,16.79 なおクロマトグラフイーの後の溶出部よりC45 135mg（収
率45％）を回収した。Melting point 167.5-169 ° C (decomposition) Elemental analysis: Calculated as C 15 H 12 N 4 O 3 S (%): C, 54.86; H, 3.68; N, 17.06 Measured value (%): C, 54.95; H, 3.97; N, 16.79 135 mg (45% yield) of C 45 was recovered from the eluate after the chromatography.
実施例102 １−メチル−２−（３−メチルイソオキサゾール−５−
イル）−1H−イミダゾ［4,5−ｃ］キノリンC102 ３−メチルイソオキサゾール−５−カルボン酸254mgの
無水HMPA20ml−無水MeCN0.4ml溶液へ−５〜０℃で塩化
チオニル226mgを加え、30分間攪拌する。３−アミノ−
４−メチルアミノキノリンA15 330mgを加え、０〜５℃で
５時間攪拌する。反応液を氷水50mlで希釈し、飽和重ソ
ウ水で中和する。析出した結晶を濾取し、水洗乾燥して
４−メチルアミノ−３−（３−メチルイソオキサゾール
−５−カルボニルアミノ）キノリンの固体361mg（収率6
7％）を得る。この固体350mgをHMPA4ml、酢酸1mlに懸濁
し、浴温180℃で40分間加熱攪拌する。放冷後、反応液
を氷水100mlへ注ぎ、重ソウ水で中和する。析出した結
晶を濾取し、水洗乾燥後、シリカゲルカラムクロマトグ
ラフイーで精製し、CH2Cl2‐MeOH（25:1 v/v）で溶出す
る。得られた結晶をCHCl3‐MeOHから再結晶してC102 の
無色結晶294mg（収率90％）を得る。Example 102 1-Methyl-2- (3-methylisoxazole-5-
Yl) -1H-imidazo [4,5-c] quinoline C 102 To a solution of 254 mg of 3-methylisoxazole-5-carboxylic acid in 20 ml of anhydrous HMPA and 0.4 ml of anhydrous MeCN, 226 mg of thionyl chloride was added at -5 to 0 ° C. Stir for minutes. 3-amino-
Add 330 mg of 4-methylaminoquinoline A 15 and stir at 0-5 ° C for 5 hours. The reaction solution is diluted with 50 ml of ice water and neutralized with saturated sodium bicarbonate water. The precipitated crystals were collected by filtration, washed with water and dried to give 4-methylamino-3- (3-methylisoxazole-5-carbonylamino) quinoline as a solid 361 mg (yield 6
7%). This solid (350 mg) is suspended in HMPA (4 ml) and acetic acid (1 ml), and the mixture is heated with stirring at a bath temperature of 180 ° C for 40 minutes. After allowing to cool, the reaction solution is poured into 100 ml of ice water and neutralized with heavy soda water. The precipitated crystals are collected by filtration, washed with water, dried, purified by silica gel column chromatography, and eluted with CH 2 Cl 2 -MeOH (25: 1 v / v). The obtained crystals are recrystallized from CHCl 3 -MeOH to obtain 294 mg of C 102 colorless crystals (yield 90%).
融点281〜284℃（分解） 元素分析：C15H12N4Oとして 計算値（％）:C,68.17;H,4.57;N,21.19 実測値（％）:C,68.29;H,4.57;N,21.21 NMR（CDCl3‐CD3OD）：δ2.46（3H,s）,4.57（3H,s）,
6.99（1H,s）,7.6〜8.7（4H,m）,9.23（1H,s）ppm 実施例103 ２−（４−フルオロフエニル）−３−メチル−3H−イミ
ダゾ［4,5−ｃ］キノリンC103 、 ２−（４−フルオロフエニル）−１−メチル−1H−イミ
ダゾ［4,5−ｃ］キノリンC97 及び２−（４−フルオロフ
エニル）−５−メチル−5H−イミダゾ［4,5−ｃ］キノ
リンC104 金属ナトリウム70mgと無水エタノール10mlより調製した
ナトリウムエチラート溶液に室温で窒素気流下にC3 520m
gを加え、５分間攪拌する。次にヨウ化メチル0.5mlを加
え、50℃で１時間攪拌する。反応液を大量の氷水中に加
え、酢酸エチルで抽出する。抽出液を水、飽和食塩水で
順次洗浄し、硫酸マグネシウムで乾燥する。溶媒を留去
し、得られる残留物をシリカゲルクロマトグルフィーに
付し精製する。クロロホルム−メタノール（30:1 v/v）
にて溶出する。Rf値0.35に対応する画分を濃縮し、得ら
れる残留物をｎ−ヘキサンで結晶化すると、90mg（収率
16％）のC103 が得られる。本品を酢酸エチル−ｎ−ヘキ
サンで再結晶すると、融点168-170℃の無色結晶とな
る。Melting point 281-284 ° C (decomposition) Elemental analysis: Calculated as C 15 H 12 N 4 O (%): C, 68.17; H, 4.57; N, 21.19 Measured value (%): C, 68.29; H, 4.57; N, 21.21 NMR (CDCl 3 -CD 3 OD): δ2.46 (3H, s), 4.57 (3H, s),
6.99 (1H, s), 7.6-8.7 (4H, m), 9.23 (1H, s) ppm Example 103 2- (4-Fluorophenyl) -3-methyl-3H-imidazo [4,5-c] Quinoline C 103 , 2- (4-fluorophenyl) -1-methyl-1H-imidazo [4,5-c] quinoline C 97 and 2- (4-fluorophenyl) -5-methyl-5H-imidazo [ 4,5-c] quinoline C 104 A sodium ethylate solution prepared from 70 mg of metallic sodium and 10 ml of absolute ethanol was added to a C 3 520 m solution at room temperature under a nitrogen stream.
Add g and stir for 5 minutes. Next, 0.5 ml of methyl iodide is added, and the mixture is stirred at 50 ° C for 1 hour. The reaction solution is added to a large amount of ice water and extracted with ethyl acetate. The extract is washed successively with water and saturated brine and dried over magnesium sulfate. The solvent is distilled off, and the resulting residue is purified by silica gel chromatography. Chloroform-methanol (30: 1 v / v)
Elute at. The fraction corresponding to an Rf value of 0.35 was concentrated and the resulting residue was crystallized from n-hexane to give 90 mg (yield
16%) of C 103 is obtained. Recrystallization of this product from ethyl acetate-n-hexane gives colorless crystals with a melting point of 168-170 ° C.
元素分析：C17H12N3Fとして 計算値（％）:C,73.63;H,4.36;N,15.15;F,6.85 実測値（％）:C,73.86;H,4.56;N,15.13;F,6.86 NMR（CDCl3）：δ4.02（s,3H）,7.17-8.77（m,8H）,9.1
0（s,1H） 次にRf値0.27に対応する画分を濃縮し、得られる残留物
をｎ−ヘキサンで結晶化すると60mg（収率11％）のC97
が得られる。本品は実施例97で別途合成した化合物C97
と融点及びNMRが完全に一致し同一のものである。更にR
f値0.12に対応する画分を濃縮し、得られる残留物を酢
酸エチルで結晶化すると340mg（収率62％）のC104 が得
られる。本品を酢酸エチル−メタノールで再結晶する
と、融点277-278℃の無色結晶となる。Elemental analysis: Calculated as C 17 H 12 N 3 F (%): C, 73.63; H, 4.36; N, 15.15; F, 6.85 Measured value (%): C, 73.86; H, 4.56; N, 15.13; F, 6.86 NMR (CDCl 3 ): δ4.02 (s, 3H), 7.17-8.77 (m, 8H), 9.1
0 (s, 1H) Then the fraction corresponding to Rf value 0.27 was concentrated and the resulting residue was crystallized with n-hexane to yield 60 mg (11% yield) of C 97.
Is obtained. This product is a compound C 97 synthesized separately in Example 97.
And melting point and NMR are completely the same and the same. Further R
Fractions corresponding to f value 0.12 are concentrated and the resulting residue is crystallized with ethyl acetate to give 340 mg (62% yield) of C 104 . Recrystallization of this product from ethyl acetate-methanol gives colorless crystals with a melting point of 277-278 ° C.
元素分析：C17H12N3Fとして 計算値（％）:C,73.63;H,4.36;N,15.15;F,6.85 実測値（％）:C,73.64;H,4.36;N,15.05;F,6.76 NMR（CDCl3）：δ4.23（s,3H）,7.03-8.93（m,8H）,8.5
6（s,1H）． 実施例104 ３−メチル−２−（３−メチルイソオキサゾール−５−
イル）−3H−イミダゾ［4,5−ｃ］キノリンC105 ,1−メ
チル−２−（３−メチルイソオキサゾール−５−イル）
−1H−イミダゾ［4,5−ｃ］キノリンC102 および５−メ
チル−２−（３−メチルイソオキサゾール−５−イル）
−5H−イミダゾ［4,5−ｃ］キノリンC106 ２−（３−メチルイソオキサゾール−５−イル）−3H−
イミダゾ［4,5−ｃ］キノリンC45 450mgのTHF（30ml）溶
液へ60％油性水素化ナトリウム80mgを加え、60℃に1.5
時間攪拌する。０〜５℃でヨウ化メチル385mgのTHF（2m
l）溶液を滴下し、その温度で30分間攪拌後、さらに40
℃で４時間攪拌する。反応液を減圧乾固し、残留物をシ
リカゲルカラムクロマトグラフイーに付す。CH2Cl2‐Me
OH（50:1 v/v）の溶出部より得られた結晶を酢酸エチル
から再結晶して３−メチル体C105 の無色結晶58mg（収率
12％）を得る。Elemental analysis: Calculated as C 17 H 12 N 3 F (%): C, 73.63; H, 4.36; N, 15.15; F, 6.85 Measured value (%): C, 73.64; H, 4.36; N, 15.05; F, 6.76 NMR (CDCl 3 ): δ4.23 (s, 3H), 7.03-8.93 (m, 8H), 8.5
6 (s, 1H). Example 104 3-methyl-2- (3-methylisoxazole-5-
Yl) -3H-imidazo [4,5-c] quinoline C 105 , 1-methyl-2- (3-methylisoxazol-5-yl)
-1H-imidazo [4,5-c] quinoline C 102 and 5-methyl-2- (3-methylisoxazol-5-yl)
-5H-imidazo [4,5-c] quinoline C 106 2- (3-methylisoxazol-5-yl) -3H-
Imidazo [4,5-c] quinoline C 45 To a solution of 450 mg in THF (30 ml), 80 mg of 60% oily sodium hydride was added, and the mixture was heated to 60 ° C. for 1.5 minutes.
Stir for hours. Methyl iodide 385mg THF (2m
l) Add the solution dropwise and stir at that temperature for 30 minutes, then add 40 more
Stir at 4 ° C for 4 hours. The reaction solution is dried under reduced pressure and the residue is subjected to silica gel column chromatography. CH 2 Cl 2 ‐Me
The crystals obtained from the OH (50: 1 v / v) eluate were recrystallized from ethyl acetate to give 3-methyl C 105 colorless crystals (58 mg, yield).
12%).
融点179.5〜182℃ 元素分析：C15H12N4O・1/4H2Oとして 計算値（％）:C,67.03;H,4.69;N,20.84 実測値（％）:C,67.16;H,4.98;N,20.62 NMR（CDCl3‐CD3OD）：δ2.46（3H,s）,4.35（3H,s）,
7.13（1H,s）,7.6〜8.7（4H,m）,9.13（1H,s）ppm 同混合溶媒で溶出される画分より１−メチル体C102 42mg
（収率９％）を得る。これは実施例102で得られた化合
物と一致した。Mp 179.5 to 182 ° C. Elemental analysis: C 15 H 12 N 4 O · 1 / 4H 2 O Calculated (%): C, 67.03; H, 4.69; N, 20.84 Found (%): C, 67.16; H , 4.98; N, 20.62 NMR (CDCl 3 -CD 3 OD): δ2.46 (3H, s), 4.35 (3H, s),
7.13 (1H, s), 7.6 to 8.7 (4H, m), 9.13 (1H, s) ppm 1-methyl form C 102 42 mg from the fraction eluted with the same mixed solvent
(Yield 9%) is obtained. This was consistent with the compound obtained in Example 102.
さらにCH2Cl2‐MeOH（25:1 v/v）で溶出し、溶出液を濃
縮する。得られた結晶を酢酸エチル−メタノールで再結
晶し、5-Me体C106 の無色結晶322mg（68％）を得る。Further elute with CH 2 Cl 2 -MeOH (25: 1 v / v) and concentrate the eluate. The obtained crystals are recrystallized from ethyl acetate-methanol to obtain 322 mg (68%) of 5-Me form C 106 as colorless crystals.
融点308〜309（分解） 元素分析：C15H12N4Oとして 計算値（％）:C,68.17;H,4.57;N,21.19 実測値（％）:C,68.14;H,4.76;N,21.12 NMR（CDCl3‐CD3OD）：δ2.42（3H,s）,4.40（3H,s）,
6.99（1H,s）,7.6〜8.9（4H,m）,9.07（1H,s）ppm 実施例105 ２−（４−フルオロフエニル）−７−メチル−1H−イミ
ダゾ［4,5−ｄ］チエノ［2,3−ｂ］ピリジンF1 ４−フルオロ安息香酸308mgの無水HMPA5ml−無水MeCN0.
5ml溶液に窒素気流下に塩化チオニル250mgを−５〜０℃
の温度を保ちながら滴下する。同温度で30分間攪拌後、
ジアミノチエノピリジンD1 358mgを加え、０〜５℃で３
時間攪拌する。反応液を氷水で希釈し、飽和重ソウ水で
中和し、析出した結晶を濾取、水洗乾燥して４−アミノ
−２−メチル−３−（４−フルオロベンゾイルアミノ）
−チエノ［2,3−ｂ］キノリンE1の粗結晶630mgを得る。
これをPPA15mlに懸濁し、窒素気流下に140℃で１時間攪
拌する。Melting point 308-309 (decomposition) Elemental analysis: Calculated as C 15 H 12 N 4 O (%): C, 68.17; H, 4.57; N, 21.19 Measured value (%): C, 68.14; H, 4.76; N , 21.12 NMR (CDCl 3 -CD 3 OD): δ2.42 (3H, s), 4.40 (3H, s),
6.99 (1H, s), 7.6-8.9 (4H, m), 9.07 (1H, s) ppm Example 105 2- (4-Fluorophenyl) -7-methyl-1H-imidazo [4,5-d] Thieno [2,3-b] pyridine F 1 4-Fluorobenzoic acid 308 mg anhydrous HMPA 5 ml anhydrous MeCN0.
Add 250 mg of thionyl chloride to a 5 ml solution under a nitrogen stream at -5 to 0 ° C.
Drop while maintaining the temperature. After stirring at the same temperature for 30 minutes,
Add 358 mg of diaminothienopyridine D 1 and add 3 at 0-5 ° C.
Stir for hours. The reaction mixture was diluted with ice water, neutralized with saturated sodium bicarbonate water, and the precipitated crystals were collected by filtration, washed with water and dried to give 4-amino-2-methyl-3- (4-fluorobenzoylamino).
630 mg of crude crystals of thieno [2,3-b] quinoline E 1 are obtained.
This is suspended in 15 ml of PPA and stirred under a nitrogen stream at 140 ° C for 1 hour.
放冷後、氷水を加え、水酸化ナトリウム水溶液で中和
し、酢酸エチルで抽出する。抽出液を水洗乾燥後、溶媒
を留去し、得られる残渣をシリカゲルカラムクロマトグ
ラフイーに付し、クロロホルム−メタノール（25:1 v/
v）より溶出される画分よりF1 の結晶457mg（収率81％）
を得る。これをエタノールから再結晶すると融点313-31
6℃の無色結晶を得る。After allowing to cool, ice water is added, the mixture is neutralized with an aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with water and dried, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography, and chloroform-methanol (25: 1 v /
457 mg of F 1 crystals (81% yield) from the fraction eluted from v)
To get When recrystallized from ethanol, the melting point was 313-31.
A colorless crystal of 6 ° C is obtained.
元素分析：C15H10N3SFとして 計算値（％）:C,63.58;H,3.55;N,14.83;S,11.31 実測値（％）:C,63.32;H,3.79;N,14.61;S,11.09 実施例106 ２−（２−チエニル）−７−メチル−1H−イミダゾ［4,
5−ｄ］チエノ［2,3−ｂ］ピリジンF2 ２−チオフエンカルボン酸212mgのHMPA4ml−アセトニト
リル0.4ml溶液へ窒素気流下に塩化チオニル188mgを−５
〜０℃で滴下し、同温度で30分間攪拌する。ジアミノチ
エノピリジンD1 269mgを加え０〜５℃で３時間攪拌し、
実施例105と同様の処理をしてE2の粗結晶403mgを得る。
これをダウサームA20mlに懸濁し、窒素気流下に３時間
還流する。放冷後、ヘキサンで希釈して析出する結晶を
濾取し、シリカゲルカラムクロマトグラフイーに付し、
クロロホルム−メタノール（25:1 v/v）から溶出される
画分からF2 の結晶286mg（収率70％）を得る。本品をメ
タノール−酢酸エチルから再結晶すると融点284-287℃
の無色結晶となる。Elemental analysis: Calculated as C 15 H 10 N 3 SF (%): C, 63.58; H, 3.55; N, 14.83; S, 11.31 Measured value (%): C, 63.32; H, 3.79; N, 14.61; S, 11.09 Example 106 2- (2-thienyl) -7-methyl-1H-imidazo [4,
5-d] thieno [2,3-b] pyridine F 2 To a solution of 212 mg of 2-thiophenecarboxylic acid in 4 ml of HMPA and 0.4 ml of acetonitrile, under a nitrogen stream, 188 mg of thionyl chloride was added to -5.
Add dropwise at ~ 0 ° C and stir at the same temperature for 30 minutes. Add 269 mg of diaminothienopyridine D 1 and stir at 0-5 ° C. for 3 hours,
The same treatment as in Example 105 was performed to obtain 403 mg of crude crystals of E 2 .
This is suspended in 20 ml of Dowtherm A and refluxed under a nitrogen stream for 3 hours. After allowing to cool, it was diluted with hexane and the precipitated crystals were collected by filtration and subjected to silica gel column chromatography.
From the fraction eluted from chloroform-methanol (25: 1 v / v), 286 mg of F 2 crystals (yield 70%) is obtained. Recrystallization of this product from methanol-ethyl acetate gave a melting point of 284-287 ° C.
Of colorless crystals.
元素分析：C13H9N3S2として 計算値（％）:C,57.54;H,3.34;N,15.48;S,23.68 実測値（％）:C,57.46;H,3.60;N,15.39;S,23.67 実施例107-114 実施例106と同様にして表４に示す反応条件で目的物質
を得る。目的物質の物性を表５に示す。Elemental analysis: Calculated as C 13 H 9 N 3 S 2 (%): C, 57.54; H, 3.34; N, 15.48; S, 23.68 Measured value (%): C, 57.46; H, 3.60; N, 15.39 S, 23.67 Examples 107-114 The target substances are obtained under the reaction conditions shown in Table 4 in the same manner as in Example 106. Table 5 shows the physical properties of the target substance.
実施例115 ２−フエニル−1H−イミダゾ［4,5−ｄ］チエノ［3,4−
ｂ］ピリジンH1 安息香酸187mgの無水HMPA5ml−無水MeCN0.5mlの溶液へ
窒素気流下に塩化チオニル174mgを０℃で滴下し、同温
度で30分間攪拌する。ジアミノチエノピリジンD3 230mg
を加え、さらに３時間攪拌し、氷水で希釈し、重ソウ水
で中和後、析出した結晶を濾取し、水洗乾燥するとG1の
粗結晶280mgを得る。これをHMPA4.2ml−酢酸1.1mlに懸
濁し、170℃で30分間加温する。放冷後、氷水で希釈
し、酢酸エチルで抽出する。抽出液を水洗乾燥した後、
溶媒を留去し、得られる残渣をシリカゲルカラムクロマ
トグラフイーに付し、クロロホルム−メタノール（50:2
v/v）から溶出される画分からH1 の結晶170mg（収率51
％）を得る。本品を酢酸エチル−メタノールから再結晶
すると融点308-312℃（分解）の無色結晶となる。 Example 115 2-phenyl-1H-imidazo [4,5-d] thieno [3,4-
b] pyridine H 1 To a solution of 187 mg of benzoic acid in 5 ml of anhydrous HMPA and 0.5 ml of anhydrous MeCN, 174 mg of thionyl chloride was added dropwise at 0 ° C under a nitrogen stream, and the mixture was stirred at the same temperature for 30 minutes. Diaminothienopyridine D 3 230mg
Was added, and the mixture was further stirred for 3 hours, diluted with ice water, neutralized with heavy soup water, and the precipitated crystals were collected by filtration, washed with water and dried to obtain 280 mg of G 1 crude crystals. This is suspended in 4.2 ml of HMPA-1.1 ml of acetic acid and heated at 170 ° C. for 30 minutes. After allowing to cool, dilute with ice water and extract with ethyl acetate. After washing the extract with water and drying,
The solvent was distilled off, the resulting residue was subjected to silica gel column chromatography, and chloroform-methanol (50: 2
170 mg of H 1 crystals (yield 51
%). Recrystallization of this product from ethyl acetate-methanol gives colorless crystals with a melting point of 308-312 ° C (decomposition).
元素分析：C14H9N3S・1/3H2O 計算値（％）:C,65.35;H,3.79;N,16.33 実測値（％）:C,65.29;H,3.73;N,16.13 実施例116 ２−（４−フルオロフエニル）−1H−イミダゾ［4,5−
ｄ］チエノ［3,4−ｂ］ピリジンH2 実施例115と同様にして４−フルオロ安息香酸281mgとジ
アミノチエノピリジンD3 300mgから出発してH2 の結晶240
mg（収率50％）を得る。メタノール−酢酸エチルから再
結晶すると融点302-305℃の無色結晶となる。Elemental analysis: C 14 H 9 N 3 S ・ 1 / 3H 2 O Calculated value (%): C, 65.35; H, 3.79; N, 16.33 Measured value (%): C, 65.29; H, 3.73; N, 16.13 Example 116 2- (4-fluorophenyl) -1H-imidazo [4,5-
d] Thieno [3,4-b] pyridine H 2 Crystals of H 2 starting in the same manner as in Example 115 starting from 281 mg of 4-fluorobenzoic acid and 300 mg of diaminothienopyridine D 3 240
mg (yield 50%) is obtained. Recrystallization from methanol-ethyl acetate gives colorless crystals with a melting point of 302-305 ° C.
元素分析：C14H8N3SFとして 計算値（％）:C,62.44;H,2.99;N,15.60 実測値（％）:C,62.23;H,3.26;N,15.28 実施例117 ２−（５−クロロチオフエン−２−イル）−1H−イミダ
ゾ［4,5−ｄ］チエノ［3,4−ｂ］ピリジンH3 実施例115と同様にして５−クロロ−２−チオフエンカ
ルボン酸325mgとジアミノチエノピリジンD3 300mgから出
発してH3 の結晶259mg（収率46％）を得る。酢酸エチル
−メタノールから再結晶すると融点301-304℃（分解）
の無色結晶となる。Elemental analysis: Calculated as C 14 H 8 N 3 SF (%): C, 62.44; H, 2.99; N, 15.60 Measured value (%): C, 62.23; H, 3.26; N, 15.28 Example 117 2- (5-chlorothiophen-2-yl) -1H-imidazo [4,5-d] thieno [3,4-b] pyridine H 3 In the same manner as in Example 115, 5-chloro-2-thiophenecarboxylic acid (325 mg) was used. Starting from 300 mg of diaminothienopyridine D 3 259 mg of crystals of H 3 (yield 46%) are obtained. Recrystallized from ethyl acetate-methanol, melting point 301-304 ℃ (decomposition)
Of colorless crystals.
元素分析：C12H6N3ClS2として 計算値（％）:C,49.39;H,2.07;N,14.40 実測値（％）:C,49.09;H,2.17;N,14.16 実施例118 ２−（４−メトキシフエニル）−1H−イミダゾ［4,5−
ｄ］チエノ［3,2−ｂ］ピリジンK1 ４−メトキシ安息香酸233mgのHMPA4ml−MeCN0.4ml溶液
に０℃で塩化チオニル174mgを加え、同温度で30分間攪
拌する。次にジアミノチエノピリジンD4 230mgを加え、
４時間攪拌後、氷水で希釈、重ソウ水で中和する。析出
した結晶を濾取し、水洗乾燥するとJ1の結晶（融点122-
6℃（分解））348mg（収率84％）を得る。次にJ1 330mg
をダウサームA6.6ml中で２時間還流し、放冷後、ヘキサ
ンを加え、放置して析出した結晶を濾取し、K1 の結晶30
0mg（収率95％）を得る。本品を酢酸エチル−メタノー
ルから再結晶すると融点285-287℃の無色結晶となる。Elemental analysis: Calculated as C 12 H 6 N 3 ClS 2 (%): C, 49.39; H, 2.07; N, 14.40 Measured value (%): C, 49.09; H, 2.17; N, 14.16 Example 118 2 -(4-Methoxyphenyl) -1H-imidazo [4,5-
d] thieno [3,2-b] pyridine K 1 To a solution of 4-methoxybenzoic acid (233 mg) in HMPA (4 ml) -MeCN (0.4 ml) was added thionyl chloride (174 mg) at 0 ° C, and the mixture was stirred at the same temperature for 30 minutes. Then add 230 mg of diaminothienopyridine D 4 ,
After stirring for 4 hours, dilute with ice water and neutralize with heavy soup water. The precipitated crystals are collected by filtration, washed with water and dried to give J 1 crystals (melting point 122-
6 ° C. (decomposition)) 348 mg (84% yield) are obtained. Then J 1 330mg
Was refluxed in 6.6 ml of Dowtherm A for 2 hours, allowed to cool, hexane was added, the mixture was allowed to stand and the precipitated crystals were collected by filtration to give K 1 crystals 30
0 mg (95% yield) are obtained. Recrystallization of this product from ethyl acetate-methanol gives colorless crystals with a melting point of 285-287 ℃.
元素分析：C15H11N3OS・1/5CH3OOC2H5として 計算値（％）:C,63.48;H,4.25;N,14.06 実測値（％）:C,63.20;H,4.38;N,13.86 実施例119-123 実施例118と同様にして、表６に示す反応条件で目的物
質を得る。目的物質の物性を表７に示す。Elemental analysis: Calculated as C 15 H 11 N 3 OS ・ 1 / 5CH 3 OOC 2 H 5 (%): C, 63.48; H, 4.25; N, 14.06 Measured value (%): C, 63.20; H, 4.38 N, 13.86 Examples 119-123 In the same manner as in Example 118, the target substances were obtained under the reaction conditions shown in Table 6. Table 7 shows the physical properties of the target substance.
3,4−ジアミノキノリン類 原料の3,4−ジアミノキノリン類は文献（J.Am.Chem.So
c.,69,365（1947）;J.Am.Chem.Soc.,73,2413（1951））
に記載の方法に準じて、３−ニトロ−４−ヒドロキシキ
ノリン類からクロル化、アミノ化、還元によつて合成し
た。下の表にそれらの融点を示す。 3,4-Diaminoquinolines The starting 3,4-diaminoquinolines are available in the literature (J. Am. Chem. So.
c., 69 , 365 (1947); J. Am. Chem. Soc., 73 , 2413 (1951))
Synthesized from 3-nitro-4-hydroxyquinolines by chlorination, amination, and reduction according to the method described in 1. The table below shows their melting points.
参考例１ ３−アミノ−４−メチルアミノキノリンA15 ４−クロロ−３−ニトロキノリン2.0gを無水エタノール
20mlに懸濁し、30％メチルアミン−エタノール溶液15ml
を加える。室温で30分間攪拌後、反応液を減圧濃縮す
る。残渣に水を加え、析出する結晶を濾取、水洗乾燥す
ると1.82g（収率93％）の４−メチルアミノ−３−ニト
ロキノリンが得られる。本品を酢酸エチルで再結晶する
と、融点172-173℃の黄色結晶となる（元素分析：C10H9
N3O2として、計算値:C,59.11;H,4.46;N,20.68;実測値:
C,59.33;H,4.59;N,20.67）。４−メチルアミノ−３−ニ
トロキノリン1.7gを75mlのエタノールに懸濁し、10％パ
ラジウム炭素300mgを加え、接触還元に付す。理論量の
水素吸収後、反応液から触媒を除き、減圧濃縮する。得
られる残留物をシリカゲルカラムクロマトグラフイーに
付して精製する。クロロホルム−メタノール（2:1 v/
v）で溶出すると600mg（収率41％）の３−アミノ−４−
メチルアミノキノリンA15 が油状物として得られる。 Reference Example 1 3-amino-4-methylaminoquinoline A 15 4-chloro-3-nitroquinoline 2.0 g anhydrous ethanol
Suspended in 20 ml, 30% methylamine-ethanol solution 15 ml
Add. After stirring at room temperature for 30 minutes, the reaction solution is concentrated under reduced pressure. Water is added to the residue, and the precipitated crystals are collected by filtration, washed with water and dried to give 1.82 g (yield 93%) of 4-methylamino-3-nitroquinoline. Recrystallization of this product from ethyl acetate gives yellow crystals with a melting point of 172-173 ° C (elemental analysis: C 10 H 9
As N 3 O 2, Calcd: C, 59.11; H, 4.46 ; N, 20.68; Found:
C, 59.33; H, 4.59; N, 20.67). 1.7 g of 4-methylamino-3-nitroquinoline is suspended in 75 ml of ethanol, 300 mg of 10% palladium on carbon is added, and the mixture is subjected to catalytic reduction. After absorbing a theoretical amount of hydrogen, the catalyst is removed from the reaction solution, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography. Chloroform-methanol (2: 1 v /
Elution with v) gives 600 mg (41% yield) of 3-amino-4-
Methylaminoquinoline A 15 is obtained as an oil.
NMR（CD3OD）：δ3.05（s,3H）,7.17-7.50（m,2H）7.60
-8.15（m,2H）,8.38（s,1H）． 参考例２ ３−アミノ−４−エチルアミノキノリンA16 ４−クロロ−３−ニトロキノリン1.40gの無水エタノー
ル30ml懸濁液に室温下過剰のエチルアミンガスを導入
し、３時間攪拌する。反応液を実施例98と同様の処理を
行なうと1.41g（収率97％）の４−エチルアミノ−３−
ニトロキノリンが得られる。本品を酢酸エチル−ｎ−ヘ
キサンで再結晶すると、融点151-152℃の黄色結晶とな
る（元素分析：C11H11N3O2としての計算値:C,60.82;H,
5.10;N,19.34;実測値:C,60.93;H,5.07;N,19.27）。４−
エチルアミノ−３−ニトロキノリン1.34gをエタノール4
0mlに懸濁し、10％パラジウム炭素200mgを加え、参考例
１と同様にして接触還元に付し、精製すると0.95g（82
％）の３−アミノ−４−エチルアミノキノリンA16 が油
状物として得られる。NMR (CD 3 OD): δ3.05 (s, 3H), 7.17-7.50 (m, 2H) 7.60
-8.15 (m, 2H), 8.38 (s, 1H). Reference Example 2 3-amino-4-ethylaminoquinoline A 16 To a suspension of 1.40 g of 4-chloro-3-nitroquinoline in 30 ml of absolute ethanol was introduced excess ethylamine gas at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was treated similarly to that in Example 98 to give 1.41 g (yield 97%) of 4-ethylamino-3-.
Nitroquinoline is obtained. Recrystallization of this product from ethyl acetate-n-hexane gives yellow crystals with a melting point of 151-152 ° C (elemental analysis: calculated as C 11 H 11 N 3 O 2 : C, 60.82; H,
5.10; N, 19.34; Found: C, 60.93; H, 5.07; N, 19.27). 4-
Ethylamino-3-nitroquinoline 1.34 g ethanol 4
Suspended in 0 ml, added with 10% palladium carbon (200 mg), subjected to catalytic reduction in the same manner as in Reference Example 1, and purified to obtain 0.95 g (82
%) 3-Amino-4-ethylaminoquinoline A 16 is obtained as an oil.
NMR（CD3OD）：δ1.24（t,3H）,3.35（q,2H）,7.33-7.6
3（m,2H）,7.77-8.03（m,2H）,8.30（s,1H） 参考例３ （１）５−ニトロ−２−メチルチエノ［2,3−ｂ］ピリ
ジン−４（7H）−オン 2 ２−メチルチエノ［2,3−ｂ］ピリジン−４（7H）−オ
ン 1 1.65gの酢酸45ml溶液へ約110℃で濃硝酸（ｄ＝1.
38）1.24gの酢酸5ml溶液を滴下する。反応液を同温度で
10分間攪拌後、放冷し、析出した結晶を濾取、酢酸エチ
ルで洗浄すると2の淡黄色結晶1.07g（収率51％）を得
る。NMR (CD 3 OD): δ1.24 (t, 3H), 3.35 (q, 2H), 7.33-7.6
3 (m, 2H), 7.77-8.03 (m, 2H), 8.30 (s, 1H) Reference example 3 (1) 5-Nitro-2-methylthieno [2,3-b] pyridin-4 (7H) -one 2 2-Methylthieno [2,3-b] pyridin-4 (7H) -one 1 1.65 g of acetic acid 45 ml Concentrated nitric acid (d = 1.
38) Add 1.24 g of acetic acid in 5 ml dropwise. The reaction solution at the same temperature
After stirring for 10 minutes, the mixture was allowed to cool, and the precipitated crystals were collected by filtration and washed with ethyl acetate to give 1.07 g (yield 51%) of pale yellow crystals of 2 .
融点280-282℃（分解） 元素分析：C8H6N2O3Sとして 計算値（％）:C,45.71;H,2.87;N,13.32;S,15.25 実測値（％）:C,45.64;H,3.42;N,13.20;S,15.20 （２）４−クロロ−５−ニトロ−２−メチルチエノ［2,
3−ｂ］ピリジン 3 ５−ニトロ−２−メチルチエノ［2,3−ｂ］ピリジン−
４（7H）−オン 2 2.26gをオキシ塩化リン10ml中で１
時間還流する。これを減圧乾固し、得られる残渣を酢酸
エチルに溶かし、水、アンモニア水、水で順次洗浄後、
無水硫酸マグネシウムで乾燥し、活性炭を加え、濾過す
る。濾液を減圧濃縮し、得られる粗結晶を酢酸エチル−
ヘキサンから再結晶して3の無色結晶1.90g（収率68％）
を得る。Melting point 280-282 ° C (decomposition) Elemental analysis: Calculated as C 8 H 6 N 2 O 3 S (%): C, 45.71; H, 2.87; N, 13.32; S, 15.25 Measured value (%): C, 45.64; H, 3.42; N, 13.20; S, 15.20 (2) 4-chloro-5-nitro-2-methylthieno [2,
3-b] pyridine 3 5-nitro-2-methylthieno [2,3-b] pyridine -
2.26 g of 4 (7H) -one 2 was added to 1 in 10 ml of phosphorus oxychloride.
Reflux for an hour. This was dried under reduced pressure, the resulting residue was dissolved in ethyl acetate, washed successively with water, aqueous ammonia, and water,
Dry over anhydrous magnesium sulfate, add activated carbon and filter. The filtrate was concentrated under reduced pressure, and the resulting crude crystals were washed with ethyl acetate-
Recrystallization from hexane gave 1.90 g of colorless crystals of 3 (68% yield).
To get
融点96-98℃ 元素分析：C8H5N2O2SClとして 計算値（％）:C,42.02;H,2.20;N,12.25;S,14.02 実測値（％）:C,41.92;H,2.48;N,12.16;S,14.12 （３）４−アミノ−５−ニトロ−２−メチルチエノ［2,
3−ｂ］ピリジン 4 ４−クロロ−５−ニトロ−２−メチルチエノ［2,3−
ｂ］ピリジン 3 1.60gのイソプロパノール50ml溶液へ
約55℃でアンモニアガスを通じながら４時間攪拌する。
これを減圧乾固し、得られる残渣をエーテルで洗浄後、
水に懸濁し、1N水酸化ナトリウム7mlを加えて攪拌す
る。結晶を濾取し、水および少量のエタノールで洗浄す
ると4のオレンジ色結晶1.37g（収率93％）を得る。Melting point 96-98 ° C Elemental analysis: Calculated as C 8 H 5 N 2 O 2 SCl (%): C, 42.02; H, 2.20; N, 12.25; S, 14.02 Measured value (%): C, 41.92; H , 2.48; N, 12.16; S, 14.12 (3) 4-amino-5-nitro-2-methylthieno [2,
3-b] pyridine 4 4-chloro-5-nitro-2-methylthieno [2,3-
b] Pyridine 3 1.60 g of isopropanol in 50 ml of solution was stirred at about 55 ° C. for 4 hours while passing ammonia gas.
This is dried under reduced pressure, the resulting residue is washed with ether,
Suspend in water, add 7 ml of 1N sodium hydroxide and stir. The crystals are collected by filtration and washed with water and a small amount of ethanol to give 1.37 g (yield 93%) of orange crystals of 4 .
融点238-240℃ 元素分析：C8H7N3O2Sとして 計算値（％）:C,45.92;H,3.37;.N,20.08;S,15.32 実測値（％）:C,45.71;H,3.40;N,19.84;S,15.44 （４）4,5−ジアミノ−２−メチルチエノ［2,3−ｂ］ピ
リジンD1 ４−アミノ−５−ニトロ−２−メチルチエノ［2,3−
ｂ］ピリジン4 1.25gと10％パラジウム炭素360mgのエタ
ノール40ml懸濁液を室温にて水素気流下に２時間攪拌す
る。反応液を濾過し、濾液を濃縮し、得られる残渣をク
ロロホルムで洗浄し、D1 の無色結晶866mg（収率81％）
を得る。Melting point 238-240 ° C Elemental analysis: Calculated as C 8 H 7 N 3 O 2 S (%): C, 45.92; H, 3.37; .N, 20.08; S, 15.32 Measured value (%): C, 45.71; H, 3.40; N, 19.84; S, 15.44 (4) 4,5-Diamino-2-methylthieno [2,3-b] pyridine D 1 4-amino-5-nitro-2-methylthieno [ 2,3-
b] A suspension of 1.25 g of pyridine 4 and 360 mg of 10% palladium on carbon in 40 ml of ethanol is stirred at room temperature under a hydrogen stream for 2 hours. The reaction solution was filtered, the filtrate was concentrated, the obtained residue was washed with chloroform, and 866 mg of colorless crystals of D 1 (yield 81%)
To get
融点204-209℃ 元素分析：C8H9N3Sとして 計算値（％）:C,53.60;H,5.06;N,23.44;S,17.88 実測値（％）:C,53.56;H,5.11;N,23.24;S,18.01 参考例４ （１）５−ニトロ−チエノ［2,3−ｂ］ピリジン−４（7
H）−オン 6 チエノ［2,3−ｂ］ピリジン−４（7H）−オン 5 3.4g
とプロピオン酸105mlの溶液へ100℃で濃硝酸（ｄ＝1.3
8）2.79gを加え、浴温130℃で１時間攪拌する。放冷
後、析出した結晶を濾取、水、メタノール、アセトンで
順次洗浄すると6の淡黄色結晶3.4g（収率77％）が得ら
れる。Melting point 204-209 ° C Elemental analysis: Calculated as C 8 H 9 N 3 S (%): C, 53.60; H, 5.06; N, 23.44; S, 17.88 Measured value (%): C, 53.56; H, 5.11 ; N, 23.24; S, 18.01 Reference example 4 (1) 5-nitro-thieno [2,3-b] pyridine-4 (7
H) -one 6 thieno [2,3-b] pyridin-4 (7H) -one 5 3.4 g
And 105 ml of propionic acid at 100 ℃ concentrated nitric acid (d = 1.3
8) Add 2.79 g and stir at a bath temperature of 130 ° C for 1 hour. After cooling, the precipitated crystals are collected by filtration and washed with water, methanol and acetone in that order to obtain 3.4 g of pale yellow crystals of 6 (yield 77%).
融点288-291℃ （２）４−クロロ−５−ニトロチエノ［2,3−ｂ］ピリ
ジン7 6 3.4gとオキシ塩化リン34mlの混合物を浴温115℃で１
時間攪拌する。減圧乾固し、得られる残渣をクロロホル
ムに溶かし、氷水で洗浄後、乾燥し、溶媒を留去する。
得られる残渣をシリカゲルカラムクロマトグラフイー
（塩化メチレン−エーテル50:1 v/v）で精製すると7の
結晶3.51g（収率94％）が得られる。融点110-113℃ （３）４−アミノ−５−ニトロチエノ［2,3−ｂ］ピリ
ジン8 7 3.36gのｉ−プロパノール160ml懸濁液にアンモニアガ
スを45-50℃で４時間通じる。溶媒を留去し、残渣に水
を加え、濾過し、水、冷エーテルで洗浄すると8の結晶
2.65g（収率87％）を得る。Melting point 288-291 ° C. (2) 4-chloro-5-nitrothieno [2,3-b] pyridin 7 6 3.4 g and a mixture of 34 ml of phosphorus oxychloride were mixed at a bath temperature of 115 ° C.
Stir for hours. It is evaporated to dryness under reduced pressure, the resulting residue is dissolved in chloroform, washed with ice water and dried, and the solvent is distilled off.
The resulting residue was purified by silica gel column chromatography (methylene chloride - ether 50: 1 v / v) to give the 7 crystals 3.51 g (94% yield). Melting point 110-113 ° C. (3) 4-amino-5-nitrothieno [2,3-b] pyridine 8 7 3.36 g of a suspension of 160 ml of i-propanol in ammonia gas at 45-50 ° C. Understand time The solvent was distilled off, water was added to the residue, filtered, and washed with water and cold ether to give 8 crystals.
2.65 g (87% yield) are obtained.
融点227-228.5℃（メタノール−エーテルより） （４）4,5−ジアミノチエノ［2,3−ｂ］ピリジンD2 8 2.57gのアルコール溶液に塩化第１スズ11.1gを加え、
75℃で３時間攪拌する。反応液に活性炭を加え、濾過
し、濾液を減圧濃縮する。残留物を酢酸エチルに溶か
し、炭酸水素ナトリウム9.2gの５％水溶液で塩基性と
し、酢酸エチル抽出する。酢酸エチル層を希塩酸で抽
出、希塩酸層を活性炭処理後、10％水酸化ナトリウムで
pH10とする。再び酢酸エチルで抽出を行い、抽出液を乾
燥し、濃縮し、得られる残渣を酢酸エチル−エーテルか
ら再結晶して、D2 の淡黄色結晶1.65g（収率76％）を得
る。Melting point 227-228.5 ° C (from methanol-ether) (4) 11.1 g of stannous chloride was added to an alcohol solution of 4,5-diaminothieno [2,3-b] pyridine D 2 8 2.57 g,
Stir at 75 ° C. for 3 hours. Activated carbon is added to the reaction solution, filtered, and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, made basic with a 5% aqueous solution of sodium hydrogencarbonate (9.2 g) and extracted with ethyl acetate. The ethyl acetate layer was extracted with diluted hydrochloric acid, the diluted hydrochloric acid layer was treated with activated carbon, and then with 10% sodium hydroxide.
Adjust to pH 10. Extraction is performed again with ethyl acetate, the extract is dried and concentrated, and the obtained residue is recrystallized from ethyl acetate-ether to obtain 1.65 g (yield 76%) of pale yellow crystals of D 2 .
融点159-160.5℃ 元素分析：C7H7N3S・1/8H2Oとして 計算値（％）:C,50.20;H,4.36;N,25.09 実測値（％）:C,50.54;H,4.24;N,24.95 参考例５ （１）３−ニトロチエノ［3,4−ｂ］ピリジン−４（1
H）−オン 10 チエノ［3,4−ｂ］ピリジン−４（1H）−オン 9 4.00g
の酢酸120ml懸濁液に硝酸（ｄ＝1.38）3.00gを加え、70
℃で30分間加温する。放冷後、析出した結晶を濾取し、
水、メタノール−エーテルで洗浄すると10の結晶2.51g
（収率48％）が得られる。本品はジメチルスルホキシド
−メタノールで再結晶すると融点329-332℃の黄色結晶
となる。Melting point 159-160.5 ℃ Elemental analysis: Calculated as C 7 H 7 N 3 S ・ 1 / 8H 2 O (%): C, 50.20; H, 4.36; N, 25.09 Measured value (%): C, 50.54; H , 4.24; N, 24.95 Reference Example 5 (1) 3-nitrothieno [3,4-b] pyridine-4 (1
H) -one 10 thieno [3,4-b] pyridin-4 (1H) -one 9 4.00 g
3.00 g of nitric acid (d = 1.38) was added to 120 ml of acetic acid suspension of
Warm for 30 minutes at ℃. After allowing to cool, the precipitated crystals are collected by filtration,
2.51 g of 10 crystals when washed with water and methanol-ether
(Yield 48%) is obtained. Recrystallization of this product from dimethylsulfoxide-methanol gives yellow crystals with a melting point of 329-332 ° C.
元素分析：C7H4N2O3Sとして 計算値（％）:C,42.85;H,2.05;N,14.27 実測値（％）:C,42.75;H,2.30;N,14.13 （２）４−クロロ−３−ニトロチエノ［3,4−ｂ］ピリ
ジン 11 ３−ニトロチエノ［3,4−ｂ］ピリジン−４（1H）−オ
ン 10 3.00gをオキシ塩化リン9ml中で浴温105℃に１時
間攪拌する。これを減圧乾固し、得られる残渣をクロロ
ホルムに溶かし、アンモニア水、水で洗浄後、無水硫酸
マグネシウムで乾燥する。溶媒を留去し、得られる残渣
をシリカゲルクロマトグラフイーに付し、塩化メチレン
−エーテル（50:1 v/v）から溶出される画分より11の結
晶2.02g（収率62％）を得る。本品をエーテル−石油エ
ーテルから再結晶すると融点139-140℃の無色結晶とな
る 元素分析：C7H3N2O2ClS・1/8H2Oとして 計算値（％）:C,38.77;H,1.51;N,12.92 実測値（％）:C,38.60;H,1.55;N,12.79 （３）４−アミノ−３−ニトロチエノ［3,4−ｂ］ピリ
ジン12 ４−クロロ−３−ニトロチエノ［3,4−ｂ］ピリジン 1
1 1.25gのイソプロパノール37mlの懸濁液へ室温でアン
モニアガスを通じながら３時間攪拌する。反応液を減圧
乾固し、残渣に水を加えて攪拌後、結晶を濾取、水洗
し、乾燥すると12の結晶1.09g（収率62％）を得る。本
品をクロロホルム−メタノールから再結晶すると融点30
7-309℃の黄色結晶となる。Elemental analysis: Calculated as C 7 H 4 N 2 O 3 S (%): C, 42.85; H, 2.05; N, 14.27 Measured value (%): C, 42.75; H, 2.30; N, 14.13 (2) 4-Chloro-3-nitrothieno [3,4-b] pyridin 11 3-Nitrothieno [3,4-b] pyridin-4 (1H) -one 10 3.00 g in 9 ml of phosphorus oxychloride at a bath temperature of 105 ° C. Stir for hours. This is dried under reduced pressure, the resulting residue is dissolved in chloroform, washed with aqueous ammonia and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to silica gel chromatography to obtain 2.02 g (yield 62%) of 11 crystals from the fraction eluted from methylene chloride-ether (50: 1 v / v). . Ether The product - Recrystallization from petroleum ether the colorless crystals of melting point 139-140 ° C. Elemental analysis: C 7 H 3 N 2 O 2 ClS · 1 / 8H 2 O Calculated (%): C, 38.77; H, 1.51; N, 12.92 Found (%): C, 38.60; H, 1.55; N, 12.79 (3) 4-Amino-3-nitrothieno [3,4-b] pyridine 12 4- Chloro-3-nitrothieno [3,4-b] pyridine 1
1 A suspension of 1.25 g of isopropanol in 37 ml is stirred at room temperature for 3 hours while passing ammonia gas. The reaction mixture was concentrated to dryness under reduced pressure, after stirring water was added to the residue, the crystals were filtered off, washed with water to obtain the dried 12 crystals 1.09 g (62% yield). Recrystallization of this product from chloroform-methanol gave a melting point of 30.
It becomes yellow crystals at 7-309 ℃.
元素分析：C7H5N3O2Sとして 計算値（％）:C,43.07;H,2.58;N,21.52 実測値（％）:C,42.93;H,2.69;N,21.36 （４）3,4−ジアミノチエノ［3,4−ｂ］ピリジンD3 ４−アミノ−３−ニトロチエノ［3,4−ｂ］ピリジン12
620mgをエタノール50mlに溶かし塩化第一スズ・水和物
3.59gを加え、70℃で１時間攪拌する。溶媒を減圧留去
し、残渣を酢酸エチルに溶かし、重ソウ水で中和後、析
出した結晶を濾別、酢酸エチル−水でよく洗浄する。濾
液および洗液を濃縮し、得られる残渣をアルミナカラム
クロマトグラフイーに付し、クロロホルム−メタノール
（20:1 v/v）から溶出される画分よりD3 の結晶490mg
（収率93％）を得る。本品をエーテル−メタノールから
再結晶すると融点140-144℃の無色結晶となる。Elemental analysis: Calculated as C 7 H 5 N 3 O 2 S (%): C, 43.07; H, 2.58; N, 21.52 Measured value (%): C, 42.93; H, 2.69; N, 21.36 (4) 3,4-Diaminothieno [3,4-b] pyridine D 3 4-Amino-3-nitrothieno [3,4-b] pyridine 12
Dissolve 620 mg in 50 ml of ethanol and stannous chloride hydrate
Add 3.59 g and stir at 70 ° C. for 1 hour. The solvent is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, neutralized with sodium bicarbonate water, and the precipitated crystals are separated by filtration and washed well with ethyl acetate-water. The filtrate and washings were concentrated, the resulting residue was subjected to alumina column chromatography, and 490 mg of crystals of D 3 from the fraction eluted from chloroform-methanol (20: 1 v / v).
(Yield 93%) is obtained. Recrystallization of this product from ether-methanol gives colorless crystals with a melting point of 140-144 ℃.
元素分析：C7H7N3S・2/3H2Oとして 計算値（％）:C,47.44;H,4.74;N,23.71 実測値（％）:C,47.68;H,4.85;N,23.24 参考例６ （１）６−ニトロチエノ［3,2−ｂ］ピリジン−７（4
H）−オン 14 チエノ［3,2−ｂ］ピリジン−７（4H）−オン 13 3.1g
をプロピオン酸90ml中で110℃に加熱、発煙硝酸1.5mlを
加えて１時間還流する。放冷後、エーテル50mlで希釈
し、析出した結晶を濾取、水、エーテル−メタノールで
洗浄し14の結晶3.13g（収率78％）を得る。本品をジメ
チルスルホキシド−メタノールから再結晶すると融点32
8-331℃（分解）の無色結晶となる。Elemental analysis: Calculated as C 7 H 7 N 3 S ・ 2 / 3H 2 O (%): C, 47.44; H, 4.74; N, 23.71 Measured value (%): C, 47.68; H, 4.85; N, 23.24 Reference example 6 (1) 6-nitrothieno [3,2-b] pyridine-7 (4
H) -one 14 thieno [3,2-b] pyridin-7 (4H) -one 13 3.1 g
Is heated to 110 ° C. in 90 ml of propionic acid, 1.5 ml of fuming nitric acid is added, and the mixture is refluxed for 1 hour. After allowing to cool, the mixture is diluted with 50 ml of ether, and the precipitated crystals are collected by filtration and washed with water and ether-methanol to give 14 crystals (3.13 g, yield 78%). Recrystallization of this product from dimethylsulfoxide-methanol gave a melting point of 32.
It becomes colorless crystals at 8-331 ℃ (decomposition).
元素分析：C7H4N2O3Sとして 計算値（％）:C,42.85;H,2.05;N,14.27 実測値（％）:C,42.88;H,2.17;N,14.21 （２）７−クロロ−６−ニトロチエノ−［3,2−ｂ］ピ
リジン 15 ６−ニトロチエノ［3,2−ｂ］ピリジン−７（4H）−オ
ン 14 2.7gをオキシ塩化リン中110℃で１時間攪拌す
る。反応液を減圧乾固し、得られる残渣を塩化メチレン
に溶かし、アンモニア水で中和し、塩化メチレンで抽出
する。抽出液を水洗乾燥後、溶媒を留去して得られる粗
結晶をシリカゲルクロマトグラフイーに付し、塩化メチ
レン−エーテル（50:1 v/v）で溶出する画分から15の結
晶2.64g（収率90％）を得る。本品をエーテルから再結
晶すると融点124-125.5℃の無色結晶となる。Elemental analysis: Calculated as C 7 H 4 N 2 O 3 S (%): C, 42.85; H, 2.05; N, 14.27 Measured value (%): C, 42.88; H, 2.17; N, 14.21 (2) 7-Chloro-6-nitrothieno- [3,2-b] pyridine 15 6-Nitrothieno [3,2-b] pyridin-7 (4H) -one 14 2.7 g of phosphorus oxychloride was stirred at 110 ° C. for 1 hour. . The reaction solution is evaporated to dryness under reduced pressure, the resulting residue is dissolved in methylene chloride, neutralized with aqueous ammonia, and extracted with methylene chloride. After washing the extract was dried, the crude crystals obtained by distilling off the solvent by silica gel chromatography, methylene chloride - ether (50: 1 v / v) of 15 from the fraction eluted with crystals 2.64 g (yield Rate 90%). Recrystallization of this product from ether gives colorless crystals with a melting point of 124-125.5 ° C.
元素分析：C7H3N2O2ClSとして 計算値（％）:C,39.17;H,1.40;N,13.05 実測値（％）:C,38.96;H,1.70;N,12.92 （３）７−アミノ−６−ニトロチエノ［3,2−ｂ］ピリ
ジン16 ７−クロロ−６−ニトロチエノ［3,2−ｂ］ピリジン 1
5 2.55gのイソプロパノール130ml懸濁液にアンモニアガ
スを通じながら室温で15分間、さらに浴温45℃で４時間
攪拌する。反応液を濃縮し、残渣に水を加え、攪拌後、
結晶を濾取して水およびエーテルで洗浄すると16の結晶
2.30g（収率99％）が得られる。本品をクロロホルム−
メタノールから再結晶すると融点266-268.5℃の黄色結
晶となる。Elemental analysis: Calculated as C 7 H 3 N 2 O 2 ClS (%): C, 39.17; H, 1.40; N, 13.05 Measured value (%): C, 38.96; H, 1.70; N, 12.92 (3) 7-Amino-6-nitrothieno [3,2-b] pyridin 16 7-chloro-6-nitrothieno [3,2-b] pyridine 1
5 Ammonia gas was passed through a suspension of 2.55 g of isopropanol in 130 ml, and the mixture was stirred at room temperature for 15 minutes and at a bath temperature of 45 ° C. for 4 hours. The reaction solution is concentrated, water is added to the residue, and after stirring,
16 crystals when collected by filtration and washed with water and ether
2.30 g (99% yield) are obtained. This product is chloroform-
Recrystallization from methanol gives yellow crystals with a melting point of 266-268.5 ° C.
元素分析：C7H5N3O2Sとして 計算値（％）:C,43.07;H,2.58;N,21.52 実測値（％）:C,43.02;H,2.76;N,21.46 （４）6,7−ジアミノチエノ［3,2−ｂ］ピリジンD4 ７−アミノ−６−ニトロチエノ［3,2−ｂ］ピリジン16
2.3gの無水エタノール160ml溶液へ塩化第一スズ・水和
物12.5gを加え、70℃で1.5時間攪拌する。溶媒を留去
し、残渣を酢酸エチルに溶かし、重ソウ水で中和後、析
出する結晶を濾別、酢酸エチル−水でよく洗浄する。濾
液および洗液を濃縮し、残渣をシリカゲルカラムクロマ
トグラフイーに付し、クロロホルム−メタノール（10:1
v/v）から溶出される画分からD4 の結晶1.91g（収率97
％）を得る。本品をメタノール−エーテルから再結晶す
ると融点157-159℃の無色結晶となる。Elemental analysis: Calculated as C 7 H 5 N 3 O 2 S (%): C, 43.07; H, 2.58; N, 21.52 Measured value (%): C, 43.02; H, 2.76; N, 21.46 (4) 6,7-Diaminothieno [3,2-b] pyridine D 4 7-Amino-6-nitrothieno [3,2-b] pyridine 16
12.3 g of stannous chloride hydrate is added to a solution of 2.3 g of anhydrous ethanol in 160 ml, and the mixture is stirred at 70 ° C. for 1.5 hours. The solvent is evaporated, the residue is dissolved in ethyl acetate, neutralized with sodium bicarbonate water, the precipitated crystals are filtered off, and washed well with ethyl acetate-water. The filtrate and washings were concentrated, the residue was subjected to silica gel column chromatography, and chloroform-methanol (10: 1
1.94 g of D 4 crystals (yield 97
%). Recrystallization of this product from methanol-ether gives colorless crystals with a melting point of 157-159 ° C.
元素分析：C7H7N3S・1/4H2O 計算値（％）:C,49.54;H,4.45;N,24.76 実測値（％）:C,49.79;H,4.35;N,24.43 製剤例 ２−（３−メチルイソオキサゾ−５−イル）−1H−イミ
ダゾ［4,5−ｃ］キノリン ……10mg 小麦でんぷん ……48mg ステアリン酸マグネシウム……2mg 上記の成分を混和してカプセル剤とする。Elemental analysis: C 7 H 7 N 3 S ・ 1 / 4H 2 O Calculated value (%): C, 49.54; H, 4.45; N, 24.76 Measured value (%): C, 49.79; H, 4.35; N, 24.43 Formulation example 2- (3-methylisoxazo-5-yl) -1H-imidazo [4,5-c] quinoline …… 10 mg Wheat starch …… 48 mg Magnesium stearate …… 2 mg Capsules containing the above ingredients Use as an agent.
発明の効果 本発明化合物はベンゾジアゼピン・レセプターに対する
高い親和性を示す。このレセプターに結合する薬物はそ
の調節作用の相違によつて三種類に分類されている。す
なわち、アゴニストは抗不安薬や抗痙攣薬、アンタゴニ
ストはベンゾジアゼピン中毒や過剰摂取事故の処置薬、
インバースアゴニストは精神機能賦活薬としての用途が
それぞれ期待される。EFFECTS OF THE INVENTION The compounds of the present invention exhibit high affinity for the benzodiazepine receptor. Drugs that bind to this receptor are classified into three types according to the difference in their regulatory action. That is, an agonist is an anti-anxiety drug or an anti-convulsant drug, an antagonist is a drug for treating benzodiazepine poisoning or an overdose accident,
Inverse agonists are expected to be used as psychoactive drugs, respectively.
以下に本発明化合物についての試験例を示すが、被験化
合物番号は実施例および表中で用いたものと対応する。The test examples of the compounds of the present invention are shown below, and the test compound numbers correspond to those used in the examples and tables.
試験例１ ベンゾジアゼピンレセプター結合試験 Ｍhler＆Okada,Science,198,849-851（1977）の方法
を一部改変して行なつた。11〜13週令のウイスター系雄
性ラツトの大脳皮質からレセプター標品を作製し、これ
に対するトリチウム標識ジアゼパムの特異的結合を指標
にして被験化合物の阻害力を以下の方法で求めた。すな
わち、2nMのトリチウム標識ジアゼパムおよび５〜６種
の濃度の異なる被験化合物の水溶液を温度０℃で60分間
インキユベートした。得られた濃度・作用曲線から50％
阻害濃度（IC 50）を求め、さらにトリチウム標識ジア
ゼパムの解離定数（Kd）および濃度（Ｌ）から被験化合
物の抑制定数（Ki）を求めた。結果を下記表に示す。Test Example 1 Benzodiazepine Receptor Binding Test The method of Mhler & Okada, Science, 198 , 849-851 (1977) was partially modified. A receptor preparation was prepared from the cerebral cortex of Wistar male rats aged 11 to 13 weeks, and the inhibitory potency of the test compound was determined by the following method using the specific binding of tritium-labeled diazepam to the receptor preparation as an index. That is, an aqueous solution of 2 nM tritium-labeled diazepam and 5 to 6 kinds of test compounds having different concentrations was incubated at a temperature of 0 ° C. for 60 minutes. 50% from the obtained concentration-action curve
The inhibitory concentration (IC 50) was determined, and the inhibition constant (Ki) of the test compound was determined from the dissociation constant (Kd) and concentration (L) of tritium-labeled diazepam. The results are shown in the table below.
試験例２ ベンチレンテトラゾール痙攣抑制試験 この試験でアゴニスト作用を調べた。被験化合物を１群
８〜16匹の雄性マウスに静脈内投与直後、ベンチレンテ
トラゾール125mg/kgを皮下投与した。その後２時間の観
察から痙攣による死亡数50％抑制する用量（ED50）をPr
obit法で求めた。 Test Example 2 Bentilentetrazole Convulsive Inhibition Test The agonistic action was investigated in this test. Immediately after intravenous administration of the test compound to 8 to 16 male mice per group, 125 mg / kg of benylenetetrazole was subcutaneously administered. From the observation for 2 hours after that, the dose (ED 50 ) to suppress 50% of deaths due to convulsions was determined by Pr
Obtained by the obit method.
試験例３ ベンチレンテトラゾール痙攣増強試験 この試験でインバースアゴニスト作用を調べた。被験化
合物を１群８〜16匹の雄性マウスに静脈内投与直後、ベ
ンチレンテトラゾール90mg/kg（痙攣発現閾値以下の用
量）を皮下投与した。その後２時間の観察から痙攣によ
る死亡数が50％の被験動物に発現する用量（ED50）をPr
obit法で求めた。 Test Example 3 Bentilentetrazole Convulsion Enhancement Test In this test, the inverse agonist effect was investigated. Immediately after intravenous administration of the test compound to 8 to 16 male mice per group, 90 mg / kg of ventilenetetrazole (dose below the convulsion threshold) was subcutaneously administered. From the observation for 2 hours after that, the dose (ED 50 ) expressed in test animals with 50% deaths due to convulsions was determined as Pr.
Obtained by the obit method.
筋弛緩作用（Traction Test） Courvoisierらの方法（S.Courvoiserら、“Psychotropi
c Drugs",S.Garattini,R.Ducrot編、373頁、Elsevier P
ublishing Co.,Amsterdam,1957）に準じて行なつた。一
群10匹のDS系雄性マウスに被験化合物を経口投与し、30
分後に直径1mmの針金にぶらさげ、10秒以内に片足をか
けた場合、筋弛緩作用なしと判定した。Probit法により
ED50を算出した。 Muscle Relaxation (Traction Test) Method of Courvoisier et al. (S. Courvoiser et al., “Psychotropi
c Drugs ", S. Garattini, R. Ducrot, ed., page 373, Elsevier P
ublishing Co., Amsterdam, 1957). Oral administration of the test compound to 10 male DS mice per group
After 1 minute, the wire was hung on a wire with a diameter of 1 mm, and when one leg was put on within 10 seconds, it was judged that there was no muscle relaxing action. By Probit method
The ED 50 was calculated.
抗コンフリクト作用 Gellerらの方法［I.Geller and J.Seifter,Psychopharm
acol.,1,482（1960）］に従つてコンフリクト行動が完
成している一群５匹以上のウィスター系雄性ラツトを使
用した。被験化合物経口投与30分後から１時間にわたる
試験の間に罰期で受ける電気刺激が12回以上の場合を有
効と判定した。Probit法によりED50を算出した。Anti-conflict action Geller's method [I. Geller and J. Seifter, Psychopharm
acol., 1 , 482 (1960)], and a group of 5 or more Wistar male rats whose conflict behavior has been completed was used. It was judged to be effective when electrical stimulation received 12 times or more in the penal period during the test from 30 minutes after the oral administration of the test compound to 1 hour. The ED 50 was calculated by the Probit method.
Claims (2)
キシ、アルキルチオ、ニトロ、ハロゲン、アミノ、アル
カノイルアミノおよびアルコキシカルボニルから選択さ
れる１または２個により置換されていてもよいフエニ
ル、またはアルキル、アルコキシおよびハロゲンから選
択される１または２個により置換されていてもよく、イ
ソオキサゾリル、イソチアゾリル、ピラゾリル、オキサ
ゾリル、チアゾリル、イミダゾリル、チアジアゾリル、
オキサジアゾリル、チエニル、フリルおよびピリジルか
ら選択されるヘテロ環残基;Qは水素、アルキル、アシ
ル、アルキルスルホニルまたはアリルスルホニル、 R1、R2、R3およびR4はそれぞれ水素、ハロゲン、アルキ
ル、アルコキシまたはハロアルキルを表わし、Ｑは１、
３または５位の窒素原子の上に存在し、点線は環上の３
個の２重結合の組合わせを示しており、（2-3、3a-3b、
4-5）位、（1-3b、2-3、3a-4）位および（1-2、3a-3b、
4-5）位に存在することを意味する。） で示される化合物またはその塩。1. A general formula: (In the formula, R is phenyl optionally substituted by 1 or 2 selected from trifluoromethyl, alkyl, alkoxy, alkylthio, nitro, halogen, amino, alkanoylamino and alkoxycarbonyl, or alkyl, alkoxy and It may be substituted by 1 or 2 selected from halogen, and isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl,
A heterocyclic residue selected from oxadiazolyl, thienyl, furyl and pyridyl; Q is hydrogen, alkyl, acyl, alkylsulfonyl or allylsulfonyl, R 1 , R 2 , R 3 and R 4 each represent hydrogen, halogen, alkyl, alkoxy or haloalkyl, and Q is 1,
It exists on the nitrogen atom at the 3 or 5 position, and the dotted line is 3 on the ring.
Shows the combination of two double bonds, (2-3, 3a-3b,
4-5) position, (1-3b, 2-3, 3a-4) position and (1-2, 3a-3b,
4-5) means to exist in the position. ) The compound or its salt shown by these.
キシ、アルキルチオ、ニトロ、ハロゲン、アミノ、アル
カノイルアミノおよびアルコキシカルボニルから選択さ
れる１または２個により置換されていてもよいフエニ
ル、またはアルキル、アルコキシおよびハロゲンから選
択される１または２個により置換されていてもよく、イ
ソオキサゾリル、イソチアゾリル、ピラゾリル、オキサ
ゾリル、チアゾリル、イミダゾリル、チアジアゾリル、
オキサジアゾリル、チエニル、フリルおよびピリジルか
ら選択されるヘテロ環残基;Qは水素、アルキル、アシ
ル、アルキルスルホニルまたはアリルスルホニル、 R1、R2、R3およびR4はそれぞれ水素、ハロゲン、アルキ
ル、アルコキシまたはハロアルキルを表わし、Ｑは１、
３または５位の窒素原子の上に存在し、点線は環上の３
個の２重結合の組合わせを示しており、（2-3、3a-3b、
4-5）位、（1-3b、2-3、3a-4）位および（1-2、3a-3b、
4-5）位に存在することを意味する。） で示される化合物またはその塩を含有することを特徴と
する向精神薬。2. A general formula: (In the formula, R is phenyl optionally substituted by 1 or 2 selected from trifluoromethyl, alkyl, alkoxy, alkylthio, nitro, halogen, amino, alkanoylamino and alkoxycarbonyl, or alkyl, alkoxy and It may be substituted by 1 or 2 selected from halogen, and isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, thiadiazolyl,
A heterocyclic residue selected from oxadiazolyl, thienyl, furyl and pyridyl; Q is hydrogen, alkyl, acyl, alkylsulfonyl or allylsulfonyl, R 1 , R 2 , R 3 and R 4 each represent hydrogen, halogen, alkyl, alkoxy or haloalkyl, and Q is 1,
It exists on the nitrogen atom at the 3 or 5 position, and the dotted line is 3 on the ring.
Shows the combination of two double bonds, (2-3, 3a-3b,
4-5) position, (1-3b, 2-3, 3a-4) position and (1-2, 3a-3b,
4-5) means to exist in the position. ) A psychotropic drug comprising a compound represented by: or a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24812086A JPH07620B2 (en) | 1985-10-18 | 1986-10-17 | Condensed imidazopyridine derivative |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60-234357 | 1985-10-18 | ||
| JP23435785 | 1985-10-18 | ||
| JP61-119681 | 1986-05-23 | ||
| JP11968186 | 1986-05-23 | ||
| JP24812086A JPH07620B2 (en) | 1985-10-18 | 1986-10-17 | Condensed imidazopyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6399069A JPS6399069A (en) | 1988-04-30 |
| JPH07620B2 true JPH07620B2 (en) | 1995-01-11 |
Family
ID=27313882
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP24812086A Expired - Fee Related JPH07620B2 (en) | 1985-10-18 | 1986-10-17 | Condensed imidazopyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07620B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0579836A1 (en) * | 1991-12-12 | 1994-01-26 | Kyowa Hakko Kogyo Co., Ltd. | Thienoimidazopyridone derivative |
| NZ507760A (en) | 1998-03-26 | 2002-10-25 | Japan Tobacco Inc | Amide derivatives and nociceptin antagonists |
-
1986
- 1986-10-17 JP JP24812086A patent/JPH07620B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6399069A (en) | 1988-04-30 |
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